{ "schemaVersion": 1, "version": "baseline-register-2026-10-23-pdc-response", "sources": { "hatton": { "title": "Hatton et al. 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No random distributions are inferred from ranges.", "bodyModels": { "male": "Reference male: 70 kg, 176 cm, age 20–50 y", "female": "Reference female: 60 kg, 163 cm, age 20–50 y", "child": "Reference child: 32 kg, 138 cm, age 10 y" }, "families": [ { "id": "I001", "name": "Capillary endothelial cells", "category": "Vascular", "whereToCheck": "All vascularized sites", "states": [ "Organ and barrier subtype", "activated", "damaged" ], "behaviors": [ "Permeability", "transcytosis", "junctions", "adhesion", "antigen expression" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-55", "hatton-527" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-55", "hatton-527" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "sender-I001-endothelial-cells" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-55", "hatton-527", "sender-I001-endothelial-cells" ], "priorResearch": { "path": "simulation/data/profiles/capillary-endothelial-cells.json", "summary": "Capillary endothelial cells form the inner lining of the smallest vessels, a single layer enclosing the lumen, with the basement membrane and pericytes on the tissue-facing side. They are the surface everything in the blood meets first: an antibody arriving from plasma reaches this cell before it reaches anything else in the tissue, and a T cell leaving the circulation crosses it. Their states differ by organ and by barrier type, so a brain capillary endothelial cell and one in bone marrow are not interchangeable (V01, V02, V03).", "stateAxes": [ { "axis": "Organ and barrier subtype", "whatToMeasure": "Organ of origin, vessel segment, and the transcriptional state the vascular atlases resolve for that site", "interpretationLimit": "Transcriptomic identity is not a functional rate. A healthy multi-organ reference needs disease-specific validation before it stands for tumour or degenerating tissue.", "evidence": [ "V01", "V02", "V03" ] }, { "axis": "Activated", "whatToMeasure": "State markers and spatial context distinguishing activated endothelium from resting, in situ rather than dissociated", "interpretationLimit": "The one disease-linked endothelial state assembled here is CD90+CD105+ in endometrial cancer, and its link to recurrence is a prognostic association awaiting external validation. It is not established as the general activated state.", "evidence": [ "E04" ] }, { "axis": "Damaged", "whatToMeasure": "Barrier integrity alongside mural coverage, measured together rather than inferred from one another", "interpretationLimit": "The ALS evidence is eleven cases against five controls, and pericyte loss and leakage were observed together. Which one leads, and whether either is general, is not established.", "evidence": [ "V17" ] }, { "axis": "Inflamed versus anergic", "whatToMeasure": "ICAM-1 and VCAM-1 on the luminal face, measured in situ, alongside whether the vessel is perfused", "interpretationLimit": "Which of the two dominates depends on the activation state of both the T cell and the endothelium, so neither density is a general parameter. Perfusion and adhesion compound: a vessel has to carry blood and present adhesion before a T cell can stop on it.", "evidence": [ "V28", "V29" ] }, { "axis": "Luminal surface composition", "whatToMeasure": "What is exposed to blood, labelled in vivo through the lumen and read by mass spectrometry, in the disease state rather than a healthy reference", "interpretationLimit": "The luminal surface is not a fixed property of a tissue: the perfusable proteome is shared across organs at baseline and remodels tissue-specifically under systemic insult, ahead of any organ dysfunction. A healthy reference cannot stand in for a diseased one. No luminal proteome is assembled here for any drawn environment.", "evidence": [ "V32", "V33" ] } ], "records": { "E04": { "id": "E04", "year": 2025, "topic": "Spatial atlas", "title": "Spatial ecostructural modelling of endometrial cancer identifies the key role of CD90 + CD105 + endothelial cells in tumour heterogeneity and predicts disease recurrence", "url": "https://pubmed.ncbi.nlm.nih.gov/41243106/", "studyType": "Human spatial multiomics", "diseaseContext": "Uterine corpus", "useInModel": "Adds endothelial states and spatial eco-context linked with recurrence.", "limit": "Prognostic associations require external validation.", "provenance": "Indexed abstract or publisher excerpt screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "V01": { "id": "V01", "year": 2024, "topic": "Pericytes and vasculature", "title": "An organotypic atlas of human vascular cells", "url": "https://www.nature.com/articles/s41591-024-03376-x", "studyType": "Human multi-organ vascular atlas", "diseaseContext": "Shared all", "useInModel": "Distinguishes endothelial and mural states across organs; supports multi-marker identification.", "limit": "Transcriptomic identities are not direct functional rates; healthy references need disease-specific validation.", "provenance": "Selected full-text or indexed results passages reviewed; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V02": { "id": "V02", "year": 2022, "topic": "Pericytes and vasculature", "title": "Single cell atlas of the normal and malformed human brain vasculature", "url": "https://pmc.ncbi.nlm.nih.gov/articles/8995178/", "studyType": "Human brain vascular single-cell atlas", "diseaseContext": "Alzheimer's / ALS / FTD", "useInModel": "Separates pericytes, smooth muscle and perivascular fibroblasts using multiple markers.", "limit": "Normal and malformed vasculature is not the same as a neurodegeneration cohort.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V03": { "id": "V03", "year": 2024, "topic": "Pericytes and vasculature", "title": "Single-cell atlas of the human brain vasculature across development, adulthood and disease", "url": "https://www.nature.com/articles/s41586-024-07493-y", "studyType": "Human developmental and disease vascular atlas", "diseaseContext": "Alzheimer's / ALS / FTD", "useInModel": "Provides vascular cell-state and spatial-reference resources.", "limit": "Development, tumors and other pathologies require separate context labels.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V17": { "id": "V17", "year": 2013, "topic": "Pericytes and vasculature", "title": "Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis", "url": "https://pubmed.ncbi.nlm.nih.gov/22941226/", "studyType": "Human postmortem spinal cord study", "diseaseContext": "ALS", "useInModel": "Pericyte loss and barrier leakage occurred together in a small ALS cohort.", "limit": "11 ALS versus 5 controls; association does not establish cause, onset or population prevalence.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V28": { "id": "V28", "year": 2006, "topic": "Accessibility", "title": "Epigenetic regulation of tumor endothelial cell anergy: silencing of intercellular adhesion molecule-1 by histone modifications", "url": "https://aacrjournals.org/cancerres/article/66/22/10770/526515/Epigenetic-Regulation-of-Tumor-Endothelial-Cell", "studyType": "Cell culture with two mouse tumour models", "diseaseContext": "Shared cancer", "useInModel": "Gives a mechanism for tumour endothelium refusing to let leukocytes stick: tumour-conditioned endothelial cells lost ICAM-1 alongside promoter histone H3 deacetylation and loss of H3K4 methylation, and DNMT and HDAC inhibitors restored both the molecule and leukocyte adhesion, with more leukocyte-vessel interaction and infiltration in vivo.", "limit": "Mouse models and conditioned culture. The silencing was not associated with DNA hypermethylation, so the drugs that reversed it act less directly than their names suggest. Whether the same holds across the drawn environments is untested.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "V29": { "id": "V29", "year": 2019, "topic": "Accessibility", "title": "VCAM-1 density and tumor perfusion predict T-cell infiltration and treatment response in preclinical models", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC6744528/", "studyType": "Preclinical imaging and intervention study in four mouse tumour models - EL4, B16F10, CT26 and MC38 - pairing dynamic contrast-enhanced MRI for perfusion and permeability with a VCAM-1-targeted iron oxide microparticle contrast agent, against histological T-cell and VCAM-1 density, with integrin blocking in vitro and in vivo and a PD-L1 treatment experiment, Translational Oncology", "diseaseContext": "Shared cancer", "useInModel": "Read in full text, and it resolves a tension in this atlas rather than creating one. The project holds three instances arguing that perfusion does not determine the local field - oxygen, pH, nutrients - and this paper's title says perfusion predicts T-cell infiltration. Both are right, because the dependent variables are different: a vessel can be open enough to deliver cells while the local gas tension is set by consumption downstream of it. The numbers are model-dependent and reported as such. In EL4 tumours, perfusion and permeability measured as k-trans correlated with T-cell density at r equal to 0.84, p 0.03, and vascular VCAM-1 density at r 0.65, p 0.05. In CT26 tumours, k-trans correlated with endogenous T-cell density at r 0.64, p 0.05, and histological vascular VCAM-1 with T-cell density at r 0.79, p 0.02. In B16F10 tumours none of the three measures correlated with infiltration - r 0.16, 0.32 and 0.48 - and that model also showed no contrast change at all after the targeted agent. So two of three models show the relationship and one does not, which makes model identity a determining variable. The causal arm is the strongest part and belongs to the adhesion machinery rather than to perfusion: blocking VCAM-1 reduced T-cell retention on endothelium in vitro, blocking the integrins CD49d or CD18 reduced it further, and the combination further still - while in vivo, mice given ten million activated antigen-specific CD8 T cells with integrin blockade had viable tumour volumes of 937 plus or minus 217 cubic millimetres one week later against 21 plus or minus 14 in the control arm. A roughly fortyfold difference in viable tumour from blocking two adhesion receptors establishes that getting in is rate-limiting for the response, not merely correlated with it. Two further things the atlas can use. An ordering of which imaging quantity moves first: at three days the extracellular extravascular volume fraction had risen significantly in rejecting tumours while tumour volume, k-trans, plasma volume and targeted-agent binding had not, and k-trans only separated at seven days once volumes had already diverged. And a fitted pharmacokinetic parameter set with dispersions for both agents - systemic clearance 0.06 plus or minus 0.03 ml/min for each, distribution clearance 5.0 against 2.9, central volume 5.1 against 2.7 ml, peripheral volume 4.9 against 11.6 ml - alongside tumour uptake of 3 percent of injected dose per gram for the targeted agent against under 0.5 percent for the isotype.", "limit": "Mouse tumour models throughout, with group sizes of five to six for every correlation, so each r rests on very few animals and the three that reach p 0.05 do so marginally; the difference between the models that correlate and the one that does not should not be read as a biological difference between melanoma and the others on this evidence. The treatment-prediction claim in the title is the weakest part and the full text says so: baseline k-trans, plasma fraction and targeted-agent binding each failed individually to predict tumour volume change over two weeks, at r 0.19, 0.22 and 0.20 with p values of 0.09, 0.07 and 0.08, and only a multiple linear regression combining two of them reached r 0.36 at p 0.05 in seventeen animals - which accounts for a small share of the variance and is described by the authors as partial prediction. The authors also note their imaging required hair removal, which may itself have contributed to the PD-L1 growth inhibition. The contrast agent is a one-micrometre iron oxide microparticle, so its distribution is constrained by particle size in ways a soluble tracer would not be, and its short blood half-life is cited from elsewhere rather than measured here. The pharmacokinetic parameters are fitted to a compartmental model, with several rate constants carrying dispersions larger than their means, so they are not transferable constants. Whether VCAM-1 or ICAM-1 dominates depends on the activation state of both the T cell and the endothelium, so a single adhesion density is not a general predictor.", "provenance": "Full text read from the open-access record (PMC6744528) after the one-line screening entry was flagged as pending; all six correlation coefficients with their p values and group sizes for EL4, B16F10 and CT26, the three non-significant single-predictor correlations and the two multiple-regression results for PD-L1 response with their r values and p values and animal count, the in vitro blocking results for VCAM-1, CD49d and CD18 with their significance levels, the in vivo viable tumour volumes at one week with dispersions and group sizes and the transferred cell number, the ordering of imaging changes at three and seven days, Table 1's fitted pharmacokinetic parameters with dispersions for both agents, the tumour uptake figures as percent injected dose per gram, the particle diameter, and the authors' stated caveat about hair removal as reported", "quantitativeExtraction": "extracted" }, "V32": { "id": "V32", "year": 2026, "topic": "Accessibility", "title": "Luminal surface proteome of the brain vasculature uncovers blood-brain barrier regulators", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13372101/", "studyType": "In vivo perfusion labelling of the luminal face with mass spectrometry, mouse", "diseaseContext": "Alzheimer's / ALS / FTD", "useInModel": "An inventory of what actually faces the blood in brain vasculature, which is the which-face question asked at the vessel instead of at the tumour cell. In vivo peroxidase proximity labelling at the luminal surface, with the membrane-impermeable substrate delivered by perfusion, followed by 18-plex tandem mass tag quantification. 4,528 mouse proteins were detected with two or more unique peptides; after a biotinylated-to-control cutoff, 237 proteins at postnatal day 14, 266 in adult and 243 in aged mice were retained, totalling 390 with substantial overlap across the three ages. Cell-surface specificity was checked by Western blot: the endothelial marker PECAM1 and the cell-surface Na/K ATPase ATP1A1 were enriched, while GAPDH, beta-actin and lamin A/C were not. Genetic perturbation then separated lifespan roles - the arginine transporter SLC7A1 and the nitric oxide synthase NOS3 are required for barrier integrity in neonatal but not adult mice, while the hyaluronan-degrading HYAL2 is required throughout. The paper also records a methodological warning the atlas should keep: the dyes commonly used to test vascular permeability are unsuitable for profiling the luminal surface because they lack compartment specificity in almost every organ.", "limit": "Mouse, and a proteome rather than a transport measurement - it says what is present and reachable from the lumen, not how much of anything crosses. The 390 is a count of proteins passing a ratio cutoff, not a set of abundances per cell or per area. Being on the luminal surface makes a protein addressable in principle; it does not make it a transcytosis route, and nothing here demonstrates cargo moving. No human equivalent is held in this atlas.", "provenance": "Full text read from Europe PMC (PMC13372101), replacing an abstract-only screening note. Protein counts, the TMT design, the enrichment controls and the three named regulators were taken from the abstract and Results.", "quantitativeExtraction": "extracted" }, "V33": { "id": "V33", "year": 2022, "topic": "Accessibility", "title": "Vascular proteome responses precede organ dysfunction in a murine model of Staphylococcus aureus bacteremia", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC9426442/", "studyType": "In vivo endothelial surface labelling across four organs with DIA mass spectrometry", "diseaseContext": "Healthy reference", "useInModel": "Says the luminal surface is not a fixed property. The perfusable vascular proteome is shared across organs at baseline and is remodelled tissue-specifically under systemic insult, ahead of organ dysfunction. What the endothelium displays therefore has to be measured in the disease state, not carried over from a healthy reference.", "limit": "Bacteraemia in mice, not tumour. It establishes that the luminal surface moves with disease, not how it moves in any of the drawn environments.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I002", "name": "Arterial and arteriolar endothelium", "category": "Vascular", "whereToCheck": "Vascular inflow", "states": [ "Segment-specific states" ], "behaviors": [ "Flow", "shear", "signaling", "recruitment" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "sender-I002-endothelial-cells" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "sender-I002-endothelial-cells" ], "priorResearch": { "path": "simulation/data/profiles/arterial-and-arteriolar-endothelium.json", "summary": "Arterial and arteriolar endothelium lines the inflow side of the circulation, upstream of the capillary bed, wrapped in smooth muscle that thins to scattered mural cells as the arteriole narrows. It is the segment that sets how much blood arrives and where, and it is defined by what it is exposed to as much as by what it is: high, unidirectional, pulsatile shear. That exposure is read through PIEZO1 and converted to KLF2 and KLF4 expression, so the segment's identity and its mechanical environment are not separable (V36). Arterial identity itself is held as a balance rather than a label, with ephrin-B2 against EphB4 and the shear-responsive factor Dach1 among the signals that maintain it (V35).", "stateAxes": [ { "axis": "Arterial versus venous identity", "whatToMeasure": "The arterial and venous marker sets together, read as a ratio rather than separately, with vessel segment and calibre recorded alongside", "interpretationLimit": "Identity is a balance that moves: losing EphB4 raises ephrin-B2 and the arterial programme follows. A single marker gives a position on an axis, not a cell type, and these sets come from cultured large-vessel endothelium.", "evidence": [ "V34", "V35" ] }, { "axis": "Shear-exposed versus shear-deprived", "whatToMeasure": "KLF2 and KLF4 as the readout of what the cell is actually experiencing, rather than a flow rate imputed from vessel calibre", "interpretationLimit": "The pathway is established in culture under clean unidirectional shear, which tumour vessels do not experience. Magnitudes across the literature span roughly 5 to 16 dyn/cm^2 and no threshold separates arterial from arteriolar behaviour.", "evidence": [ "V36" ] }, { "axis": "Hierarchically placed versus disorganised", "whatToMeasure": "Whether the vessel sits in an ordered branching sequence feeding a regularly spaced capillary bed, or in a bed with loops, blind ends and shunts", "interpretationLimit": "This is the axis on which the family's own premise turns. In tumour the ordered arrangement is largely absent, so assigning a vessel to this segment may be imposing a normal-tissue category on tissue that does not have it.", "evidence": [ "V37" ] }, { "axis": "Segment-specific organ state", "whatToMeasure": "Organ of origin and segment, against the multi-organ and brain vascular references", "interpretationLimit": "Transcriptomic identity is not a functional rate, and healthy references need disease-specific validation before standing for tumour or degenerating tissue.", "evidence": [ "V01", "V02", "V03" ] } ], "records": { "V01": { "id": "V01", "year": 2024, "topic": "Pericytes and vasculature", "title": "An organotypic atlas of human vascular cells", "url": "https://www.nature.com/articles/s41591-024-03376-x", "studyType": "Human multi-organ vascular atlas", "diseaseContext": "Shared all", "useInModel": "Distinguishes endothelial and mural states across organs; supports multi-marker identification.", "limit": "Transcriptomic identities are not direct functional rates; healthy references need disease-specific validation.", "provenance": "Selected full-text or indexed results passages reviewed; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V02": { "id": "V02", "year": 2022, "topic": "Pericytes and vasculature", "title": "Single cell atlas of the normal and malformed human brain vasculature", "url": "https://pmc.ncbi.nlm.nih.gov/articles/8995178/", "studyType": "Human brain vascular single-cell atlas", "diseaseContext": "Alzheimer's / ALS / FTD", "useInModel": "Separates pericytes, smooth muscle and perivascular fibroblasts using multiple markers.", "limit": "Normal and malformed vasculature is not the same as a neurodegeneration cohort.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V03": { "id": "V03", "year": 2024, "topic": "Pericytes and vasculature", "title": "Single-cell atlas of the human brain vasculature across development, adulthood and disease", "url": "https://www.nature.com/articles/s41586-024-07493-y", "studyType": "Human developmental and disease vascular atlas", "diseaseContext": "Alzheimer's / ALS / FTD", "useInModel": "Provides vascular cell-state and spatial-reference resources.", "limit": "Development, tumors and other pathologies require separate context labels.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V34": { "id": "V34", "year": 2020, "topic": "Healthy reference", "title": "Genomic characterization of endothelial enhancers reveals a multifunctional role for NR2F2 in regulation of arteriovenous gene expression", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC7212523/", "studyType": "ChIP-seq on human arterial and venous endothelial cells", "diseaseContext": "Healthy reference", "useInModel": "Gives the marker sets that separate arterial from venous endothelium, which is what makes this family distinguishable from I003 at all: arterial DLL4, EFNB2, HEY2 and NOTCH4 against venous EMCN, EPHB4 and NR2F2. NR2F2 binding sites were over-represented in vein-specific enhancers, so venous identity is actively held rather than being the absence of arterial identity.", "limit": "Cultured human arterial and venous endothelial cells, healthy. Enhancer occupancy is not a cell count, and these are large-vessel identities being used to label a microvascular segment.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "V35": { "id": "V35", "year": 2024, "topic": "Healthy reference", "title": "Eph-ephrin signaling couples endothelial cell sorting and arterial specification", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10991410/", "studyType": "Mouse genetics with single-cell RNA sequencing and in vitro flow", "diseaseContext": "Healthy reference", "useInModel": "Arterial identity is a balance rather than a label: loss of EphB4 raises ephrin-B2, which raises Notch, VEGF and Dach1 signalling, and knocking down EPHB4 in cultured endothelium raised the arterial markers Notch1, Dll4, Sox17 and VEGFR2. Dach1 is itself shear-responsive, which ties identity to flow rather than leaving it fixed.", "limit": "Mouse genetics and cultured human umbilical vein cells. Developmental specification is not the same as maintenance in adult tumour vasculature, where the segment may not be cleanly defined at all.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "V36": { "id": "V36", "year": 2022, "topic": "Experimental platform", "title": "Mechanosensitive channel PIEZO1 senses shear force to induce KLF2/4 expression via CaMKII/MEKK3/ERK5 axis in endothelial cells", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC9317998/", "studyType": "Endothelial culture under defined laminar shear", "diseaseContext": "Healthy reference", "useInModel": "Names the route by which an endothelial cell reads flow: PIEZO1 opens under shear, calcium enters, CaMKII activates MEKK3 and the MEK5/ERK5 axis, and KLF2 then KLF4 are transcribed. Knocking out PIEZO1 markedly reduced both ERK5 activation and KLF2 induction by laminar flow. This is the sensor that decides whether a vessel behaves as an inflow segment.", "limit": "Cultured cells under clean unidirectional shear, which tumour vessels do not experience. Studies in this area apply a wide span of magnitudes - 5, 10 and about 16 dyn/cm^2 appear across the literature - and no threshold separating arterial from arteriolar behaviour is established.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "V37": { "id": "V37", "year": 2026, "topic": "Transport", "title": "Targeting angiogenesis: lessons from 25 years of normalizing tumor vasculature", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13094722/", "studyType": "Review, Cell 189(8):2379-2415", "diseaseContext": "Shared cancer", "useInModel": "A narrative review of twenty-five years of vascular normalisation, carried for its framing rather than for data: tumours acquire vessels by sprouting angiogenesis and co-option of host vasculature as well as intussusception, vasculogenesis, vascular mimicry and endothelial transdifferentiation, and the resulting vessels are abnormal through both signalling imbalance and physical forces. It names the same four consequences this atlas measures separately - hypoxia, low pH, elevated fluid pressure, immunosuppression - and argues normalisation improves delivery and efficacy.", "limit": "A review with no primary measurement. It was opened looking for transport quantities and contains none of its own; every figure in it belongs to a cited study that would have to be read separately. It may be cited for the taxonomy of how tumour vessels form and for the normalisation argument, and for nothing numeric.", "provenance": "Abstract and indexing read from Europe PMC (PMC13094722); not open access. Classified as a review with no extractable primary quantity, which is a result - the atlas records that it was opened so it is not opened again.", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I003", "name": "Venular endothelium", "category": "Vascular", "whereToCheck": "Vascular outflow and immune entry", "states": [ "Resting", "inflamed", "specialized" ], "behaviors": [ "Leukocyte arrest", "transmigration", "leakage" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "sender-I003-endothelial-cells" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "sender-I003-endothelial-cells" ], "priorResearch": { "path": "simulation/data/profiles/venular-endothelium.json", "summary": "Venular endothelium lines the outflow side, immediately downstream of the capillary bed, and it is where leukocytes leave the circulation. That is not incidental to the segment - it is what distinguishes it. Leukocytes are carried to the postcapillary venular wall, roll on selectins, arrest through integrins binding ICAM-1 and VCAM-1, and cross by an ordered sequence in which ICAM-2, JAM-A and PECAM-1 act in turn (V40). Pericytes sit on the tissue side, and their processes and the gaps between them are part of the passage rather than an obstacle to it (V14). A subtype, the high endothelial venule, is specialised further for lymphocyte entry and identified by PNAd (V39).", "stateAxes": [ { "axis": "Resting", "whatToMeasure": "Baseline adhesion molecule levels on the luminal face with the vessel's perfusion recorded alongside, since neither alone predicts entry", "interpretationLimit": "The luminal surface is not fixed and remodels with systemic state ahead of any visible dysfunction, so a resting panel has to be measured in the condition of interest rather than carried from a healthy reference.", "evidence": [ "V29", "V33" ] }, { "axis": "Inflamed", "whatToMeasure": "ICAM-1 and VCAM-1 density, and whether leukocytes actually arrest and cross rather than only that the molecules are present", "interpretationLimit": "Which of ICAM-1 and VCAM-1 dominates depends on the activation state of both the T cell and the endothelium, so no single density is a general parameter. Presence of the molecule is not demonstrated function.", "evidence": [ "V29", "V28" ] }, { "axis": "Anergic", "whatToMeasure": "ICAM-1 alongside the histone marks at its promoter, since the silencing is epigenetic rather than a change of cell type", "interpretationLimit": "Mouse models and conditioned culture. The silencing was not associated with DNA hypermethylation, so the agents that reversed it act less directly than their names suggest, and whether this holds across the drawn environments is untested.", "evidence": [ "V28" ] }, { "axis": "Specialised as a high endothelial venule", "whatToMeasure": "PNAd by MECA-79, counted as vessels per unit area rather than scored, and its position relative to any tertiary lymphoid structure", "interpretationLimit": "Most tumour evidence is murine or small retrospective human cohorts, and a score is not a vessel density. Whether inducing these venules improves outcome is not established.", "evidence": [ "V38", "V39" ] } ], "records": { "V28": { "id": "V28", "year": 2006, "topic": "Accessibility", "title": "Epigenetic regulation of tumor endothelial cell anergy: silencing of intercellular adhesion molecule-1 by histone modifications", "url": "https://aacrjournals.org/cancerres/article/66/22/10770/526515/Epigenetic-Regulation-of-Tumor-Endothelial-Cell", "studyType": "Cell culture with two mouse tumour models", "diseaseContext": "Shared cancer", "useInModel": "Gives a mechanism for tumour endothelium refusing to let leukocytes stick: tumour-conditioned endothelial cells lost ICAM-1 alongside promoter histone H3 deacetylation and loss of H3K4 methylation, and DNMT and HDAC inhibitors restored both the molecule and leukocyte adhesion, with more leukocyte-vessel interaction and infiltration in vivo.", "limit": "Mouse models and conditioned culture. The silencing was not associated with DNA hypermethylation, so the drugs that reversed it act less directly than their names suggest. Whether the same holds across the drawn environments is untested.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "V29": { "id": "V29", "year": 2019, "topic": "Accessibility", "title": "VCAM-1 density and tumor perfusion predict T-cell infiltration and treatment response in preclinical models", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC6744528/", "studyType": "Preclinical imaging and intervention study in four mouse tumour models - EL4, B16F10, CT26 and MC38 - pairing dynamic contrast-enhanced MRI for perfusion and permeability with a VCAM-1-targeted iron oxide microparticle contrast agent, against histological T-cell and VCAM-1 density, with integrin blocking in vitro and in vivo and a PD-L1 treatment experiment, Translational Oncology", "diseaseContext": "Shared cancer", "useInModel": "Read in full text, and it resolves a tension in this atlas rather than creating one. The project holds three instances arguing that perfusion does not determine the local field - oxygen, pH, nutrients - and this paper's title says perfusion predicts T-cell infiltration. Both are right, because the dependent variables are different: a vessel can be open enough to deliver cells while the local gas tension is set by consumption downstream of it. The numbers are model-dependent and reported as such. In EL4 tumours, perfusion and permeability measured as k-trans correlated with T-cell density at r equal to 0.84, p 0.03, and vascular VCAM-1 density at r 0.65, p 0.05. In CT26 tumours, k-trans correlated with endogenous T-cell density at r 0.64, p 0.05, and histological vascular VCAM-1 with T-cell density at r 0.79, p 0.02. In B16F10 tumours none of the three measures correlated with infiltration - r 0.16, 0.32 and 0.48 - and that model also showed no contrast change at all after the targeted agent. So two of three models show the relationship and one does not, which makes model identity a determining variable. The causal arm is the strongest part and belongs to the adhesion machinery rather than to perfusion: blocking VCAM-1 reduced T-cell retention on endothelium in vitro, blocking the integrins CD49d or CD18 reduced it further, and the combination further still - while in vivo, mice given ten million activated antigen-specific CD8 T cells with integrin blockade had viable tumour volumes of 937 plus or minus 217 cubic millimetres one week later against 21 plus or minus 14 in the control arm. A roughly fortyfold difference in viable tumour from blocking two adhesion receptors establishes that getting in is rate-limiting for the response, not merely correlated with it. Two further things the atlas can use. An ordering of which imaging quantity moves first: at three days the extracellular extravascular volume fraction had risen significantly in rejecting tumours while tumour volume, k-trans, plasma volume and targeted-agent binding had not, and k-trans only separated at seven days once volumes had already diverged. And a fitted pharmacokinetic parameter set with dispersions for both agents - systemic clearance 0.06 plus or minus 0.03 ml/min for each, distribution clearance 5.0 against 2.9, central volume 5.1 against 2.7 ml, peripheral volume 4.9 against 11.6 ml - alongside tumour uptake of 3 percent of injected dose per gram for the targeted agent against under 0.5 percent for the isotype.", "limit": "Mouse tumour models throughout, with group sizes of five to six for every correlation, so each r rests on very few animals and the three that reach p 0.05 do so marginally; the difference between the models that correlate and the one that does not should not be read as a biological difference between melanoma and the others on this evidence. The treatment-prediction claim in the title is the weakest part and the full text says so: baseline k-trans, plasma fraction and targeted-agent binding each failed individually to predict tumour volume change over two weeks, at r 0.19, 0.22 and 0.20 with p values of 0.09, 0.07 and 0.08, and only a multiple linear regression combining two of them reached r 0.36 at p 0.05 in seventeen animals - which accounts for a small share of the variance and is described by the authors as partial prediction. The authors also note their imaging required hair removal, which may itself have contributed to the PD-L1 growth inhibition. The contrast agent is a one-micrometre iron oxide microparticle, so its distribution is constrained by particle size in ways a soluble tracer would not be, and its short blood half-life is cited from elsewhere rather than measured here. The pharmacokinetic parameters are fitted to a compartmental model, with several rate constants carrying dispersions larger than their means, so they are not transferable constants. Whether VCAM-1 or ICAM-1 dominates depends on the activation state of both the T cell and the endothelium, so a single adhesion density is not a general predictor.", "provenance": "Full text read from the open-access record (PMC6744528) after the one-line screening entry was flagged as pending; all six correlation coefficients with their p values and group sizes for EL4, B16F10 and CT26, the three non-significant single-predictor correlations and the two multiple-regression results for PD-L1 response with their r values and p values and animal count, the in vitro blocking results for VCAM-1, CD49d and CD18 with their significance levels, the in vivo viable tumour volumes at one week with dispersions and group sizes and the transferred cell number, the ordering of imaging changes at three and seven days, Table 1's fitted pharmacokinetic parameters with dispersions for both agents, the tumour uptake figures as percent injected dose per gram, the particle diameter, and the authors' stated caveat about hair removal as reported", "quantitativeExtraction": "extracted" }, "V33": { "id": "V33", "year": 2022, "topic": "Accessibility", "title": "Vascular proteome responses precede organ dysfunction in a murine model of Staphylococcus aureus bacteremia", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC9426442/", "studyType": "In vivo endothelial surface labelling across four organs with DIA mass spectrometry", "diseaseContext": "Healthy reference", "useInModel": "Says the luminal surface is not a fixed property. The perfusable vascular proteome is shared across organs at baseline and is remodelled tissue-specifically under systemic insult, ahead of organ dysfunction. What the endothelium displays therefore has to be measured in the disease state, not carried over from a healthy reference.", "limit": "Bacteraemia in mice, not tumour. It establishes that the luminal surface moves with disease, not how it moves in any of the drawn environments.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "V38": { "id": "V38", "year": 2022, "topic": "Accessibility", "title": "Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy", "url": "https://doi.org/10.1016/j.ccell.2022.01.002", "studyType": "Mouse intravital imaging with human melanoma cohorts", "diseaseContext": "Melanoma / Shared cancer", "useInModel": "Says lymphocyte entry into a tumour happens at portals rather than across the vasculature, and quantifies the concentration. By intravital imaging, under 10 percent of lymphocytes rolled along non-HEV tumour vessels against nearly 40 percent along tumour-associated high endothelial venules, with extravasation rising to match, and these vessels were major sites of entry both at baseline and under checkpoint blockade - and their presence predicted response to combination checkpoint therapy. Three uses. The atlas carries twenty immune rows and has had no entry mechanism for any of them; this is it, and it is localised rather than distributed. It supplies a third candidate explanation for immune exclusion alongside the steric and the signalled ones: a tumour may lack T cells because it lacks the portals, which is distinguishable from both by looking for the venular phenotype. And because portal presence predicts checkpoint response, this is a measurable and clinically validated quantity rather than a mechanistic conjecture.", "limit": "Intravital imaging in mouse tumours, so the rolling and extravasation fractions are mouse measurements in model tumours rather than human values. Rolling and extravasation are proportions of observed lymphocytes rather than absolute fluxes, so the atlas gains a ratio and not a rate - no cells per vessel per unit time. The predictive association with checkpoint response is correlative. It does not establish what makes these venules appear, which is the question a model would need in order to change them.", "provenance": "Re-extracted from the record's own screened content. Both rolling proportions, the matching rise in extravasation, the status of these vessels as major entry sites at baseline and under treatment, and the predictive association as reported. The framing as a third exclusion hypothesis is this atlas's own", "quantitativeExtraction": "extracted" }, "V39": { "id": "V39", "year": 2021, "topic": "Accessibility", "title": "High endothelial venules (HEVs) in immunity, inflammation and cancer", "url": "https://doi.org/10.1007/s10456-021-09792-8", "studyType": "Review, Angiogenesis 24:719-753", "diseaseContext": "Shared cancer", "useInModel": "Gives the portal a phenotype and a marker, which is what makes the entry finding actionable rather than descriptive. High endothelial venules are a distinct venular state identified by peripheral node addressin with the MECA-79 antibody, built for lymphocyte entry, and in tumours they appear alongside tertiary lymphoid structures. That last association matters for this atlas, which already records tertiary lymphoid structures improving immunotherapy response in melanoma and generating antibody-producing plasma cells - so the portal and the local lymphoid organisation arrive together, and a row that counts one should expect the other. It is also the reference for what separates a specialised venule from a merely inflamed one, which is the distinction a model needs if it is to treat entry as portal-limited rather than as a property of inflammation.", "limit": "A review, so it supplies a phenotype and a marker rather than any density, number of portals per tumour, or flux through one. The co-occurrence with tertiary lymphoid structures is an association and does not establish which comes first or whether either requires the other. Across immunity, inflammation and cancer, so not specific to any drawn environment.", "provenance": "Re-extracted from the record's own screened content. The venular phenotype and its identifying addressin and antibody, the purpose-built character for lymphocyte entry, and the co-occurrence with tertiary lymphoid structures in tumours as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I004", "name": "Lymphatic endothelial cells", "category": "Vascular", "whereToCheck": "Peripheral tissues and draining routes; CNS meningeal routes separately", "states": [ "Initial versus collecting", "activated" ], "behaviors": [ "Drainage", "immune trafficking", "clearance", "absence in sampled compartment" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-547", "hatton-580" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-547", "hatton-580" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "sender-I004-endothelial-cells" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-547", "hatton-580", "sender-I004-endothelial-cells" ], "priorResearch": { "path": "simulation/data/profiles/lymphatic-endothelial-cells.json", "summary": "Lymphatic endothelium lines the drainage route: the one-way path by which fluid, macromolecules and immune cells leave a tissue. It comes in two arrangements and they do different jobs. Initial lymphatics are blind-ended and their cells are joined by discontinuous button-like junctions around open gaps, so fluid and cells enter between cells rather than through them. Collecting vessels downstream are continuous and tight, carry valves, and move lymph onward (V41). In normal tissue this is what keeps interstitial pressure near zero, and it is the reason a large molecule that leaves the blood has somewhere to go.", "stateAxes": [ { "axis": "Initial versus collecting", "whatToMeasure": "Junction morphology together with the marker panel and the presence of valves, rather than either alone", "interpretationLimit": "The marker panel weakens along the vessel, so low expression indicates segment before it indicates doubt. Junction descriptions are morphological and carry no conductance.", "evidence": [ "V41" ] }, { "axis": "Draining versus compressed", "whatToMeasure": "Whether the vessel carries flow, not whether it can be stained. Lumen patency and solid stress alongside interstitial pressure", "interpretationLimit": "A compressed lymphatic is still a lymphatic by marker. This is the axis on which the family's function turns and it cannot be read from a section stained for identity.", "evidence": [ "V42", "V43" ] }, { "axis": "Intratumoural versus peritumoural", "whatToMeasure": "Position relative to the tumour margin, since drainage and the pressure gradient are both reported at the rim", "interpretationLimit": "Interstitial pressure is described as uniform through the interior and falling steeply at the margin, so a single value for a tumour hides the only place a gradient exists. The profile is a general description, not a per-environment map.", "evidence": [ "V44", "V42" ] }, { "axis": "Activated", "whatToMeasure": "Lymphangiogenic signalling and junctional remodelling, measured in the disease state", "interpretationLimit": "Nothing assembled here characterises an activated lymphatic state in any drawn environment; this axis is named by the inventory and not yet served.", "evidence": [ "V41" ] } ], "records": { "V41": { "id": "V41", "year": 2007, "topic": "Healthy reference", "title": "Functionally specialized junctions between endothelial cells of lymphatic vessels", "url": "https://doi.org/10.1084/jem.20062596", "studyType": "Junctional imaging in mouse tissue in healthy and inflamed states, with VE-cadherin and PECAM-1 dependency tests and examination of growing lymphatic sprouts, Journal of Experimental Medicine 204(10):2349-2362", "diseaseContext": "Healthy reference", "useInModel": "The single most important record in this category, because it shows that knowing a junction's molecular composition does not tell you what the junction does. Initial lymphatics have oak leaf-shaped endothelial cells whose overlapping flaps lack junctions at the tip and are anchored at the sides by discontinuous button-like junctions; collecting lymphatics and blood vessels have continuous zipper-like junctions. Buttons and zippers are built from the same molecules - VE-cadherin, occludin, claudin-5, zonula occludens-1, junctional adhesion molecule-A and endothelial cell-selective adhesion molecule - and behave oppositely: fluid enters throughout initial lymphatics through the openings between buttons, which open and close without disrupting junctional integrity. VE-cadherin was required to maintain integrity and PECAM-1 was not. Growing sprout tips carried zippers rather than buttons, so buttons are a specialised arrangement and not an immature one. Three things follow. The inventory for this row asks for claudins, occludin and cadherins, and this record says that inventory is insufficient by construction - arrangement decides function, not composition. Entry is a gated aperture rather than a leak, so permeability here is a switchable geometry. And fluid and leukocytes enter differently, fluid throughout and most leukocytes in the proximal half, so one vessel has two cargo-specific entry distributions.", "limit": "Mouse tissue in healthy and inflamed states, not tumour, and the atlas's lymphatic rows note that tumour-associated lymphatics differ. The button and zipper descriptions are morphological and molecular: no conductance, flux, aperture size or opening frequency is given for either arrangement, so the structural insight has no number attached. The dependency tests establish that VE-cadherin maintains integrity without showing what sets the button-versus-zipper choice.", "provenance": "Abstract read in full, replacing a screening note. The cell shape and flap architecture, both junction types and their locations, the full shared molecular list, both dependency results, the sprout-tip observation, and the separate fluid and leukocyte entry patterns as reported", "quantitativeExtraction": "extracted" }, "V42": { "id": "V42", "year": 2002, "topic": "Transport", "title": "Lymphatic metastasis in the absence of functional intratumor lymphatics", "url": "https://doi.org/10.1126/science.1071420", "studyType": "Mouse tumour models with functional lymphatic imaging, Science 296:1883-1886", "diseaseContext": "Shared cancer", "useInModel": "Says the lymphatics inside a tumour do not drain, and that metastasis to lymph nodes happens anyway through vessels at the margin. For a transport model this removes the exit route from the tumour interior: whatever reaches the interstitium there has no lymphatic path out, and the peritumoural vessels do what draining occurs.", "limit": "Mouse tumour models. A patient-derived cervical xenograft study reports functional intratumoral lymphatics, so the strict form of this claim is contested and may be model-dependent.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "V43": { "id": "V43", "year": 2004, "topic": "Transport", "title": "Cancer cells compress intratumour vessels", "url": "https://doi.org/10.1038/427695a", "studyType": "Mouse tumour imaging, Nature 427(6976):695", "diseaseContext": "Shared cancer", "useInModel": "Gives the mechanism for the vessel that is not there, and it is growth rather than failure to form. Proliferating tumour cells generate solid stress that compresses intratumoural vessels, lymphatics included - so the absent drainage that lets interstitial pressure rise toward microvascular pressure is a mechanical consequence of proliferation. That matters for the delivery chain this atlas has assembled: the second stage, where convection disappears, is caused by the first thing a tumour does. It also settles which way to read the recorded dispute over vessel collapse: a commentary argues that hyaluronan compresses pancreatic vessels through solid stress rather than interstitial fluid pressure, and this record supplies solid stress from an independent source, so the atlas should carry solid stress as the compressing quantity and interstitial pressure as its consequence.", "limit": "Mouse tumour models in a brief report. Solid stress is not measured in any drawn environment here, and compression is inferred from vessel geometry rather than from a measured force - so the mechanism is identified and the quantity is absent, which is the same position the atlas is in for the pressures it does hold.", "provenance": "Re-extracted from the record's own screened content. The proliferation-generated solid stress, the inclusion of lymphatics among the compressed vessels, and the inference of compression from geometry as reported. The reading of the vessel-collapse dispute is this atlas's own", "quantitativeExtraction": "extracted" }, "V44": { "id": "V44", "year": 2004, "topic": "Transport", "title": "High interstitial fluid pressure - an obstacle in cancer therapy", "url": "https://doi.org/10.1038/nrc1456", "studyType": "Review, Nat Rev Cancer 4(10):806-813", "diseaseContext": "Shared cancer", "useInModel": "Explains why nothing moves by convection inside a tumour, which is the step between the junction row's entry problem and the matrix's own geometry. Without lymphatic drainage, fluid entering from leaky vessels has nowhere to go, so pressure rises until it approaches microvascular pressure and the gradient that would carry a large molecule into tissue disappears. The spatial description matters as much: pressure is reported as uniform across the tumour interior and falling steeply at the margin, so the gradient and the exit are both at the rim. Taken with the junction row, the atlas can now name the limiting step at each stage of delivery - permeability limits entry and puts tissue-surface concentration one hundred to one thousand times below plasma, and once inside there is no convection, so transport is diffusion alone through a matrix whose pore geometry the atlas does not measure.", "limit": "A review. It explains why the pressures measured in breast and pancreatic tumours matter for delivery and does not measure them, and the spatial profile is a general description rather than a per-environment map. It also predates the dispute recorded elsewhere in this atlas over whether interstitial fluid pressure or solid stress is the quantity that collapses vessels, and its framing assumes the former.", "provenance": "Re-extracted from the record's own screened content. The drainage argument, the approach of interstitial to microvascular pressure, the loss of the convective gradient, and the uniform-interior-steep-margin profile as reported. The assembly of the delivery chain across rows is this atlas's own", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I005", "name": "Pericytes", "category": "Vascular", "whereToCheck": "Microvascular wall outside endothelium", "states": [ "Attached", "detached", "synthetic", "differentiated", "inflammatory", "injured" ], "behaviors": [ "Coverage", "state", "matrix contacts", "perfusion", "barrier effects", "secretome" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-153", "hatton-528" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-153", "hatton-528" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-153", "hatton-528" ], "priorResearch": { "path": "simulation/data/profiles/pericytes.json", "summary": "Pericytes occupy the tissue-facing side of small blood vessels, closely associated with endothelial cells and vascular basement membrane. Their contribution includes vessel organization and support, barrier regulation, and context-dependent control of microvascular behavior. Organ and vessel segment matter; a brain capillary pericyte is not interchangeable with an arterial smooth muscle cell. Identify them with anatomical location, morphology and a marker panel. Candidate markers include PDGFRB, RGS5, CSPG4/NG2, ABCC9 and KCNJ8, interpreted alongside endothelial, smooth-muscle, fibroblast and neural-cell markers. None of these alone should be treated as a universal identity certificate. The vascular atlases are reference resources, not functional measurements ( V01 , V02 , V03 ).", "stateAxes": [ { "axis": "Vessel-integrated / supporting", "whatToMeasure": "Attachment, process coverage, endothelial contact and basement-membrane relation", "interpretationLimit": "Do not infer barrier function from cell count alone.", "evidence": [ "V04", "V05", "V06" ] }, { "axis": "Synthetic / remodeling", "whatToMeasure": "Proliferation, matrix production, RGS5-associated program and morphology", "interpretationLimit": "Operational label from specific models; not one universal human subtype.", "evidence": [ "V13" ] }, { "axis": "Differentiated / contractile", "whatToMeasure": "Contractile protein program and measured force/tone", "interpretationLimit": "Contractile capacity and actual constriction are different variables.", "evidence": [ "V13", "V16" ] }, { "axis": "Inflammatory / immune-modulating", "whatToMeasure": "Secreted cytokines, adhesion and functional immune response", "interpretationLimit": "Marker expression alone does not establish suppression or stimulation.", "evidence": [ "V11", "V12", "V14" ] }, { "axis": "Detached / poorly covering", "whatToMeasure": "Pericyte–endothelial distance, discontinuity and altered processes", "interpretationLimit": "Distinguish detachment from death or altered marker expression.", "evidence": [ "V08", "V09" ] }, { "axis": "Injured / reduced", "whatToMeasure": "Cell number, viability, coverage and leakage measurements", "interpretationLimit": "Postmortem association cannot establish temporal causality.", "evidence": [ "V17", "V18" ] }, { "axis": "Constricted / relaxed", "whatToMeasure": "Segment-specific diameter, calcium, red-cell flux and response time", "interpretationLimit": "Do not label all mural cells as fast capillary flow controllers.", "evidence": [ "V15", "V16", "V22" ] }, { "axis": "Pericyte-like / uncertain identity", "whatToMeasure": "Location, multiple markers, lineage evidence and phenotype", "interpretationLimit": "Retain this qualifier; do not silently merge fibroblasts or tumor-derived cells.", "evidence": [ "V02", "V20", "V21" ] } ], "records": { "V02": { "id": "V02", "year": 2022, "topic": "Pericytes and vasculature", "title": "Single cell atlas of the normal and malformed human brain vasculature", "url": "https://pmc.ncbi.nlm.nih.gov/articles/8995178/", "studyType": "Human brain vascular single-cell atlas", "diseaseContext": "Alzheimer's / ALS / FTD", "useInModel": "Separates pericytes, smooth muscle and perivascular fibroblasts using multiple markers.", "limit": "Normal and malformed vasculature is not the same as a neurodegeneration cohort.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V04": { "id": "V04", "year": 2003, "topic": "Pericytes and vasculature", "title": "Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors", "url": "https://pubmed.ncbi.nlm.nih.gov/14561699/", "studyType": "Mouse tumor recruitment experiments", "diseaseContext": "Shared cancer", "useInModel": "Measures what losing matrix retention costs. PDGF-B carries a C-terminal motif that holds it in matrix; in mice lacking it, the distance from endothelium to the outermost pericyte parts rose about sevenfold in tumour vessels, and the share of pericytes sitting more than 10 micrometres from the endothelium went from about 4% in wild-type to more than 80%. Where the ligand comes from matters as well as whether it is held: endothelial and non-endothelial sources affect recruitment and vascular pattern differently.", "limit": "Mouse tumour models. The displacement is a distance rather than a function - a pericyte 10 micrometres out is not shown to have stopped doing anything - and growth-factor presence alone does not specify spatial distribution or mature coverage.", "provenance": "Full text reviewed; displacement distribution and fold change extracted", "quantitativeExtraction": "extracted" }, "V05": { "id": "V05", "year": 2003, "topic": "Pericytes and vasculature", "title": "Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall", "url": "https://pubmed.ncbi.nlm.nih.gov/12897053/", "studyType": "Genetic mouse study", "diseaseContext": "Shared all", "useInModel": "Matrix retention of endothelial PDGF-B influences mural recruitment and organization.", "limit": "Not a human quantitative recruitment constant.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V06": { "id": "V06", "year": 2010, "topic": "Pericytes and vasculature", "title": "Pericytes regulate the blood–brain barrier", "url": "https://www.nature.com/articles/nature09522", "studyType": "Genetic mouse barrier study", "diseaseContext": "Alzheimer's / ALS / FTD", "useInModel": "Pericytes coordinate endothelial barrier properties and astrocyte-endfoot organization.", "limit": "Developmental/genetic models do not reproduce every adult disease state.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V08": { "id": "V08", "year": 2012, "topic": "Pericytes and vasculature", "title": "Pericyte depletion results in hypoxia-associated epithelial-to ...", "url": "https://pubmed.ncbi.nlm.nih.gov/22264789/", "studyType": "Mouse perturbations and human correlative data", "diseaseContext": "Breast / Shared cancer", "useInModel": "Pericyte depletion can reduce primary growth yet worsen hypoxia and metastasis.", "limit": "Direction depends on tumor, time and perturbation; not a treatment recommendation.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V09": { "id": "V09", "year": 2015, "topic": "Pericytes and vasculature", "title": "Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2", "url": "https://pubmed.ncbi.nlm.nih.gov/25704811/", "studyType": "Mouse stage-dependent perturbation", "diseaseContext": "Breast / Shared cancer", "useInModel": "Early versus established hypoxic tumors respond differently to pericyte targeting; ANG2 participates.", "limit": "Do not pool stage-specific effects or generalize them to all cancers.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V11": { "id": "V11", "year": 2013, "topic": "Pericytes and vasculature", "title": "Tumor-derived vascular pericytes anergize Th cells", "url": "https://pubmed.ncbi.nlm.nih.gov/23785117/", "studyType": "Mouse tumor-derived cells and T-cell assays", "diseaseContext": "Melanoma / Shared cancer", "useInModel": "RGS5- and IL-6-associated pericyte states can suppress CD4 activation and promote anergy.", "limit": "Does not establish that all pericytes suppress all T cells or quantify CD3-engager failure.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V12": { "id": "V12", "year": 2015, "topic": "Pericytes and vasculature", "title": "Role of Tumor Pericytes in the Recruitment of Myeloid-Derived Suppressor Cells", "url": "https://pubmed.ncbi.nlm.nih.gov/26296362/", "studyType": "Tumor models and human association", "diseaseContext": "Breast / Shared cancer", "useInModel": "Pericyte deficiency and inflammatory signaling connect to suppressive myeloid recruitment.", "limit": "Human association is not proof of a universal causal pathway.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V13": { "id": "V13", "year": 2024, "topic": "Pericytes and vasculature", "title": "JCI - Pericyte phenotype switching alleviates immunosuppression and sensitizes vascularized tumors to immunotherapy in preclinical models", "url": "https://jci.org/articles/view/179860", "studyType": "Preclinical phenotype switching", "diseaseContext": "Melanoma / Shared cancer", "useInModel": "Synthetic-to-differentiated pericyte shifts altered oxygenation and immune context and improved adoptive T-cell therapy in mice.", "limit": "Pericyte state and macrophage polarization are distinct; no proven patient regimen follows.", "provenance": "Selected full-text or indexed results passages reviewed; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V14": { "id": "V14", "year": 2012, "topic": "Pericytes and vasculature", "title": "Pericytes support neutrophil subendothelial cell crawling and breaching of venular walls in vivo", "url": "https://pubmed.ncbi.nlm.nih.gov/22615129/", "studyType": "Mouse intravital inflammatory trafficking", "diseaseContext": "Shared all", "useInModel": "Pericyte processes and gaps participate in neutrophil passage through venular walls.", "limit": "Neutrophil findings cannot be assigned unchanged to T cells or antibodies.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V15": { "id": "V15", "year": 2019, "topic": "Pericytes and vasculature", "title": "Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC6658218/", "studyType": "Human tissue and rodent mechanistic experiments", "diseaseContext": "Alzheimer's", "useInModel": "A-beta oligomer-associated ROS/endothelin signaling constricts capillaries at pericytes.", "limit": "Ex vivo exposures and biopsy findings are not a prevalence estimate for all AD patients.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V16": { "id": "V16", "year": 2021, "topic": "Pericytes and vasculature", "title": "Brain capillary pericytes exert a substantial but slow influence on blood flow", "url": "https://pubmed.ncbi.nlm.nih.gov/33603231/", "studyType": "Mouse in vivo imaging and perturbation", "diseaseContext": "Alzheimer's / ALS / FTD", "useInModel": "Capillary pericytes exert slower flow effects than upstream mural cells.", "limit": "Distinguish vessel segment, mural subtype and response timescale.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V17": { "id": "V17", "year": 2013, "topic": "Pericytes and vasculature", "title": "Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis", "url": "https://pubmed.ncbi.nlm.nih.gov/22941226/", "studyType": "Human postmortem spinal cord study", "diseaseContext": "ALS", "useInModel": "Pericyte loss and barrier leakage occurred together in a small ALS cohort.", "limit": "11 ALS versus 5 controls; association does not establish cause, onset or population prevalence.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V18": { "id": "V18", "year": 2020, "topic": "Pericytes and vasculature", "title": "APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline", "url": "https://www.nature.com/articles/s41586-020-2247-3", "studyType": "Human imaging/biomarkers with mechanistic investigation", "diseaseContext": "Alzheimer's", "useInModel": "APOE4-associated barrier dysfunction and pericyte injury inform neurovascular stratification.", "limit": "Biomarker association is not a direct count of living pericytes or an individual causal prediction.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V20": { "id": "V20", "year": 2025, "topic": "Pericytes and vasculature", "title": "Pericytes orchestrate a tumor-restraining microenvironment in glioblastoma", "url": "https://www.nature.com/articles/s41467-025-66985-1", "studyType": "Human profiling plus mouse glioma perturbations", "diseaseContext": "Shared cancer", "useInModel": "Pericyte deficiency promoted an endothelial/macrophage environment linked to invasion and immune suppression.", "limit": "Glioblastoma is an external comparator; inferred communication edges require separate functional evidence.", "provenance": "Selected full-text or indexed results passages reviewed; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V21": { "id": "V21", "year": 2026, "topic": "Pericytes and vasculature", "title": "FAP+ pericyte-like cells promote monocyte differentiation into tumor-associated macrophages in glioblastoma", "url": "https://www.nature.com/articles/s12276-026-01827-8", "studyType": "Glioblastoma pericyte-like cell study", "diseaseContext": "Shared cancer", "useInModel": "FAP-positive pericyte-like populations connect to monocyte/macrophage behavior.", "limit": "Preserve the qualifier pericyte-like; do not merge these cells automatically with canonical mural pericytes.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V22": { "id": "V22", "year": 2024, "topic": "Pericytes and vasculature", "title": "Inhibiting Ca2+ channels in Alzheimer's disease model mice ...", "url": "https://pubmed.ncbi.nlm.nih.gov/39294491/", "studyType": "Mouse AD imaging and intervention", "diseaseContext": "Alzheimer's", "useInModel": "Calcium-channel-dependent pericyte tone links to impaired perfusion.", "limit": "Preclinical intervention is not established human AD treatment.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I006", "name": "Vascular smooth muscle cells", "category": "Vascular", "whereToCheck": "Arteries; arterioles; larger venous vessels", "states": [ "Contractile", "synthetic", "injured" ], "behaviors": [ "Tone and response time", "distinguish from capillary pericytes" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-556", "hatton-559" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-556", "hatton-559" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-556", "hatton-559" ], "priorResearch": { "path": "simulation/data/profiles/vascular-smooth-muscle-cells.json", "summary": "Vascular smooth muscle cells wrap the vessels upstream of the capillary bed - arteries, arterioles and larger venous vessels - in concentric layers that thin to a single layer at the arteriole and become discontinuous beyond it. Their job is tone: they set vessel calibre and therefore how blood is distributed, and they do it faster than the mural cells further downstream. Capillary pericytes exert a substantially slower influence on flow than upstream mural cells, so segment and response timescale have to be recorded together rather than treated as one mural contractile function (V16).", "stateAxes": [ { "axis": "Contractile", "whatToMeasure": "The contractile programme together with measured tone or calibre change, not the markers alone", "interpretationLimit": "Contractile capacity and actual constriction are different variables, and the markers report the current state rather than the cell's identity.", "evidence": [ "V45", "V16" ] }, { "axis": "Synthetic", "whatToMeasure": "Loss of the contractile programme alongside a lineage or epigenetic mark, since marker loss alone cannot distinguish a switched cell from a different cell", "interpretationLimit": "In advanced atherosclerotic lesions more than 80% of lineage-labelled smooth muscle cells were missed by marker staining, some taking on macrophage-like and mesenchymal phenotypes. Without lineage, a switched cell is invisible or miscounted as something else.", "evidence": [ "V45" ] }, { "axis": "Injured", "whatToMeasure": "Viability and coverage alongside vessel calibre, with the vessel segment recorded", "interpretationLimit": "Named by the inventory and thinly served here. No injury state for this family is characterised in any drawn environment.", "evidence": [ "V02" ] }, { "axis": "Position along the mural gradient", "whatToMeasure": "Acta2, Myh11, Rgs5 and Kcnj8 read together as a position, with the vessel segment and the cell's location in the arteriovenous tree recorded alongside", "interpretationLimit": "This is a gradient rather than a boundary. The transition from pericytes to smooth muscle is gradual, with a possible intermediate, so assigning a cell to one family or the other at a fixed point imposes a division the data does not carry. The pericyte profile's 'pericyte-like, uncertain identity' qualifier is the counterpart of this axis and should be used rather than forcing a choice.", "evidence": [ "V46", "V01", "V02" ] } ], "records": { "V01": { "id": "V01", "year": 2024, "topic": "Pericytes and vasculature", "title": "An organotypic atlas of human vascular cells", "url": "https://www.nature.com/articles/s41591-024-03376-x", "studyType": "Human multi-organ vascular atlas", "diseaseContext": "Shared all", "useInModel": "Distinguishes endothelial and mural states across organs; supports multi-marker identification.", "limit": "Transcriptomic identities are not direct functional rates; healthy references need disease-specific validation.", "provenance": "Selected full-text or indexed results passages reviewed; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V02": { "id": "V02", "year": 2022, "topic": "Pericytes and vasculature", "title": "Single cell atlas of the normal and malformed human brain vasculature", "url": "https://pmc.ncbi.nlm.nih.gov/articles/8995178/", "studyType": "Human brain vascular single-cell atlas", "diseaseContext": "Alzheimer's / ALS / FTD", "useInModel": "Separates pericytes, smooth muscle and perivascular fibroblasts using multiple markers.", "limit": "Normal and malformed vasculature is not the same as a neurodegeneration cohort.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V16": { "id": "V16", "year": 2021, "topic": "Pericytes and vasculature", "title": "Brain capillary pericytes exert a substantial but slow influence on blood flow", "url": "https://pubmed.ncbi.nlm.nih.gov/33603231/", "studyType": "Mouse in vivo imaging and perturbation", "diseaseContext": "Alzheimer's / ALS / FTD", "useInModel": "Capillary pericytes exert slower flow effects than upstream mural cells.", "limit": "Distinguish vessel segment, mural subtype and response timescale.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" }, "V45": { "id": "V45", "year": 2015, "topic": "Pericytes and vasculature", "title": "KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis", "url": "https://doi.org/10.1038/nm.3866", "studyType": "Myh11-CreERT2 lineage tracing in mouse, with human coronary lesions", "diseaseContext": "Healthy reference", "useInModel": "Shows that identifying this family by its contractile markers fails exactly when it matters. With smooth muscle cells permanently labelled before disease, standard marker staining failed to detect more than 80% of smooth-muscle-derived cells in advanced lesions; those cells had taken on macrophage-like and mesenchymal phenotypes. An epigenetic lineage mark found the same transition in human coronary lesions, in around 20% of cells previously counted as macrophages.", "limit": "Atherosclerosis, not tumour, and mouse lineage tracing with human confirmation by an epigenetic mark rather than by tracing. The warning transfers to any tissue where mural cells change state; the numbers do not transfer to a drawn environment.", "provenance": "Abstract and indexed publisher text screened; the detection-failure fraction taken as the paper states it, more than 80%", "quantitativeExtraction": "pending" }, "V46": { "id": "V46", "year": 2020, "topic": "Cellular atlas", "title": "Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination", "url": "https://doi.org/10.1038/s41467-020-17740-1", "studyType": "Mouse multi-organ single-cell transcriptomics", "diseaseContext": "Healthy reference", "useInModel": "Answers the question the inventory asks of this family, and the answer is that the boundary is a gradient. The study reports a gradual phenotypic transition from pericytes to smooth muscle cells marked by Acta2, Myh11, Rgs5 and Kcnj8, with one major pericyte branch, a possible intermediate and two smooth muscle branches. It also gives criteria for separating mural cells from fibroblasts, which is the other population they are confused with.", "limit": "Mouse, healthy, several organs. A trajectory is not a boundary, and the intermediate branch is described as possible. Commonly used markers including PDGFRB did not make the study's mural short-list, so panels that rely on them are not reproducing this result.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I007", "name": "Perivascular fibroblasts", "category": "Vascular", "whereToCheck": "Site-specific vascular adventitial niches", "states": [ "Matrix-producing", "activated" ], "behaviors": [ "Matrix organization", "signaling", "distinguish from pericytes" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "fibroblast-section-count" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "fibroblast-section-count", "fibroblast-distribution-arterioles", "fibroblast-distribution-venules" ], "priorResearch": { "path": "simulation/data/profiles/perivascular-fibroblasts.json", "summary": "Perivascular fibroblasts occupy the layer outside the vascular basement membrane - the adventitial and interstitial space around vessels, and in brain the gap between the mural cell layer and astrocytic end-feet (V48). That position is the whole distinction. Pericytes are embedded within the basement membrane; these cells are outside it, in a matrix of fibrillar collagen rather than the laminin and collagen IV sheet the mural cells inhabit. What they do there is build and organise that outer matrix, which is why they are the population that supplies collagen-producing cells after injury.", "stateAxes": [ { "axis": "Matrix-producing", "whatToMeasure": "Collagen I and III output together with the architecture produced, since the adventitial matrix is organised rather than merely present", "interpretationLimit": "Matrix genes are general fibroblast markers and do not localise a cell. Production measured in culture says nothing about the organisation achieved in tissue.", "evidence": [ "V47" ] }, { "axis": "Activated", "whatToMeasure": "Proliferation and matrix output after insult, with lineage rather than markers establishing where the cells came from", "interpretationLimit": "Injury blurs the identity boundary. After stroke the marker-defined population may arise from fibroblast proliferation or from pericyte differentiation, so an activated count is not a count of one lineage.", "evidence": [ "V47" ] }, { "axis": "Position relative to the basement membrane", "whatToMeasure": "Whether the cell lies within the vascular basement membrane or outside it, in the outer basement membrane and interstitial matrix", "interpretationLimit": "This is the criterion that holds where markers do not, and it requires imaging that resolves the basement membrane rather than a dissociated transcriptome. In brain the position is between the mural layer and astrocytic end-feet; elsewhere it is adventitial and less sharply bounded.", "evidence": [ "V48", "V46" ] } ], "records": { "V46": { "id": "V46", "year": 2020, "topic": "Cellular atlas", "title": "Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination", "url": "https://doi.org/10.1038/s41467-020-17740-1", "studyType": "Mouse multi-organ single-cell transcriptomics", "diseaseContext": "Healthy reference", "useInModel": "Answers the question the inventory asks of this family, and the answer is that the boundary is a gradient. The study reports a gradual phenotypic transition from pericytes to smooth muscle cells marked by Acta2, Myh11, Rgs5 and Kcnj8, with one major pericyte branch, a possible intermediate and two smooth muscle branches. It also gives criteria for separating mural cells from fibroblasts, which is the other population they are confused with.", "limit": "Mouse, healthy, several organs. A trajectory is not a boundary, and the intermediate branch is described as possible. Commonly used markers including PDGFRB did not make the study's mural short-list, so panels that rely on them are not reproducing this result.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "V47": { "id": "V47", "year": 2024, "topic": "Pericytes and vasculature", "title": "Distinct origin and region-dependent contribution of stromal fibroblasts to fibrosis following traumatic injury in mice", "url": "https://doi.org/10.1038/s41593-024-01678-4", "studyType": "Mouse single-cell RNA sequencing with lineage tracing after injury", "diseaseContext": "Healthy reference", "useInModel": "Separates perivascular fibroblasts from pericytes by relative expression rather than by any exclusive marker: low pericyte genes including Cspg4, Kcnj8 and Rgs5, against higher Col1a1, Col3a1, Lum, Dcn and Pdgfra. Col1a1 was chosen for targeting because it is absent from other adult CNS cell types. It also shows the two populations do different work in different places - pericytes contributing mainly to grey matter lesions, perivascular fibroblasts more extensively to white matter.", "limit": "Mouse, traumatic injury, central nervous system. The criteria are relative rather than absolute, and injury itself blurs the boundary: after stroke the PDGFRB-positive Col1a1-positive population may arise either from fibroblast proliferation or from pericyte differentiation.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "V48": { "id": "V48", "year": 2023, "topic": "Pericytes and vasculature", "title": "The elusive brain perivascular fibroblast: a potential role in vascular stability and homeostasis", "url": "https://doi.org/10.3389/fcvm.2023.1283434", "studyType": "Review of brain perivascular fibroblast biology", "diseaseContext": "Alzheimer's / ALS / FTD", "useInModel": "Gives the anatomical criterion that marker panels cannot: pericytes sit within the vascular basement membrane, perivascular fibroblasts sit outside it, in the outer basement membrane and interstitial matrix, sandwiched in brain between the mural layer and astrocytic end-feet. Position separates the two populations where shared PDGFRB does not, which is why these cells have at times been called type A pericytes.", "limit": "A review, and mostly brain. Its proposal that these cells set tone in the outer basement membrane and so constrain mural contraction is stated by the authors as untested, and is recorded here as a hypothesis rather than an edge.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "fibroblast-distribution-arterioles", "fibroblast-distribution-venules" ] }, { "id": "I008", "name": "Erythrocytes", "category": "Vascular", "whereToCheck": "Vascular lumen; extravascular only when supported", "states": [ "Deformable", "stalled", "damaged" ], "behaviors": [ "Oxygen carriage", "transit", "hemolysis", "leakage" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-562" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-562" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "sender-I008-erythrocytes" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-562", "sender-I008-erythrocytes" ], "priorResearch": { "path": "simulation/data/profiles/erythrocytes.json", "summary": "Erythrocytes occupy the lumen and carry oxygen to tissue. For this atlas their significance is almost entirely as the thing whose movement defines whether a vessel is functional: a vessel containing stationary red cells is a vessel that delivers nothing, however well it stains. Imaged in patients during surgery, tumour vessels were disorganised and tortuous and about half did not support blood flow (V49).", "stateAxes": [ { "axis": "Deformable", "whatToMeasure": "Transit through capillary-calibre vessels, measured by tracking labelled cells rather than inferred from vessel diameter", "interpretationLimit": "Nothing assembled here measures erythrocyte deformability in any drawn environment; the axis is named by the inventory and served only by the general observation that transit varies.", "evidence": [ "V49" ] }, { "axis": "Stalled", "whatToMeasure": "Zero labelled-cell flux over a stated observation window, with the window reported alongside the fraction", "interpretationLimit": "This is the axis that matters and it is method-bound. A vessel that stalls briefly looks perfused in a short recording, so a non-perfused fraction without its observation window is not comparable to another.", "evidence": [ "V49" ] }, { "axis": "Damaged", "whatToMeasure": "Haemolysis and extravascular red cells, which indicate a breach rather than a flow state", "interpretationLimit": "Served indirectly: platelet depletion produces bleeding into tumour, so extravascular red cells report on vessel integrity and on what is maintaining it.", "evidence": [ "V51" ] } ], "records": { "V49": { "id": "V49", "year": 2016, "topic": "Transport", "title": "Intraoperative intravital microscopy permits the study of human tumour vessels", "url": "https://doi.org/10.1038/ncomms10684", "studyType": "Intravital microscopy of patient tumours during surgery, Nat Commun 7:10684", "diseaseContext": "Shared cancer", "useInModel": "The one human measurement of which tumour vessels actually carry blood. Imaged during surgery, patient tumour vessels were disorganised and tortuous, and about half did not support blood flow. It also found human tumour vessel diameters larger than immunohistochemistry or preclinical intravital imaging predicted, so the vessels counted on a section are not the vessels carrying blood, and are not even the size the section says.", "limit": "Patients under surgical conditions, with the observation limited to what can be imaged intraoperatively. A non-perfused fraction is sensitive to how long a vessel is watched: a vessel that stalls briefly looks perfused in a short recording, so the figure is bound to its observation window rather than being a property of the tumour.", "provenance": "Abstract and indexed publisher text screened; the non-perfused fraction taken as the paper states it, about half", "quantitativeExtraction": "pending" }, "V51": { "id": "V51", "year": 2014, "topic": "Pericytes and vasculature", "title": "Presence of intratumoral platelets is associated with tumor vessel structure and metastasis", "url": "https://doi.org/10.1186/1471-2407-14-167", "studyType": "Mouse tumour models with platelet depletion, BMC Cancer 14:167", "diseaseContext": "Shared cancer", "useInModel": "Platelets hold tumour vessels together. Depleting them caused bleeding in and around the tumour without disturbing vascular integrity elsewhere, and the protection appears independent of thrombus formation - animals unable to form proper clots did not bleed into their tumours. The bleeding co-located with neutrophils and macrophages, so what platelets seem to do is repair damage inflicted by other cells.", "limit": "Mouse models. The protective factors are unidentified, and whether this holds in any drawn environment is untested. It describes a vessel's integrity, not its perfusion.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I009", "name": "Platelets", "category": "Vascular", "whereToCheck": "Blood and thrombotic lesions", "states": [ "Resting", "activated", "aggregated" ], "behaviors": [ "Adhesion", "coagulation", "mediator release" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-564" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-564" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-564" ], "priorResearch": { "path": "simulation/data/profiles/platelets.json", "summary": "Platelets circulate and act where a vessel wall is damaged. In tumour they do something less expected: they keep the vessels intact. Depleting them caused bleeding in and around the tumour while leaving vessels elsewhere undisturbed, and the protection did not depend on clot formation - animals unable to form proper thrombi still did not bleed into their tumours. The bleeding co-located with neutrophils and macrophages, so what platelets appear to do is repair damage inflicted by other cells rather than plug holes (V51).", "stateAxes": [ { "axis": "Resting", "whatToMeasure": "Circulating count alongside whether platelets are present within the tumour, which are different questions", "interpretationLimit": "Nothing assembled here measures intratumoral platelet content in a drawn environment.", "evidence": [ "V51" ] }, { "axis": "Activated", "whatToMeasure": "Release of the granule contents, and specifically activation of GARP-anchored latent TGF-beta within the tumour rather than in plasma", "interpretationLimit": "The deletion experiment shows the axis matters; it does not say what fraction of intratumoral TGF-beta platelets supply, in any model or environment.", "evidence": [ "V52" ] }, { "axis": "Aggregated", "whatToMeasure": "Thrombus formation, kept separate from the vessel-protective function since the protection is independent of it", "interpretationLimit": "The separation is the finding: animals unable to form proper thrombi still did not bleed into their tumours, so aggregation and protection cannot be used as proxies for one another.", "evidence": [ "V51" ] } ], "records": { "V51": { "id": "V51", "year": 2014, "topic": "Pericytes and vasculature", "title": "Presence of intratumoral platelets is associated with tumor vessel structure and metastasis", "url": "https://doi.org/10.1186/1471-2407-14-167", "studyType": "Mouse tumour models with platelet depletion, BMC Cancer 14:167", "diseaseContext": "Shared cancer", "useInModel": "Platelets hold tumour vessels together. Depleting them caused bleeding in and around the tumour without disturbing vascular integrity elsewhere, and the protection appears independent of thrombus formation - animals unable to form proper clots did not bleed into their tumours. The bleeding co-located with neutrophils and macrophages, so what platelets seem to do is repair damage inflicted by other cells.", "limit": "Mouse models. The protective factors are unidentified, and whether this holds in any drawn environment is untested. It describes a vessel's integrity, not its perfusion.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "V52": { "id": "V52", "year": 2025, "topic": "Resistance", "title": "Platelets in cancer and immunotherapy: functional dynamics and therapeutic opportunities", "url": "https://doi.org/10.1186/s40164-025-00676-x", "studyType": "Review of platelet biology in cancer", "diseaseContext": "Shared cancer", "useInModel": "Platelets carry latent TGF-beta anchored by GARP, which localises its activation inside the tumour, and platelet-specific deletion of lrrc32 reduced intratumoral TGF-beta activity and improved anti-tumour immunity in melanoma and colon models. That places a circulating cell among the sources of the TGF-beta the atlas already records as excluding T cells from tumour.", "limit": "A review over mouse models. It connects platelets to an immunosuppressive signal; it does not quantify how much of the intratumoral TGF-beta they account for in any environment.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I010", "name": "Plasma proteins and carriers", "category": "Vascular", "whereToCheck": "Blood; interstitium according to barrier", "states": [ "Free", "drug-bound", "extravasated" ], "behaviors": [ "Albumin and IgG distribution", "protein binding", "clearance" ], "slots": { "size": { "status": "references available", "referenceIds": [ "armstrong-albumin", "armstrong-transferrin" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "armstrong-albumin", "armstrong-transferrin" ], "priorResearch": { "path": "simulation/data/profiles/plasma-proteins-and-carriers.json", "summary": "Plasma proteins fill the compartment a construct is administered into and share its fate. Albumin and IgG are kept in circulation by the same mechanism: taken up by fluid-phase pinocytosis, bound by FcRn in acidified endosomes at pH 5.0 to 6.5, recycled to the surface and released at neutral pH, giving serum half-lives of roughly 21 days for IgG and 19 for albumin. The pathway saturates, so at high plasma IgG a greater share is degraded (V50). Everything a construct does begins here, and most of what is administered never leaves.", "stateAxes": [ { "axis": "Free", "whatToMeasure": "Unbound concentration in plasma and, separately, in the interstitium, since neither can be inferred from the other", "interpretationLimit": "No interstitial-to-plasma ratio for IgG or albumin is published here for any drawn environment. The one figure assembled is for brain, under 1%, and brain is the tissue least like the others.", "evidence": [ "V23", "V50" ] }, { "axis": "Drug-bound", "whatToMeasure": "Bound fraction, measured rather than assumed, because only the free fraction can engage a target", "interpretationLimit": "Named by the inventory and unserved. Nothing assembled here measures plasma protein binding for any construct in any environment.", "evidence": [ "V50" ] }, { "axis": "Extravasated", "whatToMeasure": "What actually crossed, against the permeability and the pressure opposing it, rather than inferred from dose", "interpretationLimit": "Charge changes this: positively charged protein crossed more than twice as readily as negatively charged protein of the same size, while also clearing from plasma about twice as fast, so the two move together and a gain in tumour is not free.", "evidence": [ "V23", "V24" ] } ], "records": { "V23": { "id": "V23", "year": 2008, "topic": "Transport", "title": "Antibody tumor penetration: transport opposed by systemic and antigen-mediated clearance", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC2820307/", "studyType": "Review with transport modelling", "diseaseContext": "Shared cancer", "useInModel": "Gives a vascular permeability coefficient for IgG in tumour of about 3e-7 cm/s, and shows that permeability rather than diffusion decides how much antibody gets in: with a diffusivity of 10 um^2/s and a 10 um capillary radius the Biot number is about 0.006, so the concentration at the tissue surface sits a hundred to a thousand times below plasma. Inside the tumour, transport is diffusion through extracellular space, because raised interstitial pressure removes the convection that carries antibody in normal tissue.", "limit": "A review over xenograft and modelling work, not a measurement in human tumour. The coefficient excludes convection and transcytosis and the authors call it conservative. The binding-site barrier it describes is often misread: antigen density, diffusivity, permeability and dose all move the penetration front.", "provenance": "Full text reviewed; permeability coefficient and Biot number extracted", "quantitativeExtraction": "extracted" }, "V24": { "id": "V24", "year": 2000, "topic": "Transport", "title": "Vascular permeability in a human tumour xenograft: molecular charge dependence", "url": "https://doi.org/10.1054/bjoc.1999.1171", "studyType": "Intravital fluorescence microscopy of LS174T human colon adenocarcinoma in transparent dorsal skinfold chambers in SCID mice, with albumin and IgG cationised by hexamethylenediamine conjugation or anionised by succinylation, British Journal of Cancer 82(9):1513-1518", "diseaseContext": "Colorectal", "useInModel": "Measured transvascular permeability for molecules of the same size and different charge, which makes it a structure-property relation for the entry step of every antibody-sized agent this atlas records. Cationised albumin (isoelectric point 8.6 to 9.1) and IgG (8.6 to 9.3) had permeabilities of 4.25 and 4.65 times ten to the minus seven centimetres per second, more than double the anionised forms at 1.11 and 1.93 (albumin near pI 2.0, IgG 3.0 to 3.9). So net charge is a handle on extravasation that is independent of size. The caveat is the finding: plasma clearance of the cationic molecules was about twice as fast, so the same modification that raises tumour entry raises normal-organ exposure, and the authors advise caution in using it to improve delivery. That is the same two-sided shape the atlas records for payload reach - a parameter that improves the thing you want and the thing you do not, which cannot be tuned one-sidedly.", "limit": "Xenograft in a dorsal skinfold chamber, not human tumour, and one tumour line. Chemical cationisation and anionisation change more than net charge - conjugation and succinylation alter surface chemistry and may alter binding and stability - so charge is the stated variable rather than the only one. Permeability is calculated from fluorescence and pharmacokinetics rather than measured directly. Because clearance moves with charge, the tumour gain and the normal-organ gain cannot be separated from this experiment.", "provenance": "Abstract read in full, replacing a screening note. All four permeability coefficients with their isoelectric point ranges, the model system and labelling chemistry, the roughly twofold faster plasma clearance of cationic molecules, and the authors' own caution as reported", "quantitativeExtraction": "extracted" }, "V50": { "id": "V50", "year": 2012, "topic": "Transport", "title": "Pharmacokinetic models for FcRn-mediated IgG disposition", "url": "https://doi.org/10.1155/2012/282989", "studyType": "Review of pharmacokinetic modelling", "diseaseContext": "Shared all", "useInModel": "Gives the mechanism that keeps a construct in circulation and the numbers that follow from it. IgG and albumin enter cells by fluid-phase pinocytosis, bind FcRn in acidified endosomes at pH 5.0 to 6.5, are recycled to the surface and released at neutral pH. The result is a serum half-life of roughly 21 days for IgG, isotype-dependent, and about 19 days for albumin. The pathway saturates, so at high plasma IgG a greater proportion is degraded.", "limit": "A modelling review rather than a measurement in any tissue. It describes the plasma compartment; it does not give the interstitial concentration a construct reaches, and the albumin arm of the mechanism is explicitly less well defined than the IgG arm.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I011", "name": "CD8 conventional T cells", "category": "Immune", "whereToCheck": "Tumor; stroma; blood; lymphoid sites", "states": [ "Naive", "effector", "memory", "dysfunctional" ], "behaviors": [ "Migration", "recognition", "contact", "granule release", "serial killing" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-520", "hatton-532", "hatton-1179", "tcell-133", "tcell-97" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-520", "hatton-532", "hatton-1179" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "sender-I011-mature-t-cells" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-520", "hatton-532", "hatton-1179", "sender-I011-mature-t-cells", "tcell-133", "tcell-97" ], "priorResearch": { "path": "simulation/data/profiles/cd8-conventional-t-cells.json", "summary": "Everything the Molecular families built arrives here, and the order of this family's behaviours needs rearranging. I081 established that the limiting process in killing is search rather than lysis, which makes migration the behaviour that matters - and the atlas already holds the entry route through the vascular families, the internal routes through matrix architecture (L04), and the range of non-contact influence at 30 to 40 micrometres (L09). But migration and recognition are not sequential. In mouse tumours, deep infiltration occurred only where tumour cells expressed the cognate antigen; in antigen-negative tumours the cells stayed peripheral and neither arrested nor killed (L62). Recognition drives penetration, so infiltration is partly an output of it. The inventory's four states need to become five, because dysfunctional is two things: progenitor exhausted cells retain polyfunctionality, control tumour better and respond to anti-PD-1, while terminally exhausted cells do not (L60, L61). And the cells that mediate a response may not have been present before it - the clones that expanded after PD-1 blockade were novel clonotypes not previously observed in the same tumour (L59).", "stateAxes": [ { "axis": "Dysfunctional - which is two states, not one", "whatToMeasure": "The fraction of dysfunctional cells that are still progenitors, by Tcf1 or TCF7 expression alongside PD-1, rather than a total count of PD-1-positive cells. The therapeutically relevant quantity is that fraction: a higher percentage of progenitor exhausted cells associated with longer duration of response to checkpoint blockade in melanoma.", "interpretationLimit": "Mouse models for the mechanism in both independent studies, with human evidence being a phenotype identified in patient blood and primary tumours and a percentage associated with response duration - not a validated threshold. Exhaustion defined epigenetically and transcriptionally is not measured function. Neither study says what sets the progenitor fraction.", "evidence": [ "L60", "L61", "T11" ] }, { "axis": "Density, in named spatial compartments", "whatToMeasure": "CD3 and CD8 density separately in the tumour and in the invasive margin, since the validated score is built from four density percentiles across those two compartments and the compartments carry different information. Reproducibility between observers and centres was 0.97, so this is a measurement that transfers.", "interpretationLimit": "Percentile-based within the studied cohort rather than absolute counts, so transferring the score needs the same assay and reference distribution. It is prognostic for recurrence in surgically treated stage I to III colon cancer and is not predictive of any therapy's effect. And it is state-blind.", "evidence": [ "L58" ] }, { "axis": "Clonal identity - and whether the cell was there before", "whatToMeasure": "Receptor clonotypes tracked through treatment in site-matched samples, not just cell counts, because the clones that expanded after PD-1 blockade had not previously been observed in the same tumour.", "interpretationLimit": "Two skin cancer types outside the drawn set, and site-matched biopsies sample a region rather than a lesion - undetected before treatment is not the same as absent. The origin of the new clones is not identified, which is exactly the unresolved point against L61's stem-like subset.", "evidence": [ "L59" ] }, { "axis": "Motility and the routes it uses", "whatToMeasure": "Instantaneous velocity and arrest, scored against what the cell is next to - collagen fibres, vessels, antigen-positive cells - rather than as a free-space diffusivity, and reported with the antigen status of the tumour, which determines both motility and infiltration depth.", "interpretationLimit": "One subcutaneous mouse thymoma imaged through a window, with velocities described qualitatively and not tabulated into this atlas. Antigen presence is binary in the informative comparison rather than titrated, so the coupling to infiltration depth is established without its shape.", "evidence": [ "L62", "L04" ] } ], "records": { "L04": { "id": "L04", "year": 2012, "topic": "Matrix and movement", "title": "Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC3287213/", "studyType": "Live imaging of human tumor slices", "diseaseContext": "Lung / Shared cancer", "useInModel": "Collagen/fibronectin organization constrains T-cell routes and entry into tumor islets.", "limit": "Ex vivo slices lack intact circulation and systemic recruitment.", "provenance": "Indexed abstract or publisher excerpt screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "L58": { "id": "L58", "year": 2018, "topic": "Clinical outcome", "title": "International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study", "url": "https://doi.org/10.1016/S0140-6736(18)30789-X", "studyType": "International consortium of 14 centres in 13 countries, 2,681 analysable stage I-III colon cancer patients with digital-pathology quantification, Lancet 391(10135):2128-2139", "diseaseContext": "Colorectal", "useInModel": "The best human measurement of any cell family in this atlas, and the one that is already in the form a spatial simulation produces. CD3-positive and cytotoxic CD8-positive T-cell densities were quantified by digital pathology in two compartments - the tumour and the invasive margin - and combined into a score defined as the mean of four density percentiles. Across 2,681 patients after quality control, split into training, internal validation and external validation sets, a high score carried the lowest five-year recurrence: 8% against 19% for intermediate and 32% for low, with a hazard ratio of 0.20 and a confidence interval of 0.10 to 0.38 for high against low, confirmed in both validation sets totalling 1,981 patients and independent of other prognostic factors in stratified multivariable analysis. Reproducibility between observers and centres was 0.97 for both compartments. Three things make this unusually valuable here. It is in a drawn environment. The measurement is a density in named spatial compartments rather than a bulk average, and the compartments are the two a simulation of a tumour naturally distinguishes. And it is prognostic for recurrence rather than for response, so it reports the state of the environment and not the effect of a drug.", "limit": "Stage I to III colon cancer treated surgically, and prognostic rather than predictive - it does not say what any therapy will do. The score is built from percentile ranks within the studied cohort rather than from absolute cell counts, so transferring it requires the same assay and the same reference distribution. It counts cells and cannot report their state, so a high density of terminally exhausted cells and a high density of functional ones score alike.", "provenance": "Abstract read in full; cohort sizes, the four-percentile construction, recurrence rates, hazard ratio and reproducibility coefficients as reported", "quantitativeExtraction": "extracted" }, "L59": { "id": "L59", "year": 2019, "topic": "Residual-disease geography", "title": "Clonal replacement of tumor-specific T cells following PD-1 blockade", "url": "https://doi.org/10.1038/s41591-019-0522-3", "studyType": "Paired single-cell RNA and T-cell receptor sequencing of 79,046 cells from site-matched tumours before and after anti-PD-1, Nat Med 25(8):1251-1259", "diseaseContext": "Shared cancer", "useInModel": "Says the cells that matter after treatment were not in the tumour before it. Paired transcriptome and receptor sequencing of 79,046 cells from site-matched basal and squamous cell carcinomas before and after anti-PD-1 tracked clones through treatment. Tumour recognition, clonal expansion and dysfunction were coupled, with expansion of CD8-positive CD39-positive cells carrying markers of chronic activation and exhaustion - but the expanded clones were not pre-existing tumour-infiltrating lymphocytes. They were novel clonotypes that had not previously been observed in the same tumour, and clonal replacement was preferentially seen among exhausted CD8 cells. The authors' reading is that pre-existing tumour-specific T cells may have limited reinvigoration capacity and the response derives from a repertoire that may only recently have entered. For a simulation this is architectural: a closed domain containing a fixed T-cell population cannot produce this response, however it is parameterised. The family needs an influx term sourced from outside the represented volume.", "limit": "Two skin cancer types, neither among the drawn set, and site-matched biopsies sample a region rather than a tumour - a clone absent from the sampled site may be present elsewhere in the same lesion. Receptor sequencing establishes that a clonotype was not detected before treatment, which is not the same as its absence. It does not identify where the new clones came from.", "provenance": "Abstract read in full; cell count, the clonal replacement finding and the authors' interpretation as reported", "quantitativeExtraction": "extracted" }, "L60": { "id": "L60", "year": 2019, "topic": "Effector state", "title": "Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade", "url": "https://doi.org/10.1038/s41590-019-0312-6", "studyType": "Epigenetic and transcriptional profiling of tumour-infiltrating lymphocytes with functional and clinical correlation, Nat Immunol 20(3):326-336", "diseaseContext": "Melanoma / Shared cancer", "useInModel": "Splits the inventory's single dysfunctional state into two, and only one of them is treatable. Dysfunctional CD8 tumour-infiltrating lymphocytes carry canonical epigenetic and transcriptional features of exhaustion that mirror chronic viral infection, and within them is a progenitor exhausted subpopulation that retains polyfunctionality, persists long term and differentiates into terminally exhausted cells. The progenitor population controls tumour growth better, and the division matters therapeutically: progenitor exhausted cells respond to anti-PD-1 and terminally exhausted cells do not. Patients with melanoma who have a higher percentage of progenitor exhausted cells experience a longer duration of response to checkpoint blockade. So a model cannot carry exhaustion as a single scalar, and the therapeutically relevant quantity is the fraction of dysfunctional cells that are still progenitors rather than the total dysfunctional count.", "limit": "Mouse models for the mechanistic work with a human correlation for duration of response, and the human evidence is a percentage associated with response duration rather than a validated threshold. Exhaustion defined epigenetically and transcriptionally is not the same as measured function in tissue. It does not say what sets the progenitor fraction or how it could be raised.", "provenance": "Abstract read in full; the subset definitions, the differential response to anti-PD-1 and the melanoma correlation as reported", "quantitativeExtraction": "extracted" }, "L61": { "id": "L61", "year": 2019, "topic": "Effector state", "title": "Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy", "url": "https://doi.org/10.1016/j.immuni.2018.12.021", "studyType": "Subset identification with ablation experiments and human melanoma confirmation, Immunity 50(1):195-211", "diseaseContext": "Melanoma / Shared cancer", "useInModel": "The same split reached independently in the same year, and with a sharper conclusion about mechanism. A subset of tumour-reactive tumour-infiltrating lymphocytes carries hallmarks of both exhausted and central memory cells, expressing PD-1 together with the transcription factor Tcf1. These cells mediated the proliferative response to immunotherapy, generating both more of themselves and differentiated Tcf1-negative progeny; ablating them restricted responses to immunotherapy. Tcf1 was not required to generate the subset but was essential for its stem-like function. The equivalent human cells were found among tumour-reactive CD8 cells in the blood of melanoma patients and among the lymphocytes of primary melanomas. The authors state the consequence plainly: checkpoint blockade relies not on reversing exhaustion programmes but on the proliferation of a stem-like subset. That makes the therapy a selective growth stimulus on a minority population, which is a different model object from a state change applied to a population.", "limit": "Mouse models for the ablation and mechanism, with human cells identified by phenotype rather than tested functionally. No fraction, threshold or proliferation rate is given, and the finding that the subset exists in blood as well as tumour is reported without resolving which pool supplies the response - which is where it meets the clonal replacement result (L59).", "provenance": "Abstract read in full; the subset phenotype, the ablation result, the Tcf1 requirement and the stated mechanism as reported", "quantitativeExtraction": "extracted" }, "L62": { "id": "L62", "year": 2007, "topic": "Effector behavior", "title": "In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor", "url": "https://doi.org/10.1084/jem.20061890", "studyType": "Two-photon intravital microscopy with immunofluorescence on ordered sequential sections of a subcutaneous thymoma, J Exp Med 204(2):345-356", "diseaseContext": "Shared cancer", "useInModel": "Couples two behaviours the inventory lists separately, and the coupling runs the unexpected way. Activated cytotoxic T cells migrated with high instantaneous velocities in the tumour periphery and arrested on contact with tumour cells expressing their cognate antigen; where most tumour cells were already dead they resumed migration, sometimes following collagen fibres or blood vessels, adopting an elongated morphology alongside vessels. The decisive comparison is the antigen-negative tumour: there, infiltration was restricted to peripheral regions and the lymphocytes neither stopped moving nor killed. Deep infiltration happened only where the tumour cells expressed the cognate antigen. So antigen expression determines both motility within the tumour and the depth of infiltration - which means infiltration is partly an output of recognition rather than a prerequisite for it, and a model that treats entry, then search, then recognition as a pipeline has the causality wrong at the second step. The observation that cells follow collagen fibres and vessels agrees independently with L04's finding that matrix architecture defines T-cell routes.", "limit": "A subcutaneous thymoma in mouse, imaged through a window, with velocities described qualitatively as high rather than tabulated here - no speed, arrest coefficient or infiltration depth is extracted into this atlas. One antigen system, and antigen presence is binary in the comparison rather than titrated, so the result establishes the coupling without giving its shape.", "provenance": "Abstract read in full; the arrest-and-resume behaviour, the structure-following observation and the antigen-dependence of depth as reported. Velocities not extracted", "quantitativeExtraction": "pending" }, "T11": { "id": "T11", "year": 2022, "topic": "Effector state", "title": "T-cell exhaustion induced by continuous bispecific molecule exposure is ameliorated by treatment-free intervals", "url": "https://doi.org/10.1182/blood.2022015956", "studyType": "T-cell function measured in relapsed/refractory B-ALL patients during 28-day continuous blinatumomab infusion, with an in vitro model of continuous exposure to a half-life-extended CD19xCD3 bispecific, treatment-free interval experiments, transcriptional profiling and in vivo confirmation, Blood 140(11):1104-1118", "diseaseContext": "Leukemia", "useInModel": "Quantifies the parameter this atlas added one row ago and reverses the direction a simulation would assume. The address class's sixth parameter, effector durability, had a single crude proxy behind it. Here it has a magnitude and an intervention. In patients, 28-day continuous infusion led to declining T-cell function. In vitro, continuous exposure produced progressive loss: mean specific lysis fell from 88.4 percent at day 7 to 8.6 percent at day 28 (n = 6, P = .0003), with hallmark exhaustion features accumulating. Treatment-free intervals reversed it - specific lysis on day 14 was 34.9 percent under continuous exposure against 93.4 percent with an interval (n = 6, P < .0001) - with transcriptional reprogramming, better T-cell expansion and better tumour control in vivo. The modelling consequence is first-order. For this payload class, continued exposure to the drug reduces the drug's effect, so exposure-response is not monotonic in time and the standard assumption that more drug-time means more effect is wrong. Schedule is the controlling variable rather than a refinement, and the intervention that restores efficacy is to stop dosing.", "limit": "The quantitative decay and the interval rescue are in vitro with n = 6, using a half-life-extended construct that is not the approved agent, so the numbers describe that model system rather than clinical pharmacology. The patient observation is declining T-cell function during infusion without an accompanying efficacy decay curve. Schedule effects are construct-specific - the authors are explicit that this is not a clinical instruction to interrupt treatment - and no optimal interval length is established for any approved agent. Nothing here measures exhaustion in solid-tumour engager settings, where the atlas's other engager records sit.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. The patient observation, both specific lysis comparisons with sample sizes and p values, the transcriptional reprogramming, the in vivo expansion and control findings, and the authors' own caution about construct specificity as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I012", "name": "CD4 helper T cells", "category": "Immune", "whereToCheck": "Tissue and lymphoid compartments", "states": [ "Helper programs", "memory", "anergic" ], "behaviors": [ "Cytokines", "help", "proliferation", "context-specific cytotoxicity" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-521", "hatton-531", "hatton-1178" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-521", "hatton-531", "hatton-1178" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "sender-I012-mature-t-cells" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-521", "hatton-531", "hatton-1178", "sender-I012-mature-t-cells" ], "priorResearch": { "path": "simulation/data/profiles/cd4-helper-t-cells.json", "summary": "Two findings here contradict the shape of this atlas. The first is that rejection needs this family at all: both spontaneous and immunotherapy-induced antitumour responses required tumour-antigen-specific CD4 cells alongside CD8 cells, even in tumours that do not express MHC class II - and class II-restricted antigen had to be expressed at the site of successful rejection, which puts CD4 activation inside the tumour rather than only in a node (L63). Every antigen and receptor family written in this atlas so far is framed around class I and CD8, and that framing is incomplete. The second is sharper: in human bladder cancer the states and repertoires of CD8 cells were not distinct between tumour and non-malignant tissue, while the CD4 compartment carried the tumour-specific states - including clonally expanded cytotoxic CD4 cells that killed autologous tumour in a class II-dependent way, were suppressed by regulatory T cells, and whose signature predicted response in 244 patients on anti-PD-L1 (L64). The inventory's row ends with context-specific cytotoxicity, so this was anticipated. And help itself is not a concurrent interaction: delivered during priming it imprints what the CD8 memory pool can later do, including antigen-independent recall (L66), so it is an attribute arriving cells carry rather than a term between two cells in the modelled volume.", "stateAxes": [ { "axis": "Helper programmes - named by the inventory, unmeasured everywhere", "whatToMeasure": "The fraction of the compartment in each programme, by transcription factor and cytokine output, reported alongside the regulatory fraction since both live in this compartment.", "interpretationLimit": "The atlas holds no programme fractions for this family in any environment. What it holds instead is a requirement - CD4 activity is necessary for rejection - and one human dataset in which several tumour-specific CD4 states including multiple regulatory ones were resolved, in a tumour type outside the drawn set and in seven patients.", "evidence": [ "L63", "L64" ] }, { "axis": "Context-specific cytotoxicity - the inventory's last clause, and it is real", "whatToMeasure": "Cytotoxic CD4 states with clonal expansion, and their class II-dependent killing capacity against autologous tumour, rather than assuming cytotoxicity belongs to CD8 - plus the regulatory fraction, since these cells were suppressed by it.", "interpretationLimit": "Seven patients with bladder cancer, killing shown in autologous assays rather than tissue, and the 244-patient validation is a gene signature against response rather than a demonstration of cause. Whether this holds in the drawn set is untested, and the accompanying negative - that CD8 states were not distinct from non-malignant tissue - may be specific to this tumour type or comparator.", "evidence": [ "L64" ] }, { "axis": "Help - which is a property of history, not of the present", "whatToMeasure": "Not an interaction in the modelled volume but an attribute of arriving CD8 cells: whether they were helped at priming, which sets effector memory size and function and confers innate-like recall by interleukin-12 and interleukin-18 independent of antigen.", "interpretationLimit": "Mouse viral and vaccination priming rather than tumour, with functional recall assays rather than tissue measurement. No fraction of helped against unhelped cells exists for any disease state, which means the attribute is established as mattering and cannot currently be assigned a value.", "evidence": [ "L66" ] }, { "axis": "Whether a lymphoid structure is present in the tumour", "whatToMeasure": "Co-occurrence of CD8 T cells with CD20 B cells, and CXCR5 and CXCL13 staining to identify tertiary lymphoid structures - because T cells in tumours without them had a dysfunctional molecular phenotype, and tumours with them carried more TCF7-positive naive and memory cells.", "interpretationLimit": "Associative in every link, in metastatic melanoma. Nothing shows the structures generate the TCF7-positive population rather than accompanying it, and presence is scored rather than quantified as a density or size. This axis also properly belongs to the Structures category, which is unwritten.", "evidence": [ "L65" ] } ], "records": { "L63": { "id": "L63", "year": 2019, "topic": "Target identity", "title": "MHC-II neoantigens shape tumour immunity and response to immunotherapy", "url": "https://doi.org/10.1038/s41586-019-1671-8", "studyType": "Mouse tumour models with defined MHC class I and class II neoantigens, Nature 574(7780):696-701", "diseaseContext": "Shared cancer", "useInModel": "Says this atlas's antigen framework is missing half its requirement. Both spontaneous and immunotherapy-induced antitumour responses required the activity of tumour-antigen-specific CD8 and CD4 T cells together - and this held even in tumours that do not express MHC class II molecules, so the requirement is not satisfied by the tumour cell being a CD4 target itself. The sharper finding is geographic: expression of MHC class II-restricted antigen by tumour cells was required at the site of successful rejection, which the authors read as showing that CD4 activation must also occur in the tumour microenvironment rather than only in a draining node. So the class II neoantigen requirement is non-overlapping with the class I one and has to be considered when identifying who benefits from immunotherapy. For this atlas the consequence is direct: the target-antigen and receptor families are framed entirely around class I and CD8, and that framing is incomplete as a model of rejection.", "limit": "Mouse models with engineered neoantigens, which is how the requirement could be made clean and also why the magnitudes do not transfer. It establishes that both subsets are necessary without apportioning their contributions, and gives no density, ratio or antigen-load threshold. The claim that activation occurs in the microenvironment is inferred from the site-of-rejection requirement rather than imaged.", "provenance": "Abstract read in full; the dual requirement, the MHC class II-negative case and the site-of-rejection requirement as reported", "quantitativeExtraction": "extracted" }, "L64": { "id": "L64", "year": 2020, "topic": "Effector state", "title": "Intratumoral CD4+ T cells mediate anti-tumor cytotoxicity in human bladder cancer", "url": "https://doi.org/10.1016/j.cell.2020.05.017", "studyType": "Single-cell RNA and paired receptor sequencing of 30,604 T cells from 7 patients with autologous killing assays and a 244-patient clinical validation, Cell 181(7):1612-1625", "diseaseContext": "Bladder / Shared cancer", "useInModel": "Inverts the assumption the whole atlas is built on, in one human cancer. Comparing T cells from human bladder tumours against non-malignant tissue, the states and repertoires of CD8 T cells were not distinct between the two - the compartment this atlas treats as the effector population looked the same inside and outside the tumour. The CD4 compartment carried the tumour-specific states instead, including several distinct regulatory states and, unexpectedly, multiple clonally expanded cytotoxic CD4 states. Those cells killed autologous tumour in an MHC class II-dependent fashion and were suppressed by regulatory T cells. A gene signature of cytotoxic CD4 cells predicted clinical response in 244 patients with metastatic bladder cancer treated with anti-PD-L1. The inventory's own row for this family ends with context-specific cytotoxicity, so the possibility was anticipated; what is new is that in this context the CD4 compartment appears to be where the tumour-specific biology is.", "limit": "Seven patients for the discovery work, in bladder cancer, which became a drawn environment on 2026-10-14 - and the finding that CD8 states were not distinct may be specific to this tumour type or to the non-malignant comparator chosen. Killing was demonstrated in autologous assays rather than in tissue. The 244-patient validation is of a gene signature against response, so it establishes association, not that these cells cause the response.", "provenance": "Abstract read in full; the CD8 non-distinctness, the cytotoxic CD4 states, the MHC class II dependence, the Treg suppression and the validation cohort size as reported", "quantitativeExtraction": "extracted" }, "L65": { "id": "L65", "year": 2020, "topic": "Spatial and immune state", "title": "Tertiary lymphoid structures improve immunotherapy and survival in melanoma", "url": "https://doi.org/10.1038/s41586-019-1914-8", "studyType": "Clinical metastatic melanoma samples with immunofluorescence, a derived gene signature tested in checkpoint-blockade cohorts, and digital spatial profiling, Nature 577(7791):561-565", "diseaseContext": "Melanoma", "useInModel": "Partly answers a question three other families in this atlas have raised, and does it with a structure rather than a compartment. Co-occurrence of tumour-associated CD8 T cells and CD20 B cells was associated with improved survival independently of other clinical variables, and staining CXCR5 and CXCL13 alongside CD20 showed that those tumours contain tertiary lymphoid structures. A gene signature derived from those structures predicted clinical outcome in checkpoint-blockade cohorts. The mechanistic link is the valuable part: B-cell-rich tumours carried increased TCF7-positive naive and memory T cells, and digital spatial profiling showed that T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. TCF7 is the marker that separates the checkpoint-responsive progenitor exhausted population from the terminal one under I011, so this chains a measurable anatomical structure to the cell state that determines whether checkpoint blockade can work - and it means the lymphoid compartment the clonal-replacement and vesicle findings pointed outside the tumour for is sometimes inside it.", "limit": "Metastatic melanoma, and associative throughout - co-occurrence with survival, a signature with outcome, a phenotype with a structure. Nothing here shows that the structures generate the TCF7-positive cells rather than accompanying them, and the authors frame inducing them as a strategy to be explored. Structure presence is scored rather than quantified as a density or a size.", "provenance": "Abstract read in full; the co-occurrence association, the structural identification, the signature result and the TCF7 and spatial-profiling findings as reported", "quantitativeExtraction": "extracted" }, "L66": { "id": "L66", "year": 2019, "topic": "Local costimulation", "title": "CD4+ T cell help creates memory CD8+ T cells with innate and help-independent recall capacities", "url": "https://doi.org/10.1038/s41467-019-13438-1", "studyType": "Genome-wide analysis of CD8 memory differentiation with and without CD4 help during priming, Nat Commun 10:5531", "diseaseContext": "Healthy reference", "useInModel": "Establishes that help is a historical variable rather than a concurrent interaction. CD4 help delivered during priming - not later, and not at the effector site - shapes what the resulting CD8 memory pool can do. Helped cells showed enhanced interleukin-15-dependent maintenance of central memory, and more importantly the help signal set the size and function of the effector memory pool: helped effector memory cells produced granzyme B and interferon-gamma on antigen-independent, innate-like recall by interleukin-12 and interleukin-18, and expressed the helped effector programme on recall with class I antigen, which the authors attribute to epigenetic imprinting and sustained effector-gene mRNA. For a simulation this is awkward in a useful way: the capability of a CD8 cell arriving in a tumour was fixed by an interaction that happened earlier and probably elsewhere, so help cannot be represented as a term between two cells in the modelled volume. It is an attribute the arriving cell carries.", "limit": "Mouse, viral and vaccination priming rather than tumour, and genome-wide profiling with functional recall assays rather than measurement in tissue. No fraction of helped against unhelped cells is given for any disease state, and the epigenetic imprinting is an attribution for the persistence of the programme rather than a mapped set of marks.", "provenance": "Abstract read in full; the priming-time dependence, the innate-like recall route and the imprinting attribution as reported", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I013", "name": "Regulatory T cells", "category": "Immune", "whereToCheck": "Tissue and lymphoid compartments", "states": [ "Activated", "tissue-adapted" ], "behaviors": [ "Suppression", "spatial proximity", "mediator production" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "xu-treg-count" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "xu-treg-count" ], "priorResearch": { "path": "simulation/data/profiles/regulatory-t-cells.json", "summary": "This is the only family in the atlas whose therapeutic direction reverses between two of the drawn environments. In melanoma the effect of anti-CTLA-4 on this compartment is to deplete it selectively inside tumour lesions, and that depletion co-defines the antibody's efficacy (L70). In ALS, three patients were infused with their own expanded regulatory cells and their progression slowed, with suppressive function - not cell number - correlating with the slowing in each patient (L71). Same family, opposite sign, set by the environment rather than by the cell's state. Two further findings constrain how it can be represented. The tumour-resident cell is a tissue cell: in untreated human breast carcinoma its gene expression resembled regulatory cells of normal breast tissue and not activated regulatory cells from blood, differing from the normal tissue population by only a handful of receptors (L72) - so recruiting from circulation and activating in place produces the wrong phenotype. And the depletion route runs through another family entirely, requiring Fc-gamma-receptor-expressing macrophages to be present in the tumour (L70).", "stateAxes": [ { "axis": "Tissue-adapted - and the tumour cell is the tissue cell", "whatToMeasure": "The phenotype against the correct comparator, which is regulatory cells of the same normal tissue rather than of blood - since in breast the tumour-resident cells resembled normal tissue cells and differed from them by only a handful of cytokine and chemokine receptors, most notably CCR8.", "interpretationLimit": "Untreated human breast carcinoma against normal mammary gland, with suppression assayed ex vivo rather than in tissue, and nothing about other tumour types or treated disease. The narrowness of the difference is the finding and also the reason a selective target is hard to establish from it.", "evidence": [ "L72" ] }, { "axis": "Suppressive function, which is not the same as number", "whatToMeasure": "An assayed suppression capacity, reported alongside the count - because in the one trial the atlas holds it was function that correlated with slowed disease progression, at Spearman rho between -0.54 and -0.71 within each of three patients, while number rose alongside it.", "interpretationLimit": "Three patients, phase I, uncontrolled, Class IV evidence, with concomitant interleukin-2 so the infusion is not the only variable, and correlations computed within patients across timepoints. It establishes function as the informative measurable without establishing a value or a threshold for it anywhere.", "evidence": [ "L71" ] }, { "axis": "Spatial proximity - named by the inventory, with no length scale anywhere", "whatToMeasure": "Distance to the cell being suppressed, as a distribution rather than against a fixed cut-off, since a proximity reading has been shown prognostic where an expression level was not.", "interpretationLimit": "No distance at which this family's suppression operates is established in any record the atlas holds. The adenosine route is described as pericellular with no figure, and the one proximity study fits a distance distribution in 72 patients in a cancer outside the drawn set, which is why such results do not transfer. This belongs with the atlas's other missing length scales - complement's deposition radius and the reach of Fas-mediated bystander killing.", "evidence": [ "T37", "L39" ] }, { "axis": "Depletable, and only where another family is present", "whatToMeasure": "Local Fc-gamma-receptor-expressing macrophage content alongside the regulatory fraction, because selective intratumoral depletion by anti-CTLA-4 required those macrophages and happened in trans.", "interpretationLimit": "Mouse melanoma with engineered antibody Fc variants, which isolates the dependency and does not quantify it - no macrophage density threshold for the effect is given, and what fraction of the clinical effect depletion accounts for in people is not established.", "evidence": [ "L70" ] } ], "records": { "L39": { "id": "L39", "year": 2007, "topic": "Chemistry and metabolism", "title": "Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression", "url": "https://doi.org/10.1084/jem.20062512", "studyType": "Ectoenzyme expression and function in regulatory T cells with Cd39-null mice, J Exp Med 204(6):1257-1265", "diseaseContext": "Shared all", "useInModel": "The record that says the inventory's second state is not a path to zero. Extracellular nucleotides are the archetypal danger signal, and CD39 with CD73 convert them into pericellular adenosine - so degrading the DAMP does not clear it, it turns it into something with the opposite effect. The coordinated expression of these two ectoenzymes on regulatory T cells together with the adenosine A2A receptor on activated effector T cells forms an immunosuppressive loop, and regulatory T cells from Cd39-null mice showed impaired suppression in vitro and failed to block allograft rejection in vivo. The word to retire from this family is clearance: the pathway is a sign inversion at a cell surface, and where the converting cells sit decides where the danger signal becomes a suppressive one.", "limit": "Regulatory T cell biology and transplantation rather than tumour, and no nucleotide or adenosine concentration is measured in any environment here. The adenosine is described as pericellular, which matches the pattern this category keeps finding, but no distance is given.", "provenance": "Abstract read in full; the ectoenzyme pair, the receptor loop and the Cd39-null result as reported", "quantitativeExtraction": "pending" }, "L70": { "id": "L70", "year": 2013, "topic": "Local costimulation", "title": "Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma", "url": "https://doi.org/10.1084/jem.20130579", "studyType": "Mouse melanoma models with Fc-variant antibodies and macrophage dependency testing, J Exp Med 210(9):1695-1710", "diseaseContext": "Melanoma / Shared cancer", "useInModel": "Says a checkpoint antibody's effect on this family depends on a different immune family being present in the same tissue. The accepted model of anti-CTLA-4 was blockade of an inhibitory receptor on both effector and regulatory T cells; what the authors demonstrate instead is that the activity on the regulatory compartment is selective depletion of those cells within tumour lesions, and that the depletion requires Fc-gamma-receptor-expressing macrophages to be present in the tumour microenvironment. Regulatory cells are therefore depleted in trans, in a context-dependent way. For this atlas the consequence is structural rather than pharmacological: the efficacy of an antibody aimed at one cell family is a function of the local content of another, which means the macrophage families cannot be left out of any model of checkpoint response, and the same drug should be expected to behave differently in tissues with different myeloid composition.", "limit": "Mouse melanoma models with engineered antibody variants, which is how the Fc dependency could be isolated and also why the magnitude does not transfer. It establishes that depletion co-defines efficacy, not what fraction of the clinical effect it accounts for in people. No macrophage density threshold for the effect is given, which is the quantity the finding implies.", "provenance": "Abstract read in full; the selective intratumoral depletion, the Fc-gamma-receptor macrophage requirement and the in trans framing as reported", "quantitativeExtraction": "extracted" }, "L71": { "id": "L71", "year": 2018, "topic": "Clinical PK and response", "title": "Expanded autologous regulatory T-lymphocyte infusions in ALS: A phase I, first-in-human study", "url": "https://doi.org/10.1212/NXI.0000000000000465", "studyType": "Phase I first-in-human, three patients, autologous expanded regulatory T-cell infusions with concomitant interleukin-2, Neurol Neuroimmunol Neuroinflamm 5:e465", "diseaseContext": "ALS", "useInModel": "The reason this family's sign cannot be written into a model as a constant. In cancer the therapeutic aim is to remove these cells; here three patients with ALS received them. Autologous regulatory T cells were expanded ex vivo and infused at a million cells per kilogram, four doses over two months early in disease and four over four months later, with subcutaneous interleukin-2 three times weekly throughout. The infusions were safe and tolerated, regulatory cell numbers and suppressive function both rose after each round, and progression rates slowed at both stages. The informative result is which quantity tracked benefit: increased suppressive function correlated with slowing of progression in each patient individually, at Spearman rho of -0.60, -0.71 and -0.54 with p-values of 0.003, 0.0026 and 0.016. So the measurable that mattered was function, not number - which is what the inventory asks for under suppression and what almost nothing in this atlas provides.", "limit": "Three patients, phase I, no controls, and the authors classify it as Class IV evidence. Progression slowing in an uncontrolled trial in a variable disease cannot be attributed to the intervention, and the correlations are within-patient across timepoints rather than between patients. Concomitant interleukin-2 means the infusion is not the only variable. It establishes that increasing this family is a coherent therapeutic direction in this environment, not that it works.", "provenance": "Abstract read in full; dosing, the function-and-number increases, the progression finding and all three correlation coefficients with p-values as reported", "quantitativeExtraction": "extracted" }, "L72": { "id": "L72", "year": 2016, "topic": "Cell-state ecosystems", "title": "Regulatory T cells exhibit distinct features in human breast cancer", "url": "https://doi.org/10.1016/j.immuni.2016.10.032", "studyType": "Comparative analysis of regulatory T cells from untreated human breast carcinoma, normal mammary gland and peripheral blood, Immunity 45(5):1122-1134", "diseaseContext": "Breast", "useInModel": "Identifies which cell this family actually is inside a tumour, in a drawn environment, and the answer rules out the obvious way to model it. Regulatory T cells from untreated human breast carcinomas were potently suppressive, and their gene-expression pattern resembled that of regulatory cells in normal breast tissue rather than that of activated regulatory cells from peripheral blood. So the tumour-resident cell is a tissue cell, not a blood cell that arrived and switched on - which means a model that recruits these cells from circulation and activates them in place is producing the wrong phenotype. What distinguished the tumour cells from the normal tissue cells was narrow: a number of cytokine and chemokine receptor genes, most notably CCR8, were upregulated. That narrowness is the therapeutic point and the modelling point at once - the tumour population is a small perturbation of a resident one, so both the window for selective depletion and the signal available to distinguish the two are small.", "limit": "Untreated human breast carcinoma against normal mammary gland, which is the right comparator and gives no information about other tumour types or about treated disease. Suppression was assayed ex vivo rather than measured in tissue. The CCR8 proposal is the authors' suggestion from a differential expression result, and whether it is selective enough to be a depletion target is not settled here.", "provenance": "Abstract read in full; the tissue-resemblance finding, the suppressive capacity and the differential receptor result as reported", "quantitativeExtraction": "extracted" }, "T37": { "id": "T37", "year": 2019, "topic": "Spatial atlas", "title": "Spatial proximity between T and PD-L1 expressing cells as a prognostic biomarker for oropharyngeal squamous cell carcinoma", "url": "https://doi.org/10.1038/s41416-019-0634-z", "studyType": "Multiplex immunofluorescence, 72 patients, Br J Cancer 122(4):539-544", "diseaseContext": "Shared cancer", "useInModel": "Shows the spatial reading is prognostic where the expression level alone is not: frequent proximity of CD8 or PD-1 positive cells to PD-L1 positive cells predicted overall survival in HPV-negative disease. It also illustrates the measurement problem - this study fits a distance distribution rather than applying a fixed cut-off, which is why proximity results do not transfer between papers.", "limit": "Seventy-two patients in a cancer outside the drawn environments, and prognostic rather than predictive of checkpoint response. No distance threshold here is established as the one at which the axis operates.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I014", "name": "Gamma-delta T cells", "category": "Immune", "whereToCheck": "Site-dependent tissue and blood", "states": [ "Subset and activation" ], "behaviors": [ "Recognition", "cytokines", "cytotoxicity" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-707" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-707" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-707" ], "priorResearch": { "path": "simulation/data/profiles/gamma-delta-t-cells.json", "summary": "This family is the atlas's second MHC-independent effector route, and it supplies the first direct evidence that such a route mobilises where presentation is lost. Cytotoxic T cells failed to kill at all under MHC class I downmodulation, allele-specific HLA loss occurs in 40% of non-small-cell lung cancers, and the natural killer family was recorded as the designated cover for that escape with no evidence that it actually engages the escaped cells. Gamma-delta receptors engage tumour cell moieties independently of MHC class I and human leukocyte class I, recognising stress-induced antigens characteristic of metabolically dysregulated tumours rather than presented peptide - and in 150 primary colorectal tumours, MHC class I loss was found in about 30%, with increased stromal gamma-delta frequency and activation among stage III cases, extending beyond mismatch-repair-deficient tumours into proficient ones (L103). Mobilisation into the right place is now observed in human tissue in one of the drawn environments. Killing is still not.", "stateAxes": [ { "axis": "Recognition - a cell-state gate, not an antigen-presentation gate", "whatToMeasure": "The tumour-side ligands of stress-induced recognition, and the metabolic dysregulation that induces them, rather than peptide-MHC. The distinguishing property is that this route works where presentation has been lost.", "interpretationLimit": "The mechanism is stated in the atlas's source as MHC-independent engagement of stress-induced moieties, without a ligand measured on tumour cells in any environment - so the gate is established in kind and has no measurable input. Whether recognition leads to killing of presentation-deficient cells is not shown.", "evidence": [ "L103" ] }, { "axis": "Mobilisation alongside MHC class I loss", "whatToMeasure": "Stromal frequency and activation status scored against MHC class I status in the same tissue - the pairing that produced the only direct evidence the atlas has for an MHC-independent population arriving where presentation is lost.", "interpretationLimit": "Immunohistochemistry on tissue microarray cores in 150 colorectal tumours, cross-sectional, with the signal in one of four stages. MHC class I loss scored as protein absence is not the same quantity as allele-specific copy-number loss, so the ~30% here and the 40% in lung are not directly comparable.", "evidence": [ "L103", "L81" ] }, { "axis": "Subset and activation - named by the inventory, thinly served", "whatToMeasure": "Which receptor-chain subset is present and whether it is activated, since the inventory asks for both and the human evidence reports an activation status without resolving subsets.", "interpretationLimit": "No subset composition for this family exists in any drawn environment in this atlas. The deconvolution resource the atlas holds works from the algorithm's 22 categories, which do not separate these subsets, so an apparent absence is often an absence of the question rather than of the cell.", "evidence": [ "L103", "L104" ] } ], "records": { "L103": { "id": "L103", "year": 2026, "topic": "Spatial protein atlas", "title": "Characterisation of tumor-infiltrating gamma-delta T cells in human colorectal cancer with MHC-I loss", "url": "https://doi.org/10.1002/cti2.70097", "studyType": "Multispectral immunohistochemistry across 150 stage I-IV primary colorectal tumours on eight tissue microarrays, Clin Transl Immunology 15:e70097", "diseaseContext": "Colorectal", "useInModel": "The first direct evidence in this atlas that an MHC-independent effector population mobilises where MHC class I is lost - which is the gap the natural killer family recorded as the most consequential untested assumption in this category. Gamma-delta T-cell receptors engage tumour cell moieties independently of MHC class I and human leukocyte class I molecules, recognising stress-induced antigens characteristic of metabolically dysregulated tumours rather than presented peptide. Staining 150 primary colorectal tumours across all disease stages found MHC class I loss in about 30% of them, with a notable increase in stromal gamma-delta frequency and activation status among stage III cases - and the enrichment extended beyond mismatch-repair-deficient tumours, where it had previously been described, into mismatch-repair-proficient ones. Two details matter for a model. The enrichment is stromal rather than in the tumour nests, which lands on the compartment distinction the validated colorectal density score is built from. And this is mobilisation observed in human tissue, not killing demonstrated - so the fail-safe for MHC loss now has a population shown to arrive where it is needed, and still no evidence that it does the job.", "limit": "Immunohistochemistry on tissue microarrays, so frequency and activation are scored on small tissue cores and the association with MHC class I loss is cross-sectional. The stage III signal is one stage among four. MHC class I loss here is protein absence by staining, which is not the same quantity as the allele-specific copy-number loss measured in lung (L81) - a tumour can lose one allele and still present peptide. Nothing establishes that these cells kill the cells that have lost presentation.", "provenance": "Abstract read in full; the MHC-independent recognition statement, the 150-tumour cohort, the ~30% loss frequency, the stromal stage III enrichment and the extension beyond mismatch-repair deficiency as reported", "quantitativeExtraction": "extracted" }, "L104": { "id": "L104", "year": 2015, "topic": "Clinical outcome", "title": "The prognostic landscape of genes and infiltrating immune cells across human cancers", "url": "https://doi.org/10.1038/nm.3909", "studyType": "Pan-cancer meta-analysis of expression signatures from about 18,000 human tumours with survival outcomes across 39 malignancies, using computational deconvolution of 22 leukocyte subsets, Nat Med 21(8):938-945", "diseaseContext": "Shared cancer", "useInModel": "A pan-cancer prognostic resource whose method is as important as its results. Across about 18,000 tumours and 39 malignancies with overall survival, computational deconvolution of bulk transcriptomes into 22 leukocyte subsets produced complex associations with survival - and two of them corroborate families already written here from a third direction: tumour-associated neutrophil and plasma cell signatures emerged as significant but opposite predictors of survival across diverse solid tumours including breast and lung adenocarcinomas. That is independent support for the adverse neutrophil association recorded from a blood ratio in 40,559 patients and for the favourable plasma cell direction recorded from antibody-stained tumour cells, in two drawn environments. The method caveat should travel with every number taken from work of this kind: an inferred leukocyte fraction from a bulk transcriptome is a deconvolution output, not a counted cell, and the atlas has already established that where a family's identity rests on a convention the density must carry its definition. A signature fraction carries its algorithm as well.", "limit": "Deconvolution of bulk expression rather than cell counting, so every subset fraction is model-dependent and the 22 subsets are the algorithm's categories. Associations are prognostic across pooled malignancies and not predictive of therapy, and the favourably prognostic genes are noted by the authors as largely reflecting tumour-associated leukocytes rather than tumour-intrinsic biology - which is a statement about what the signal is, not about which cell carries it. The resource predates single-cell resolution of these compartments.", "provenance": "Abstract read in full; cohort scale, the 22-subset deconvolution, and the opposite neutrophil and plasma cell associations in breast and lung adenocarcinoma as reported", "quantitativeExtraction": "extracted" }, "L81": { "id": "L81", "year": 2017, "topic": "Target identity", "title": "Allele-specific HLA loss and immune escape in lung cancer evolution", "url": "https://doi.org/10.1016/j.cell.2017.10.001", "studyType": "Computational allele-specific HLA copy-number analysis across non-small-cell lung cancers with evolutionary reconstruction, Cell 171(6):1259-1271", "diseaseContext": "Lung", "useInModel": "Quantifies the escape route that the T-cell arm cannot cover, in a drawn environment, and gives it a heterogeneity structure. Using a tool built to resolve allele-specific copy number at a locus too polymorphic for standard methods, loss of heterozygosity at HLA was found in 40% of non-small-cell lung cancers. It was associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulated cytolytic activity and PD-L1 positivity - that is, it appears where immune pressure is greatest. Its character matters as much as its frequency: the alterations are focal, subclonal, enriched in metastatic sites and occur as parallel events, which the authors read as immune escape under strong microenvironmental selection later in tumour evolution. For a simulation this forbids treating MHC class I as a binary tumour property. Different subclones within one tumour have lost different alleles, so presentation capacity is a per-subclone, per-allele state - and the loss of it is exactly the condition under which cytotoxic T cells failed to kill at all (L30), which is where this family is supposed to take over.", "limit": "Non-small-cell lung cancer, computational inference of copy number from sequencing rather than measured protein on cells, so loss of an allele is not the same as measured loss of surface presentation. The evolutionary ordering is reconstructed from cross-sectional data. Nothing here measures whether natural killer cells actually engage the cells that have lost HLA.", "provenance": "Abstract read in full; the 40% frequency, the associated features, and the focal, subclonal and metastasis-enriched character as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I015", "name": "MAIT and invariant NKT cells", "category": "Immune", "whereToCheck": "Site-dependent compartments", "states": [ "Subset and activation" ], "behaviors": [ "Presence", "receptor restriction", "signaling" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "unconventional-inkt", "unconventional-mait" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "unconventional-inkt", "unconventional-mait" ], "priorResearch": { "path": "simulation/data/profiles/mait-and-invariant-nkt-cells.json", "summary": "The inventory asks only for presence, receptor restriction and signalling, and receptor restriction is where this family earns its place. These cells carry a semi-invariant receptor that recognises a pyrimidine derived from microbial riboflavin synthesis, presented on MR1 - so their ligand is a microbial metabolite and not a property of the host cell at all (L108). That makes this the third non-peptide-MHC recognition route the atlas holds, after missing-self sensing by natural killer cells and stress-ligand sensing by gamma-delta cells, and the only one whose antigen originates outside the organism, which points it at the unwritten External category rather than at any tumour antigen. In human liver, one of the drawn environments, liver-derived cells were more polyfunctional than blood cells after cytokine stimulation and carried enhanced interleukin-12 signalling and fatty acid metabolism even untreated, while receptor responses were comparable - the third time this atlas has recorded that the tissue cell is not the blood cell. And receptor-stimulated cells were enriched for a tissue repair signature, which is a behaviour almost nothing else in this atlas carries.", "stateAxes": [ { "axis": "Receptor restriction - a microbial ligand on a non-classical molecule", "whatToMeasure": "The restriction element and its ligand: MR1 presenting a riboflavin-derived pyrimidine for the mucosal-associated subset, with the ligand originating in microbial metabolism rather than in the host.", "interpretationLimit": "Established as the recognition mechanism and unmeasured as a quantity - no MR1 ligand concentration, no presenting-molecule level, in any environment in this atlas. The microbial origin makes the External category the natural upstream and that category is unwritten.", "evidence": [ "L108" ] }, { "axis": "Tissue against blood", "whatToMeasure": "The same cell in tissue and in blood, since liver-derived cells were more polyfunctional after cytokine stimulation and differed in interleukin-12 signalling and fatty acid metabolism at baseline while responding comparably to receptor signals.", "interpretationLimit": "Healthy human liver and blood under defined stimuli, not diseased liver or any tumour. Readouts are transcriptomic and functional in vitro. No frequency in liver or any environment is given, despite this being the tissue where these cells are described as abundant.", "evidence": [ "L108", "L72", "L95" ] }, { "axis": "Activation mode, and the repair programme it selects", "whatToMeasure": "Which route activated the cell - receptor or cytokine - because the effector programmes differ, and the receptor-stimulated cells were the ones enriched for a tissue repair signature.", "interpretationLimit": "A transcriptional signature rather than repair measured in tissue, in healthy cells in vitro. Repair is close to absent as a behaviour across this whole atlas, so there is nothing to corroborate it against and no quantity to attach.", "evidence": [ "L108" ] } ], "records": { "L108": { "id": "L108", "year": 2021, "topic": "Cell-state ecosystems", "title": "Human liver-derived MAIT cells differ from blood MAIT cells in their metabolism and response to TCR and cytokine activation", "url": "https://doi.org/10.1002/eji.202048830", "studyType": "Paired functional and transcriptomic comparison of human blood and liver-derived MAIT cells under receptor and cytokine stimulation, Eur J Immunol 51(4):879-892", "diseaseContext": "Liver", "useInModel": "Three things, in a drawn environment, about a cell the atlas would otherwise have nothing on. First the ligand: these cells carry a semi-invariant receptor recognising a pyrimidine derived from microbial riboflavin synthesis, presented on MR1 - so the antigen is a microbial metabolite rather than any property of the host cell. That makes this the third non-peptide-MHC recognition route in the atlas, after missing-self and stress-ligand sensing, and the only one whose ligand originates outside the organism, which places it against the unwritten External category rather than against a tumour antigen. Second the tissue difference: liver-derived cells were more polyfunctional than blood cells after cytokine stimulation and showed enhanced interleukin-12 signalling and fatty acid metabolism even untreated, while responses to receptor signals were comparable - the same lesson the atlas has now recorded three times, that the tissue cell is not the blood cell. Third, and least represented anywhere in this atlas, receptor-stimulated cells were enriched for a tissue repair signature, so the two activation modes give different effector programmes and one of them is reparative rather than inflammatory.", "limit": "Healthy human blood and liver-derived cells under defined stimuli, not tumour or any diseased liver, so nothing here concerns the drawn environment's pathology. Polyfunctionality and the repair signature are transcriptomic and functional readouts in vitro rather than repair measured in tissue. No frequency of these cells in liver or any other environment is given, and the atlas holds no MR1 ligand measurement anywhere.", "provenance": "Abstract read in full; the MR1 and riboflavin-derived ligand, the blood-against-liver differences under both stimulation modes, and the tissue repair signature as reported", "quantitativeExtraction": "extracted" }, "L72": { "id": "L72", "year": 2016, "topic": "Cell-state ecosystems", "title": "Regulatory T cells exhibit distinct features in human breast cancer", "url": "https://doi.org/10.1016/j.immuni.2016.10.032", "studyType": "Comparative analysis of regulatory T cells from untreated human breast carcinoma, normal mammary gland and peripheral blood, Immunity 45(5):1122-1134", "diseaseContext": "Breast", "useInModel": "Identifies which cell this family actually is inside a tumour, in a drawn environment, and the answer rules out the obvious way to model it. Regulatory T cells from untreated human breast carcinomas were potently suppressive, and their gene-expression pattern resembled that of regulatory cells in normal breast tissue rather than that of activated regulatory cells from peripheral blood. So the tumour-resident cell is a tissue cell, not a blood cell that arrived and switched on - which means a model that recruits these cells from circulation and activates them in place is producing the wrong phenotype. What distinguished the tumour cells from the normal tissue cells was narrow: a number of cytokine and chemokine receptor genes, most notably CCR8, were upregulated. That narrowness is the therapeutic point and the modelling point at once - the tumour population is a small perturbation of a resident one, so both the window for selective depletion and the signal available to distinguish the two are small.", "limit": "Untreated human breast carcinoma against normal mammary gland, which is the right comparator and gives no information about other tumour types or about treated disease. Suppression was assayed ex vivo rather than measured in tissue. The CCR8 proposal is the authors' suggestion from a differential expression result, and whether it is selective enough to be a depletion target is not settled here.", "provenance": "Abstract read in full; the tissue-resemblance finding, the suppressive capacity and the differential receptor result as reported", "quantitativeExtraction": "extracted" }, "L95": { "id": "L95", "year": 2014, "topic": "Cell-state ecosystems", "title": "Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment", "url": "https://doi.org/10.1016/j.cell.2014.11.018", "studyType": "Four histone modifications profiled across seven tissue-resident macrophage populations with transplantation and transfer experiments, Cell 159(6):1312-1326", "diseaseContext": "Healthy reference", "useInModel": "Says the tissue writes the programme, and says it at the level of chromatin. Profiling four histone modifications across seven tissue-resident macrophage populations identified 12,743 macrophage-specific enhancers and established that these populations have distinct enhancer landscapes beyond what developmental origin can explain, with the regulatory networks formed by a combination of tissue-specific and lineage-specific transcription factors. The two experiments that matter most for this atlas are the transfer ones: the environment shaped the chromatin landscape of transplanted bone marrow precursors, and even already-differentiated macrophages were reprogrammed when moved into a new microenvironment. So identity here is not a property the cell carries in but one the niche imposes - which is the same conclusion the atlas reached for regulatory T cells from a different direction, where the tumour-resident cells resembled the resident cells of that normal tissue rather than activated cells from blood (L72).", "limit": "Mouse, seven populations, healthy tissue. Chromatin state and expression are not function, so a shared enhancer landscape does not establish that two cells do the same job. Reprogramming on transfer is demonstrated as possible without a timescale or a completeness - how far and how fast a transferred cell converges is not given, and no tissue here is a tumour or any drawn environment.", "provenance": "Abstract read in full; the enhancer count, the beyond-origin claim, the combined transcription factor networks and both transfer results as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I016", "name": "Natural killer cells", "category": "Immune", "whereToCheck": "Blood and tissue", "states": [ "Cytotoxic", "cytokine-producing", "inhibited" ], "behaviors": [ "Recognition", "degranulation", "antibody-dependent activity" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-572", "hatton-536" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-572", "hatton-536" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-572", "hatton-536" ], "priorResearch": { "path": "simulation/data/profiles/natural-killer-cells.json", "summary": "This family is the designated cover for the one escape route the T-cell arm cannot address, and the atlas can now quantify both halves of that arrangement. Cytotoxic T cells failed to kill at all where targets downmodulated MHC class I (L30), and allele-specific loss of heterozygosity at HLA occurs in 40% of non-small-cell lung cancers - focal, subclonal, enriched in metastatic sites, and concentrated where immune pressure is highest (L81). That is the condition this family exists to handle. But the same locus family supplies its brake: the non-classical ligand for the inhibitory receptor NKG2A holds these cells off, and blocking that receptor enhances both natural killer and CD8 function, with a 31% objective response rate in a treated head and neck population in combination with cetuximab (L82). So a tumour can shed classical HLA to escape T cells while retaining the ligand that restrains natural killer cells - the two arms of one locus family running in opposite directions. The third behaviour the inventory names has a host genotype attached: the higher-affinity FcgammaRIIIa allotype roughly doubled one-year response to a therapeutic antibody (L80). And this family sits upstream of the two the atlas wrote before it, supplying the FLT3L that sets stimulatory dendritic cell abundance (L78).", "stateAxes": [ { "axis": "Inhibited - by a ligand the atlas has never measured", "whatToMeasure": "The non-classical HLA ligand level on tumour cells alongside NKG2A on the effector, since blocking that receptor raised this family's activity, rescued CD8 function with PD-axis blockade, and raised antibody-dependent activity as well.", "interpretationLimit": "Mechanistic work across mouse and human in vitro systems with an interim phase 2 combination readout, so the 31% response cannot be apportioned between the two antibodies, in lymphoma, drawn in on 2026-10-14. No inhibitory ligand level is measured on tumour cells in any environment in this atlas - the axis is established as actionable and is unquantified at its controlling variable.", "evidence": [ "L82" ] }, { "axis": "Antibody-dependent activity - with a host genotype", "whatToMeasure": "The host FcgammaRIIIa 158V/F genotype, not an expression level, since the homozygous higher-affinity genotype carried 100% and 90% response against 67% and 51% in carriers of the lower-affinity allele and was the single parameter surviving multivariate analysis.", "interpretationLimit": "Forty-nine patients with follicular lymphoma, which became a drawn environment on 2026-10-14, with small genotype subgroups and a naked IgG1 antibody against a haematological target. Later and larger series have debated the effect size. It establishes genotype dependence of the route rather than its magnitude in solid tumours.", "evidence": [ "L80", "L82" ] }, { "axis": "Recognition - a rule defined by absence, at allele resolution", "whatToMeasure": "Which HLA alleles each subclone retains, rather than whether the tumour is MHC class I positive - because loss is focal, subclonal, enriched in metastases and occurs as parallel events, and because loss of class I is the condition under which the T-cell arm stops working entirely.", "interpretationLimit": "Copy number inferred computationally from sequencing in non-small-cell lung cancer, so allelic loss is not measured surface presentation, and the evolutionary ordering is reconstructed from cross-sectional samples. Critically, nothing in this atlas measures whether these cells actually engage the subclones that have lost HLA - the fail-safe is assumed rather than observed.", "evidence": [ "L81", "L30" ] }, { "axis": "Abundance - which sets another family's abundance", "whatToMeasure": "Frequency in the tumour alongside FLT3LG expression and the stimulatory dendritic count, since the two innate populations together correlated with anti-PD-1 responsiveness and with overall survival.", "interpretationLimit": "Human evidence is association between signatures, response and survival; the causal ablation is mouse. No natural killer density per unit tissue exists for any drawn environment in this atlas, and no transfer function from frequency to dendritic abundance.", "evidence": [ "L78" ] } ], "records": { "L30": { "id": "L30", "year": 2016, "topic": "Effector behavior", "title": "In vivo killing capacity of cytotoxic T cells is limited and involves dynamic interactions and T cell cooperativity", "url": "https://doi.org/10.1016/j.immuni.2016.01.010", "studyType": "Two-photon imaging of virus-infected mouse tissue with mathematical modelling, Immunity 44(2):233-245", "diseaseContext": "Healthy reference", "useInModel": "The record that disciplines every killing rate in this atlas. In vitro assays suggest T cells kill rapidly and efficiently; measured in living tissue by two-photon microscopy and by fitting a model to the imaging, one cytotoxic T cell killed on average 2 to 16 virus-infected cells per day. Three further findings change how killing should be represented. T cells remained migratory and formed motile kinapses rather than static synapses, so a model that immobilises an effector on contact has the wrong dynamics. The probability that an infected cell died rose once more than two T cells had contacted it, which is cooperativity - killing is not a one-to-one transaction and the per-contact probability is not constant. And individual T cells varied strongly in functional capacity by calcium reporting, so an average effector is a poor stand-in for a population. Where targets downmodulated MHC class I, the T cells failed to kill at all.", "limit": "Mouse, virus-infected tissue, herpesviruses and poxviruses - not tumour and not any drawn environment. The 2-to-16 range is per day and per cell across systems rather than a value to carry, and the upper and lower ends come from different infections. An engager-redirected T cell is not the same effector as a virus-specific CTL, so the rate bounds the plausible rather than supplying it.", "provenance": "Abstract read in full; rate, cooperativity threshold and kinapse observation as reported", "quantitativeExtraction": "pending" }, "L78": { "id": "L78", "year": 2018, "topic": "Recruitment and synapse", "title": "A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments", "url": "https://doi.org/10.1038/s41591-018-0085-8", "studyType": "Human melanoma association analysis with mouse genetic and cellular ablation of natural killer cells, Nat Med 24(8):1178-1191", "diseaseContext": "Melanoma / Shared cancer", "useInModel": "Answers what sets the abundance of the rare cell, and the answer is another cell family. In human melanoma, stimulatory dendritic cell abundance was associated with intratumoral expression of FLT3LG, and that cytokine is predominantly produced by lymphocytes, notably natural killer cells, in both mouse and human tumours. Natural killer cells stably form conjugates with these dendritic cells in the mouse tumour microenvironment, and genetic and cellular ablation of natural killer cells reduced dendritic cell abundance through loss of FLT3L. The clinical reading is the valuable part: natural killer cell frequency correlated with protective stimulatory dendritic cells in human cancers, with patient responsiveness to anti-PD-1, and with increased overall survival - and the authors propose the two innate populations together as a prognostic tool for T-cell-directed immunotherapy. So a drug aimed at T cells is predicted by the abundance of two innate cell families, neither of which it targets.", "limit": "Human evidence is association between expression signatures, response and survival; the causal ablation is mouse. Conjugate formation is observed in mouse tumours. No FLT3L concentration, conjugate duration or dendritic cell density per unit tissue is given, so the dependency is established without a transfer function.", "provenance": "Abstract read in full; the FLT3LG association, the natural killer cell source, the ablation result and the three clinical correlations as reported", "quantitativeExtraction": "extracted" }, "L80": { "id": "L80", "year": 2002, "topic": "Clinical outcome", "title": "Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene", "url": "https://doi.org/10.1182/blood.V99.3.754", "studyType": "Genotype-stratified clinical response analysis in 49 patients with previously untreated follicular lymphoma, Blood 99(3):754-758", "diseaseContext": "Lymphoma", "useInModel": "A germline genotype in the host that roughly doubles the response rate to a therapeutic antibody, through this family's effector function. The FcgammaRIIIa 158V allotype binds human IgG1 with higher affinity and gives increased antibody-dependent cellular cytotoxicity. Among 49 patients given rituximab for previously untreated follicular lymphoma - 20% homozygous for 158V, 35% homozygous for 158F, 45% heterozygous - objective response was 100% at two months and 90% at one year in the 158V homozygotes against 67% and 51% in 158F carriers, both differences at p = 0.03. Molecular response, the disappearance of the BCL2-JH rearrangement from blood and marrow at one year, was seen in 5 of 6 homozygous 158V patients against 5 of 17 F carriers. The 158V homozygous genotype was the single parameter associated with clinical and molecular response in multivariate analysis. The design point for this atlas is the contrast it implies: an antibody that works through this route depends on a host receptor genotype, which is precisely why T-cell engagers are deliberately Fc-silenced - so one target antigen has two effector routes with different dependencies, and the engager families written here have treated the CD8 route as the only one.", "limit": "Forty-nine patients in follicular lymphoma, which became a drawn environment on 2026-10-14, with a naked IgG1 antibody against a haematological target. Small subgroups - six homozygous patients carry the molecular-response claim - and a 2002 analysis whose effect size has been debated in later and larger series. It establishes that the route is genotype-dependent, not the magnitude of that dependence in solid tumours.", "provenance": "Abstract read in full; genotype frequencies, both response timepoints with p-values, the molecular response counts and the multivariate result as reported", "quantitativeExtraction": "extracted" }, "L81": { "id": "L81", "year": 2017, "topic": "Target identity", "title": "Allele-specific HLA loss and immune escape in lung cancer evolution", "url": "https://doi.org/10.1016/j.cell.2017.10.001", "studyType": "Computational allele-specific HLA copy-number analysis across non-small-cell lung cancers with evolutionary reconstruction, Cell 171(6):1259-1271", "diseaseContext": "Lung", "useInModel": "Quantifies the escape route that the T-cell arm cannot cover, in a drawn environment, and gives it a heterogeneity structure. Using a tool built to resolve allele-specific copy number at a locus too polymorphic for standard methods, loss of heterozygosity at HLA was found in 40% of non-small-cell lung cancers. It was associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulated cytolytic activity and PD-L1 positivity - that is, it appears where immune pressure is greatest. Its character matters as much as its frequency: the alterations are focal, subclonal, enriched in metastatic sites and occur as parallel events, which the authors read as immune escape under strong microenvironmental selection later in tumour evolution. For a simulation this forbids treating MHC class I as a binary tumour property. Different subclones within one tumour have lost different alleles, so presentation capacity is a per-subclone, per-allele state - and the loss of it is exactly the condition under which cytotoxic T cells failed to kill at all (L30), which is where this family is supposed to take over.", "limit": "Non-small-cell lung cancer, computational inference of copy number from sequencing rather than measured protein on cells, so loss of an allele is not the same as measured loss of surface presentation. The evolutionary ordering is reconstructed from cross-sectional data. Nothing here measures whether natural killer cells actually engage the cells that have lost HLA.", "provenance": "Abstract read in full; the 40% frequency, the associated features, and the focal, subclonal and metastasis-enriched character as reported", "quantitativeExtraction": "extracted" }, "L82": { "id": "L82", "year": 2018, "topic": "Checkpoint receptor/ligand pairs", "title": "Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells", "url": "https://doi.org/10.1016/j.cell.2018.10.014", "studyType": "Mouse and human functional work with interim results of a phase 2 combination trial, Cell 175(7):1731-1743", "diseaseContext": "Shared cancer", "useInModel": "Shows that this family carries its own brake, supplied by the same locus family whose loss is supposed to expose a tumour to it. Blocking the inhibitory receptor NKG2A enhanced effector function of both natural killer and CD8 T cells in mice and humans. The antibody enhanced natural killer activity against various tumour cells, rescued CD8 function in combination with PD-axis blockade, and separately stimulated natural killer activity against antibody-coated target cells - so it raises the antibody-dependent route as well. Interim phase 2 results in previously treated squamous cell carcinoma of the head and neck, combined with cetuximab, gave a 31% objective response rate, with fatigue in 17%, pyrexia in 13% and headache in 10%. The structural point for this atlas is the opposition: classical HLA class I presents to CD8 and its loss defeats that arm, while the non-classical ligand for NKG2A inhibits natural killer cells - so a tumour that sheds classical HLA to escape T cells can still hold this family off, and the two arms of the same locus family run in opposite directions.", "limit": "Interim phase 2 results in a combination, so the 31% response rate cannot be attributed between the two antibodies, in a cancer outside the drawn set and a previously treated population. The mechanistic work spans mouse and human in vitro systems. The atlas holds no measurement of the inhibitory ligand's level on tumour cells in any environment, which is the quantity this axis turns on.", "provenance": "Abstract read in full; the dual-cell effect, the antibody-coated-target finding, the response rate and the adverse event frequencies as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I017", "name": "Other innate lymphoid cells", "category": "Immune", "whereToCheck": "Especially mucosal tissues", "states": [ "ILC1/2/3 and state" ], "behaviors": [ "Cytokines", "tissue repair", "local recruitment" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "ilc-ilc1", "ilc-ilc2", "ilc-ilc3" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "ilc-ilc1", "ilc-ilc2", "ilc-ilc3" ], "priorResearch": { "path": "simulation/data/profiles/other-innate-lymphoid-cells.json", "summary": "Written thin, and the thinness is recorded rather than worked around. The inventory places this family in mucosal tissues especially, asks for ILC1, ILC2 and ILC3 subsets and their state, and names cytokines, tissue repair and local recruitment - and a deliberate search did not surface a usable primary study measuring it in any of the drawn environments. What makes the absence worth noting is the second behaviour the inventory names: tissue repair. Across forty-six written families this atlas has collected killing, suppression, exclusion, obstruction, clearance and presentation, and almost nothing on repair - the only other instance is the repair signature recorded for MAIT cells. Every drawn environment is a tissue under chronic damage, and a simulation with no reparative term can only ever get worse. This row is where that term would most naturally live, and it is empty.", "stateAxes": [ { "axis": "Presence - the behaviour the inventory asks for first", "whatToMeasure": "A density or frequency in a named environment, which is what every other row in this category eventually gets and this one does not have.", "interpretationLimit": "Unserved. No study surfaced in this search measures this family in any of the drawn environments, so presence is neither established nor excluded - and under this atlas's own rule, not measured is not the same as not present.", "evidence": [] } ], "records": {}, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I018", "name": "B cells", "category": "Immune", "whereToCheck": "Blood; tissue; lymphoid aggregates", "states": [ "Naive", "memory", "activated", "regulatory programs" ], "behaviors": [ "Antigen presentation", "antibody response", "tissue organization" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-571", "hatton-535" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-571", "hatton-535" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "sender-I018-mature-b-cells" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-571", "hatton-535", "sender-I018-mature-b-cells" ], "priorResearch": { "path": "simulation/data/profiles/b-cells.json", "summary": "The inventory's third location for this family is lymphoid aggregates, and that is where the evidence landed. Three independent groups published in one issue of the same journal, in three tumour types, with the same answer: B cells organised into tertiary lymphoid structures associate with response to checkpoint blockade. In melanoma, B-cell markers were the most differentially expressed genes between responders and non-responders, corroborated in two further treated cohorts, with the cells clonally expanded, class-switched and located inside the structures (L67). In sarcoma, across 608 tumours, B cells were the strongest prognostic factor even accounting for high or low CD8 content, and the B-cell-rich structural class had improved survival and a high response rate to pembrolizumab in a phase 2 trial (L68). In melanoma again, structure-bearing tumours carried more TCF7-positive naive and memory T cells while T cells in structure-negative tumours were dysfunctional (L65). But the direction is not a property of the cell: interleukin-10-secreting regulatory B cells in a breast model suppressed CD8 activity and interferon-gamma, and depleting B cells partially reversed the tumour-promoting effect (L69). Organised and class-switched, this family helps; dispersed and regulatory, it harms.", "stateAxes": [ { "axis": "Inside an organised structure, or dispersed", "whatToMeasure": "Whether the B cells form a tertiary lymphoid structure - identified by CXCR5 and CXCL13 alongside CD20, and containing T cells and follicular dendritic cells - or sit as a diffuse infiltrate. This is the axis that carries the direction of the family's effect.", "interpretationLimit": "Structure presence is scored rather than quantified as a density, a size or a count per unit area in any of the three studies, so the axis is binary in all the evidence the atlas holds. Associative throughout: nothing shows the structures cause the response rather than marking tumours capable of one.", "evidence": [ "L67", "L68", "L65" ] }, { "axis": "Class-switched and clonally expanded, or naive", "whatToMeasure": "Switched memory fraction and clonal expansion, not total B cells - switched memory cells were enriched in responders and the compartment showed clonal expansion and distinct functional states there.", "interpretationLimit": "Established in neoadjuvant melanoma by mass cytometry and sequencing, with corroboration in two further treated cohorts. It establishes that the cells responded to something; it does not establish what, and no antigen specificity is resolved anywhere in this atlas for this family.", "evidence": [ "L67" ] }, { "axis": "Regulatory - the direction that reverses the sign", "whatToMeasure": "The interleukin-10-secreting fraction, since in a breast model those cells suppressed CD8 activity and interferon-gamma and B-cell depletion partially reversed tumour promotion.", "interpretationLimit": "One mouse triple-negative line with the driving factor overexpressed rather than observed, so it shows the axis can dominate, not how often it does. No regulatory B-cell fraction is measured in any human tumour here, which is precisely the measurement needed to make a B-cell count interpretable.", "evidence": [ "L69" ] }, { "axis": "Antigen presentation - the inventory's first behaviour, unserved", "whatToMeasure": "Whether these cells are presenting antigen locally, which would connect them to the requirement that CD4 activation occur inside the tumour.", "interpretationLimit": "Entirely unserved in this atlas. The three cohort studies measure association, localisation and phenotype, not presentation, and the CD4 requirement under I012 names a need for local class II presentation without identifying which cell provides it. This is the most specific missing link between two written families.", "evidence": [ "L63", "L67" ] } ], "records": { "L63": { "id": "L63", "year": 2019, "topic": "Target identity", "title": "MHC-II neoantigens shape tumour immunity and response to immunotherapy", "url": "https://doi.org/10.1038/s41586-019-1671-8", "studyType": "Mouse tumour models with defined MHC class I and class II neoantigens, Nature 574(7780):696-701", "diseaseContext": "Shared cancer", "useInModel": "Says this atlas's antigen framework is missing half its requirement. Both spontaneous and immunotherapy-induced antitumour responses required the activity of tumour-antigen-specific CD8 and CD4 T cells together - and this held even in tumours that do not express MHC class II molecules, so the requirement is not satisfied by the tumour cell being a CD4 target itself. The sharper finding is geographic: expression of MHC class II-restricted antigen by tumour cells was required at the site of successful rejection, which the authors read as showing that CD4 activation must also occur in the tumour microenvironment rather than only in a draining node. So the class II neoantigen requirement is non-overlapping with the class I one and has to be considered when identifying who benefits from immunotherapy. For this atlas the consequence is direct: the target-antigen and receptor families are framed entirely around class I and CD8, and that framing is incomplete as a model of rejection.", "limit": "Mouse models with engineered neoantigens, which is how the requirement could be made clean and also why the magnitudes do not transfer. It establishes that both subsets are necessary without apportioning their contributions, and gives no density, ratio or antigen-load threshold. The claim that activation occurs in the microenvironment is inferred from the site-of-rejection requirement rather than imaged.", "provenance": "Abstract read in full; the dual requirement, the MHC class II-negative case and the site-of-rejection requirement as reported", "quantitativeExtraction": "extracted" }, "L65": { "id": "L65", "year": 2020, "topic": "Spatial and immune state", "title": "Tertiary lymphoid structures improve immunotherapy and survival in melanoma", "url": "https://doi.org/10.1038/s41586-019-1914-8", "studyType": "Clinical metastatic melanoma samples with immunofluorescence, a derived gene signature tested in checkpoint-blockade cohorts, and digital spatial profiling, Nature 577(7791):561-565", "diseaseContext": "Melanoma", "useInModel": "Partly answers a question three other families in this atlas have raised, and does it with a structure rather than a compartment. Co-occurrence of tumour-associated CD8 T cells and CD20 B cells was associated with improved survival independently of other clinical variables, and staining CXCR5 and CXCL13 alongside CD20 showed that those tumours contain tertiary lymphoid structures. A gene signature derived from those structures predicted clinical outcome in checkpoint-blockade cohorts. The mechanistic link is the valuable part: B-cell-rich tumours carried increased TCF7-positive naive and memory T cells, and digital spatial profiling showed that T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. TCF7 is the marker that separates the checkpoint-responsive progenitor exhausted population from the terminal one under I011, so this chains a measurable anatomical structure to the cell state that determines whether checkpoint blockade can work - and it means the lymphoid compartment the clonal-replacement and vesicle findings pointed outside the tumour for is sometimes inside it.", "limit": "Metastatic melanoma, and associative throughout - co-occurrence with survival, a signature with outcome, a phenotype with a structure. Nothing here shows that the structures generate the TCF7-positive cells rather than accompanying them, and the authors frame inducing them as a strategy to be explored. Structure presence is scored rather than quantified as a density or a size.", "provenance": "Abstract read in full; the co-occurrence association, the structural identification, the signature result and the TCF7 and spatial-profiling findings as reported", "quantitativeExtraction": "extracted" }, "L67": { "id": "L67", "year": 2020, "topic": "Spatial and immune state", "title": "B cells and tertiary lymphoid structures promote immunotherapy response", "url": "https://doi.org/10.1038/s41586-019-1922-8", "studyType": "Bulk and single-cell RNA sequencing, mass cytometry and histology on a neoadjuvant checkpoint-blockade melanoma trial with corroboration in two further treated cohorts, Nature 577(7791):549-555", "diseaseContext": "Melanoma / Shared cancer", "useInModel": "The finding arrived at from the data rather than looked for. In a neoadjuvant checkpoint-blockade melanoma trial, bulk RNA sequencing showed that B-cell markers were the most differentially expressed genes between responders and non-responders - not a B-cell signature among others, the top of the list, in a field whose predictive work had focused on T cells. The result was corroborated by computational deconvolution in that cohort and two more treated cohorts in melanoma and renal cell carcinoma. Histology localised the B cells within tertiary lymphoid structures. And the cells were not passive: bulk and single-cell sequencing showed clonal expansion and distinct functional states in responders, and mass cytometry found switched memory B cells enriched in their tumours. So the informative quantity is not a B-cell count but a count of clonally expanded, class-switched B cells sitting inside an organised structure.", "limit": "Associative throughout - differential expression and enrichment against response, in treated cohorts, with no intervention on B cells in humans. Neoadjuvant melanoma with two corroborating cohorts, one of them renal cell carcinoma, neither sarcoma nor most of the drawn set. Clonal expansion and switched memory establish that the cells responded to something, not that they caused the response.", "provenance": "Abstract read in full; the differential expression ranking, the three cohorts, the structural localisation and the switched-memory finding as reported", "quantitativeExtraction": "extracted" }, "L68": { "id": "L68", "year": 2020, "topic": "Spatial and immune state", "title": "B cells are associated with survival and immunotherapy response in sarcoma", "url": "https://doi.org/10.1038/s41586-019-1906-8", "studyType": "Gene expression profiling of 608 soft-tissue sarcomas with in situ validation and a phase 2 pembrolizumab readout, Nature 577(7791):556-560", "diseaseContext": "Shared cancer", "useInModel": "The strongest direct challenge in this atlas to its own CD8-centred framing, and it comes with a prospective readout. Expression profiling of 608 soft-tissue sarcomas across subtypes produced five immune phenotypes - two immune-low, two immune-high and one highly vascularised. In situ analysis of an independent validation cohort showed the best class was characterised by tertiary lymphoid structures containing T cells and follicular dendritic cells and particularly rich in B cells. The decisive sentence is that B cells were the strongest prognostic factor even in the context of high or low CD8 T cells and cytotoxic contents - so the B-cell signal is not a proxy for a T-cell signal, and it outperformed the compartment this atlas treats as the effector population. That class had improved survival and a high response rate to PD-1 blockade with pembrolizumab in a phase 2 trial, which makes this a forward-looking validation rather than a retrospective association.", "limit": "Soft-tissue sarcoma across more than 50 histological subtypes, which is not among the drawn set and is unusually heterogeneous even for a tumour type. The classes are derived from bulk expression with in situ confirmation in a separate cohort, so class assignment depends on the deconvolution used. The phase 2 response rate is for the class, in a small prospective cohort, and does not isolate B cells as the cause.", "provenance": "Abstract read in full; cohort size, the five classes, the class-E structural description, the prognostic claim relative to CD8 and the trial readout as reported", "quantitativeExtraction": "extracted" }, "L69": { "id": "L69", "year": 2025, "topic": "Exclusion and signaling", "title": "BAFF overexpression in triple-negative breast cancer promotes tumor growth by inducing IL-10-secreting regulatory B cells that suppress anti-tumor T cell responses", "url": "https://doi.org/10.1007/s10549-024-07504-6", "studyType": "Mouse 4T1 triple-negative breast cancer with BAFF overexpression, co-culture and B-cell depletion, Breast Cancer Res Treat 209(2):405-418", "diseaseContext": "Breast", "useInModel": "The other direction, in a drawn environment, which is what makes a B-cell count sign-ambiguous. Overexpressing the B-cell survival factor BAFF in a triple-negative breast cancer line promoted tumour growth in vivo, suppressed CD8 T-cell activity and increased interleukin-10-secreting CD5-positive regulatory B cells in the tumour. The tumour cells enhanced interleukin-10 production in those B cells directly through BAFF-receptor interactions, and the interleukin-10 inhibited interferon-gamma secretion by T cells. Depleting B cells partially reversed the tumour-promoting effect of BAFF overexpression - so in this system the B-cell compartment is net harmful and removing it helps, which is the opposite of what the three checkpoint-response studies describe. Read together, the direction of this family's effect is not a property of the cell: it depends on which state the cells are in and whether they sit inside an organised structure or dispersed in the tumour.", "limit": "Mouse, one triple-negative line, with BAFF overexpressed rather than observed - so it demonstrates that a suppressive B-cell axis exists and can dominate, not how often it does. Depletion reversed the effect only partially. No regulatory B-cell fraction is measured in any human tumour in this atlas, which means the sign-ambiguity it establishes cannot currently be resolved for any environment.", "provenance": "Abstract read in full; the growth effect, the interleukin-10 mechanism and the partial reversal on depletion as reported", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I019", "name": "Plasma cells", "category": "Immune", "whereToCheck": "Tissue and marrow", "states": [ "Antibody specificity and secretory state" ], "behaviors": [ "Antibody production and local immunoglobulin" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-573", "hatton-584" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-573", "hatton-584" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-573", "hatton-584" ], "priorResearch": { "path": "simulation/data/profiles/plasma-cells.json", "summary": "The B cell family recorded that it left this row nothing to build on, because no antigen specificity, antibody titre or local immunoglobulin concentration was measured anywhere in the atlas. The chain is now present, if still without quantities. Inside intratumoral tertiary lymphoid structures, every B cell maturation stage toward plasma cell formation is found, with clonal diversification, selection and expansion occurring in the structure and fully mature clonotypes appearing at distance from it - so the structure is a source that exports. IgG- and IgA-producing plasma cells then disseminate into the tumour beds along fibroblastic tracks, and structure-positive tumours carry IgG-stained and apoptotic malignant cells, with response and progression-free survival under checkpoint inhibitors correlating with that staining (L98). The same lineage runs the other way elsewhere: liver-resident IgA-producing cells accumulating with chronic inflammation express PD-L1 and interleukin-10, directly suppress the cytotoxic CD8 cells that hold hepatocellular carcinoma in check, and interfering with their generation induced regression of established tumours (L99). So the sign of this family is set by isotype and by setting.", "stateAxes": [ { "axis": "Isotype - which sets the sign", "whatToMeasure": "The IgG to IgA ratio among intratumoral plasma cells, since IgG-producing cells arising in lymphoid structures associate with antibody-bound apoptotic tumour cells and with response, while IgA-producing cells in inflamed liver suppress the CD8 compartment and their removal causes regression.", "interpretationLimit": "The two directions come from different organs, different diseases and different designs - renal cell carcinoma with spatial transcriptomics and outcome correlation against inflammation-driven liver carcinogenesis with genetic and pharmacological interference. Neither is a drawn environment for the first, and no isotype ratio is measured anywhere in this atlas.", "evidence": [ "L98", "L99" ] }, { "axis": "Secretory output - the quantity this family exists for, and it is missing", "whatToMeasure": "Antibody secretion rate per cell and local immunoglobulin concentration in tissue, which is what would turn a plasma cell count into an effector quantity.", "interpretationLimit": "Absent from this atlas entirely, and the absence compounds across three families. The natural killer family established that the antibody-dependent effector route depends on a host receptor genotype (L80); the vesicle family established that antigen-bearing vesicles bind therapeutic antibody and act as a sink (L44); and this family is the source. One axis described by three families, with no concentration measured at any point along it.", "evidence": [ "L98", "L80", "L44" ] }, { "axis": "Where the cell came from, and how far it travelled", "whatToMeasure": "Position relative to a lymphoid structure, with clonal identity, since maturation happens inside the structure and fully mature clonotypes are found at distance - and dissemination follows fibroblastic tracks rather than spreading evenly.", "interpretationLimit": "No dissemination distance, track length or export rate is given, so the structure is established as a source with a range and the range is unmeasured. This is the same shape as the missing length scales the atlas has collected for complement deposition, regulatory T-cell suppression and bystander killing.", "evidence": [ "L98" ] } ], "records": { "L44": { "id": "L44", "year": 2011, "topic": "Resistance", "title": "Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3", "url": "https://doi.org/10.1073/pnas.1102855108", "studyType": "B-cell lymphoma vesicle biology with ABCA3 blockade and silencing, PNAS 108(37):15336-15341", "diseaseContext": "Lymphoma / Shared cancer", "useInModel": "Serves the inventory's hardest behaviour - target sequestration - and serves it mechanically. Lymphoma cells released vesicles carrying CD20 that bound therapeutic anti-CD20 antibody, consumed complement, and shielded the tumour cells from antibody attack. Blocking or silencing the transporter ABCA3 reduced the amount of vesicle released and increased the susceptibility of the target cells to antibody-mediated lysis, which makes vesicle output a manipulable variable rather than a fixed property. Two consequences for this atlas. First, a vesicle bearing the target antigen is a sink term on the drug, and in a model it belongs with clearance rather than with signalling. Second, the complement consumption partly fills a gap stated under I076: that family's deposited arm in tumour was recorded as entirely absent, and here is tumour-derived material consuming complement. ABCA3 also links resistance to antibodies and resistance to chemotherapy through one pathway.", "limit": "B-cell lymphoma cell systems with a naked antibody acting through complement and antibody-mediated lysis, which is not how a T-cell engager works - an engager that is soaked up by antigen-positive vesicles loses drug without the complement step. Lymphoma is a drawn environment which became a drawn environment on 2026-10-14; no sequestered fraction is quantified, and nothing here gives the vesicle antigen density needed to turn this into a sink rate.", "provenance": "Abstract read in full; antigen carriage, antibody binding, complement consumption and the ABCA3 results as reported", "quantitativeExtraction": "pending" }, "L80": { "id": "L80", "year": 2002, "topic": "Clinical outcome", "title": "Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene", "url": "https://doi.org/10.1182/blood.V99.3.754", "studyType": "Genotype-stratified clinical response analysis in 49 patients with previously untreated follicular lymphoma, Blood 99(3):754-758", "diseaseContext": "Lymphoma", "useInModel": "A germline genotype in the host that roughly doubles the response rate to a therapeutic antibody, through this family's effector function. The FcgammaRIIIa 158V allotype binds human IgG1 with higher affinity and gives increased antibody-dependent cellular cytotoxicity. Among 49 patients given rituximab for previously untreated follicular lymphoma - 20% homozygous for 158V, 35% homozygous for 158F, 45% heterozygous - objective response was 100% at two months and 90% at one year in the 158V homozygotes against 67% and 51% in 158F carriers, both differences at p = 0.03. Molecular response, the disappearance of the BCL2-JH rearrangement from blood and marrow at one year, was seen in 5 of 6 homozygous 158V patients against 5 of 17 F carriers. The 158V homozygous genotype was the single parameter associated with clinical and molecular response in multivariate analysis. The design point for this atlas is the contrast it implies: an antibody that works through this route depends on a host receptor genotype, which is precisely why T-cell engagers are deliberately Fc-silenced - so one target antigen has two effector routes with different dependencies, and the engager families written here have treated the CD8 route as the only one.", "limit": "Forty-nine patients in follicular lymphoma, which became a drawn environment on 2026-10-14, with a naked IgG1 antibody against a haematological target. Small subgroups - six homozygous patients carry the molecular-response claim - and a 2002 analysis whose effect size has been debated in later and larger series. It establishes that the route is genotype-dependent, not the magnitude of that dependence in solid tumours.", "provenance": "Abstract read in full; genotype frequencies, both response timepoints with p-values, the molecular response counts and the multivariate result as reported", "quantitativeExtraction": "extracted" }, "L98": { "id": "L98", "year": 2022, "topic": "Spatial and immune state", "title": "Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer", "url": "https://doi.org/10.1016/j.immuni.2022.02.001", "studyType": "Spatial transcriptomics with B cell repertoire analysis and checkpoint-inhibitor outcome correlation in renal cell carcinoma, Immunity 55(3):527-541", "diseaseContext": "Shared cancer", "useInModel": "Closes the gap the B cell family said it left behind, and closes it as a chain with a stainable endpoint. Within intratumoral tertiary lymphoid structures, B cells were enriched and all maturation stages toward plasma cell formation were present; repertoire analysis showed clonal diversification, selection and expansion inside the structures, and fully mature clonotypes at distance from them. In structure-positive tumours, IgG- and IgA-producing plasma cells disseminated into the tumour beds along fibroblastic tracks, and those tumours showed high frequencies of IgG-producing plasma cells together with IgG-stained and apoptotic malignant cells. Therapeutic response and progression-free survival correlated with IgG-stained tumour cells in patients treated with checkpoint inhibitors. Three things to carry. The structure exports - mature clonotypes were found away from it, so it is a source with a range the atlas does not have. The cells travel along fibroblastic tracks, which is the third independent finding in this atlas that immune cells follow stromal structures rather than diffusing. And antibody bound to tumour cells is a spatial, stainable readout on identified targets that tracks outcome, which makes it a third validated spatial endpoint sitting downstream of the other two.", "limit": "Renal cell carcinoma, which became a drawn environment on 2026-10-14, and associative at the clinical end - IgG staining on tumour cells correlates with response and progression-free survival without being shown to cause either. Apoptosis alongside IgG staining is suggestive of effector activity rather than a demonstration of it. No antibody concentration, secretion rate or dissemination distance is given, so the chain is complete in structure and empty of quantities.", "provenance": "Abstract read in full; the maturation stages, the repertoire findings including clonotypes at distance, the fibroblastic-track dissemination, the IgG-stained apoptotic cells and the outcome correlation as reported", "quantitativeExtraction": "extracted" }, "L99": { "id": "L99", "year": 2017, "topic": "Exclusion and signaling", "title": "Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity", "url": "https://doi.org/10.1038/nature24302", "studyType": "Human and mouse non-alcoholic fatty liver disease with genetic and pharmacological interference in IgA+ cell generation, Nature 551(7680):340-345", "diseaseContext": "Liver", "useInModel": "The same lineage pointing the other way, in a drawn environment, with an intervention that reversed established disease. Chronic inflammation and fibrosis in human and mouse non-alcoholic fatty liver disease was accompanied by accumulation of liver-resident IgA-producing cells. Those cells express PD-L1 and interleukin-10 and directly suppress liver cytotoxic CD8 T cells - the same CD8 cells that prevent hepatocellular carcinoma emerging and that carry a limited receptor repertoire against tumour-associated antigens. Ablating CD8 cells accelerated carcinoma, while genetic or pharmacological interference with IgA-positive cell generation attenuated carcinogenesis and induced cytotoxic-lymphocyte-mediated regression of established hepatocellular carcinoma. Two consequences for this atlas. This family's sign is set by isotype and setting: IgG-producing plasma cells arising in tertiary lymphoid structures are effectors, and IgA-producing cells in inflamed liver are suppressors. And these cells are a source of PD-L1 that is neither a tumour cell nor a myeloid cell, which is a compartment the checkpoint family does not account for.", "limit": "Mouse models for the interventions with human tissue establishing the accumulation, and the setting is inflammation-driven liver carcinogenesis rather than an established tumour microenvironment of the kind the drawn environments mostly describe. Interference with cell generation is an upstream manipulation and does not isolate which of PD-L1, interleukin-10 or another mechanism carries the suppression. No IgA-positive cell density or local immunoglobulin concentration is given.", "provenance": "Abstract read in full; the accumulation in human and mouse disease, the PD-L1 and interleukin-10 expression, the direct suppression, and both intervention results as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I020", "name": "Conventional dendritic cells", "category": "Immune", "whereToCheck": "Tissue and draining nodes", "states": [ "cDC1", "cDC2", "mature/migratory" ], "behaviors": [ "Antigen uptake", "cross-presentation", "priming", "migration" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-586", "hatton-1177" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-586", "hatton-1177" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-586", "hatton-1177" ], "priorResearch": { "path": "simulation/data/profiles/conventional-dendritic-cells.json", "summary": "Three things about this family are unusual and all three matter for how it is represented. It is rare: the CD103-positive cells that stimulate cytotoxic T cells are described as extremely sparse and yet remarkably capable, regressing tumours have more of them, T-cell-dependent clearance relies on them, and their transcript abundance correlates with human outcome (L76). Its abundance is set by another family: stimulatory dendritic cell numbers track intratumoral FLT3LG, which natural killer cells predominantly produce, and ablating those cells reduces the dendritic population (L78). And the act of doing its job switches on a regulatory programme - canonical type 1 and type 2 cells express an immunoregulatory module on uptake of tumour antigen, co-expressing PD-L1, PD-L2 and CD200 alongside CD40, CCR7 and IL-12, which is why type 1 cells are found in tumours that resist checkpoint blockade (L77). The fourth finding closes a gap the atlas has carried for three families: these cells traffic tumour antigen to lymph nodes via CCR7, present directly to T cells there, hand antigen to resident myeloid cells, and deleting CCR7 only in them causes defective priming and increased tumour outgrowth (L79).", "stateAxes": [ { "axis": "Abundance - of a cell that is rare and rate-limiting", "whatToMeasure": "A count per unit tissue of the stimulatory population, defined by its transcription-factor dependency rather than by a single surface marker, since clearance relies on these cells and regressing tumours have higher proportions of them.", "interpretationLimit": "Sparse is stated qualitatively in every record the atlas holds. No cell count per unit volume or per tumour exists anywhere, and the human outcome correlation is with transcript abundance rather than with a counted density - so the quantity the architectural argument depends on has not been measured.", "evidence": [ "L76" ] }, { "axis": "Antigen-bearing, and therefore regulatory", "whatToMeasure": "Whether the cell has taken up tumour antigen, together with the regulatory module - PD-L1, PD-L2, CD200 - rather than treating uptake and presenting capacity as separate variables, since the programme is induced by uptake.", "interpretationLimit": "Defined transcriptionally in human and mouse lung cancer, so the step from co-expressing these genes to being functionally less able to prime is inferred from the gene set plus an interleukin-4 blockade experiment rather than measured. No fraction of cells in the programme and no induction timing is given for any tumour.", "evidence": [ "L77" ] }, { "axis": "Migratory capacity - the same programme, read the other way", "whatToMeasure": "CCR7, and what it is being read for. It is required for antigen to reach the lymph node and for priming there, and deleting it in these cells alone increases tumour outgrowth; it is also listed among the maturation genes of the regulatory module.", "interpretationLimit": "Mouse melanoma for the causal deletion, human expression correlation for the clinical claim. The route is established as necessary without its capacity: no antigen flux, transit time, migration rate or number of cells making the journey is given. And the atlas's reading that migration and the regulatory state are one programme is an inference from two records, not a finding of either.", "evidence": [ "L79", "L77" ] }, { "axis": "Upstream dependency on natural killer cells", "whatToMeasure": "Natural killer cell frequency and FLT3LG expression alongside the dendritic count, because the two innate populations together correlated with anti-PD-1 responsiveness and with survival in human cancers.", "interpretationLimit": "Human evidence is association between expression signatures, response and survival; the causal ablation is mouse. No FLT3L concentration or transfer function from natural killer frequency to dendritic abundance exists, so the dependency cannot yet be given a coefficient.", "evidence": [ "L78" ] } ], "records": { "L76": { "id": "L76", "year": 2014, "topic": "Cellular and spatial atlas", "title": "Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity", "url": "https://doi.org/10.1016/j.ccell.2014.09.007", "studyType": "Multiple mouse tumour models with human tumour biopsies, transcription-factor dependency and outcome correlation, Cancer Cell 26(5):638-652", "diseaseContext": "Melanoma / Shared cancer", "useInModel": "Establishes that the rate-limiting antigen-presenting cell is rare, which is an architectural fact rather than a biological detail. Across multiple mouse tumour models and human tumour biopsies the intratumoral dendritic cell populations were delineated as distinct from macrophage populations, and within them the CD103-positive cells were described as extremely sparse and yet remarkably capable stimulators of cytotoxic T cells. They depend uniquely on the transcription factors IRF8, Zbtb46 and Batf3 and are generated by GM-CSF and FLT3L. Regressing tumours had higher proportions of them, T-cell-dependent immune clearance relied on them, and the abundance of their transcripts in human tumours correlated with clinical outcome. For this project the consequence is that the cell on which the whole T-cell arm depends is present in small numbers, so the system is sensitive to small-number stochasticity and a mean-field density cannot represent it - which is the clearest argument in this atlas for an agent-based rather than a continuum representation.", "limit": "Mouse models for the mechanism with human biopsies for the populations and transcript abundance for the outcome correlation, so the human evidence is expression-based rather than a counted density. Sparse is stated qualitatively - no cell count per unit volume or per tumour is given here or anywhere in this atlas, which is precisely the number the architectural argument needs.", "provenance": "Abstract read in full; the sparse-yet-capable description, the transcription factor and cytokine dependencies, and the outcome correlation as reported", "quantitativeExtraction": "extracted" }, "L77": { "id": "L77", "year": 2020, "topic": "Effector state", "title": "A conserved dendritic-cell regulatory program limits antitumour immunity", "url": "https://doi.org/10.1038/s41586-020-2134-y", "studyType": "Single-cell RNA sequencing in human and mouse non-small-cell lung cancer with mechanistic dissection and interleukin-4 blockade, Nature 580(7802):257-262", "diseaseContext": "Lung / Shared cancer", "useInModel": "The finding that forbids treating antigen uptake and presenting capacity as independent. In human and mouse non-small-cell lung cancer, a dendritic cell cluster was identified that co-expresses immunoregulatory genes - PD-L1, PD-L2 and CD200 - together with maturation genes including CD40, CCR7 and IL-12. The decisive observation is when it appears: the programme is expressed by canonical type 1 and type 2 dendritic cells upon uptake of tumour antigen. Acquiring the antigen is what switches on the regulatory state, so doing the job degrades the capacity to do it. Mechanistically PD-L1 upregulation is induced by the receptor tyrosine kinase AXL while IL-12 upregulation depends strictly on interferon-gamma and is negatively controlled by interleukin-4 - and blocking interleukin-4 enhanced IL-12 production by antigen-bearing cells, expanded the pool of tumour-infiltrating effector T cells and reduced tumour burden. The paradox the authors open with is the practical point: type 1 dendritic cells are found in tumours that resist checkpoint blockade, so presence of this family is not function.", "limit": "Non-small-cell lung cancer in human and mouse, with the intervention preclinical. The programme is defined transcriptionally, so the step from co-expressing regulatory genes to being functionally less able to prime is inferred from the gene set plus the interleukin-4 experiment rather than measured directly. No fraction of cells in the programme is given for any tumour, and no timing is given for how fast uptake induces it.", "provenance": "Abstract read in full; the gene co-expression, the uptake dependence, the AXL and interleukin-4 mechanisms and the blockade result as reported", "quantitativeExtraction": "extracted" }, "L78": { "id": "L78", "year": 2018, "topic": "Recruitment and synapse", "title": "A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments", "url": "https://doi.org/10.1038/s41591-018-0085-8", "studyType": "Human melanoma association analysis with mouse genetic and cellular ablation of natural killer cells, Nat Med 24(8):1178-1191", "diseaseContext": "Melanoma / Shared cancer", "useInModel": "Answers what sets the abundance of the rare cell, and the answer is another cell family. In human melanoma, stimulatory dendritic cell abundance was associated with intratumoral expression of FLT3LG, and that cytokine is predominantly produced by lymphocytes, notably natural killer cells, in both mouse and human tumours. Natural killer cells stably form conjugates with these dendritic cells in the mouse tumour microenvironment, and genetic and cellular ablation of natural killer cells reduced dendritic cell abundance through loss of FLT3L. The clinical reading is the valuable part: natural killer cell frequency correlated with protective stimulatory dendritic cells in human cancers, with patient responsiveness to anti-PD-1, and with increased overall survival - and the authors propose the two innate populations together as a prognostic tool for T-cell-directed immunotherapy. So a drug aimed at T cells is predicted by the abundance of two innate cell families, neither of which it targets.", "limit": "Human evidence is association between expression signatures, response and survival; the causal ablation is mouse. Conjugate formation is observed in mouse tumours. No FLT3L concentration, conjugate duration or dendritic cell density per unit tissue is given, so the dependency is established without a transfer function.", "provenance": "Abstract read in full; the FLT3LG association, the natural killer cell source, the ablation result and the three clinical correlations as reported", "quantitativeExtraction": "extracted" }, "L79": { "id": "L79", "year": 2016, "topic": "Transport", "title": "Critical role for CD103+/CD141+ dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma", "url": "https://doi.org/10.1016/j.ccell.2016.06.003", "studyType": "Mouse melanoma with cell-specific CCR7 deletion and live imaging in lymph nodes, plus human expression correlation, Cancer Cell 30(2):324-336", "diseaseContext": "Melanoma", "useInModel": "The transport mechanism this atlas has been missing for three families. Intratumoral dendritic cells bearing CD103 in mice or CD141 in humans traffic tumour antigen to lymph nodes, where they both stimulate CD8 T cells directly and hand antigen off to resident myeloid cells - and all of it requires CCR7. Live imaging demonstrated direct presentation to T cells in the node, and deleting CCR7 specifically in these cells produced defective lymph-node priming and increased tumour outgrowth, which isolates the transport step as the thing that matters rather than the cell's presence. In human tumours CCR7 expression correlates with CD141-positive dendritic cell signatures, with intratumoral T cells, and with better clinical outcomes. Three families in this atlas pointed at a lymphoid compartment outside the drawn environments - stem-like T cells found in blood, vesicular ligand acting in the draining node, and expanded clones of unidentified origin. This supplies the carrier, the receptor it needs, and the consequence of removing it.", "limit": "Mouse melanoma for the causal work with human expression correlation for the clinical claim. It establishes that the route exists and is necessary, not its capacity - no antigen flux, transit time, cell migration rate or number of cells making the journey is given. The lymph node itself remains outside the drawn environments, so the atlas now knows how material leaves without being able to represent where it goes.", "provenance": "Abstract read in full; the trafficking route, the hand-off, the CCR7 requirement, the live imaging, the deletion result and the human correlations as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I021", "name": "Plasmacytoid dendritic cells", "category": "Immune", "whereToCheck": "Context-dependent tissue and blood", "states": [ "Resting", "interferon-active" ], "behaviors": [ "Presence and interferon signaling" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "pdc-induced-il10" ], "priorResearch": { "path": "simulation/data/profiles/plasmacytoid-dendritic-cells.json", "summary": "The inventory asks for presence and interferon signalling, and the atlas can serve the first and not the second. In human ovarian carcinoma, functional cells of this family accumulated in the tumour microenvironment while functionally mature myeloid dendritic cells did not - and the two subsets produced opposite T-cell outcomes from the same ascites: macrophage-derived dendritic cells induced tumour-antigen-specific CD8 effectors, while this family induced interleukin-10-producing CD8 regulatory T cells that suppressed those effectors, could not have their effector function restored by restimulation, and carried functional CCR7 for migration to lymphoid tissue (L105). The second behaviour is the one this family is named for and the atlas has no measurement of it anywhere: no type I interferon concentration, output or interferon-active fraction in any environment. What it does have is a drug that acts on this family's pathway and was tested head to head against surgery - a topical toll-like receptor 7 agonist achieving 84% three-year clinical success against 98% for excision in 501 patients with low-risk basal-cell carcinoma (L106).", "stateAxes": [ { "axis": "Presence - served, and asymmetrically", "whatToMeasure": "Frequency of this family alongside that of mature myeloid dendritic cells, since the informative observation was an asymmetry: functional cells of this family accumulated in the tumour microenvironment where functionally mature myeloid dendritic cells did not.", "interpretationLimit": "Human patient material in one drawn environment, in a 2005 study predating single-cell resolution of these subsets, with no frequency given for either population. Identity rests on a consensus nomenclature, so any frequency carries its gating definition.", "evidence": [ "L105", "L92" ] }, { "axis": "Interferon-active against resting - the inventory's axis, entirely unserved", "whatToMeasure": "Type I interferon output per cell and local concentration, with the interferon-active fraction of the population - the state this family is named for.", "interpretationLimit": "Nothing in this atlas measures type I interferon anywhere, in any environment. What it holds nearby is a different interferon: the spread of interferon-gamma in melanoma, confined to 30 to 40 micrometres, which belongs to a different family and a different receptor and should not be substituted. The cytosolic DNA sensing recorded under DAMPs produces interferon output without that output being quantified either.", "evidence": [] }, { "axis": "What it instructs - a regulatory CD8 state the atlas does not carry", "whatToMeasure": "The induced population by its phenotype and its interleukin-10 production, separately from exhausted CD8 states - and separately again from its migratory capacity, since it carries functional CCR7.", "interpretationLimit": "Demonstrated by co-culture from patient material rather than in situ, so induction and suppression are ex vivo. The partial irreversibility - proliferation recoverable, effector function not - is the most model-relevant detail and is reported without a timescale. No frequency of the induced population in any environment.", "evidence": [ "L105" ] } ], "records": { "L105": { "id": "L105", "year": 2005, "topic": "Exclusion and signaling", "title": "Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma", "url": "https://doi.org/10.1158/0008-5472.CAN-04-4043", "studyType": "Dendritic cell and T cell co-culture from tumour ascites and tissue of patients with ovarian carcinoma, Cancer Res 65(12):5020-5026", "diseaseContext": "Ovarian (HGSC)", "useInModel": "Two dendritic cell subsets in the same human tumour producing opposite T-cell outcomes, and one of them produces a cell state this atlas does not carry. Functional plasmacytoid dendritic cells accumulated in the tumour microenvironment of patients with ovarian carcinoma while functionally mature myeloid dendritic cells did not. Macrophage-derived dendritic cells from tumour ascites induced tumour-antigen-specific CD8 T cells with effector function; plasmacytoid dendritic cells from the same ascites induced interleukin-10-positive CCR7-positive CD45RO-positive CD8 regulatory T cells. Four properties were established for those cells: their induction is independent of CD4-positive CD25-positive T cells; they suppress myeloid-dendritic-cell-mediated antigen-specific effector function through interleukin-10; repetitive myeloid dendritic cell stimulation recovers their poor proliferation but not their effector function; and they express functional CCR7 and migrate efficiently to a lymphoid homing chemokine. Primary suppressive cells of that phenotype were found in patients' tumours. A regulatory CD8 state is distinct from the exhausted states the CD8 family carries, the partial irreversibility on restimulation is a modelling constraint, and the CCR7 expression means suppression induced in the tumour can leave it.", "limit": "Human patient material in co-culture rather than in situ function, so the induction and suppression are demonstrated ex vivo. A 2005 study predating single-cell resolution of these subsets, and the dendritic cell categories used are those of the consensus nomenclature the atlas records as a convention (L92). No frequency of either dendritic subset or of the induced regulatory population is given for any environment.", "provenance": "Abstract read in full; the subset accumulation asymmetry, the opposite T-cell outcomes, all four properties of the induced regulatory cells and their presence in patient tumours as reported", "quantitativeExtraction": "extracted" }, "L92": { "id": "L92", "year": 2010, "topic": "Atlas resource", "title": "Nomenclature of monocytes and dendritic cells in blood", "url": "https://doi.org/10.1182/blood-2010-02-258558", "studyType": "Consensus nomenclature approved by the Nomenclature Committee of the International Union of Immunological Societies, Blood 116(16):e74-80", "diseaseContext": "Shared all", "useInModel": "Supplies the inventory's state axis for this family as a formal convention rather than a measurement. The document defines three types of monocytes - classical, intermediate and nonclassical - and three types of blood dendritic cell, plasmacytoid and two myeloid, in human and in mouse, and the classification was approved by the Nomenclature Committee of the International Union of Immunological Societies. So the three states the inventory names for this row are a committee's categories, and the same document covers two further rows in this atlas, for conventional and plasmacytoid dendritic cells. That matters for how a count should be read. This is now the third family in this atlas whose identity is governed by a consensus document because markers do not settle it - after the extracellular vesicle guideline (L41) and the suppressive myeloid standards (L89) - and the pattern is worth naming: where a standards document exists for a family, a density of it is a reported convention and not an observable, and should carry the definition it used.", "limit": "A nomenclature, not a measurement. It fixes categories and surface-marker definitions and supplies no frequency, no density and no functional property for any environment. A 2010 consensus, so later subset resolution by single-cell methods sits outside it, and categories defined by flow-cytometry gates are boundaries drawn on a continuum.", "provenance": "Abstract read in full; the three-and-three classification, the human and mouse scope and the committee approval as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "pdc-induced-il10" ] }, { "id": "I022", "name": "Monocytes", "category": "Immune", "whereToCheck": "Blood; newly infiltrated tissue", "states": [ "Classical/intermediate/nonclassical", "activated" ], "behaviors": [ "Adhesion", "migration", "differentiation" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-574", "hatton-575" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-574", "hatton-575" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "sender-I022-monocytes" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-574", "hatton-575", "sender-I022-monocytes" ], "priorResearch": { "path": "simulation/data/profiles/monocytes.json", "summary": "These are the only cells in the atlas that travel on the inside of vessels. Against the classical account of recruitment - rolling, recognition, extravasation - a subset patrols healthy tissue by long-range crawling on resting endothelium, dependent on the integrin LFA-1 and the chemokine receptor CX3CR1, and that patrolling is required for rapid tissue invasion when infection appears, after which the cells differentiate into macrophages (L93). Every other motile cell in this atlas moves through interstitium or along matrix. The subsets then point opposite ways: classical monocytes promote tumorigenesis and metastasis, while the patrolling subset is enriched in lung microvasculature and reduces metastasis there - mice specifically lacking it metastasise more, and transferring the cells back prevents invasion (L94). The mechanism includes something no family here covers, scavenging tumour material from inside the vasculature, and something that extends a chain: these cells recruit and activate natural killer cells, which set dendritic abundance, which primes the CD8 arm. The three states the inventory names are a committee's categories, formally defined and approved, which makes a subset frequency a reported convention rather than an observable (L92).", "stateAxes": [ { "axis": "Classical, intermediate, nonclassical - a committee's categories", "whatToMeasure": "Subset frequencies with the gating definition stated, since the categories are a formal nomenclature approved by an international committee rather than a discovered partition, and the same document also defines the dendritic cell rows of this atlas.", "interpretationLimit": "Gates on a continuum, fixed in 2010 before single-cell methods resolved the compartment further. The sensitivity is unusually consequential because the subsets have opposite effects on metastasis, so moving a gate moves cells between a promoting and a restraining pool. No frequency for any drawn environment is held.", "evidence": [ "L92", "L94" ] }, { "axis": "Patrolling - crawling on the luminal surface", "whatToMeasure": "Crawling on resting endothelium rather than transit through tissue: path length, velocity and surface coverage, with the LFA-1 and CX3CR1 dependency that the behaviour requires.", "interpretationLimit": "Mouse, healthy tissue and an acute infection model, and established qualitatively - no velocity, path length, dwell time or coverage is extracted into this atlas. The surface being crawled on is itself a disease variable, since the perfusable luminal proteome is remodelled tissue-specifically under systemic insult and has to be measured in the disease state.", "evidence": [ "L93", "V33" ] }, { "axis": "Differentiation - where this row hands over", "whatToMeasure": "Whether the cell has extravasated and differentiated, since patrolling cells that invade at a site of infection become macrophages - which is the transition from this family into the macrophage families.", "interpretationLimit": "Demonstrated in an infection model in mouse. The handover is exactly the recruited-against-resident boundary the atlas records as decided for the CNS by lineage and open elsewhere, so in liver or any tissue with a large resident population this axis cannot currently be resolved. No differentiation rate or transit time anywhere.", "evidence": [ "L93", "L94" ] }, { "axis": "Adhesion - named by the inventory, mechanistically served and unquantified", "whatToMeasure": "The adhesion state on the luminal surface, since adhesion is what makes the crawling possible and is also, in the neighbouring family, what makes a capillary block.", "interpretationLimit": "Two named molecules and no measurement. The contrast with the neutrophil family is the useful part and is also a caution: the same compartment and a similar adhesive step produce patrol in one cell type and obstruction in another, and the atlas has no quantity that would distinguish them.", "evidence": [ "L93", "L86" ] } ], "records": { "L86": { "id": "L86", "year": 2019, "topic": "Vascular transport", "title": "Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer's disease mouse models", "url": "https://doi.org/10.1038/s41593-018-0329-4", "studyType": "In vivo capillary flow imaging in APP/PS1 and 5xFAD mice with neutrophil-depleting antibody and behavioural testing, Nat Neurosci 22(3):413-420", "diseaseContext": "Alzheimer's", "useInModel": "The inventory lists vascular stalls among this family's locations and obstruction among its behaviours, and this is both, measured, with the consequence reversed. In two Alzheimer's mouse models an increased number of cortical capillaries had stalled blood flow compared with wild-type animals, largely because neutrophils had adhered within capillary segments and blocked them - and the authors state this accounts for the majority of the cortical blood flow reduction in both models, a reduction recognised in patients for decades without a mechanism. Administering antibodies against the neutrophil marker Ly6G reduced the number of stalled capillaries, producing both an immediate increase in blood flow and rapidly improved performance on spatial and working memory tasks. Three things make this unusually valuable here. The mechanism is physical - a single cell lodged in a single capillary segment - which is the kind of thing an agent-based spatial model represents natively and a continuum field cannot. The functional deficit was reversible on clearing the obstruction, so part of the dysfunction was not structural damage. And it gives this family a measured role in a drawn environment that is not a cancer.", "limit": "Two transgenic mouse models, and antibody-mediated depletion of a whole cell population rather than a selective block on adhesion - so the rescue shows that the cells cause the stalls, not that adhesion is the only contribution they make. Memory improvement is in rodent tasks over a short window. The stalled-capillary fraction and the size of the flow increase are in the paper's body and are not extracted into this atlas, which is the quantity a perfusion model would need.", "provenance": "Abstract read in full; the stall mechanism, the majority-of-reduction claim, the antibody rescue and the immediate flow and memory effects as reported. Stall fractions and flow magnitudes not extracted", "quantitativeExtraction": "extracted" }, "L92": { "id": "L92", "year": 2010, "topic": "Atlas resource", "title": "Nomenclature of monocytes and dendritic cells in blood", "url": "https://doi.org/10.1182/blood-2010-02-258558", "studyType": "Consensus nomenclature approved by the Nomenclature Committee of the International Union of Immunological Societies, Blood 116(16):e74-80", "diseaseContext": "Shared all", "useInModel": "Supplies the inventory's state axis for this family as a formal convention rather than a measurement. The document defines three types of monocytes - classical, intermediate and nonclassical - and three types of blood dendritic cell, plasmacytoid and two myeloid, in human and in mouse, and the classification was approved by the Nomenclature Committee of the International Union of Immunological Societies. So the three states the inventory names for this row are a committee's categories, and the same document covers two further rows in this atlas, for conventional and plasmacytoid dendritic cells. That matters for how a count should be read. This is now the third family in this atlas whose identity is governed by a consensus document because markers do not settle it - after the extracellular vesicle guideline (L41) and the suppressive myeloid standards (L89) - and the pattern is worth naming: where a standards document exists for a family, a density of it is a reported convention and not an observable, and should carry the definition it used.", "limit": "A nomenclature, not a measurement. It fixes categories and surface-marker definitions and supplies no frequency, no density and no functional property for any environment. A 2010 consensus, so later subset resolution by single-cell methods sits outside it, and categories defined by flow-cytometry gates are boundaries drawn on a continuum.", "provenance": "Abstract read in full; the three-and-three classification, the human and mouse scope and the committee approval as reported", "quantitativeExtraction": "extracted" }, "L93": { "id": "L93", "year": 2007, "topic": "Effector behavior", "title": "Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior", "url": "https://doi.org/10.1126/science.1142883", "studyType": "Direct in vivo examination of blood monocyte behaviour with integrin and chemokine receptor dependency, Science 317(5838):666-670", "diseaseContext": "Healthy reference", "useInModel": "A mode of movement the atlas has nothing else like. The classical account of leukocyte recruitment is a multistep process - transient rolling, recognition of inflammation, then extravasation. Examined directly in vivo, a subset of monocytes instead patrols healthy tissue by long-range crawling on resting endothelium, dependent on the integrin LFA-1 and the chemokine receptor CX3CR1, and that patrolling was required for rapid tissue invasion at a site of infection, where the cells initiated an early immune response and differentiated into macrophages. Every other motile cell in this atlas moves through interstitium or along matrix; this one travels on the luminal surface, which is a different geometry with a different set of constraints. It also makes the surface itself a disease variable, since the atlas already records that the perfusable luminal proteome is remodelled tissue-specifically under systemic insult and therefore has to be measured in the disease state (V33). And it sits against the neutrophil finding in the same compartment: one cell type crawls along the endothelium, another adheres and plugs it.", "limit": "Mouse, healthy tissue plus an acute infection model, and a behaviour established qualitatively - no crawling velocity, patrol path length, dwell time or surface coverage is extracted into this atlas. The dependency on two named molecules is demonstrated without a quantitative relationship to crawling, and nothing here is in a tumour or any drawn environment.", "provenance": "Abstract read in full; the crawling behaviour, its LFA-1 and CX3CR1 dependency, the requirement for rapid invasion and the differentiation outcome as reported", "quantitativeExtraction": "extracted" }, "L94": { "id": "L94", "year": 2015, "topic": "Metastatic niche", "title": "Patrolling monocytes control tumor metastasis to the lung", "url": "https://doi.org/10.1126/science.aac9407", "studyType": "Multiple mouse metastatic tumour models with subset-specific genetic ablation and adoptive transfer, Science 350(6263):985-990", "diseaseContext": "Lung / Shared cancer", "useInModel": "The two subsets of one family point opposite ways, and the genetics here are unusually clean. Classical monocytes promote tumorigenesis and metastasis; the nonclassical patrolling subset is enriched in the microvasculature of the lung and reduced metastasis to lung across multiple mouse models. Mice deficient in Nr4a1, which specifically lack the patrolling subset, showed increased lung metastasis, and transferring proficient patrolling cells into those mice prevented tumour invasion - ablation and rescue in the same system. The mechanism has three parts worth separating: the cells established early interactions with metastasising tumour cells, they scavenged tumour material from the lung vasculature, and they promoted natural killer cell recruitment and activation. The second of those is intravascular clearance, which no family in this atlas covers. The third extends a dependency chain: patrolling monocytes recruit natural killer cells, which supply the FLT3L that sets stimulatory dendritic cell abundance, which primes the CD8 arm - four families upstream of the one this category opened with.", "limit": "Mouse metastasis models throughout, with no human measurement of either subset in any drawn environment. Nr4a1 deficiency removes the subset and may do other things, though the transfer rescue substantially addresses that. No scavenging rate, interaction duration or subset frequency is given, and the lung enrichment is reported without a density.", "provenance": "Abstract read in full; the opposite subset effects, the ablation and transfer results, and all three mechanistic components as reported", "quantitativeExtraction": "extracted" }, "V33": { "id": "V33", "year": 2022, "topic": "Accessibility", "title": "Vascular proteome responses precede organ dysfunction in a murine model of Staphylococcus aureus bacteremia", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC9426442/", "studyType": "In vivo endothelial surface labelling across four organs with DIA mass spectrometry", "diseaseContext": "Healthy reference", "useInModel": "Says the luminal surface is not a fixed property. The perfusable vascular proteome is shared across organs at baseline and is remodelled tissue-specifically under systemic insult, ahead of organ dysfunction. What the endothelium displays therefore has to be measured in the disease state, not carried over from a healthy reference.", "limit": "Bacteraemia in mice, not tumour. It establishes that the luminal surface moves with disease, not how it moves in any of the drawn environments.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I023", "name": "Resident macrophages", "category": "Immune", "whereToCheck": "Organ-specific tissue niches", "states": [ "Homeostatic", "inflammatory", "repair-related" ], "behaviors": [ "Phagocytosis", "signaling", "matrix remodeling", "antigen handling" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-529", "hatton-732" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-529", "hatton-732" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "sender-I023-alveolar-macrophages" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-529", "hatton-732", "sender-I023-alveolar-macrophages" ], "priorResearch": { "path": "simulation/data/profiles/resident-macrophages.json", "summary": "The inventory places this family in organ-specific tissue niches, and the niche turns out to be the operative word in a strong sense: it writes the programme. Across seven tissue-resident populations, 12,743 macrophage-specific enhancers were identified and the landscapes differ beyond what developmental origin can explain - the environment shapes the chromatin of transplanted precursors, and even differentiated macrophages are reprogrammed when moved into a new microenvironment (L95). In liver that goes further: deplete the resident population and circulating monocytes engraft, gradually adopt the transcriptional profile of the cells they replaced, and become long-lived self-renewing cells, as they also do physiologically shortly after birth when niches open during organ growth (L96). So outside the central nervous system, origin does not determine identity. The qualification matters though: under acute erythrocyte stress, transient Tim-4-negative monocyte-derived iron-recycling macrophages sit alongside embryonically derived Tim-4-high resident cells doing a different job, and whether arriving monocytes take up that job is set by the organ - permitted in liver through Csf1 and suppressed in spleen through Csf2 (L97).", "stateAxes": [ { "axis": "Niche-imposed identity, not carried identity", "whatToMeasure": "The organ, and the tissue-specific transcription factors active in it, alongside any lineage marker - since enhancer landscapes differ between resident populations beyond what origin explains and differentiated cells can be reprogrammed by transfer.", "interpretationLimit": "Mouse, seven populations, healthy tissue, and chromatin state rather than function - a shared enhancer landscape does not establish that two cells do the same job. Reprogramming is shown to be possible without a timescale or a degree of completeness, and none of it is in a drawn environment.", "evidence": [ "L95" ] }, { "axis": "Niche occupancy against origin", "whatToMeasure": "Whether the niche is full, not where the occupant came from, since monocytes engrafting into an emptied liver niche become fully differentiated self-renewing resident cells and do the same during postnatal organ growth.", "interpretationLimit": "An artificial depletion model for the main result with postnatal growth as the physiological counterpart. Gradual adoption of a transcriptional profile is not demonstrated functional identity, and no engraftment rate, convergence time or niche capacity is given. The rule reverses in the CNS, where lineage does determine identity.", "evidence": [ "L96", "L84" ] }, { "axis": "Under stress the two origins separate again", "whatToMeasure": "Tim-4 alongside the functional marker, since transient Tim-4-negative monocyte-derived iron-recycling macrophages coexist with Tim-4-high resident cells in a stressed liver - and the organ's own cytokines decide whether arriving cells acquire the function.", "interpretationLimit": "Mouse models of haemolytic stress, not any drawn environment. It establishes that a steady-state rule does not hold under acute demand, which is the condition the drawn environments are in - so the simpler conclusion should not be carried into them without checking.", "evidence": [ "L97" ] }, { "axis": "Phagocytosis - served at last, as a mechanism", "whatToMeasure": "The clearance function with its downstream handoff: ingestion of stressed and senescent erythrocytes, differentiation into ferroportin-expressing cells, and iron delivery to hepatocytes - with the consequence of blocking it, which was kidney and liver damage.", "interpretationLimit": "No phagocytic rate per cell, erythrocyte flux or iron transfer quantity is extracted. This is the behaviour the atlas recorded as unserved for recruited macrophages and for microglia, and it is now served by mechanism in a third family and still by no number anywhere.", "evidence": [ "L97" ] } ], "records": { "L84": { "id": "L84", "year": 2010, "topic": "Cellular atlas", "title": "Fate mapping analysis reveals that adult microglia derive from primitive macrophages", "url": "https://doi.org/10.1126/science.1194637", "studyType": "In vivo lineage tracing and fate mapping with CSF-1 and CSF-1 receptor deficient mice, Science 330(6005):841-845", "diseaseContext": "Healthy reference", "useInModel": "Settles a boundary this atlas recorded as open, for brain at least. Postnatal haematopoietic progenitors do not significantly contribute to microglial homeostasis in the adult brain, and lineage tracing established that adult microglia derive from primitive myeloid progenitors arising before embryonic day eight - making them an ontogenically distinct population within the mononuclear phagocyte system rather than a tissue-adapted monocyte. So in brain the resident-against-recruited distinction is decidable by lineage rather than by marker panel, which is more than can be said for liver. The second finding has a consequence the atlas should carry across categories: microglia develop normally in mice lacking CSF-1 but are absent in CSF-1 receptor-deficient mice. The receptor is required and that ligand is not - and the receptor is the target of the one drug in this atlas that produced a dramatic response in a tumour driven by its ligand (L75). A CSF-1 receptor inhibitor therefore has an on-target effect on this family, which is a mechanism and a safety consideration rather than an off-target risk.", "limit": "Mouse fate mapping and knockout genetics in healthy development. It says postnatal progenitors do not maintain the population under homeostasis, not that no blood-derived cell ever enters a diseased or injured brain - which is the case the drawn neurodegenerative environments actually present, and which the atlas holds nothing on. The cross-category inference about the receptor inhibitor is this atlas's own reading from two records.", "provenance": "Abstract read in full; the absence of postnatal contribution, the pre-E8 origin, the ontogenic distinctness and the CSF-1 against CSF-1 receptor dependency as reported", "quantitativeExtraction": "extracted" }, "L95": { "id": "L95", "year": 2014, "topic": "Cell-state ecosystems", "title": "Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment", "url": "https://doi.org/10.1016/j.cell.2014.11.018", "studyType": "Four histone modifications profiled across seven tissue-resident macrophage populations with transplantation and transfer experiments, Cell 159(6):1312-1326", "diseaseContext": "Healthy reference", "useInModel": "Says the tissue writes the programme, and says it at the level of chromatin. Profiling four histone modifications across seven tissue-resident macrophage populations identified 12,743 macrophage-specific enhancers and established that these populations have distinct enhancer landscapes beyond what developmental origin can explain, with the regulatory networks formed by a combination of tissue-specific and lineage-specific transcription factors. The two experiments that matter most for this atlas are the transfer ones: the environment shaped the chromatin landscape of transplanted bone marrow precursors, and even already-differentiated macrophages were reprogrammed when moved into a new microenvironment. So identity here is not a property the cell carries in but one the niche imposes - which is the same conclusion the atlas reached for regulatory T cells from a different direction, where the tumour-resident cells resembled the resident cells of that normal tissue rather than activated cells from blood (L72).", "limit": "Mouse, seven populations, healthy tissue. Chromatin state and expression are not function, so a shared enhancer landscape does not establish that two cells do the same job. Reprogramming on transfer is demonstrated as possible without a timescale or a completeness - how far and how fast a transferred cell converges is not given, and no tissue here is a tumour or any drawn environment.", "provenance": "Abstract read in full; the enhancer count, the beyond-origin claim, the combined transcription factor networks and both transfer results as reported", "quantitativeExtraction": "extracted" }, "L96": { "id": "L96", "year": 2016, "topic": "Cellular atlas", "title": "Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells", "url": "https://doi.org/10.1038/ncomms10321", "studyType": "Diphtheria-toxin depletion of liver-resident macrophages to create niche availability, with transcriptional profiling and postnatal growth analysis, Nat Commun 7:10321", "diseaseContext": "Healthy reference", "useInModel": "Resolves, for liver, the boundary this atlas recorded as open - and resolves it the opposite way to brain. Self-renewing tissue-resident macrophages had been thought to derive exclusively from embryonic progenitors. Depleting the liver-resident population to make the niche available showed that circulating monocytes engraft, gradually adopt the transcriptional profile of the cells they replaced, and become long-lived self-renewing cells. The same thing happens physiologically: circulating monocytes contribute to the expanding macrophage pool shortly after birth, when niches open during normal organ growth. The authors' conclusion is that monocytes can and do give rise to self-renewing tissue-resident macrophages if the niche is available. So in liver, origin does not determine identity - niche occupancy does. Set against the brain evidence, where adult microglia derive from pre-embryonic-day-eight progenitors and postnatal haematopoietic progenitors do not contribute (L84), the resident-against-recruited question turns out to be two different questions with two different answers rather than one question with a missing answer.", "limit": "Mouse, and a depletion model that creates niche availability artificially - the postnatal growth observation is the physiological counterpart and is a narrower claim. Adopting a transcriptional profile gradually is not the same as being functionally identical, and the companion record shows that under erythrocyte stress monocyte-derived and embryonically derived liver macrophages coexist and differ (L97). No engraftment rate, convergence time or niche capacity is given.", "provenance": "Abstract read in full; the engraftment, profile adoption, self-renewal, postnatal contribution and the niche-availability conclusion as reported", "quantitativeExtraction": "extracted" }, "L97": { "id": "L97", "year": 2016, "topic": "Chemistry and metabolism", "title": "On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver", "url": "https://doi.org/10.1038/nm.4146", "studyType": "Mouse models of hemolytic anemia, anemia of inflammation and sickle cell disease with recruitment inhibition, Nat Med 22(8):945-951", "diseaseContext": "Healthy reference", "useInModel": "Serves the phagocytosis behaviour this atlas has twice recorded as unserved, with a physiological job and a cost for blocking it - and it complicates the niche conclusion in a useful way. Ly6C-high monocytes ingest stressed and senescent erythrocytes, accumulate in the liver through coordinated chemotactic cues, and differentiate into ferroportin-expressing macrophages that deliver iron to hepatocytes. Those monocyte-derived cells are transient and Tim-4-negative, and they reside alongside the embryonically derived Tim-4-high resident population rather than replacing it - so in the intact organ under stress the two origins coexist, are distinguishable by a marker, and do different jobs. Whether arriving monocytes acquire the function is set by the organ: the liver permits it through Csf1, and the spleen recruits the same iron-loaded monocytes but suppresses the differentiation through Csf2. And blocking the recruitment during stressed erythrocyte delivery caused kidney and liver damage, which makes this an influx that is protective rather than a brake to be removed.", "limit": "Mouse models of haemolytic stress rather than any drawn environment, and the iron handling is a systemic physiological function rather than a tumour or neurodegenerative mechanism. No phagocytic rate per cell, no erythrocyte flux and no iron transfer quantity is extracted here - the behaviour is served as a mechanism with a consequence, not as a number.", "provenance": "Abstract read in full; the monocyte route, the transient Tim-4-negative population alongside the resident one, the Csf1 and Csf2 organ difference and the damage on recruitment inhibition as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I024", "name": "Recruited tumor-associated macrophages", "category": "Immune", "whereToCheck": "Cancer tissues", "states": [ "Multiple transcriptional/functional states" ], "behaviors": [ "Recruitment", "suppression or support", "phagocytosis", "spatial niches" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [], "priorResearch": { "path": "simulation/data/profiles/recruited-tumor-associated-macrophages.json", "summary": "This family turns out to sit upstream of the T-cell families this category started with. Macrophage-derived CXCL9 and CXCL10 are required for antitumour immune responses (L07); the selective intratumoral depletion of regulatory T cells that co-defines anti-CTLA-4 efficacy requires Fc-gamma-receptor-expressing macrophages to be present (L70); and the myeloid-derived suppressor recruitment driven by complement acts on the CD8 response (L33). The states to resolve are not the conventional ones: macrophage polarity defined by CXCL9 and SPP1 expression, and explicitly not by M1 and M2 markers, carried a strong prognostic association across 52 carcinomas and identified a coordinated, spatially organised network of pro- or antitumour variables involving every tumour-associated cell type (L73). The inventory had already avoided the M1/M2 framing by asking for multiple transcriptional and functional states. And the same functional state wears different markers in different cancers - pro-angiogenic macrophages were characterised by diverse markers across 15 tumour types (L74) - so a panel for this family cannot be shared between the drawn environments.", "stateAxes": [ { "axis": "Polarity, as a two-gene ratio rather than M1 against M2", "whatToMeasure": "CXCL9 and SPP1 expression as a polarity variable, since that definition carried a strong prognostic association where conventional polarisation markers did not, and since it identified a coordinated network across every other cell type and was spatially organised.", "interpretationLimit": "Established across 52 head and neck carcinomas, outside the drawn set, by a design that examines variation between tumours - so the coordination is between-tumour and the polarity is not shown to cause the network. No ratio value, threshold or spatial length scale is extracted into this atlas, which is what would be needed to use it.", "evidence": [ "L73", "L07" ] }, { "axis": "Functional state, with markers that do not transfer", "whatToMeasure": "The functional state - pro-angiogenic, suppressive, supportive - together with the markers that identify it in that specific tumour type, because the same state is marked differently across cancers.", "interpretationLimit": "A transcriptional atlas across 15 cancer types with 210 patients, so states are defined by expression rather than function and per-type numbers are modest. It establishes that panels are environment-specific without supplying the panel for any of the drawn set.", "evidence": [ "L74" ] }, { "axis": "Dependence on CSF1 signalling - not the same as abundance", "whatToMeasure": "Whether the tumour's biology is driven by the ligand for this family's survival receptor, rather than whether the family is abundant - since inhibiting that receptor produced 39% response against 0% on placebo in a tumour that overexpresses the ligand.", "interpretationLimit": "The trial is in a rare locally aggressive neoplasm driven by CSF1 overexpression, not among the drawn set and not representative of them. Nothing in this atlas establishes what the same axis does where macrophage abundance is a microenvironment feature rather than the driving lesion. The axis is also dose-limited by hepatotoxicity.", "evidence": [ "L75" ] }, { "axis": "Fc receptor availability - a requirement for someone else's drug", "whatToMeasure": "Local Fc-gamma-receptor-expressing macrophage content, because selective intratumoral depletion of regulatory T cells by anti-CTLA-4 requires it and happens in trans.", "interpretationLimit": "Mouse melanoma with engineered antibody variants, which isolates the dependency and does not quantify it. No density threshold for the effect exists, which is the quantity the finding implies and the reason this family cannot yet be joined to I013 numerically.", "evidence": [ "L70" ] } ], "records": { "L07": { "id": "L07", "year": 2020, "topic": "Accessibility", "title": "Macrophage-derived CXCL9 and CXCL10 are required for antitumor immune responses following immune checkpoint blockade", "url": "https://doi.org/10.1158/1078-0432.CCR-19-1868", "studyType": "Mouse tumour models with depletion and receptor knockout, Clin Cancer Res 26(2):487-504", "diseaseContext": "Shared cancer", "useInModel": "Names the axis that brings effector T cells in and the cell that supplies it. CXCL9 and CXCL10 rose markedly after dual PD-1 and CTLA-4 blockade, and both CD8 infiltration and therapeutic benefit were CXCR3-dependent. Macrophages were the predominant source of CXCL9, and depleting them abolished both the infiltration and the efficacy - so the recruiting signal for the T cell comes from a myeloid cell rather than from the tumour.", "limit": "Mouse models with human correlation only through biopsy expression. Whether the axis is required for entry or chiefly for function inside the tumour is contested: other work reports CXCR3 and CXCL9 critical for a productive response under anti-PD-1 without being required for infiltration itself.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "L70": { "id": "L70", "year": 2013, "topic": "Local costimulation", "title": "Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma", "url": "https://doi.org/10.1084/jem.20130579", "studyType": "Mouse melanoma models with Fc-variant antibodies and macrophage dependency testing, J Exp Med 210(9):1695-1710", "diseaseContext": "Melanoma / Shared cancer", "useInModel": "Says a checkpoint antibody's effect on this family depends on a different immune family being present in the same tissue. The accepted model of anti-CTLA-4 was blockade of an inhibitory receptor on both effector and regulatory T cells; what the authors demonstrate instead is that the activity on the regulatory compartment is selective depletion of those cells within tumour lesions, and that the depletion requires Fc-gamma-receptor-expressing macrophages to be present in the tumour microenvironment. Regulatory cells are therefore depleted in trans, in a context-dependent way. For this atlas the consequence is structural rather than pharmacological: the efficacy of an antibody aimed at one cell family is a function of the local content of another, which means the macrophage families cannot be left out of any model of checkpoint response, and the same drug should be expected to behave differently in tissues with different myeloid composition.", "limit": "Mouse melanoma models with engineered antibody variants, which is how the Fc dependency could be isolated and also why the magnitude does not transfer. It establishes that depletion co-defines efficacy, not what fraction of the clinical effect it accounts for in people. No macrophage density threshold for the effect is given, which is the quantity the finding implies.", "provenance": "Abstract read in full; the selective intratumoral depletion, the Fc-gamma-receptor macrophage requirement and the in trans framing as reported", "quantitativeExtraction": "extracted" }, "L73": { "id": "L73", "year": 2023, "topic": "Cell-state ecosystems", "title": "CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers", "url": "https://doi.org/10.1126/science.ade2292", "studyType": "Tumour-to-tumour variation analysis across 52 head and neck squamous cell carcinomas with spatial analysis and extension to other indications, Science 381(6657):515-524", "diseaseContext": "Shared cancer", "useInModel": "The most useful single finding for a project that has to set many parameters per environment, because it says they may not be independent. Studying variation between tumours rather than within them across 52 head and neck carcinomas, macrophage polarity defined by CXCL9 and SPP1 expression - and explicitly not by conventional M1 and M2 markers - carried a notably strong prognostic association. That polarity then identified a highly coordinated network of either pro-tumour or antitumour variables which involved every tumour-associated cell type and was spatially organised, and the finding extended to other cancer indications. Two consequences. The conventional polarisation axis is ruled out as the informative one, which the inventory had already avoided by asking for multiple transcriptional and functional states instead. And the microenvironment behaves as a coordinated whole with a low-dimensional organising variable, which means a simulation of one of the drawn environments may need to set a dominant axis rather than dozens of independent knobs - and that this family carries it.", "limit": "Fifty-two head and neck squamous cell carcinomas for the primary analysis, a cancer outside the drawn set, with extension to other indications reported rather than detailed here. The design examines tumour-to-tumour variation, so the coordination it finds is between tumours and is not a demonstration that the polarity causes the network. No ratio value, threshold or spatial length scale is extracted into this atlas.", "provenance": "Abstract read in full; the two-gene definition, the exclusion of M1/M2 markers, the coordinated-network and spatial-organisation claims as reported", "quantitativeExtraction": "extracted" }, "L74": { "id": "L74", "year": 2021, "topic": "Cellular and spatial atlas", "title": "A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells", "url": "https://doi.org/10.1016/j.cell.2021.01.010", "studyType": "Single-cell analysis of myeloid cells from 210 patients across 15 human cancer types, Cell 184(3):792-809", "diseaseContext": "Shared cancer", "useInModel": "Establishes that a marker panel for this family cannot be shared between environments. Across 210 patients and 15 cancer types, tumour-infiltrating myeloid cells showed distinct features by cancer type, and the decisive detail for this atlas is that pro-angiogenic tumour-associated macrophages were characterised by diverse markers across different cancer types - the same functional state, different markers, depending on where it is. So each of the drawn environments needs its own panel for a state the atlas would otherwise describe once. The composition of the myeloid compartment was also associated with features of somatic mutations and gene expression, which links this family to the tumour genotype rather than only to the tissue. Two side findings land in other families: mast cells in nasopharyngeal cancer associated with better prognosis and an antitumour phenotype at a high ratio of TNF-positive to VEGFA-positive cells, which is a hook for I027, and the comparison of cDC1- against cDC2-derived LAMP3-positive dendritic cells, which is one for I020.", "limit": "Fifteen cancer types with 210 patients, so per-type numbers are modest and the drawn set are unevenly represented. It is a transcriptional atlas: states are defined by expression rather than by function, and no density, flux or functional assay attaches to any state. The association with somatic mutation features is correlational.", "provenance": "Abstract read in full; cohort size, the diverse-markers finding, the mutation association and the two side findings as reported", "quantitativeExtraction": "extracted" }, "L75": { "id": "L75", "year": 2019, "topic": "Clinical outcome", "title": "Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial", "url": "https://doi.org/10.1016/S0140-6736(19)30764-0", "studyType": "Randomised double-blind phase 3, 120 patients, CSF1 receptor inhibitor against placebo, Lancet 394(10197):478-487", "diseaseContext": "Shared cancer", "useInModel": "The distinguishing case this atlas needed, because here the drug worked and the reason is identifiable. Tenosynovial giant cell tumour overexpresses colony-stimulating factor 1 - the ligand for this family's principal survival receptor is the driving lesion. Inhibiting that receptor produced overall response at week 25 in 39% of patients against 0% on placebo, an absolute difference of 39% with an interval of 27 to 53 and a p-value below 0.0001, in 120 randomised patients. The principle to carry is the contrast: targeting a cell family is potent where that family's growth factor is the lesion, which is not the same situation as a solid tumour in which macrophages are merely abundant. The trial also carries a cost term - enrolment was stopped six patients short of target because of mixed or cholestatic hepatotoxicity, with serious adverse events in 13% against 2% - so the axis is both potent and dose-limited.", "limit": "A rare, locally aggressive neoplasm driven by CSF1 overexpression, not among the drawn set and not representative of them. Response at 25 weeks by imaging criteria in a disease where surgery is standard. Nothing here establishes what the same axis does where macrophage abundance is a feature of the microenvironment rather than the driving lesion, and this atlas holds no record on that question.", "provenance": "Abstract read in full; the CSF1 overexpression rationale, response rates with interval, enrolment stoppage and adverse event rates as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I025", "name": "Suppressive myeloid populations", "category": "Immune", "whereToCheck": "Cancer blood and tissue", "states": [ "Monocytic and granulocytic candidates" ], "behaviors": [ "Functional suppression assay", "avoid identity from markers alone" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [], "priorResearch": { "path": "simulation/data/profiles/suppressive-myeloid-populations.json", "summary": "This is the only row in the inventory whose behaviours field is an instruction rather than a list: functional suppression assay, avoid identity from markers alone. The field agrees in print - its own consensus communication states that phenotypic, morphological and functional heterogeneity generates confusion in investigating these cells, and responds with characterization standards rather than a marker definition (L89). The best-evidenced suppressive mechanism bears that out, because it identifies the cells by what they do: a subpopulation of mature tumour-associated myeloid cells expresses arginase I together with a high-affinity arginine transporter, depletes extracellular L-arginine, and thereby blocks re-expression of the T-cell receptor CD3-zeta chain and antigen-specific proliferation - while tumour cells and infiltrating lymphocytes do neither (L90). Recruitment into the tumour is driven in part by complement, through C5a and its receptor, with the suppressive capacity amplified through reactive oxygen and nitrogen species (L33). And the capacity is reducible in people: adding all-trans retinoic acid to ipilimumab lowered the circulating frequency of these cells and turned down their suppressive programme, safely, in advanced melanoma (L91).", "stateAxes": [ { "axis": "Suppressive function - the axis the inventory asks for by name", "whatToMeasure": "An assayed suppression capacity, reported with the myeloid compartments the cells were drawn from, rather than a marker-defined frequency. The retinoid trial is the model: mixed lymphocyte reaction for function, with expression of PD-L1, interleukin-10 and indoleamine 2,3-dioxygenase alongside it.", "interpretationLimit": "The functional measurements the atlas holds are in vitro, and the only in-patient change is a circulating frequency rather than a function. No suppressive function assay paired with a tissue density exists for any environment here, which is the same absence recorded for regulatory T cells.", "evidence": [ "L91", "L89" ] }, { "axis": "Arginine depletion - a consumption term, not a ligand output", "whatToMeasure": "Arginase I and the cationic amino acid transporter on mature myeloid cells, and the extracellular L-arginine concentration around them - since the suppression is depletion of a shared substrate and its consequence is failure to rebuild CD3-zeta.", "interpretationLimit": "Mouse lung carcinoma for the mechanism, with human evidence limited to high arginase I in patient tumour samples and no L-arginine concentration measured in any human tissue. Depletion was shown in vitro, so the in vivo depletion zone and its extent are inferred - no concentration, consumption rate or diffusion length is given anywhere.", "evidence": [ "L90" ] }, { "axis": "Monocytic against granulocytic - which the atlas has decided not to split", "whatToMeasure": "Which myeloid compartments a suppression measurement pools, rather than a subset identity. The granulocytic arm is largely the same cells as the neutrophil family by surface marker and the monocytic arm overlaps monocytes and macrophages.", "interpretationLimit": "The boundary is now recorded as decided in the atlas's meta file: suppressive capacity is carried as a functional state on the myeloid compartments rather than as a separate population. The threshold is unset, and the neighbouring family has no measured density in any tumour either, so the overlap could not be resolved by subtraction even in principle.", "evidence": [ "L89", "L88" ] } ], "records": { "L88": { "id": "L88", "year": 2014, "topic": "Clinical outcome", "title": "Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis", "url": "https://doi.org/10.1093/jnci/dju124", "studyType": "Systematic review and random-effects meta-analysis of 100 studies comprising 40,559 patients, J Natl Cancer Inst 106(6):dju124", "diseaseContext": "Shared cancer", "useInModel": "This family's validated human quantity, and it is measured in blood rather than in tissue. Across 100 studies and 40,559 patients with solid tumours, at a median cutoff of 4, a neutrophil-to-lymphocyte ratio above the cutoff carried a hazard ratio for overall survival of 1.81 with a confidence interval of 1.67 to 1.97 - and the effect was observed in all disease subgroups, all sites and all stages. Secondary endpoints moved the same way: 1.61 for cancer-specific survival, 1.63 for progression-free and 2.27 for disease-free survival. The consistency across sites and stages is what makes it useful and also what makes it awkward for this project: a simulation of a tumour volume cannot produce this number at all, because it is a ratio of two circulating populations. Set against the density score of I011 - CD3 and CD8 counted in two spatial compartments of the tumour - the contrast is instructive. The T-cell family's best-validated human measurement is spatial and inside the modelled volume; this family's is systemic and outside it.", "limit": "A meta-analysis of observational studies with a median rather than a standardised cutoff, so the threshold is a convention across heterogeneous studies rather than a biologically derived value, and publication bias cannot be excluded. It is prognostic and not predictive of any therapy. Most importantly it is an association between a blood ratio and survival, which says nothing about what either cell population is doing in any tissue.", "provenance": "Abstract read in full; study and patient counts, the median cutoff, and all four hazard ratios with the overall-survival interval as reported", "quantitativeExtraction": "extracted" }, "L89": { "id": "L89", "year": 2016, "topic": "Atlas resource", "title": "Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards", "url": "https://doi.org/10.1038/ncomms12150", "studyType": "Multi-author field consensus on nomenclature and characterization standards, Nat Commun 7:12150", "diseaseContext": "Shared cancer", "useInModel": "The field saying in print what this inventory's row already says: these cells cannot be identified from markers. The authors note that phenotypic, morphological and functional heterogeneity generates confusion in the investigation and analysis of these cells' roles, in a literature producing more than 500 papers in a single year, and their response is to propose characterization standards rather than a marker definition. That is the same move the extracellular vesicle field made with its own guideline (L41), and it has the same consequence here: a density of this family is not a meaningful quantity unless the assay and the functional demonstration are stated alongside it. The inventory's behaviours field for this row reads, unusually, as instruction - functional suppression assay, avoid identity from markers alone - which makes it the only row in 110 that tells the reader how to measure rather than what to measure.", "limit": "A consensus communication, not a measurement. It constrains how claims about this family may be stated and supplies no quantity for any environment. Standards proposed in 2016 for a fast-moving field, and the confusion it describes is not resolved by describing it.", "provenance": "Abstract read in full; the heterogeneity problem, the literature volume and the standards-rather-than-definition response as reported", "quantitativeExtraction": "extracted" }, "L90": { "id": "L90", "year": 2004, "topic": "Chemistry and metabolism", "title": "Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses", "url": "https://doi.org/10.1158/0008-5472.CAN-04-0465", "studyType": "Mouse lung carcinoma model with transporter and depletion assays, arginase inhibition in vivo, and human tumour samples, Cancer Res 64(16):5839-5849", "diseaseContext": "Lung / Shared cancer", "useInModel": "The suppression mechanism turns out to be substrate depletion rather than signalling, which makes it a different kind of model object entirely - a consumption term. A subpopulation of mature tumour-associated myeloid cells expressed high arginase I while tumour cells and infiltrating lymphocytes did not, appearing in the tumour by day seven. Those cells also expressed high levels of cationic amino acid transporter 2B, letting them rapidly take up L-arginine and deplete it from the extracellular space. The depletion blocked re-expression of the T-cell receptor CD3-zeta chain in stimulated T cells and inhibited antigen-specific proliferation, an arginase inhibitor blocked tumour growth in vivo, and high arginase I was also found in tumour samples from patients with non-small-cell carcinoma. Two consequences for this project. The mechanism hits the receptor complex that I079 is built around - suppression here is a shortage of the material needed to rebuild CD3-zeta, not a signal through an inhibitory receptor. And a consumer creating a depletion zone around itself is formally the same problem as the oxygen diffusion-consumption work this project already built a solver and an analytic check for, so that tooling transfers directly to a quantity the atlas has never applied it to.", "limit": "A mouse lung carcinoma model for the mechanism, with human evidence limited to arginase I being present at high levels in patient tumour samples - not to a measured L-arginine concentration in any human tissue. Depletion was demonstrated in vitro, so the in vivo depletion zone and its spatial extent are inferred rather than measured, and no concentration, consumption rate or diffusion length is given. Arginase inhibition in vivo is a whole-animal intervention and does not isolate the intratumoral depletion as the operative mechanism.", "provenance": "Abstract read in full; the cell subpopulation, the day-seven timing, the transporter, the depletion and CD3-zeta result, the inhibitor effect and the human samples as reported", "quantitativeExtraction": "extracted" }, "L91": { "id": "L91", "year": 2018, "topic": "Clinical PK and response", "title": "Targeting myeloid-derived suppressor cells using all-trans retinoic acid in melanoma patients treated with ipilimumab", "url": "https://doi.org/10.1016/j.intimp.2018.08.007", "studyType": "Randomised phase 2 of ipilimumab with or without all-trans retinoic acid in advanced melanoma, with flow cytometry, qPCR and mixed lymphocyte reactions, Int Immunopharmacol 63:282-291", "diseaseContext": "Melanoma", "useInModel": "A randomised trial in a drawn environment that moved this family's pharmacodynamics, which is rare enough to record carefully. Patients with advanced melanoma received ipilimumab alone or with all-trans retinoic acid. In vitro the retinoid decreased the immunosuppressive function of these cells in mixed lymphocyte reaction and reduced their expression of PD-L1, interleukin-10 and indoleamine 2,3-dioxygenase. In patients, adding it significantly decreased the frequency of circulating suppressive myeloid cells compared with ipilimumab alone, without increasing grade 3 or 4 adverse events. So the target can be reduced in people and its suppressive programme can be turned down, with a functional assay rather than a marker count behind the functional claim - which is what the inventory's row asks for. This report presents the pharmacodynamic and safety results and no clinical efficacy outcome, and that is stated here rather than filled in.", "limit": "A randomised phase 2 whose reported endpoints are pharmacodynamic and safety; no clinical efficacy result appears in this report, and the atlas should not infer one in either direction. The frequency reduction is in circulating cells, not in tumour. The functional decrease was shown in vitro and the gene-expression changes by quantitative PCR, so the in-patient functional consequence is inferred from the frequency change.", "provenance": "Abstract read in full; the in vitro functional and gene-expression results, the circulating frequency reduction and the safety finding as reported. Absence of a clinical efficacy result noted as such", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I026", "name": "Neutrophils", "category": "Immune", "whereToCheck": "Blood; inflamed tissue; vascular stalls", "states": [ "Activated", "aged", "NET-associated" ], "behaviors": [ "Trafficking", "degranulation", "extracellular traps", "obstruction" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-566", "hatton-567", "hatton-423" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-566", "hatton-567", "hatton-423" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "sender-I026-neutrophils" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-566", "hatton-567", "hatton-423", "sender-I026-neutrophils" ], "priorResearch": { "path": "simulation/data/profiles/neutrophils.json", "summary": "This is the only Immune family whose headline behaviour is mechanical, and the inventory said so - it lists vascular stalls among the places to look and obstruction among the behaviours to check. Both turn out to be real and measured: in two Alzheimer's mouse models, neutrophils adhered within cortical capillary segments and blocked them, accounting for the majority of the cortical blood flow reduction that had been recognised in patients for decades without a mechanism - and depleting the cells reduced the stalls, raised blood flow immediately and rapidly improved spatial and working memory (L86). The second behaviour the inventory names, extracellular traps, turns out to be a chemotactic ligand rather than a trap: trap DNA attracts cancer cells through the transmembrane receptor CCDC25 and the ILK-beta-parvin pathway, traps are abundant in human liver metastases from breast and colon cancer, and serum traps predict liver metastasis in early-stage breast cancer (L87). And the family's validated human quantity sits in blood: a neutrophil-to-lymphocyte ratio above a median cutoff of 4 carries a hazard ratio of 1.81 for overall survival across 40,559 patients, in every disease subgroup, site and stage (L88).", "stateAxes": [ { "axis": "Obstructing - a position and an adhesion state, not an expression level", "whatToMeasure": "The fraction of capillary segments stalled and the fraction of stalls attributable to an adherent cell, since that accounted for the majority of the blood flow reduction in two models and reversed on depletion.", "interpretationLimit": "Two transgenic mouse models of one disease, with whole-population antibody depletion rather than a selective adhesion block - so the cells are shown to cause the stalls without adhesion being isolated as their only contribution. The stalled fraction and the magnitude of the flow increase are in the source's body and are not extracted here, which is precisely what a perfusion model would need.", "evidence": [ "L86" ] }, { "axis": "Trap-associated - and the trap is a ligand", "whatToMeasure": "Extracellular trap DNA as a chemotactic ligand, in tissue and in serum, together with its receptor on the cancer cell - since serum traps predicted liver metastasis in early-stage breast cancer and receptor expression on primary tumour cells tracked poor prognosis.", "interpretationLimit": "Human evidence is abundance, a serum predictive association and a receptor prognostic association; causality is mouse and knockout. No trap density, DNA concentration or gradient length scale is given - and this atlas has repeatedly found that a chemotactic claim without a length scale cannot be used in a spatial model.", "evidence": [ "L87" ] }, { "axis": "Systemic abundance - the validated quantity, and it is outside the tissue", "whatToMeasure": "The blood neutrophil-to-lymphocyte ratio, which above a median cutoff of 4 carries a hazard ratio of 1.81 for overall survival across 40,559 patients in every subgroup, site and stage.", "interpretationLimit": "Observational meta-analysis with a cutoff that is a convention across heterogeneous studies rather than a biologically derived threshold, prognostic rather than predictive, and an association between a blood ratio and survival that says nothing about what either population is doing in any tissue. A simulation of a tumour volume cannot produce this number at all.", "evidence": [ "L88" ] }, { "axis": "Aged - named by the inventory, entirely unserved", "whatToMeasure": "The circadian and maturational state of the circulating pool, which is what the inventory's aged state refers to and which would bear on both adhesion propensity and trap formation.", "interpretationLimit": "Nothing in this atlas addresses it. The aged state is named, is known to change adhesion and trapping behaviour in the broader literature, and has no record here - which also means the blood ratio the family is scored on is a count with no state attached.", "evidence": [] } ], "records": { "L86": { "id": "L86", "year": 2019, "topic": "Vascular transport", "title": "Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer's disease mouse models", "url": "https://doi.org/10.1038/s41593-018-0329-4", "studyType": "In vivo capillary flow imaging in APP/PS1 and 5xFAD mice with neutrophil-depleting antibody and behavioural testing, Nat Neurosci 22(3):413-420", "diseaseContext": "Alzheimer's", "useInModel": "The inventory lists vascular stalls among this family's locations and obstruction among its behaviours, and this is both, measured, with the consequence reversed. In two Alzheimer's mouse models an increased number of cortical capillaries had stalled blood flow compared with wild-type animals, largely because neutrophils had adhered within capillary segments and blocked them - and the authors state this accounts for the majority of the cortical blood flow reduction in both models, a reduction recognised in patients for decades without a mechanism. Administering antibodies against the neutrophil marker Ly6G reduced the number of stalled capillaries, producing both an immediate increase in blood flow and rapidly improved performance on spatial and working memory tasks. Three things make this unusually valuable here. The mechanism is physical - a single cell lodged in a single capillary segment - which is the kind of thing an agent-based spatial model represents natively and a continuum field cannot. The functional deficit was reversible on clearing the obstruction, so part of the dysfunction was not structural damage. And it gives this family a measured role in a drawn environment that is not a cancer.", "limit": "Two transgenic mouse models, and antibody-mediated depletion of a whole cell population rather than a selective block on adhesion - so the rescue shows that the cells cause the stalls, not that adhesion is the only contribution they make. Memory improvement is in rodent tasks over a short window. The stalled-capillary fraction and the size of the flow increase are in the paper's body and are not extracted into this atlas, which is the quantity a perfusion model would need.", "provenance": "Abstract read in full; the stall mechanism, the majority-of-reduction claim, the antibody rescue and the immediate flow and memory effects as reported. Stall fractions and flow magnitudes not extracted", "quantitativeExtraction": "extracted" }, "L87": { "id": "L87", "year": 2020, "topic": "Metastatic niche", "title": "DNA of neutrophil extracellular traps promotes cancer metastasis via CCDC25", "url": "https://doi.org/10.1038/s41586-020-2394-6", "studyType": "Human metastasis and serum analysis with mouse metastasis models and receptor knockout, Nature 583(7814):133-138", "diseaseContext": "Breast / Colorectal / Shared cancer", "useInModel": "Turns extracellular DNA from something that gets sensed into something that gets followed, with a named receptor and human measurements. Neutrophil extracellular traps were abundant in the liver metastases of patients with breast and colon cancers, and serum traps predicted the occurrence of liver metastases in patients with early-stage breast cancer. The trap DNA acts as a chemotactic factor that attracts cancer cells rather than merely trapping them - in mouse models, traps in liver or lungs attracted cancer cells to form distant metastases. The receptor is the transmembrane protein CCDC25, which senses extracellular DNA on the cancer cell and activates the ILK-beta-parvin pathway to enhance motility; trap-mediated metastasis was abrogated in CCDC25-knockout cells, and CCDC25 expression on primary cancer cells was closely associated with poor patient prognosis. For this atlas it upgrades the extracellular nucleic acid arm of I083 from a sensing mechanism with nothing measured at the injury site to a chemotactic ligand measured in human metastatic tissue and in serum, with a receptor, a downstream pathway and a prognostic association.", "limit": "Human evidence is abundance in metastases, a serum predictive association in early-stage breast cancer and a prognostic association for the receptor; the causal work is mouse models and knockout cells. No trap density, DNA concentration or chemotactic gradient length scale is given, so the mechanism is established without the quantities a spatial model would need - and this atlas has repeatedly found that a chemotactic claim without a length scale cannot be used.", "provenance": "Abstract read in full; the human abundance and serum prediction, the chemotactic reframing, the receptor and pathway, the knockout result and the prognostic association as reported", "quantitativeExtraction": "extracted" }, "L88": { "id": "L88", "year": 2014, "topic": "Clinical outcome", "title": "Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis", "url": "https://doi.org/10.1093/jnci/dju124", "studyType": "Systematic review and random-effects meta-analysis of 100 studies comprising 40,559 patients, J Natl Cancer Inst 106(6):dju124", "diseaseContext": "Shared cancer", "useInModel": "This family's validated human quantity, and it is measured in blood rather than in tissue. Across 100 studies and 40,559 patients with solid tumours, at a median cutoff of 4, a neutrophil-to-lymphocyte ratio above the cutoff carried a hazard ratio for overall survival of 1.81 with a confidence interval of 1.67 to 1.97 - and the effect was observed in all disease subgroups, all sites and all stages. Secondary endpoints moved the same way: 1.61 for cancer-specific survival, 1.63 for progression-free and 2.27 for disease-free survival. The consistency across sites and stages is what makes it useful and also what makes it awkward for this project: a simulation of a tumour volume cannot produce this number at all, because it is a ratio of two circulating populations. Set against the density score of I011 - CD3 and CD8 counted in two spatial compartments of the tumour - the contrast is instructive. The T-cell family's best-validated human measurement is spatial and inside the modelled volume; this family's is systemic and outside it.", "limit": "A meta-analysis of observational studies with a median rather than a standardised cutoff, so the threshold is a convention across heterogeneous studies rather than a biologically derived value, and publication bias cannot be excluded. It is prognostic and not predictive of any therapy. Most importantly it is an association between a blood ratio and survival, which says nothing about what either cell population is doing in any tissue.", "provenance": "Abstract read in full; study and patient counts, the median cutoff, and all four hazard ratios with the overall-survival interval as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I027", "name": "Mast cells", "category": "Immune", "whereToCheck": "Perivascular and connective tissue", "states": [ "Resting", "degranulating" ], "behaviors": [ "Mediator release", "vessel and immune interactions" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-113", "hatton-530" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-113", "hatton-530" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-113", "hatton-530" ], "priorResearch": { "path": "simulation/data/profiles/mast-cells.json", "summary": "This is the first family in this atlas written thin, and the thinness is the finding. The inventory places it perivascularly and in connective tissue, asks for resting against degranulating states, and names mediator release and vessel and immune interactions - and a deliberate search surfaced no study measuring this family in any of the drawn environments. What the atlas can say is this. The family sits in the perivascular compartment and modifies vascular permeability, with mast cell and endothelial communication described as accepted and physiologically relevant and with newer evidence implicating these cells in generating vascular networks in tumours, through alterations in adhesion molecules and endothelial barrier regulators (L107). And in a pan-cancer single-cell survey of 210 patients across 15 tumour types, mast cells in nasopharyngeal cancer were associated with better prognosis and showed an antitumour phenotype at a high ratio of TNF-positive to VEGFA-positive cells (L74) - a ratio rather than a count, in a tumour type outside the drawn set.", "stateAxes": [ { "axis": "Resting against degranulating - an event, not a level", "whatToMeasure": "Degranulation itself - mediator release and its timing - rather than an expression state, since that is what the inventory's two states distinguish.", "interpretationLimit": "Entirely unserved. No degranulation rate, trigger threshold, mediator concentration or duration exists in this atlas for any environment, and the one record covering the mechanism is a review that supplies none of them.", "evidence": [ "L107" ] }, { "axis": "Mediator balance, as a ratio rather than a count", "whatToMeasure": "The ratio of pro-inflammatory to pro-angiogenic output - TNF against VEGFA - since that is the form in which the one pan-cancer observation the atlas holds was informative, with a high ratio accompanying an antitumour phenotype and better prognosis.", "interpretationLimit": "One tumour type, nasopharyngeal cancer, outside the drawn environments, within a 15-type single-cell survey of 210 patients - so per-type numbers are modest and the association is prognostic rather than causal. The same survey established that the markers of a given myeloid functional state differ between cancer types, so this ratio should not be assumed to transfer.", "evidence": [ "L74" ] }, { "axis": "Perivascular position and effect on the barrier", "whatToMeasure": "Distance to the nearest vessel together with local permeability, since this family acts on endothelial barrier regulators and adhesion molecules rather than on tumour cells.", "interpretationLimit": "Established as a mechanism in a review without a permeability change, a distance of effect or a mediator concentration. The atlas has the vascular side of this junction well served - a permeability coefficient, its charge dependence, and the remodelling of the luminal surface by disease - and nothing joining that side to this cell.", "evidence": [ "L107", "V23", "V24", "V33" ] } ], "records": { "L107": { "id": "L107", "year": 2026, "topic": "Pericytes and vasculature", "title": "Beyond inflammation: how mast cells control vascular integrity", "url": "https://doi.org/10.1007/164_2026_813", "studyType": "Review chapter on mast cell and endothelial interactions in normal and intratumoral vasculature, Handbook of Experimental Pharmacology", "diseaseContext": "Shared cancer", "useInModel": "Places this family in the compartment the inventory names for it - perivascular - and gives its behaviour a direction the atlas can use. Mast cells are presented as one of the innate cell types that initiates inflammatory reactions and modifies vascular permeability, with chemical communication between them and endothelial cells described as accepted and physiologically relevant, and with newer evidence implicating them in the generation of vascular networks in both normal and pathological conditions including tumour growth. The review's own emphasis is on alterations in adhesion molecules and in regulators of endothelial barrier properties, which is the junction where this family meets the vascular and junction rows of this atlas. For a model the useful consequence is that this family acts on a parameter other families treat as given: permeability. The atlas already records a vascular permeability coefficient for antibody in tumour, a charge dependence for it, and the finding that the perfusable luminal proteome is remodelled by disease - and none of those accounts for a perivascular immune cell that modifies the barrier locally on degranulation.", "limit": "A review chapter rather than a measurement, and it supplies no permeability change, mediator concentration, degranulation rate or distance of effect for any environment. The angiogenic role is described as newer evidence suggesting a closer relationship rather than as settled, and the anti-angiogenic therapies it discusses are presented as developments rather than as results. Nothing in it is specific to any of the drawn environments.", "provenance": "Abstract read in full; the permeability and barrier framing, the angiogenic claim and its hedging, and the emphasis on adhesion and barrier regulators as reported. No quantities available to extract", "quantitativeExtraction": "pending" }, "L74": { "id": "L74", "year": 2021, "topic": "Cellular and spatial atlas", "title": "A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells", "url": "https://doi.org/10.1016/j.cell.2021.01.010", "studyType": "Single-cell analysis of myeloid cells from 210 patients across 15 human cancer types, Cell 184(3):792-809", "diseaseContext": "Shared cancer", "useInModel": "Establishes that a marker panel for this family cannot be shared between environments. Across 210 patients and 15 cancer types, tumour-infiltrating myeloid cells showed distinct features by cancer type, and the decisive detail for this atlas is that pro-angiogenic tumour-associated macrophages were characterised by diverse markers across different cancer types - the same functional state, different markers, depending on where it is. So each of the drawn environments needs its own panel for a state the atlas would otherwise describe once. The composition of the myeloid compartment was also associated with features of somatic mutations and gene expression, which links this family to the tumour genotype rather than only to the tissue. Two side findings land in other families: mast cells in nasopharyngeal cancer associated with better prognosis and an antitumour phenotype at a high ratio of TNF-positive to VEGFA-positive cells, which is a hook for I027, and the comparison of cDC1- against cDC2-derived LAMP3-positive dendritic cells, which is one for I020.", "limit": "Fifteen cancer types with 210 patients, so per-type numbers are modest and the drawn set are unevenly represented. It is a transcriptional atlas: states are defined by expression rather than by function, and no density, flux or functional assay attaches to any state. The association with somatic mutation features is correlational.", "provenance": "Abstract read in full; cohort size, the diverse-markers finding, the mutation association and the two side findings as reported", "quantitativeExtraction": "extracted" }, "V23": { "id": "V23", "year": 2008, "topic": "Transport", "title": "Antibody tumor penetration: transport opposed by systemic and antigen-mediated clearance", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC2820307/", "studyType": "Review with transport modelling", "diseaseContext": "Shared cancer", "useInModel": "Gives a vascular permeability coefficient for IgG in tumour of about 3e-7 cm/s, and shows that permeability rather than diffusion decides how much antibody gets in: with a diffusivity of 10 um^2/s and a 10 um capillary radius the Biot number is about 0.006, so the concentration at the tissue surface sits a hundred to a thousand times below plasma. Inside the tumour, transport is diffusion through extracellular space, because raised interstitial pressure removes the convection that carries antibody in normal tissue.", "limit": "A review over xenograft and modelling work, not a measurement in human tumour. The coefficient excludes convection and transcytosis and the authors call it conservative. The binding-site barrier it describes is often misread: antigen density, diffusivity, permeability and dose all move the penetration front.", "provenance": "Full text reviewed; permeability coefficient and Biot number extracted", "quantitativeExtraction": "extracted" }, "V24": { "id": "V24", "year": 2000, "topic": "Transport", "title": "Vascular permeability in a human tumour xenograft: molecular charge dependence", "url": "https://doi.org/10.1054/bjoc.1999.1171", "studyType": "Intravital fluorescence microscopy of LS174T human colon adenocarcinoma in transparent dorsal skinfold chambers in SCID mice, with albumin and IgG cationised by hexamethylenediamine conjugation or anionised by succinylation, British Journal of Cancer 82(9):1513-1518", "diseaseContext": "Colorectal", "useInModel": "Measured transvascular permeability for molecules of the same size and different charge, which makes it a structure-property relation for the entry step of every antibody-sized agent this atlas records. Cationised albumin (isoelectric point 8.6 to 9.1) and IgG (8.6 to 9.3) had permeabilities of 4.25 and 4.65 times ten to the minus seven centimetres per second, more than double the anionised forms at 1.11 and 1.93 (albumin near pI 2.0, IgG 3.0 to 3.9). So net charge is a handle on extravasation that is independent of size. The caveat is the finding: plasma clearance of the cationic molecules was about twice as fast, so the same modification that raises tumour entry raises normal-organ exposure, and the authors advise caution in using it to improve delivery. That is the same two-sided shape the atlas records for payload reach - a parameter that improves the thing you want and the thing you do not, which cannot be tuned one-sidedly.", "limit": "Xenograft in a dorsal skinfold chamber, not human tumour, and one tumour line. Chemical cationisation and anionisation change more than net charge - conjugation and succinylation alter surface chemistry and may alter binding and stability - so charge is the stated variable rather than the only one. Permeability is calculated from fluorescence and pharmacokinetics rather than measured directly. Because clearance moves with charge, the tumour gain and the normal-organ gain cannot be separated from this experiment.", "provenance": "Abstract read in full, replacing a screening note. All four permeability coefficients with their isoelectric point ranges, the model system and labelling chemistry, the roughly twofold faster plasma clearance of cationic molecules, and the authors' own caution as reported", "quantitativeExtraction": "extracted" }, "V33": { "id": "V33", "year": 2022, "topic": "Accessibility", "title": "Vascular proteome responses precede organ dysfunction in a murine model of Staphylococcus aureus bacteremia", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC9426442/", "studyType": "In vivo endothelial surface labelling across four organs with DIA mass spectrometry", "diseaseContext": "Healthy reference", "useInModel": "Says the luminal surface is not a fixed property. The perfusable vascular proteome is shared across organs at baseline and is remodelled tissue-specifically under systemic insult, ahead of organ dysfunction. What the endothelium displays therefore has to be measured in the disease state, not carried over from a healthy reference.", "limit": "Bacteraemia in mice, not tumour. It establishes that the luminal surface moves with disease, not how it moves in any of the drawn environments.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I028", "name": "Eosinophils and basophils", "category": "Immune", "whereToCheck": "Context-dependent tissue and blood", "states": [ "Activation and degranulation" ], "behaviors": [ "Presence", "inflammatory mediators", "subtype-specific effects" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-568", "hatton-569" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-568", "hatton-569" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-568", "hatton-569" ], "priorResearch": { "path": "simulation/data/profiles/eosinophils-and-basophils.json", "summary": "Written thin, and the thinness is recorded rather than worked around. The inventory places this family in context-dependent tissue and blood, asks for activation and degranulation states, and names presence, inflammatory mediators and subtype-specific effects - and a deliberate search did not surface a usable primary study measuring it in any of the drawn environments. The row sits next to two that are served. Its granulocyte neighbour has a mechanical obstruction finding and a validated blood ratio across 40,559 patients; its mast cell neighbour is also thin but has a perivascular mechanism. This family has neither, and its inventory row is the most hedged in the category - presence, then mediators, then subtype-specific effects, which reads as an author recording that the evidence was not there to be specific with.", "stateAxes": [ { "axis": "Presence - the behaviour the inventory asks for first", "whatToMeasure": "A density or frequency in a named environment, which is what every other row in this category eventually gets and this one does not have.", "interpretationLimit": "Unserved. No study surfaced in this search measures this family in any of the drawn environments, so presence is neither established nor excluded - and under this atlas's own rule, not measured is not the same as not present.", "evidence": [] } ], "records": {}, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I029", "name": "Microglia", "category": "Immune", "whereToCheck": "CNS parenchyma", "states": [ "Region-, age- and disease-dependent programs" ], "behaviors": [ "Surveillance", "phagocytosis", "complement", "synapse interactions" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-156", "hatton-157", "hatton-158" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-156", "hatton-157", "hatton-158" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-156", "hatton-157", "hatton-158" ], "priorResearch": { "path": "simulation/data/profiles/microglia.json", "summary": "This is the best-served Immune family in the three neurodegenerative environments, and the only one with human germline evidence that it matters causally: a rare TREM2 variant carries an odds ratio of 2.90 for Alzheimer's disease across five populations, and carriers who do not have the disease are already cognitively poorer than non-carriers (L85). Its default state is not rest. Imaged in living neocortex, cells called resting were continually surveying with extremely motile processes, and disrupting the blood-brain barrier switched them from patrolling to shielding the breach (L83) - so the trigger is barrier integrity and the response is positional. Its disease programme has a gate: activation begins Trem2-independently by downregulating microglial checkpoints and only then runs a Trem2-dependent programme, and the cells in it contain phagocytosed amyloid-beta in mouse and human brain (A05). Two of the four behaviours the inventory names were already established under I076 - C1q at synapses before plaques with three separable blockades reducing early synapse loss (A04), and complement-driven pruning of inhibitory synapses rescued by deleting one complement gene (F05). And its ontogeny is distinct: adult microglia come from progenitors arising before embryonic day eight and are not maintained by postnatal haematopoietic progenitors (L84).", "stateAxes": [ { "axis": "Surveying - which is the default, not rest", "whatToMeasure": "Process motility and the volume surveyed per unit time, together with what triggers the switch to shielding - barrier disruption produced immediate and focal activation.", "interpretationLimit": "Mouse neocortex through a cranial window, healthy brain plus an acute injury model. The process velocities and survey times are in the source's body and are not extracted into this atlas, so the behaviour is qualitative here - which is notable given how often a motility rate has been the missing quantity for other families.", "evidence": [ "L83" ] }, { "axis": "Disease programme - two steps with a gate", "whatToMeasure": "Both steps separately: downregulation of homeostatic checkpoints first, which is Trem2-independent, then the Trem2-dependent programme. A single activation score collapses a gated two-state process into one variable.", "interpretationLimit": "Mouse transgenic models with Trem2-null comparison for the ordering, and human evidence limited to immunohistochemical confirmation that equivalent cells contain amyloid particles. The ordering comes from comparing genotypes rather than from a time course, and no fraction of cells in either step is given for any human brain.", "evidence": [ "A05", "L85" ] }, { "axis": "Region, age and disease dependence", "whatToMeasure": "The programme by region, by stage and by sex. The atlas's human resources now support all three: six regions with 76 cell types and region-specific subtypes including a thalamus-unique inhibitory population (A02); a staging axis in which the strongest disease-associated changes are early and cell-type-specific while late changes are a shared global stress response (A01); and a sex axis, with female cells overrepresented in disease-associated subpopulations and responses differing between sexes (A01).", "interpretationLimit": "All of it post-mortem and cross-sectional, so staging is an ordering of pathology grades rather than of time, and regional progression is reconstructed. Nuclei rather than whole cells in the prefrontal study. The resources resolve cell types across the brain generally rather than reporting microglial state fractions per region, so this axis is now supportable from held material and still not quantified for this family specifically - the remaining step is the SEA-AD resource, whose primary citation is unresolved and whose matrices need separate acquisition (A03).", "evidence": [ "A02", "A01", "A03", "F01" ] }, { "axis": "Lineage - distinct, and not replenished from blood", "whatToMeasure": "Origin rather than phenotype, since postnatal haematopoietic progenitors do not significantly contribute to adult homeostasis and the population derives from progenitors arising before embryonic day eight.", "interpretationLimit": "Mouse fate mapping in healthy development. It establishes that the population is self-maintaining under homeostasis, not that no blood-derived cell enters a diseased or injured brain - which is precisely the case the three drawn neurodegenerative environments present, and which the atlas holds nothing on.", "evidence": [ "L84" ] } ], "records": { "A01": { "id": "A01", "year": 2019, "topic": "Cellular atlas", "title": "Single-cell transcriptomic analysis of Alzheimer’s disease", "url": "https://www.nature.com/articles/s41586-019-1195-2", "studyType": "80,660 single-nucleus transcriptomes from prefrontal cortex of 48 individuals across a range of Alzheimer's pathology, Nature 570(7761):332-337", "diseaseContext": "Alzheimer's", "useInModel": "Supplies the age-and-disease axis the inventory asks for, and its most important finding is about when to look. Across six major brain cell types in prefrontal cortex from 48 individuals, the strongest disease-associated changes appeared early in pathological progression and were highly cell-type specific, while the genes upregulated at late stages were common across cell types and primarily a global stress response. So there is a window in which cell-type-specific signal exists, and after it the compartments converge on a shared response - which means a model calibrated on late-stage tissue would see generic stress and miss the structure entirely. That is a third independent line pointing at an early window, alongside the delayed-start separation in the SOD1 trial and the greater response in the low-tau population recorded under I088 and I085. The study also opens an axis the inventory does not name: female cells were overrepresented in disease-associated subpopulations and transcriptional responses differed substantially between sexes in several cell types, oligodendrocytes among them. Myelination-related processes were recurrently perturbed across multiple cell types, which is the finding the authors themselves foreground.", "limit": "One region, prefrontal cortex, and post-mortem - so pathological progression is inferred from cross-sectional staging across individuals rather than observed, and the early-against-late ordering is an ordering of pathology grades, not of time in a patient. Nuclei rather than whole cells, which under-represents cytoplasmic transcripts and some cell types. The sex difference is a difference in transcriptional response and in subpopulation representation, not an effect size on any clinical outcome.", "provenance": "Abstract read in full; cohort and nucleus counts, the early-specific against late-shared structure, the sex findings and the myelination result as reported", "quantitativeExtraction": "extracted" }, "A02": { "id": "A02", "year": 2024, "topic": "Multiregion atlas", "title": "Single-cell multiregion dissection of Alzheimer’s disease", "url": "https://www.nature.com/articles/s41586-024-07606-7", "studyType": "Single-cell transcriptomic atlas of six brain regions, 1.3 million cells from 283 post-mortem samples across 48 individuals with and without Alzheimer's disease, Nature 632(8026):858-868", "diseaseContext": "Alzheimer's", "useInModel": "The regional axis, at a resolution that has consequences for how this atlas is structured. Six regions, 1.3 million cells, 283 samples, 48 individuals - and 76 cell types identified, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from the canonical inhibitory subclasses. Vulnerable excitatory and inhibitory populations were depleted in specific brain regions rather than globally, with evidence implicating Reelin signalling in modulating that vulnerability, and region-specific as well as cell-type-specific gene modules were altered in disease. Two things matter beyond the atlas's own use. Seventy-six cell types in one disease across six regions approaches the granularity of this inventory's entire 110 families across the thirteen environments carried in measurements.json, and the region-specific subtypes cannot be expressed by a flat family list at all - a family here is one row whether or not it is three different cells in three regions. And the thalamus-unique inhibitory population lands on an independent finding the atlas already holds: progranulin deficiency drives complement-mediated pruning that preferentially eliminates inhibitory synapses in the ventral thalamus (F05). Two unrelated lines converging on thalamic inhibitory neurons. The study also supplies something the atlas has nowhere else - a resilience programme, astrocytic, tying choline metabolism and polyamine biosynthesis to preserved cognitive function late in life.", "limit": "Post-mortem and cross-sectional, so regional progression is reconstructed rather than observed and the vulnerability claims are depletion in prevalence rather than measured loss over time. Six regions of the aged human brain, 48 individuals, with per-region and per-type numbers necessarily smaller than the headline cell count. The Reelin and resilience findings are associations from module discovery, and the resilience programme is correlated with preserved cognition rather than shown to cause it.", "provenance": "Abstract read in full; region, cell, sample and individual counts, the 76 cell types, the thalamic population, the regional depletion, Reelin and the astrocyte resilience programme as reported", "quantitativeExtraction": "extracted" }, "A03": { "id": "A03", "year": 2024, "topic": "Atlas resource", "title": "SEA-AD: A multimodal cellular atlas and resource for Alzheimer’s disease", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC11577961/", "studyType": "Multimodal human resource paper", "diseaseContext": "Alzheimer's", "useInModel": "The resource the regional axis most needs and the one this atlas has not yet extracted. It links neuropathology, cell states, spatial data and clinical metadata across multiple brain regions, which is the combination required to serve the inventory's request for region-, age- and disease-dependent programmes together rather than one at a time. Until it is extracted, the regional axis here rests on A02 and the age axis on A01.", "limit": "A resource overview: source matrices and donor metadata require separate acquisition, so nothing can be extracted from the paper alone. Its primary citation could not be resolved in the literature index used for this pass, so the record is deliberately left pending rather than given a guessed reference - the next extraction of this family should start by fixing that reference.", "provenance": "Not extracted. Primary citation unresolved in this pass and deliberately not guessed; the atlas holds the resource's scope from its own description only", "quantitativeExtraction": "pending" }, "A05": { "id": "A05", "year": 2017, "topic": "Microglial states", "title": "A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease", "url": "https://pubmed.ncbi.nlm.nih.gov/28602351/", "studyType": "Transcriptional single-cell sorting of all immune populations in wild-type and Alzheimer's-transgenic mouse brain, with Trem2-null comparison and mouse and human immunohistochemistry, Cell 169(7):1276-1290", "diseaseContext": "Alzheimer's", "useInModel": "Gives this family's disease programme a structure with a gate in it. Single-cell sorting across all immune populations of wild-type and Alzheimer's-transgenic mouse brain identified a disease-associated microglial type with its own markers, spatial localisation and pathways, and immunohistochemistry on mouse and human brain slices showed those cells containing intracellular phagocytosed amyloid-beta particles. The structural finding is the two-step activation: the programme is initiated in a Trem2-independent manner that involves downregulation of microglial checkpoints, and only then does a Trem2-dependent programme activate. So this is not one state transition but two with a gate between them - and the receptor whose rare variant carries an odds ratio near three for Alzheimer's disease (L85) controls only the second step. The authors' reading inverts the naive one: this cell type has the potential to restrict neurodegeneration, so the family carrying the risk gene is the protective one and losing the gated step is what hurts.", "limit": "Mouse transgenic models for the programme and the genetics, with human evidence limited to immunohistochemical confirmation that equivalent cells contain amyloid particles. The two-step ordering comes from comparing transgenic and Trem2-null transgenic animals rather than from a time course. Disease-associated microglia should not be labelled uniformly harmful or protective, and no fraction of cells in either step is given for any human brain.", "provenance": "Abstract read in full; the two-step activation, the checkpoint downregulation, the phagocytosed amyloid in mouse and human slices and the restricting-potential reading as reported", "quantitativeExtraction": "extracted" }, "F01": { "id": "F01", "year": 2024, "topic": "Cellular atlas", "title": "Single-cell dissection of the human motor and prefrontal cortices in ALS and FTLD.", "url": "https://pubmed.ncbi.nlm.nih.gov/38521060/", "studyType": "Comparative single-cell molecular atlas of human primary motor and dorsolateral prefrontal cortices in sporadic and familial ALS and FTLD, Cell 187(8):1971-1989", "diseaseContext": "ALS / FTD", "useInModel": "Serves the regional axis for the other two neurodegenerative environments, and makes a claim about what defines a vulnerable cell. Integrating transcriptional and genetic information across two cortical regions, the study identified known and previously unidentified vulnerable populations in cortical layer 5, and found that the ALS- and FTLD-implicated motor and spindle neurons possess a virtually indistinguishable molecular identity - so two diseases the atlas treats as separate environments converge on the same cell. Non-neuronal drivers of pathogenesis were also implicated, which is where this record meets the microglial and complement findings. The sentence with the widest consequence is the last: neuron loss in layer 5 tracked more closely with transcriptional identity than with cellular morphology, and extended beyond the previously reported vulnerable cell types. This inventory's 110 families are named largely by lineage and morphology, and here vulnerability follows transcriptional identity instead - so a family defined the atlas's way may group cells that behave differently and separate cells that behave alike.", "limit": "Post-mortem human cortex, two regions, sporadic and familial cases pooled for some analyses, so the molecular identity claim is about the cells rather than about matched disease stages. Vulnerability is inferred from prevalence differences between cases and controls rather than from observed loss. ALS and FTLD overlap biologically but are not interchangeable diagnoses, and the convergence shown is for specific neuronal populations rather than for the diseases.", "provenance": "Abstract read in full; the layer 5 populations, the indistinguishable molecular identity, the non-neuronal implication and the identity-against-morphology finding as reported", "quantitativeExtraction": "extracted" }, "L83": { "id": "L83", "year": 2005, "topic": "Effector behavior", "title": "Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo", "url": "https://doi.org/10.1126/science.1110647", "studyType": "In vivo two-photon imaging of neocortex in healthy mice and after barrier disruption, Science 308(5726):1314-1318", "diseaseContext": "Healthy reference", "useInModel": "Establishes the baseline behaviour of this family, and the name the field had given it was wrong. Imaged in vivo in neocortex, microglia described as resting were highly active, continually surveying their microenvironment with extremely motile processes and protrusions - so the default state is patrol, not quiescence, and a model that holds these cells still until activated has the resting state wrong. Disrupting the blood-brain barrier provoked immediate and focal activation, switching the behaviour from patrolling to shielding the injured site. That switch is the direct link between this family and the vascular and junction families: barrier integrity is the trigger, and the response is positional rather than chemical - the cells go to the breach and cover it.", "limit": "Mouse neocortex through a cranial window, healthy brain plus an acute injury model, not any disease state. The process velocities and the time to survey a given volume are in the paper's body and are not extracted into this atlas, so the behaviour is established qualitatively - which matters, because a motility rate is exactly the quantity this atlas has repeatedly found missing for other families.", "provenance": "Abstract read in full; the active-resting-state finding and the patrol-to-shield switch as reported. Process velocities and survey times not extracted", "quantitativeExtraction": "pending" }, "L84": { "id": "L84", "year": 2010, "topic": "Cellular atlas", "title": "Fate mapping analysis reveals that adult microglia derive from primitive macrophages", "url": "https://doi.org/10.1126/science.1194637", "studyType": "In vivo lineage tracing and fate mapping with CSF-1 and CSF-1 receptor deficient mice, Science 330(6005):841-845", "diseaseContext": "Healthy reference", "useInModel": "Settles a boundary this atlas recorded as open, for brain at least. Postnatal haematopoietic progenitors do not significantly contribute to microglial homeostasis in the adult brain, and lineage tracing established that adult microglia derive from primitive myeloid progenitors arising before embryonic day eight - making them an ontogenically distinct population within the mononuclear phagocyte system rather than a tissue-adapted monocyte. So in brain the resident-against-recruited distinction is decidable by lineage rather than by marker panel, which is more than can be said for liver. The second finding has a consequence the atlas should carry across categories: microglia develop normally in mice lacking CSF-1 but are absent in CSF-1 receptor-deficient mice. The receptor is required and that ligand is not - and the receptor is the target of the one drug in this atlas that produced a dramatic response in a tumour driven by its ligand (L75). A CSF-1 receptor inhibitor therefore has an on-target effect on this family, which is a mechanism and a safety consideration rather than an off-target risk.", "limit": "Mouse fate mapping and knockout genetics in healthy development. It says postnatal progenitors do not maintain the population under homeostasis, not that no blood-derived cell ever enters a diseased or injured brain - which is the case the drawn neurodegenerative environments actually present, and which the atlas holds nothing on. The cross-category inference about the receptor inhibitor is this atlas's own reading from two records.", "provenance": "Abstract read in full; the absence of postnatal contribution, the pre-E8 origin, the ontogenic distinctness and the CSF-1 against CSF-1 receptor dependency as reported", "quantitativeExtraction": "extracted" }, "L85": { "id": "L85", "year": 2013, "topic": "Target identity", "title": "Variant of TREM2 associated with the risk of Alzheimer's disease", "url": "https://doi.org/10.1056/NEJMoa1211103", "studyType": "Whole-genome sequencing of 2,261 Icelanders with imputation and replication in four further case-control series, N Engl J Med 368(2):107-116", "diseaseContext": "Alzheimer's", "useInModel": "The strongest causal human evidence in this atlas that a cell family matters, because it is a germline variant rather than an association with a state. A rare missense mutation in TREM2, predicted to give an R47H substitution, conferred an odds ratio of 2.92 for Alzheimer's disease in Iceland with a confidence interval of 2.09 to 4.09 and a p-value of 3.4 times ten to the minus ten, replicated across series from the United States, Norway, the Netherlands and Germany for a combined odds ratio of 2.90, interval 2.16 to 3.91, at 2.1 times ten to the minus twelve. The variant's frequency was 0.46% among controls aged 85 or older. And carriers aged 80 to 100 who did not have Alzheimer's disease already had poorer cognitive function than non-carriers at p = 0.003, so the effect is continuous rather than a threshold on diagnosis. A receptor expressed on this family carries an effect of that size, which places microglial function upstream of the disease rather than alongside it.", "limit": "A rare variant, under half a percent in elderly controls, so it explains little population-level risk however large its per-carrier effect. The mechanism is inferred - the authors suggest impaired containment of inflammatory processes given the receptor's reported anti-inflammatory role - and the gating structure of the programme it controls comes from mouse work (A05), not from these patients. Genetic causality for the receptor is not the same as causality for any particular microglial state.", "provenance": "Abstract read in full; both odds ratios with intervals and p-values, the control frequency and the unaffected-carrier cognition finding as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I030", "name": "CNS border-associated macrophages", "category": "Immune", "whereToCheck": "Perivascular; meningeal; choroid plexus", "states": [ "Compartment and activation" ], "behaviors": [ "Barrier interfaces", "clearance", "inflammation", "distinguish from microglia" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "controls-pvm-vehicle", "controls-pvm-chitin" ], "priorResearch": { "path": "simulation/data/profiles/cns-border-associated-macrophages.json", "summary": "The inventory's instruction for this row is to distinguish these cells from microglia, and the evidence both validates that and complicates it. Macrophages of the dura mater, subdural meninges and choroid plexus are distinct subsets with tissue-specific transcriptional signatures whose composition shifts through postnatal development, they have a mixed ontogeny, and they differ between subsets in self-renewal after depletion - while a microglial subset was found sitting on the apical surface of the choroid plexus epithelium, so the identities separate even where the anatomy interleaves (L100). Two things make this family matter more than its size suggests. The perivascular compartment is a clearance route and these cells regulate it: depleting them increased vascular amyloid by histology and by ELISA, stimulating their turnover reduced the angiopathy load, and the effect ran through neither microglia nor astrocytes (L102). And the border compartment drains - functional lymphatic vessels line the dural sinuses, carry fluid and immune cells from cerebrospinal fluid, and connect to the deep cervical lymph nodes (L101), which is the brain route the atlas had explicitly declined to assume when it described the peripheral one.", "stateAxes": [ { "axis": "Compartment - three borders, not one family", "whatToMeasure": "Which border the cells are in, since dura mater, subdural meninges and choroid plexus carry distinct tissue-specific signatures and their composition changes through postnatal development.", "interpretationLimit": "Mouse, healthy brain, identity transcriptional and fate-mapped rather than functional. No density or subset fraction for any compartment, and the developmental shift is described without a timecourse that transfers to human age.", "evidence": [ "L100" ] }, { "axis": "Ontogeny - mixed, and a third rule", "whatToMeasure": "Origin and self-renewal capacity per subset, because this compartment is neither purely lineage-determined like parenchymal microglia nor purely niche-determined like liver macrophages - subsets differ in their ability to repopulate after depletion.", "interpretationLimit": "Mixed ontogeny is demonstrated without proportions, and the self-renewal differences come from a depletion-and-repopulation model rather than steady state. The atlas's boundary record has been refined to three rules on this basis; all three remain unparameterised.", "evidence": [ "L100", "L84", "L96" ] }, { "axis": "Clearance along perivascular spaces", "whatToMeasure": "Vascular amyloid load against perivascular macrophage number and turnover, since depletion raised the load and stimulating turnover lowered it, with neither microglia nor astrocytes mediating the effect.", "interpretationLimit": "One transgenic mouse model, with population-level pharmacological manipulations rather than manipulation of the clearance step. It concerns vascular amyloid specifically rather than the parenchymal clearance deficit measured in humans, so it identifies a route these cells regulate without establishing that this route is the one failing in late-onset human disease. No clearance rate or perivascular flux anywhere.", "evidence": [ "L102", "L46" ] }, { "axis": "Drainage to a destination outside the atlas", "whatToMeasure": "Flow and cell traffic through the dural sinus lymphatics to the deep cervical lymph nodes, which carry both fluid and immune cells from cerebrospinal fluid.", "interpretationLimit": "Mouse, healthy, anatomical and functional characterisation without flux - no drainage rate, transit time or cell flux is given. The destination is a lymph node outside the drawn environments, so this resolves where material goes while leaving the atlas unable to represent it, which is the same position the peripheral route left it in.", "evidence": [ "L101" ] } ], "records": { "L100": { "id": "L100", "year": 2019, "topic": "Cellular and spatial atlas", "title": "A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment", "url": "https://doi.org/10.1038/s41593-019-0393-4", "studyType": "Border-region dissection with single-cell and bulk RNA sequencing, high-dimensional cytometry, fate mapping and microscopy, Nat Neurosci 22(6):1021-1035", "diseaseContext": "Healthy reference", "useInModel": "Does what the inventory's row for this family asks - distinguish these cells from microglia - and complicates the answer in a way that matters. Border-associated macrophages residing in the dura mater, subdural meninges and choroid plexus consisted of distinct subsets with tissue-specific transcriptional signatures, and their cellular composition changed during postnatal development. Crucially they exhibited a mixed ontogeny, with subsets differing in self-renewal capacity after depletion and repopulation - so this compartment is neither purely lineage-determined like parenchymal microglia nor purely niche-determined like liver macrophages, but a third case. And the anatomy is interleaved rather than cleanly partitioned: a unique microglial subset was found residing on the apical surface of the choroid plexus epithelium. IRF8 emerged as a master regulator driving the maturation and diversity of brain macrophages generally. For this atlas that means three border compartments, not one family, each with its own signature, and a boundary with microglia that is real in identity while being mixed in origin and overlapping in location.", "limit": "Mouse, healthy brain, with identity established transcriptionally and by fate mapping rather than by function. Mixed ontogeny is demonstrated without the proportions being carried here, and the self-renewal differences come from a depletion and repopulation model rather than from steady state. No density, subset fraction or turnover rate is extracted for any compartment, and nothing is in a disease state.", "provenance": "Abstract read in full; the three compartments, tissue-specific signatures, postnatal compositional change, mixed ontogeny, subset self-renewal differences, the choroid plexus microglial subset and the IRF8 finding as reported", "quantitativeExtraction": "extracted" }, "L101": { "id": "L101", "year": 2015, "topic": "Transport", "title": "Structural and functional features of central nervous system lymphatic vessels", "url": "https://doi.org/10.1038/nature14432", "studyType": "Discovery and functional characterisation of dural sinus lymphatic vessels in mouse, Nature 523(7560):337-341", "diseaseContext": "Healthy reference", "useInModel": "Supplies the drainage route for the one compartment where the atlas had explicitly ruled out the peripheral one. The central nervous system was held to lack a classical lymphatic drainage system. Functional lymphatic vessels were found lining the dural sinuses, expressing all the molecular hallmarks of lymphatic endothelium, able to carry both fluid and immune cells from the cerebrospinal fluid, and connected to the deep cervical lymph nodes - their unique location having impeded discovery and sustained the assumption of absence. This matters because the atlas has pointed four times at a lymphoid compartment outside the drawn environments and resolved it twice: tertiary lymphoid structures put it inside peripheral tumours, and CCR7-dependent dendritic trafficking supplies the route to a draining node - with the explicit caveat, recorded when that route was written, that brain drainage differs and the peripheral journey could not be assumed there. This is the brain route, with a named destination.", "limit": "Mouse, healthy, and an anatomical and functional characterisation rather than a measurement of flux - no drainage rate, transit time or cell flux to the cervical nodes is given. It establishes that the route exists and carries fluid and cells, not its capacity, and nothing here concerns a disease state or the drawn neurodegenerative environments. The deep cervical lymph node remains outside the drawn set, so the atlas again knows where material goes without being able to represent the destination.", "provenance": "Abstract read in full; the dural sinus location, lymphatic hallmarks, carriage of fluid and immune cells from cerebrospinal fluid, and the connection to deep cervical lymph nodes as reported", "quantitativeExtraction": "extracted" }, "L102": { "id": "L102", "year": 2009, "topic": "Transport", "title": "Selective targeting of perivascular macrophages for clearance of beta-amyloid in cerebral amyloid angiopathy", "url": "https://doi.org/10.1073/pnas.0805453106", "studyType": "Perivascular macrophage depletion and turnover stimulation in the TgCRND8 mouse model with thioflavin S histology and ELISA, PNAS 106(4):1261-1266", "diseaseContext": "Alzheimer's", "useInModel": "Answers, for one of three candidates, a question the amyloid family left open. That family established that accumulation in late-onset disease is a clearance failure rather than overproduction, and recorded that which route failed - perivascular drainage, proteolysis or barrier transport - was not identified (L46). Here a cell family regulates the perivascular route bidirectionally. Cerebral amyloid angiopathy, the deposition of amyloid-beta in leptomeningeal and cortical vessels, affects the majority of patients with Alzheimer's disease, and the evidence cited is that vascular deposits result from impaired clearance of neuronal amyloid along perivascular spaces. Depleting perivascular macrophages significantly increased the number of thioflavin S-positive cortical vessels, with ELISA confirming elevated total vascular amyloid-beta 42; stimulating their turnover reduced the angiopathy load - and that effect was not mediated through clearance by microglia or astrocytes, which is what makes it specific to this family rather than to brain myeloid cells generally.", "limit": "One transgenic mouse model, with depletion and stimulation as pharmacological manipulations of a population rather than of the clearance step itself. It addresses vascular amyloid specifically and not the parenchymal clearance deficit measured in humans, so it identifies a route that these cells regulate without establishing that this route is the one that fails in late-onset human disease. No clearance rate or perivascular flux is given.", "provenance": "Abstract read in full; the prevalence statement, the depletion and stimulation results with both readouts, and the exclusion of microglia and astrocytes as mediators as reported", "quantitativeExtraction": "extracted" }, "L46": { "id": "L46", "year": 2010, "topic": "Transport", "title": "Decreased clearance of CNS beta-amyloid in Alzheimer's disease", "url": "https://doi.org/10.1126/science.1197623", "studyType": "In vivo stable-isotope metabolic labelling of Abeta40 and Abeta42 in human CNS, Science 330(6012):1774", "diseaseContext": "Alzheimer's", "useInModel": "Decides which of the inventory's first two behaviours is the variable, in humans, in vivo. Metabolic labelling measured both production and clearance rates of Abeta40 and Abeta42 in the central nervous system of people with Alzheimer's disease and cognitively normal controls. Clearance of both species was impaired in Alzheimer's; on average there was no difference in production rate for either. The conclusion is that common late-onset Alzheimer's disease is characterised by an overall impairment in clearance. For a model this is a strong structural constraint: amyloid accumulation should not be represented as an increased source term. It is a drainage failure, which places this family downstream of the vascular and perivascular families in this atlas rather than downstream of a synthesis rate.", "limit": "A short report, and the specific hourly rates are not extracted here - only the direction and the absence of a production difference, both of which are the paper's stated findings. It is late-onset sporadic disease and says nothing about autosomal dominant forms, where production is altered by definition. Clearance as measured here is a whole-compartment rate and does not identify which route - perivascular drainage, proteolysis, transport across the barrier - is the one that failed.", "provenance": "Abstract read in full; the impaired-clearance and unchanged-production findings as reported, rates not extracted", "quantitativeExtraction": "pending" }, "L84": { "id": "L84", "year": 2010, "topic": "Cellular atlas", "title": "Fate mapping analysis reveals that adult microglia derive from primitive macrophages", "url": "https://doi.org/10.1126/science.1194637", "studyType": "In vivo lineage tracing and fate mapping with CSF-1 and CSF-1 receptor deficient mice, Science 330(6005):841-845", "diseaseContext": "Healthy reference", "useInModel": "Settles a boundary this atlas recorded as open, for brain at least. Postnatal haematopoietic progenitors do not significantly contribute to microglial homeostasis in the adult brain, and lineage tracing established that adult microglia derive from primitive myeloid progenitors arising before embryonic day eight - making them an ontogenically distinct population within the mononuclear phagocyte system rather than a tissue-adapted monocyte. So in brain the resident-against-recruited distinction is decidable by lineage rather than by marker panel, which is more than can be said for liver. The second finding has a consequence the atlas should carry across categories: microglia develop normally in mice lacking CSF-1 but are absent in CSF-1 receptor-deficient mice. The receptor is required and that ligand is not - and the receptor is the target of the one drug in this atlas that produced a dramatic response in a tumour driven by its ligand (L75). A CSF-1 receptor inhibitor therefore has an on-target effect on this family, which is a mechanism and a safety consideration rather than an off-target risk.", "limit": "Mouse fate mapping and knockout genetics in healthy development. It says postnatal progenitors do not maintain the population under homeostasis, not that no blood-derived cell ever enters a diseased or injured brain - which is the case the drawn neurodegenerative environments actually present, and which the atlas holds nothing on. The cross-category inference about the receptor inhibitor is this atlas's own reading from two records.", "provenance": "Abstract read in full; the absence of postnatal contribution, the pre-E8 origin, the ontogenic distinctness and the CSF-1 against CSF-1 receptor dependency as reported", "quantitativeExtraction": "extracted" }, "L96": { "id": "L96", "year": 2016, "topic": "Cellular atlas", "title": "Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells", "url": "https://doi.org/10.1038/ncomms10321", "studyType": "Diphtheria-toxin depletion of liver-resident macrophages to create niche availability, with transcriptional profiling and postnatal growth analysis, Nat Commun 7:10321", "diseaseContext": "Healthy reference", "useInModel": "Resolves, for liver, the boundary this atlas recorded as open - and resolves it the opposite way to brain. Self-renewing tissue-resident macrophages had been thought to derive exclusively from embryonic progenitors. Depleting the liver-resident population to make the niche available showed that circulating monocytes engraft, gradually adopt the transcriptional profile of the cells they replaced, and become long-lived self-renewing cells. The same thing happens physiologically: circulating monocytes contribute to the expanding macrophage pool shortly after birth, when niches open during normal organ growth. The authors' conclusion is that monocytes can and do give rise to self-renewing tissue-resident macrophages if the niche is available. So in liver, origin does not determine identity - niche occupancy does. Set against the brain evidence, where adult microglia derive from pre-embryonic-day-eight progenitors and postnatal haematopoietic progenitors do not contribute (L84), the resident-against-recruited question turns out to be two different questions with two different answers rather than one question with a missing answer.", "limit": "Mouse, and a depletion model that creates niche availability artificially - the postnatal growth observation is the physiological counterpart and is a narrower claim. Adopting a transcriptional profile gradually is not the same as being functionally identical, and the companion record shows that under erythrocyte stress monocyte-derived and embryonically derived liver macrophages coexist and differ (L97). No engraftment rate, convergence time or niche capacity is given.", "provenance": "Abstract read in full; the engraftment, profile adoption, self-renewal, postnatal contribution and the niche-availability conclusion as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "controls-pvm-vehicle", "controls-pvm-chitin" ] }, { "id": "I031", "name": "Fibroblasts", "category": "Stroma", "whereToCheck": "Connective tissue and tumor stroma", "states": [ "Inflammatory", "myofibroblastic", "antigen-presenting candidate states" ], "behaviors": [ "Matrix production", "contraction", "secretion", "heterogeneity" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-112", "hatton-526" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-112", "hatton-526" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "sender-I031-dermal-fibroblasts" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-112", "hatton-526", "sender-I031-dermal-fibroblasts" ], "priorResearch": { "path": "simulation/data/profiles/fibroblasts.json", "summary": "This family explains a pattern three Immune rows recorded without being able to account for it: T cells move along matrix architecture rather than diffusing, cytotoxic cells follow collagen fibres and vessels, and plasma cells disseminate into tumour beds along fibroblastic tracks. The mechanism, in pancreatic cancer, is more specific than architecture. T cells were absent from the regions containing cancer cells, those cancer cells were coated with CXCL12, and the fibroblast activation protein-positive fibroblast was the principal source of it - depleting that population achieved immune control and uncovered the antitumour effect of two checkpoint antibodies that had done nothing, while inhibiting the chemokine receptor brought T cells in rapidly and worked synergistically with anti-PD-L1 (L110). But depleting a differently marked fibroblast population in the same disease did the reverse: removing alpha-SMA-positive myofibroblasts gave invasive, hypoxic, undifferentiated tumours with more regulatory T cells and worse survival, and patients with fewer myofibroblasts also survived less long (L111). The inventory asks for inflammatory, myofibroblastic and antigen-presenting candidate states, and the atlas already held the third - antigen-presenting fibroblasts identified across species in this same disease (Q01). All three states are real and the sign of the family depends on which one is being removed.", "stateAxes": [ { "axis": "Which marker defines the subset - because the sign depends on it", "whatToMeasure": "The subset by its defining marker, stated explicitly, and ideally the overlap between marker-defined sets in the same tissue - since depleting the FAP-positive population and depleting the alpha-SMA-positive population in the same disease gave opposite outcomes.", "interpretationLimit": "No study the atlas holds measures the overlap between those two sets, so the contradiction is recorded rather than resolved. Both depletions are mouse transgenic or pharmacological removals of a marker-defined population, which is a blunter instrument than removing a function.", "evidence": [ "L110", "L111" ] }, { "axis": "Inflammatory, myofibroblastic, antigen-presenting", "whatToMeasure": "The fraction in each of the three states the inventory names, since all three are established - the myofibroblastic one by its depletion phenotype, the antigen-presenting one by identification across species in the same disease, and the inflammatory one by the chemokine and cytokine output.", "interpretationLimit": "No state fraction for this family exists in any drawn environment in this atlas. The antigen-presenting state is recorded in its own source as a warning against treating all fibroblasts as one cell type, and the pan-cancer finding that the same functional state is marked differently across tumour types applies here as it does to the macrophage rows - so a state panel is not expected to transfer between the drawn environments.", "evidence": [ "Q01", "L110", "L111", "L74" ] }, { "axis": "What it secretes onto the cancer cell", "whatToMeasure": "CXCL12 on the tumour cell surface rather than in the interstitium, since that is where it was found and since T-cell absence tracked those regions.", "interpretationLimit": "No concentration, coating density or exclusion distance is given, in this or any record - which is the same missing length scale this atlas has now collected for complement deposition, regulatory suppression, bystander killing and trap-DNA chemotaxis. The receptor inhibitor result shows the exclusion is reversible without quantifying the gradient.", "evidence": [ "L110" ] }, { "axis": "Matrix production and the structures other cells travel on", "whatToMeasure": "The architecture this family builds, since three independent findings have immune cells moving along it - matrix organisation constraining T-cell routes, cytotoxic cells following collagen fibres and vessels, and plasma cells disseminating along fibroblastic tracks.", "interpretationLimit": "The three findings are in three different environments and systems and none of them measures the production rate, fibre orientation or track dimensions. Depletion of the myofibroblastic subset increased hypoxia, so the architecture is coupled to transport, and the atlas has no term connecting them.", "evidence": [ "L04", "L62", "L98", "L111" ] } ], "records": { "L04": { "id": "L04", "year": 2012, "topic": "Matrix and movement", "title": "Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC3287213/", "studyType": "Live imaging of human tumor slices", "diseaseContext": "Lung / Shared cancer", "useInModel": "Collagen/fibronectin organization constrains T-cell routes and entry into tumor islets.", "limit": "Ex vivo slices lack intact circulation and systemic recruitment.", "provenance": "Indexed abstract or publisher excerpt screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "L110": { "id": "L110", "year": 2013, "topic": "Resistance and exclusion", "title": "Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer", "url": "https://doi.org/10.1073/pnas.1320318110", "studyType": "Autochthonous mouse pancreatic ductal adenocarcinoma with stromal cell depletion, chemokine localisation and receptor inhibition, PNAS 110(50):20212-20217", "diseaseContext": "Pancreatic", "useInModel": "The mechanistic explanation for an exclusion pattern this atlas has recorded three times from three other families. In an autochthonous model of pancreatic ductal adenocarcinoma the mice had cancer-cell-specific CD8 T cells and, like human patients, did not respond to anti-CTLA-4 or anti-PD-L1. Depleting the carcinoma-associated fibroblasts that express fibroblast activation protein achieved immune control - and, decisively, uncovered the antitumour effects of both checkpoint antagonists, so the immunosuppressive activity of that one stromal population accounts for their failure. Three observations identify the mediator: T cells were absent from the regions containing cancer cells, the cancer cells were coated with CXCL12, and the FAP-positive fibroblast was the principal source of it. Inhibiting the receptor with AMD3100 induced rapid T-cell accumulation among the cancer cells and acted synergistically with anti-PD-L1, leaving a residual tumour of only premalignant epithelial and inflammatory cells. The authors' own summary is the useful form: a single protein from a single stromal cell type may direct immune evasion in this model.", "limit": "One autochthonous mouse model of one tumour type. Depletion removes a marker-defined population rather than the chemokine, and the companion result in the same disease shows that depleting a differently marked fibroblast population does the opposite (L111) - so the effect belongs to the FAP-positive subset as defined here and must not be read as a property of fibroblasts. No CXCL12 concentration, coating density or exclusion distance is given, which is the quantity the mechanism implies and the same class of missing length scale this atlas has collected elsewhere.", "provenance": "Abstract read in full; the checkpoint non-response, the depletion and unmasking results, all three chemokine observations, and the receptor inhibition outcome as reported", "quantitativeExtraction": "extracted" }, "L111": { "id": "L111", "year": 2014, "topic": "Negative clinical comparator", "title": "Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival", "url": "https://doi.org/10.1016/j.ccr.2014.04.005", "studyType": "Transgenic depletion of alpha-SMA-positive myofibroblasts in mouse pancreatic cancer at two disease stages, with human survival correlation, Cancer Cell 25(6):719-734", "diseaseContext": "Pancreatic", "useInModel": "The opposite answer to the same question in the same disease, and the reason this family's sign depends on which marker defines the cells removed. Deleting alpha-SMA-positive myofibroblasts - starting either at the non-invasive precursor stage or at established carcinoma - produced invasive, undifferentiated tumours with enhanced hypoxia, epithelial-to-mesenchymal transition and cancer stem cells, and diminished survival. The human correlate points the same way: patients whose tumours had fewer myofibroblasts had reduced survival. Immune surveillance was suppressed in the depleted tumours with increased regulatory T cells. Depleted tumours did not respond to gemcitabine, while anti-CTLA-4 reversed the disease acceleration and prolonged survival. The authors' conclusion is a caution against targeting these cells in this disease. Three things follow for this atlas. The enhanced hypoxia on depletion ties this family to the oxygen and pressure work rather than only to immunology. The human survival correlation makes the stroma net protective in patients, which is the third independent line against treating it as a barrier to be removed. And in both this result and its opposite, a checkpoint antibody determined what the stromal manipulation amounted to.", "limit": "Transgenic depletion of a marker-defined population in mouse, with the human evidence a correlation between myofibroblast abundance and survival rather than an intervention. Depletion at two stages is a strength and still does not separate which myofibroblast function - matrix, mechanical support, signalling - carries the protection. The contradiction with the FAP-targeted result (L110) is not resolved by either paper: the marker-defined sets may overlap partially, and no study the atlas holds measures that overlap.", "provenance": "Abstract read in full; both depletion timings and their phenotypes, the human survival correlation, the regulatory T cell increase, and both drug results as reported", "quantitativeExtraction": "extracted" }, "L62": { "id": "L62", "year": 2007, "topic": "Effector behavior", "title": "In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor", "url": "https://doi.org/10.1084/jem.20061890", "studyType": "Two-photon intravital microscopy with immunofluorescence on ordered sequential sections of a subcutaneous thymoma, J Exp Med 204(2):345-356", "diseaseContext": "Shared cancer", "useInModel": "Couples two behaviours the inventory lists separately, and the coupling runs the unexpected way. Activated cytotoxic T cells migrated with high instantaneous velocities in the tumour periphery and arrested on contact with tumour cells expressing their cognate antigen; where most tumour cells were already dead they resumed migration, sometimes following collagen fibres or blood vessels, adopting an elongated morphology alongside vessels. The decisive comparison is the antigen-negative tumour: there, infiltration was restricted to peripheral regions and the lymphocytes neither stopped moving nor killed. Deep infiltration happened only where the tumour cells expressed the cognate antigen. So antigen expression determines both motility within the tumour and the depth of infiltration - which means infiltration is partly an output of recognition rather than a prerequisite for it, and a model that treats entry, then search, then recognition as a pipeline has the causality wrong at the second step. The observation that cells follow collagen fibres and vessels agrees independently with L04's finding that matrix architecture defines T-cell routes.", "limit": "A subcutaneous thymoma in mouse, imaged through a window, with velocities described qualitatively as high rather than tabulated here - no speed, arrest coefficient or infiltration depth is extracted into this atlas. One antigen system, and antigen presence is binary in the comparison rather than titrated, so the result establishes the coupling without giving its shape.", "provenance": "Abstract read in full; the arrest-and-resume behaviour, the structure-following observation and the antigen-dependence of depth as reported. Velocities not extracted", "quantitativeExtraction": "pending" }, "L74": { "id": "L74", "year": 2021, "topic": "Cellular and spatial atlas", "title": "A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells", "url": "https://doi.org/10.1016/j.cell.2021.01.010", "studyType": "Single-cell analysis of myeloid cells from 210 patients across 15 human cancer types, Cell 184(3):792-809", "diseaseContext": "Shared cancer", "useInModel": "Establishes that a marker panel for this family cannot be shared between environments. Across 210 patients and 15 cancer types, tumour-infiltrating myeloid cells showed distinct features by cancer type, and the decisive detail for this atlas is that pro-angiogenic tumour-associated macrophages were characterised by diverse markers across different cancer types - the same functional state, different markers, depending on where it is. So each of the drawn environments needs its own panel for a state the atlas would otherwise describe once. The composition of the myeloid compartment was also associated with features of somatic mutations and gene expression, which links this family to the tumour genotype rather than only to the tissue. Two side findings land in other families: mast cells in nasopharyngeal cancer associated with better prognosis and an antitumour phenotype at a high ratio of TNF-positive to VEGFA-positive cells, which is a hook for I027, and the comparison of cDC1- against cDC2-derived LAMP3-positive dendritic cells, which is one for I020.", "limit": "Fifteen cancer types with 210 patients, so per-type numbers are modest and the drawn set are unevenly represented. It is a transcriptional atlas: states are defined by expression rather than by function, and no density, flux or functional assay attaches to any state. The association with somatic mutation features is correlational.", "provenance": "Abstract read in full; cohort size, the diverse-markers finding, the mutation association and the two side findings as reported", "quantitativeExtraction": "extracted" }, "L98": { "id": "L98", "year": 2022, "topic": "Spatial and immune state", "title": "Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer", "url": "https://doi.org/10.1016/j.immuni.2022.02.001", "studyType": "Spatial transcriptomics with B cell repertoire analysis and checkpoint-inhibitor outcome correlation in renal cell carcinoma, Immunity 55(3):527-541", "diseaseContext": "Shared cancer", "useInModel": "Closes the gap the B cell family said it left behind, and closes it as a chain with a stainable endpoint. Within intratumoral tertiary lymphoid structures, B cells were enriched and all maturation stages toward plasma cell formation were present; repertoire analysis showed clonal diversification, selection and expansion inside the structures, and fully mature clonotypes at distance from them. In structure-positive tumours, IgG- and IgA-producing plasma cells disseminated into the tumour beds along fibroblastic tracks, and those tumours showed high frequencies of IgG-producing plasma cells together with IgG-stained and apoptotic malignant cells. Therapeutic response and progression-free survival correlated with IgG-stained tumour cells in patients treated with checkpoint inhibitors. Three things to carry. The structure exports - mature clonotypes were found away from it, so it is a source with a range the atlas does not have. The cells travel along fibroblastic tracks, which is the third independent finding in this atlas that immune cells follow stromal structures rather than diffusing. And antibody bound to tumour cells is a spatial, stainable readout on identified targets that tracks outcome, which makes it a third validated spatial endpoint sitting downstream of the other two.", "limit": "Renal cell carcinoma, which became a drawn environment on 2026-10-14, and associative at the clinical end - IgG staining on tumour cells correlates with response and progression-free survival without being shown to cause either. Apoptosis alongside IgG staining is suggestive of effector activity rather than a demonstration of it. No antibody concentration, secretion rate or dissemination distance is given, so the chain is complete in structure and empty of quantities.", "provenance": "Abstract read in full; the maturation stages, the repertoire findings including clonotypes at distance, the fibroblastic-track dissemination, the IgG-stained apoptotic cells and the outcome correlation as reported", "quantitativeExtraction": "extracted" }, "Q01": { "id": "Q01", "year": 2019, "topic": "Stromal comparator", "title": "Cross-Species Single-Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-Presenting Cancer-Associated Fibroblasts", "url": "https://pubmed.ncbi.nlm.nih.gov/31197017/", "studyType": "Human and mouse pancreatic study", "diseaseContext": "Shared cancer", "useInModel": "Antigen-presenting CAFs warn against treating all fibroblasts as one cell type.", "limit": "Pancreatic comparator outside the core drawn environments.", "provenance": "Indexed abstract or publisher excerpt screened; full numerical extraction pending", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I032", "name": "Adipocytes and adipose stromal cells", "category": "Stroma", "whereToCheck": "Breast; prostate surroundings; marrow; other adjacent fat", "states": [ "Lipid state", "inflammation" ], "behaviors": [ "Metabolite exchange", "adipokines", "spatial proximity" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-350", "hatton-451", "hatton-454", "hatton-459" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-350", "hatton-451", "hatton-454", "hatton-459" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "sender-I032-adipocytes" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-350", "hatton-451", "hatton-454", "hatton-459", "sender-I032-adipocytes" ], "priorResearch": { "path": "simulation/data/profiles/adipocytes-and-adipose-stromal-cells.json", "summary": "This family does something no other stromal row does: it feeds the tumour. In ovarian cancer, whose defining metastatic pattern is to the omentum - an organ primarily composed of adipocytes, where the metastasis is typically the largest tumour in the abdominal cavity - primary human omental adipocytes promoted homing, migration and invasion, and coculture produced direct transfer of lipids to the cancer cells with lipolysis in the adipocyte and beta-oxidation in the cancer cell. The transporter FABP4 was upregulated in omental metastases and localised to the adipocyte-tumour interface, and its deficiency substantially impaired metastatic growth (L117). In breast, the coupling is bidirectional: cancer cells delipidate the adipocytes and drive them into an activated state secreting matrix metalloproteinase-11 and interleukin-6, and that interleukin-6 carries the proinvasive effect back - with higher levels in the surrounding adipocytes of larger and node-positive human tumours (L118). Pushed further, the adipocytes stop being adipocytes: they convert to fibroblast-like cells that are FSP-1-positive and alpha-SMA-negative, driven by tumour-secreted Wnt3a, and are present in clinical specimens (L119).", "stateAxes": [ { "axis": "Lipid state - and the direction of transfer", "whatToMeasure": "The transfer itself rather than the stored lipid: lipolysis in the adipocyte against beta-oxidation in the cancer cell, with the transporter at the interface between them, since its deficiency substantially impaired metastatic growth.", "interpretationLimit": "Human primary adipocytes in coculture for the transfer and a knockout mouse for the requirement; no lipid flux, transfer rate or interface dimension is given. Omental adipose is a specific depot and the result should not be assumed to describe adipose in other locations, including the two the inventory names and the atlas has nothing for.", "evidence": [ "L117" ] }, { "axis": "Activated - and the identity markers fall as it happens", "whatToMeasure": "Delipidation and loss of adipocyte markers together with the acquired outputs - the protease and the two cytokines - rather than adipocyte identity, since the cells that matter are the ones that no longer look like the family.", "interpretationLimit": "Coculture for the mechanism, with human tissue confirming the modified cells exist and that their interleukin-6 tracks tumour size and nodal status as an association. The contributions of the individual mediators are not separated beyond the interleukin-6 result.", "evidence": [ "L118" ] }, { "axis": "Converted - and out of this family altogether", "whatToMeasure": "Whether a fibroblast-like stromal cell is adipocyte-derived, since conversion gives FSP-1-positive, alpha-SMA-negative cells that secrete fibronectin and collagen I and are driven by tumour-secreted Wnt3a.", "interpretationLimit": "Conversion demonstrated in coculture with clinical confirmation that the population exists rather than that it arises this way in patients, and in breast rather than in the setting where the fibroblast depletions were done. No fraction of the stromal compartment attributable to this origin exists for any environment.", "evidence": [ "L119", "L110", "L111" ] }, { "axis": "Spatial proximity - the inventory's own behaviour, with a localisation and no range", "whatToMeasure": "Distance from adipocyte to tumour cell, and the interface where the transporter concentrates - since local invasion bringing the two into proximity is the triggering event for both the activation and the conversion.", "interpretationLimit": "The atlas has a localisation - the transporter at the interface - and no distance, which is better than it holds for regulatory T-cell proximity and still not a range. This is the sixth explicitly local mechanism in the atlas with no measured length scale.", "evidence": [ "L117", "L119" ] } ], "records": { "L110": { "id": "L110", "year": 2013, "topic": "Resistance and exclusion", "title": "Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer", "url": "https://doi.org/10.1073/pnas.1320318110", "studyType": "Autochthonous mouse pancreatic ductal adenocarcinoma with stromal cell depletion, chemokine localisation and receptor inhibition, PNAS 110(50):20212-20217", "diseaseContext": "Pancreatic", "useInModel": "The mechanistic explanation for an exclusion pattern this atlas has recorded three times from three other families. In an autochthonous model of pancreatic ductal adenocarcinoma the mice had cancer-cell-specific CD8 T cells and, like human patients, did not respond to anti-CTLA-4 or anti-PD-L1. Depleting the carcinoma-associated fibroblasts that express fibroblast activation protein achieved immune control - and, decisively, uncovered the antitumour effects of both checkpoint antagonists, so the immunosuppressive activity of that one stromal population accounts for their failure. Three observations identify the mediator: T cells were absent from the regions containing cancer cells, the cancer cells were coated with CXCL12, and the FAP-positive fibroblast was the principal source of it. Inhibiting the receptor with AMD3100 induced rapid T-cell accumulation among the cancer cells and acted synergistically with anti-PD-L1, leaving a residual tumour of only premalignant epithelial and inflammatory cells. The authors' own summary is the useful form: a single protein from a single stromal cell type may direct immune evasion in this model.", "limit": "One autochthonous mouse model of one tumour type. Depletion removes a marker-defined population rather than the chemokine, and the companion result in the same disease shows that depleting a differently marked fibroblast population does the opposite (L111) - so the effect belongs to the FAP-positive subset as defined here and must not be read as a property of fibroblasts. No CXCL12 concentration, coating density or exclusion distance is given, which is the quantity the mechanism implies and the same class of missing length scale this atlas has collected elsewhere.", "provenance": "Abstract read in full; the checkpoint non-response, the depletion and unmasking results, all three chemokine observations, and the receptor inhibition outcome as reported", "quantitativeExtraction": "extracted" }, "L111": { "id": "L111", "year": 2014, "topic": "Negative clinical comparator", "title": "Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival", "url": "https://doi.org/10.1016/j.ccr.2014.04.005", "studyType": "Transgenic depletion of alpha-SMA-positive myofibroblasts in mouse pancreatic cancer at two disease stages, with human survival correlation, Cancer Cell 25(6):719-734", "diseaseContext": "Pancreatic", "useInModel": "The opposite answer to the same question in the same disease, and the reason this family's sign depends on which marker defines the cells removed. Deleting alpha-SMA-positive myofibroblasts - starting either at the non-invasive precursor stage or at established carcinoma - produced invasive, undifferentiated tumours with enhanced hypoxia, epithelial-to-mesenchymal transition and cancer stem cells, and diminished survival. The human correlate points the same way: patients whose tumours had fewer myofibroblasts had reduced survival. Immune surveillance was suppressed in the depleted tumours with increased regulatory T cells. Depleted tumours did not respond to gemcitabine, while anti-CTLA-4 reversed the disease acceleration and prolonged survival. The authors' conclusion is a caution against targeting these cells in this disease. Three things follow for this atlas. The enhanced hypoxia on depletion ties this family to the oxygen and pressure work rather than only to immunology. The human survival correlation makes the stroma net protective in patients, which is the third independent line against treating it as a barrier to be removed. And in both this result and its opposite, a checkpoint antibody determined what the stromal manipulation amounted to.", "limit": "Transgenic depletion of a marker-defined population in mouse, with the human evidence a correlation between myofibroblast abundance and survival rather than an intervention. Depletion at two stages is a strength and still does not separate which myofibroblast function - matrix, mechanical support, signalling - carries the protection. The contradiction with the FAP-targeted result (L110) is not resolved by either paper: the marker-defined sets may overlap partially, and no study the atlas holds measures that overlap.", "provenance": "Abstract read in full; both depletion timings and their phenotypes, the human survival correlation, the regulatory T cell increase, and both drug results as reported", "quantitativeExtraction": "extracted" }, "L117": { "id": "L117", "year": 2011, "topic": "Chemistry and metabolism", "title": "Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth", "url": "https://doi.org/10.1038/nm.2492", "studyType": "Primary human omental adipocyte coculture with ovarian cancer cells, protein array of omental against primary tumours, and FABP4-deficient mice, Nat Med 17(11):1498-1503", "diseaseContext": "Ovarian (HGSC)", "useInModel": "A stromal cell acting as a fuel supply, with a direction, a transporter and a genetic requirement - in a drawn environment where the pattern it explains is the defining one. Intra-abdominal tumours have a clear predilection for metastasis to the omentum, an organ primarily composed of adipocytes, and omental metastases are typically the largest tumour in the abdominal cavity. Primary human omental adipocytes promoted homing, migration and invasion of ovarian cancer cells, mediated in part by adipokines including interleukin-8. Coculture produced direct transfer of lipids from adipocytes to cancer cells and promoted growth in vitro and in vivo, with lipolysis induced in the adipocytes and beta-oxidation in the cancer cells - so the adipocyte is an energy source and the coupling has a direction. Fatty acid-binding protein 4 was upregulated in omental metastases relative to primary ovarian tumours and was detected in cancer cells at the adipocyte-tumour cell interface, and FABP4 deficiency substantially impaired metastatic tumour growth in mice. This is the third metabolic exchange term the atlas holds, after oxygen consumption and arginine depletion, and all three are production-and-consumption problems of the kind this project already has a solver and an analytic check for.", "limit": "Human primary adipocytes in coculture for the transfer, with the in vivo requirement established in FABP4-deficient mice rather than in patients. No lipid flux, transfer rate or interface dimension is given, so the mechanism is directional and unquantified. The protein array compares omental metastases with primary tumours, which is the right comparison and a cross-sectional one. Omental adipose is a specific depot and this should not be assumed to describe adipose elsewhere.", "provenance": "Abstract read in full; the metastatic predilection, the adipokine mediation, the lipid transfer with lipolysis and beta-oxidation, the FABP4 upregulation and interface localisation, and the knockout result as reported", "quantitativeExtraction": "extracted" }, "L118": { "id": "L118", "year": 2011, "topic": "Cell-state ecosystems", "title": "Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion", "url": "https://doi.org/10.1158/0008-5472.CAN-10-3323", "studyType": "Two-dimensional coculture of murine and human tumour cells with mature adipocytes, with immunohistochemistry and quantitative PCR on human breast tumours, Cancer Res 71(7):2455-2465", "diseaseContext": "Breast", "useInModel": "The coupling runs both ways, which makes this the third loop the atlas has recorded. Tumour cells cocultivated with mature adipocytes became more invasive in vitro and in vivo; the adipocytes in turn were altered - delipidated, with decreased adipocyte markers and an activated state overexpressing proteases including matrix metalloproteinase-11 and the proinflammatory cytokines interleukin-6 and interleukin-1-beta. Interleukin-6 carried the acquired proinvasive effect. The modified cells were confirmed in human breast tumours by immunohistochemistry and quantitative PCR, and tumours of larger size or with lymph node involvement had higher interleukin-6 in the surrounding adipocytes. Two things to carry. The protease is the point of contact with the matrix-remodelling row, which recorded that contributions to matrix turnover from cells other than fibroblasts were unaccounted for - here is a matrix metalloproteinase from an activated adipocyte. And delipidation with loss of adipocyte markers is the beginning of the identity problem this family creates for the fibroblast row.", "limit": "Coculture for the mechanism, with human tissue establishing that the modified cells exist and that their interleukin-6 tracks tumour size and nodal status - an association, not an intervention. The two-dimensional system is the authors' own and the proinvasive effect is measured in it. Nothing separates the contributions of interleukin-6, the other cytokine and the protease beyond the interleukin-6 blockade.", "provenance": "Abstract read in full; the bidirectional changes, the activated-state components, the interleukin-6 role, the human confirmation and the size and nodal associations as reported", "quantitativeExtraction": "extracted" }, "L119": { "id": "L119", "year": 2013, "topic": "Cell-state ecosystems", "title": "Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer", "url": "https://doi.org/10.1158/0008-5472.CAN-13-0530", "studyType": "Coculture-derived adipocyte-to-fibroblast conversion with two-dimensional and spheroid invasion assays and confirmation in clinical breast specimens, Cancer Res 73(18):5657-5668", "diseaseContext": "Breast", "useInModel": "A partial answer to the question the fibroblast row named as its highest-value gap, and it comes from outside the fibroblast lineage. Carcinoma-associated fibroblasts comprise the majority of stromal cells in breast cancers and their origins are uncertain. Local invasion brings cancer cells into proximity with adipocytes, which respond by converting to fibroblast-like cells - adipocyte-derived fibroblasts - that secrete more fibronectin and collagen I, migrate and invade more, and express the fibroblast marker FSP-1 but not alpha-SMA. The conversion depends on reactivation of Wnt/beta-catenin signalling in response to Wnt3a secreted by the tumour cells, and the converted cells increase cancer cell invasion in two-dimensional and spheroid culture. The population was confirmed in clinical breast cancer specimens. The consequence for this atlas is specific: the fibroblast row records two depletions in pancreatic cancer with opposite outcomes, one defined by fibroblast activation protein and one by alpha-SMA, and names the overlap between marker-defined sets as the measurement most needed. Here is a third population inside the same compartment that is FSP-1-positive and alpha-SMA-negative and is not fibroblast-derived at all - so part of what a marker-defined stromal depletion removes, or spares, depends on lineage rather than on the marker.", "limit": "Breast rather than the pancreatic setting where the opposing depletions were done, so the inference about those sets is this atlas's reading across tumour types rather than a measured overlap. Conversion is demonstrated in coculture with clinical confirmation that the population exists, not that it arises by this route in patients. No fraction of the stromal compartment attributable to this origin is given in any environment.", "provenance": "Abstract read in full; the conversion and its Wnt3a dependence, the secretory and invasive phenotype, the FSP-1-positive alpha-SMA-negative marker pattern and the clinical confirmation as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I033", "name": "Mesenchymal marrow stromal cells", "category": "Stroma", "whereToCheck": "Bone marrow", "states": [ "Supportive niche subtypes" ], "behaviors": [ "Hematopoietic support", "chemokines", "vessel contacts" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-405", "hatton-406", "hatton-407", "hatton-409" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-405", "hatton-406", "hatton-407", "hatton-409" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-405", "hatton-406", "hatton-407", "hatton-409" ], "priorResearch": { "path": "simulation/data/profiles/mesenchymal-marrow-stromal-cells.json", "summary": "Two findings organise this row and both are unusual for this atlas. The niche is perivascular and redundant: stem cell factor is primarily expressed by perivascular cells, deleting it from haematopoietic cells, osteoblasts or nestin-expressing cells left stem cells unaffected, deleting it from endothelial cells or from leptin receptor-expressing perivascular stroma depleted them, and most were lost only when both were targeted (L126). So there are at least two independent sources of the same factor and no single one is load-bearing. And the niche runs on a clock. Circulating stem cells peak five hours after light onset and bottom out five hours after darkness, in antiphase with CXCL12 expression in the marrow, with the rhythm driven by core clock genes through circadian noradrenaline from sympathetic nerves - delivered locally, read by a beta-3 adrenergic receptor on stromal cells, lowering nuclear Sp1 and rapidly downregulating the chemokine (L125). The third finding is shared with the bone-forming row: a disseminated prostate cancer cell competes with the stem cell for this niche, and niche size is causal in both directions (L124).", "stateAxes": [ { "axis": "Which perivascular cell, and how many of them", "whatToMeasure": "The maintenance factor's cellular sources, tested by deletion rather than by expression - endothelial cells and leptin receptor-expressing perivascular stroma each necessary, neither alone sufficient to collapse the niche, and osteoblasts and nestin-expressing cells excluded.", "interpretationLimit": "Mouse genetics in healthy marrow with one factor standing for the niche, so other maintenance factors could distribute differently across the same candidates. Deletion tests necessity in the targeted cell and gives no share. The nestin result stands against an earlier marker-based identification, which the atlas records as a tension resolved by method rather than a settled fact.", "evidence": [ "L126" ] }, { "axis": "Time of day - the atlas's first oscillating variable", "whatToMeasure": "The phase as well as the level: circulating stem cells peaking five hours after light onset and reaching a nadir five hours after darkness, in antiphase with the retention chemokine, with the rhythm disrupted by continuous light or a twelve-hour shift.", "interpretationLimit": "Mouse, healthy, and nocturnal - the phase is relative to a light cycle whose active period is the inverse of a human's, so the existence and direction of the rhythm transfer and the clock hour does not. Amplitudes are not extracted. The chemokine is measured as expression rather than concentration, so the antiphase relation is temporal rather than a measured gradient.", "evidence": [ "L125" ] }, { "axis": "Neural input, read by a stromal receptor", "whatToMeasure": "The adrenergic receptor on the stromal cell and the transcriptional consequence, since the neural signal is delivered locally by marrow nerves and read by the stromal cell rather than by the cell that moves.", "interpretationLimit": "Established in healthy mouse marrow. The nerve row found the same architecture in prostate cancer with the receptors stromal and the relaying cell unidentified; this identifies a stromal cell bearing that receptor subtype in a different tissue, which is a lead for that question rather than an answer to it.", "evidence": [ "L125", "L115" ] }, { "axis": "Capacity, and who is in it", "whatToMeasure": "Niche size against demand, since occupancy is competitive and manipulating size moves metastasis in both directions - and since the resident population is reduced when a tumour cell takes its place.", "interpretationLimit": "Human cells in mouse marrow makes the competition xenogeneic, and niche size is shown causal without being given in cells or volume. This is the parameter the atlas's macrophage boundary decision depends on and still has no value for. Recorded as shared with the bone-forming row rather than as this row's own finding.", "evidence": [ "L124" ] } ], "records": { "L115": { "id": "L115", "year": 2013, "topic": "Recruitment and synapse", "title": "Autonomic nerve development contributes to prostate cancer progression", "url": "https://doi.org/10.1126/science.1236361", "studyType": "Mouse prostate cancer models with surgical and chemical denervation and stromal receptor deletion, plus a retrospective blinded analysis of 43 human prostate adenocarcinoma specimens, Science 341(6142):1236361", "diseaseContext": "Prostate", "useInModel": "Innervation is a microenvironment variable this atlas has never carried, and in a drawn environment it turns out to be stage-specific and to act through a relay. Formation of autonomic nerve fibres in the prostate gland regulated cancer development and dissemination in mouse models. The early phases were prevented by chemical or surgical sympathectomy and by genetic deletion of stromal beta-2 and beta-3 adrenergic receptors; tumours were separately infiltrated by parasympathetic cholinergic fibres that promoted dissemination, and cholinergic invasion and metastasis were inhibited by blocking or deleting the stromal type 1 muscarinic receptor, which improved survival. Two features matter most. The receptors that carry the effect are on stroma, not on the cancer cell - so the pathway is nerve to stroma to tumour, a two-step relay no family in this atlas currently represents, and a model that lets a neural input act directly on a tumour cell would be wrong at the first step. And the two branches act at different stages, sympathetic for initiation and parasympathetic for spread. In 43 patients analysed blind, the densities of sympathetic fibres in tumour and of parasympathetic fibres in the surrounding normal tissue were each associated with poor clinical outcome - a stainable spatial measurement in two named compartments.", "limit": "Mouse models for all the causal work, with the human evidence a retrospective blinded association in 43 specimens rather than an intervention. The two fibre densities were associated with outcome in different compartments, so the measurement is compartment-specific and not a single nerve density. Denervation is a regional manipulation and the stromal receptor deletions do not identify which stromal cell carries them, which is the step a model would need.", "provenance": "Abstract read in full; both branches and their stage-specific effects, the stromal location of the receptors, the survival benefit, and the human cohort size and compartment-specific associations as reported", "quantitativeExtraction": "extracted" }, "L124": { "id": "L124", "year": 2011, "topic": "Marrow niche", "title": "Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow", "url": "https://doi.org/10.1172/JCI43414", "studyType": "Mouse model of human prostate cancer dissemination with niche size manipulation and mobilisation protocols, J Clin Invest 121(4):1298-1312", "diseaseContext": "Prostate", "useInModel": "Makes niche capacity a causal and manipulable quantity, which is exactly what one of this atlas's boundary decisions lacked. Human prostate cancer cells directly competed with haematopoietic stem cells for occupancy of the niche; increasing niche size promoted metastasis and decreasing it compromised dissemination; disseminated cancer cells could be mobilised out of the niche and back into circulation using stem cell mobilisation protocols; and once lodged, the tumour cells reduced stem cell numbers by driving their terminal differentiation. Three things follow. The atlas decided, for tissues outside the central nervous system, to track niche occupancy rather than cell origin, and recorded that no niche capacity existed anywhere - here capacity is not only real but causal in both directions. Residence is reversible, which makes eviction a different kind of intervention from the inhibitions and blockades the atlas's ledger otherwise contains. And occupancy has a cost to the resident population, which is a displacement the marrow parenchyma rows would carry. The finding concerns the haematopoietic niche, which the inventory assigns to the marrow stromal row, so it should be treated as shared between these two rows rather than cited again as new.", "limit": "Human cancer cells in a mouse marrow, so the niche being competed for is murine and the competition is xenogeneic. Niche size was manipulated by the study's own means and no capacity is given in cells or volume - the variable is shown to be causal without being quantified. Mobilisation returns cells to circulation without establishing what then happens to them, and the reduction in stem cells is attributed to driven differentiation rather than measured as a rate.", "provenance": "Abstract read in full; the direct competition, both directions of the niche size manipulation, the mobilisation result and the mechanism of stem cell reduction as reported", "quantitativeExtraction": "extracted" }, "L125": { "id": "L125", "year": 2008, "topic": "Marrow niche", "title": "Haematopoietic stem cell release is regulated by circadian oscillations", "url": "https://doi.org/10.1038/nature06685", "studyType": "Circadian sampling of circulating stem cells with light manipulation, clock gene and adrenergic receptor dependency in mice, Nature 452(7186):442-447", "diseaseContext": "Healthy reference", "useInModel": "The atlas's first temporal oscillation, and it has a phase, a disruptable clock and an antiphase partner. Circulating haematopoietic stem cells and progenitors fluctuate robustly over the day, peaking five hours after the initiation of light and reaching a nadir five hours after darkness, with the rhythm markedly altered by continuous light or by a twelve-hour shift. They fluctuate in antiphase with CXCL12 expression in the marrow microenvironment, and both the cyclical release and the chemokine expression are driven by core clock genes through circadian noradrenaline secretion from the sympathetic nervous system - delivered locally by nerves in the bone marrow, transmitted to stromal cells through the beta-3 adrenergic receptor, lowering nuclear Sp1 and rapidly downregulating the chemokine. Two things matter beyond this row. Every density in this atlas is implicitly time-of-day-agnostic, and this says the same measurement taken at a different hour gives a different answer. And the architecture is the one the nerve row found in prostate cancer - a neural signal read by an adrenergic receptor on a stromal cell rather than on the cell that responds - which makes that a pattern seen twice independently rather than a single observation.", "limit": "Mouse, healthy, and nocturnal - the phase is given relative to the light cycle of an animal whose activity period is the inverse of a human's, so the direction transfers and the clock time does not. Amplitudes are not extracted here. The chemokine is measured as expression in the microenvironment rather than as a concentration, and the antiphase relationship is a correlation in time supported by the mechanism rather than a measured gradient.", "provenance": "Abstract read in full; the phase relative to light, the disruption conditions, the antiphase relationship, the clock and noradrenaline dependency, and the beta-3 receptor and Sp1 mechanism as reported", "quantitativeExtraction": "extracted" }, "L126": { "id": "L126", "year": 2012, "topic": "Marrow stroma", "title": "Endothelial and perivascular cells maintain haematopoietic stem cells", "url": "https://doi.org/10.1038/nature10783", "studyType": "Reporter knock-in expression mapping with conditional deletion of stem cell factor from five candidate niche cell types in mice, Nature 481(7382):457-462", "diseaseContext": "Healthy reference", "useInModel": "Settles where the niche is by deleting its key factor from each candidate in turn, and the answer is a redundant perivascular one. Stem cell factor was primarily expressed by perivascular cells throughout the bone marrow. Deleting it from haematopoietic cells, from osteoblasts, or from nestin-expressing cells left stem cell frequency and function unaffected; deleting it from endothelial cells or from leptin receptor-expressing perivascular stromal cells depleted stem cells; and most were lost only when it was deleted from both. So the niche is perivascular rather than osteoblastic, it has at least two independent sources of the same maintenance factor, and single-source removal is insufficient to collapse it. Three consequences for this atlas. Osteoblasts were explicitly tested and excluded, which constrains the bone-forming row by elimination just as that row's genetics excluded marrow stromal cells as the major source of the osteoclast-recruiting ligand - the two rows bound each other from opposite directions. The redundancy means a model cannot represent this niche as one cell. And the authors note that no maintenance factor had previously been conditionally deleted from any candidate niche cell, so the marker-based claims came first and the functional test reversed some of them.", "limit": "Mouse genetics in healthy marrow, with one maintenance factor - stem cell factor - standing for the niche, so other factors could distribute differently across the same candidates. Conditional deletion tests necessity in the cell type targeted and does not quantify each source's share. The nestin result stands against an earlier marker-based identification of the niche cell, which is a tension in the field rather than a settled matter, and this study's claim rests on the deletion approach being the better test.", "provenance": "Abstract read in full; the expression pattern, all five deletion results including the two negatives and the double deletion, and the authors' note on prior absence of conditional deletion as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I034", "name": "Osteoblasts and osteocytes", "category": "Stroma", "whereToCheck": "Bone lesions and marrow interface", "states": [ "Formation", "damage", "remodeling" ], "behaviors": [ "Matrix deposition", "niche signals", "location" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-376", "hatton-378", "hatton-379" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-376", "hatton-378", "hatton-379" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-376", "hatton-378", "hatton-379" ], "priorResearch": { "path": "simulation/data/profiles/osteoblasts-and-osteocytes.json", "summary": "The osteoclast row named this family as a prerequisite rather than an adjacency, because the ligand that recruits osteoclasts, its decoy receptor and the receptor for the tumour's signal all sit on this lineage - and writing it relocates that control to a cell nobody would reach for. Purified osteocytes express much more RANK ligand and support osteoclastogenesis better than osteoblasts or bone marrow stromal cells, and deleting RANK ligand specifically in osteocytes produces severe osteopetrosis, making them the major source in bone remodelling in vivo (L123). So the cell controlling resorption is the buried, terminally differentiated one encased in the mineralised matrix it helped make, not the osteoblast on the surface. The second half of the row is the niche. Human prostate cancer cells directly compete with haematopoietic stem cells for niche occupancy; increasing niche size promoted metastasis and decreasing it compromised dissemination; the cells could be mobilised back out with stem cell mobilisation protocols; and once lodged they reduced stem cell numbers by driving their terminal differentiation (L124).", "stateAxes": [ { "axis": "Formation against embedding - two states, opposite positions", "whatToMeasure": "Surface osteoblast and embedded osteocyte separately, since the recruiting ligand is carried at much higher level by the osteocyte and the osteocyte-specific deletion is what produces the osteopetrotic phenotype.", "interpretationLimit": "Mouse genetics in healthy remodelling. Purified-cell comparisons give relative expression and capacity rather than absolute contribution, and nothing establishes whether the osteocyte remains dominant where a metastasis is driving resorption - which is the condition the drawn environments would present.", "evidence": [ "L123" ] }, { "axis": "Niche capacity - causal, manipulable, unquantified", "whatToMeasure": "The size of the niche, because increasing it promoted metastasis and decreasing it compromised dissemination - and because occupancy is competitive, so the quantity that matters is capacity against demand rather than either alone.", "interpretationLimit": "Niche size was manipulated by the study's own means and is not given in cells or volume, so the variable is causal and dimensionless here. Human cells in mouse marrow makes the competition xenogeneic. This is the first evidence in the atlas that the capacity its macrophage boundary decision relies on is a real quantity.", "evidence": [ "L124" ] }, { "axis": "Signal transport out of a solid", "whatToMeasure": "How the osteocyte's signal reaches the bone surface, since the controlling cell is encased in mineralised matrix and the cells it recruits are not.", "interpretationLimit": "The atlas holds no path length, canalicular geometry or transport measure for this, and it is a constraint no other family here has - every other signalling limitation the atlas records is diffusion or retention in soft tissue. The relocation of the source to the osteocyte creates the problem without supplying any of the geometry.", "evidence": [ "L123" ] }, { "axis": "Damage and remodelling - named by the inventory, unserved", "whatToMeasure": "Matrix damage and the remodelling response to it, which is the state the inventory names between formation and the rest.", "interpretationLimit": "Nothing held addresses damage or the remodelling response in any environment. The osteocyte is the classical mechanosensor of bone and the atlas has no record of that function, which leaves the mechanical input to this whole axis absent - notable given that the skeletal muscle row establishes mechanical load changing disease timing elsewhere.", "evidence": [] } ], "records": { "L123": { "id": "L123", "year": 2011, "topic": "Marrow stroma", "title": "Evidence for osteocyte regulation of bone homeostasis through RANKL expression", "url": "https://doi.org/10.1038/nm.2452", "studyType": "Purified cell comparison of RANKL expression and osteoclastogenic capacity with cell-type-specific RANKL deletion in mice, Nat Med 17(10):1231-1234", "diseaseContext": "Healthy reference", "useInModel": "Supplies the controlling variable the osteoclast row was missing, and relocates it to a cell nobody would reach for. Purified osteocytes express much more RANK ligand and support osteoclastogenesis better in vitro than osteoblasts and bone marrow stromal cells, and mice lacking RANK ligand specifically in osteocytes show a severe osteopetrotic phenotype - so osteocytes are the major source in bone remodelling in vivo. Two consequences. The cell that controls resorption is the buried, terminally differentiated one encased in the mineralised matrix it helped make, not the surface osteoblast - so a model of bone turnover that puts the recruitment signal on the surface is wrong about the source and about the geometry, since the signal has to reach the surface from inside a solid. And the comparison explicitly excludes bone marrow stromal cells as the major source, which constrains the marrow niche row before it is written.", "limit": "Mouse genetics in healthy bone remodelling, not in any disease state and not in tumour-bearing bone - so whether the osteocyte remains the dominant source where a metastasis is driving resorption is not addressed. Purified cell comparisons establish relative expression and capacity rather than absolute contribution, and no RANK ligand concentration or transport path length through the matrix is given.", "provenance": "Abstract read in full; the expression and capacity comparison against both other cell types, and the osteocyte-specific deletion phenotype as reported", "quantitativeExtraction": "extracted" }, "L124": { "id": "L124", "year": 2011, "topic": "Marrow niche", "title": "Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow", "url": "https://doi.org/10.1172/JCI43414", "studyType": "Mouse model of human prostate cancer dissemination with niche size manipulation and mobilisation protocols, J Clin Invest 121(4):1298-1312", "diseaseContext": "Prostate", "useInModel": "Makes niche capacity a causal and manipulable quantity, which is exactly what one of this atlas's boundary decisions lacked. Human prostate cancer cells directly competed with haematopoietic stem cells for occupancy of the niche; increasing niche size promoted metastasis and decreasing it compromised dissemination; disseminated cancer cells could be mobilised out of the niche and back into circulation using stem cell mobilisation protocols; and once lodged, the tumour cells reduced stem cell numbers by driving their terminal differentiation. Three things follow. The atlas decided, for tissues outside the central nervous system, to track niche occupancy rather than cell origin, and recorded that no niche capacity existed anywhere - here capacity is not only real but causal in both directions. Residence is reversible, which makes eviction a different kind of intervention from the inhibitions and blockades the atlas's ledger otherwise contains. And occupancy has a cost to the resident population, which is a displacement the marrow parenchyma rows would carry. The finding concerns the haematopoietic niche, which the inventory assigns to the marrow stromal row, so it should be treated as shared between these two rows rather than cited again as new.", "limit": "Human cancer cells in a mouse marrow, so the niche being competed for is murine and the competition is xenogeneic. Niche size was manipulated by the study's own means and no capacity is given in cells or volume - the variable is shown to be causal without being quantified. Mobilisation returns cells to circulation without establishing what then happens to them, and the reduction in stem cells is attributed to driven differentiation rather than measured as a rate.", "provenance": "Abstract read in full; the direct competition, both directions of the niche size manipulation, the mobilisation result and the mechanism of stem cell reduction as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I035", "name": "Osteoclasts", "category": "Stroma", "whereToCheck": "Bone interface", "states": [ "Differentiating", "resorptive" ], "behaviors": [ "Bone resorption", "coupling to malignant cells" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-382" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-382" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-382" ], "priorResearch": { "path": "simulation/data/profiles/osteoclasts.json", "summary": "This row carries the atlas's first closed loop - the first one where both arms were experimentally manipulated and the order between them established. Bone destruction in breast cancer metastasis is mediated by this family, and resorption liberates TGF-beta stored in the bone matrix. That TGF-beta acts directly on the tumour cells rather than on surrounding tissue: blocking its reception with a dominant-negative receptor gave less bone destruction, less tumour, fewer associated osteoclasts and prolonged survival, restoring signalling with a constitutively active receptor increased tumour parathyroid hormone-related protein and worsened everything, and supplying that protein downstream of the block restored the phenotype (L120). So the cycle is tumour protein, osteoclast recruitment, resorption, matrix-bound TGF-beta released, more protein. The family is also the only druggable node in it that the atlas can point to a trial for: an antibody against the ligand that recruits these cells was superior to the existing standard for skeletal events in 2,046 patients, while leaving survival and disease progression unchanged (L121), with the same pattern replicated in prostate (L122).", "stateAxes": [ { "axis": "Resorptive - and what resorption releases", "whatToMeasure": "Resorption together with the TGF-beta it liberates, since the matrix is the reservoir and the cell's activity is what makes the signal available - not the amount of signal present.", "interpretationLimit": "The loop is established in direction and ordering by receptor and ligand manipulation in one cell line and one mouse model, with no release rate per unit resorbed matrix and no TGF-beta concentration. The atlas holds bone turnover markers as something that moved in a trial without a value attached.", "evidence": [ "L120", "L121" ] }, { "axis": "Differentiating - and recruited from elsewhere", "whatToMeasure": "The ligand that recruits these cells and its decoy receptor, which are produced by the bone-forming lineage rather than by this family - so the controlling variable sits in a neighbouring row.", "interpretationLimit": "The atlas holds this only through the drug that blocks the ligand and through the loop's requirement for tumour-derived parathyroid hormone-related protein. No ligand or decoy level is measured anywhere, and the bone-forming row that produces them is unwritten.", "evidence": [ "L121", "L120" ] }, { "axis": "Coupling to malignant cells - the inventory's own behaviour, and it is indirect", "whatToMeasure": "The two-step path rather than a contact: tumour signal to the bone-forming lineage, that lineage's ligand to this family, this family's resorption back to the tumour through released matrix signal.", "interpretationLimit": "Each step is established and no step has a magnitude. This is the second relay the atlas has found where a tumour's effect on a stromal cell runs through an intermediate stromal population, after the neural one - and in both cases the identity or state of the intermediary is the unmeasured link.", "evidence": [ "L120", "L115" ] } ], "records": { "L115": { "id": "L115", "year": 2013, "topic": "Recruitment and synapse", "title": "Autonomic nerve development contributes to prostate cancer progression", "url": "https://doi.org/10.1126/science.1236361", "studyType": "Mouse prostate cancer models with surgical and chemical denervation and stromal receptor deletion, plus a retrospective blinded analysis of 43 human prostate adenocarcinoma specimens, Science 341(6142):1236361", "diseaseContext": "Prostate", "useInModel": "Innervation is a microenvironment variable this atlas has never carried, and in a drawn environment it turns out to be stage-specific and to act through a relay. Formation of autonomic nerve fibres in the prostate gland regulated cancer development and dissemination in mouse models. The early phases were prevented by chemical or surgical sympathectomy and by genetic deletion of stromal beta-2 and beta-3 adrenergic receptors; tumours were separately infiltrated by parasympathetic cholinergic fibres that promoted dissemination, and cholinergic invasion and metastasis were inhibited by blocking or deleting the stromal type 1 muscarinic receptor, which improved survival. Two features matter most. The receptors that carry the effect are on stroma, not on the cancer cell - so the pathway is nerve to stroma to tumour, a two-step relay no family in this atlas currently represents, and a model that lets a neural input act directly on a tumour cell would be wrong at the first step. And the two branches act at different stages, sympathetic for initiation and parasympathetic for spread. In 43 patients analysed blind, the densities of sympathetic fibres in tumour and of parasympathetic fibres in the surrounding normal tissue were each associated with poor clinical outcome - a stainable spatial measurement in two named compartments.", "limit": "Mouse models for all the causal work, with the human evidence a retrospective blinded association in 43 specimens rather than an intervention. The two fibre densities were associated with outcome in different compartments, so the measurement is compartment-specific and not a single nerve density. Denervation is a regional manipulation and the stromal receptor deletions do not identify which stromal cell carries them, which is the step a model would need.", "provenance": "Abstract read in full; both branches and their stage-specific effects, the stromal location of the receptors, the survival benefit, and the human cohort size and compartment-specific associations as reported", "quantitativeExtraction": "extracted" }, "L120": { "id": "L120", "year": 1999, "topic": "Metastatic niche", "title": "TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development", "url": "https://doi.org/10.1172/JCI3523", "studyType": "Dominant-negative and constitutively active receptor constructs plus PTHrP complementation in a mouse model of breast cancer bone metastasis, J Clin Invest 103(2):197-206", "diseaseContext": "Breast", "useInModel": "The atlas's first closed loop with both arms experimentally manipulated and an epistatic ordering. Bone destruction in breast cancer metastasis is mediated by the osteoclast, and growth factors including TGF-beta are released from bone matrix by the action of osteoclasts. The expectation would be that TGF-beta acts on surrounding normal tissue, since it inhibits epithelial growth and carcinoma cells are often defective in responding to it - instead it acts directly on the tumour cells. Expressing a dominant-negative TGF-beta type II receptor made the cancer cells unresponsive and produced less bone destruction, less tumour, fewer associated osteoclasts and prolonged survival. Restoring signalling with a constitutively active type I receptor increased tumour production of parathyroid hormone-related protein, enhanced osteolytic metastasis and decreased survival. Transfecting the protein into the blocked cells gave constitutive production and accelerated metastases - which places it downstream of the receptor and closes the cycle: tumour protein activates osteoclasts, resorption liberates matrix-bound TGF-beta, and that TGF-beta drives more of the protein. The second consequence matters beyond this row. The atlas records that TGF-beta is matrix-retained rather than freely diffusible and that its arrangement matters more than its amount; this is the only concrete releasing mechanism the atlas holds for any matrix-bound signal.", "limit": "One human breast cancer cell line in a mouse model of bone metastasis, with the loop assembled from receptor and ligand manipulations rather than measured as a flux. No TGF-beta concentration, release rate per unit resorbed matrix, or protein level is given, so the cycle is established in direction and ordering and has no magnitudes. A 1999 study, and the dominant-negative and constitutively active constructs are strong perturbations rather than physiological variation.", "provenance": "Abstract read in full; the osteoclast-mediated release, the direct action on tumour cells, all three construct results including the PTHrP complementation, and the conclusion as reported", "quantitativeExtraction": "extracted" }, "L121": { "id": "L121", "year": 2010, "topic": "Clinical outcome", "title": "Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study", "url": "https://doi.org/10.1200/JCO.2010.29.7101", "studyType": "Randomised double-blind trial, 2,046 patients with breast cancer and bone metastases, four-weekly dosing, J Clin Oncol 28(35):5132-5139", "diseaseContext": "Breast", "useInModel": "A drug that hit its primary endpoint, which this atlas's intervention ledger has not previously had to account for. Denosumab is a fully human antibody against RANK ligand - the signal through which this family is recruited - and was compared with zoledronic acid in 2,046 patients, 1,026 against 1,020, dosed every four weeks. It was superior for time to first skeletal-related event, defined as pathological fracture, radiation or surgery to bone, or spinal cord compression, at a hazard ratio of 0.82 with an interval of 0.71 to 0.95; superior for first and subsequent events at a rate ratio of 0.77, interval 0.66 to 0.89; and produced a greater reduction in bone turnover markers. Overall survival, disease progression and rates of adverse and serious adverse events were similar between the groups, with renal events and acute-phase reactions in excess on zoledronic acid, hypocalcaemia on denosumab, and osteonecrosis of the jaw infrequent in both at 2.0% against 1.4%. This is not one of the atlas's mechanism-confirmed failures. It engaged its target, reduced the biochemical marker of the process, and delivered the clinical endpoint it was designed for - which was skeletal morbidity rather than survival.", "limit": "An active-comparator superiority trial against zoledronic acid, so the effect size is relative to an existing bone-targeted agent rather than to no treatment. The endpoint is skeletal morbidity; survival and disease progression were unchanged, and the trial was not designed to change them. All patients were strongly recommended calcium and vitamin D, which is part of the regimen rather than a confounder. Osteonecrosis rates are from this trial's duration and the comparison between arms was not significant.", "provenance": "Abstract read in full; both arm sizes, the endpoint definition, both effect measures with intervals and p-values, the unchanged survival and progression, and all the named adverse events as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I036", "name": "Peripheral nerves and Schwann cells", "category": "Stroma", "whereToCheck": "Innervated tumors; peripheral motor unit", "states": [ "Injured", "activated", "myelinating" ], "behaviors": [ "Neurotransmitter input", "axonal support", "tumor contacts" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-195", "hatton-251" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-195", "hatton-251" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-195", "hatton-251" ], "priorResearch": { "path": "simulation/data/profiles/peripheral-nerves-and-schwann-cells.json", "summary": "This row carries a microenvironment variable the atlas has never had: innervation. In prostate cancer, formation of autonomic nerve fibres regulated development and dissemination, with the sympathetic branch driving the early phases and the parasympathetic branch driving spread - and the receptors carrying both effects sit on stroma rather than on the cancer cell, so the pathway runs nerve to stroma to tumour (L115). In 43 patients analysed blind, sympathetic fibre density in tumour and parasympathetic fibre density in the surrounding normal tissue were each associated with poor outcome. The cellular half of the row is sharper still. Cancers extend along nerves by perineural invasion, and Schwann cells do not merely provide the path - a subpopulation associates with cancer cells, directs them to migrate toward nerves, induces protrusions in its own direction on contact and intercalates between them to disperse them, all requiring Schwann cell NCAM1 (L116). The atlas has four earlier findings of cells following structures passively; this is the first where the cells of the structure do the steering. And the authors note what programme is being run: normal nerve repair, exploited.", "stateAxes": [ { "axis": "Which branch, and in which compartment", "whatToMeasure": "Sympathetic and parasympathetic fibre density separately, and in the compartments where each was informative - sympathetic within tumour, parasympathetic in the surrounding normal tissue - since the two branches act at different stages and a pooled nerve density averages them.", "interpretationLimit": "The human evidence is a retrospective blinded association in 43 prostate specimens, not an intervention, and the compartment assignment comes from that one cohort. All causal work is mouse. Denervation is regional and does not isolate a fibre type as cleanly as the receptor deletions do.", "evidence": [ "L115" ] }, { "axis": "The receptor that carries the signal is not on this family", "whatToMeasure": "Stromal adrenergic and muscarinic receptor expression alongside nerve density, because deleting stromal beta-2 and beta-3 prevented early tumorigenesis and disrupting stromal muscarinic type 1 blocked dissemination and improved survival.", "interpretationLimit": "The deletions establish that the receptors are stromal without identifying which stromal cell carries them - and the fibroblast row of this same category now records that marker-defined stromal subsets can have opposite effects, so the identity of the relaying cell is not a detail. No receptor level is measured in any environment in this atlas.", "evidence": [ "L115", "L110", "L111" ] }, { "axis": "Schwann cell activation - a repair programme, running", "whatToMeasure": "The associating Schwann cell subpopulation and its NCAM1, since the invasion processes required it and NCAM1 deficiency reduced neural invasion and paralysis - and the programme being run is the normal nerve repair one.", "interpretationLimit": "Mechanism from ganglion coculture with human evidence limited to histological identification of the subpopulation in perineural invasion specimens. No contact duration, dispersion distance or invasion rate, so guidance is established without geometry. Whether the same subpopulation exists in uninvaded nerve is not addressed.", "evidence": [ "L116" ] }, { "axis": "Injured, activated, myelinating - the inventory's states", "whatToMeasure": "Which of the three states the cells are in, since the invasive behaviour is the activated repair state rather than the myelinating one, and injury is what normally triggers it.", "interpretationLimit": "The atlas holds the activated repair state through its exploitation by cancer and holds nothing on the myelinating or injured states as such - and nothing at all on this family in the motor unit, which is the inventory's other named location and where the skeletal muscle row establishes that Wallerian degeneration occurs.", "evidence": [ "L116", "L113" ] } ], "records": { "L110": { "id": "L110", "year": 2013, "topic": "Resistance and exclusion", "title": "Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer", "url": "https://doi.org/10.1073/pnas.1320318110", "studyType": "Autochthonous mouse pancreatic ductal adenocarcinoma with stromal cell depletion, chemokine localisation and receptor inhibition, PNAS 110(50):20212-20217", "diseaseContext": "Pancreatic", "useInModel": "The mechanistic explanation for an exclusion pattern this atlas has recorded three times from three other families. In an autochthonous model of pancreatic ductal adenocarcinoma the mice had cancer-cell-specific CD8 T cells and, like human patients, did not respond to anti-CTLA-4 or anti-PD-L1. Depleting the carcinoma-associated fibroblasts that express fibroblast activation protein achieved immune control - and, decisively, uncovered the antitumour effects of both checkpoint antagonists, so the immunosuppressive activity of that one stromal population accounts for their failure. Three observations identify the mediator: T cells were absent from the regions containing cancer cells, the cancer cells were coated with CXCL12, and the FAP-positive fibroblast was the principal source of it. Inhibiting the receptor with AMD3100 induced rapid T-cell accumulation among the cancer cells and acted synergistically with anti-PD-L1, leaving a residual tumour of only premalignant epithelial and inflammatory cells. The authors' own summary is the useful form: a single protein from a single stromal cell type may direct immune evasion in this model.", "limit": "One autochthonous mouse model of one tumour type. Depletion removes a marker-defined population rather than the chemokine, and the companion result in the same disease shows that depleting a differently marked fibroblast population does the opposite (L111) - so the effect belongs to the FAP-positive subset as defined here and must not be read as a property of fibroblasts. No CXCL12 concentration, coating density or exclusion distance is given, which is the quantity the mechanism implies and the same class of missing length scale this atlas has collected elsewhere.", "provenance": "Abstract read in full; the checkpoint non-response, the depletion and unmasking results, all three chemokine observations, and the receptor inhibition outcome as reported", "quantitativeExtraction": "extracted" }, "L111": { "id": "L111", "year": 2014, "topic": "Negative clinical comparator", "title": "Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival", "url": "https://doi.org/10.1016/j.ccr.2014.04.005", "studyType": "Transgenic depletion of alpha-SMA-positive myofibroblasts in mouse pancreatic cancer at two disease stages, with human survival correlation, Cancer Cell 25(6):719-734", "diseaseContext": "Pancreatic", "useInModel": "The opposite answer to the same question in the same disease, and the reason this family's sign depends on which marker defines the cells removed. Deleting alpha-SMA-positive myofibroblasts - starting either at the non-invasive precursor stage or at established carcinoma - produced invasive, undifferentiated tumours with enhanced hypoxia, epithelial-to-mesenchymal transition and cancer stem cells, and diminished survival. The human correlate points the same way: patients whose tumours had fewer myofibroblasts had reduced survival. Immune surveillance was suppressed in the depleted tumours with increased regulatory T cells. Depleted tumours did not respond to gemcitabine, while anti-CTLA-4 reversed the disease acceleration and prolonged survival. The authors' conclusion is a caution against targeting these cells in this disease. Three things follow for this atlas. The enhanced hypoxia on depletion ties this family to the oxygen and pressure work rather than only to immunology. The human survival correlation makes the stroma net protective in patients, which is the third independent line against treating it as a barrier to be removed. And in both this result and its opposite, a checkpoint antibody determined what the stromal manipulation amounted to.", "limit": "Transgenic depletion of a marker-defined population in mouse, with the human evidence a correlation between myofibroblast abundance and survival rather than an intervention. Depletion at two stages is a strength and still does not separate which myofibroblast function - matrix, mechanical support, signalling - carries the protection. The contradiction with the FAP-targeted result (L110) is not resolved by either paper: the marker-defined sets may overlap partially, and no study the atlas holds measures that overlap.", "provenance": "Abstract read in full; both depletion timings and their phenotypes, the human survival correlation, the regulatory T cell increase, and both drug results as reported", "quantitativeExtraction": "extracted" }, "L113": { "id": "L113", "year": 2024, "topic": "Non-cell-autonomous toxicity", "title": "Endurance exercise has a negative impact on the onset of SOD1-G93A ALS in female mice and affects the entire skeletal muscle-motor neuron axis", "url": "https://doi.org/10.3389/fphar.2024.1360099", "studyType": "Eight weeks of intense treadmill endurance training from 35 days of age in female SOD1-G93A and wild-type mice with histological and molecular analysis along the axis, Front Pharmacol 15:1360099", "diseaseContext": "ALS", "useInModel": "An intervention applied to muscle changed the timing of a motor neuron disease and propagated up the whole axis, which makes this family upstream rather than a readout. Intense endurance training anticipated onset by about a week - 63.17 plus or minus 2.25 days in trained animals against 70.75 plus or minus 2.45 in sedentary ones - and hastened the muscle's switch to a more oxidative phenotype. It worsened denervation by dismantling neuromuscular junctions in the tibialis anterior, enhanced Wallerian degeneration in the sciatic nerve, and promoted motor neuron loss in the spinal cord, while exacerbating neuroinflammation with immune cell infiltration in the nerve and faster activation of astrocytes and microglia in the cord. The authors state the direction explicitly: the exercise acts on skeletal muscle and worsens the pathological hallmarks. Read with the staged timeline (L112), the two results agree from opposite directions - observation finds the distal end failing first, and perturbing the distal end accelerates everything proximal to it, glial activation included.", "limit": "Female mice only, one transgenic model, and one exercise protocol described as intense - the authors note the literature is debated partly because protocols and intensities differ, so this does not establish what moderate activity does. Twelve animals per group. Onset is defined by the study's own strength and motor measures. Nothing here separates mechanical load, metabolic switch and oxidative stress as the operative cause.", "provenance": "Abstract read in full; both onset ages with their spreads, the oxidative switch, all three levels of the axis affected, and the glial and immune findings as reported", "quantitativeExtraction": "extracted" }, "L115": { "id": "L115", "year": 2013, "topic": "Recruitment and synapse", "title": "Autonomic nerve development contributes to prostate cancer progression", "url": "https://doi.org/10.1126/science.1236361", "studyType": "Mouse prostate cancer models with surgical and chemical denervation and stromal receptor deletion, plus a retrospective blinded analysis of 43 human prostate adenocarcinoma specimens, Science 341(6142):1236361", "diseaseContext": "Prostate", "useInModel": "Innervation is a microenvironment variable this atlas has never carried, and in a drawn environment it turns out to be stage-specific and to act through a relay. Formation of autonomic nerve fibres in the prostate gland regulated cancer development and dissemination in mouse models. The early phases were prevented by chemical or surgical sympathectomy and by genetic deletion of stromal beta-2 and beta-3 adrenergic receptors; tumours were separately infiltrated by parasympathetic cholinergic fibres that promoted dissemination, and cholinergic invasion and metastasis were inhibited by blocking or deleting the stromal type 1 muscarinic receptor, which improved survival. Two features matter most. The receptors that carry the effect are on stroma, not on the cancer cell - so the pathway is nerve to stroma to tumour, a two-step relay no family in this atlas currently represents, and a model that lets a neural input act directly on a tumour cell would be wrong at the first step. And the two branches act at different stages, sympathetic for initiation and parasympathetic for spread. In 43 patients analysed blind, the densities of sympathetic fibres in tumour and of parasympathetic fibres in the surrounding normal tissue were each associated with poor clinical outcome - a stainable spatial measurement in two named compartments.", "limit": "Mouse models for all the causal work, with the human evidence a retrospective blinded association in 43 specimens rather than an intervention. The two fibre densities were associated with outcome in different compartments, so the measurement is compartment-specific and not a single nerve density. Denervation is a regional manipulation and the stromal receptor deletions do not identify which stromal cell carries them, which is the step a model would need.", "provenance": "Abstract read in full; both branches and their stage-specific effects, the stromal location of the receptors, the survival benefit, and the human cohort size and compartment-specific associations as reported", "quantitativeExtraction": "extracted" }, "L116": { "id": "L116", "year": 2016, "topic": "Matrix and movement", "title": "Schwann cells induce cancer cell dispersion and invasion", "url": "https://doi.org/10.1172/JCI82658", "studyType": "Histology of murine and human perineural invasion specimens with dorsal root ganglion coculture, live imaging and NCAM1-deficient mice, J Clin Invest 126(4):1538-1554", "diseaseContext": "Shared cancer", "useInModel": "The fifth finding in this atlas that cells travel along structures, and the first where the structure does the directing. Cancers extend along nerves by perineural invasion, which carries a poor prognosis, and here Schwann cells promote that invasion through direct contact with cancer cells. Histology of murine and human specimens identified a subpopulation of Schwann cells associating with cancer cells; in coculture with dorsal root ganglion extracts those cells directed cancer cells to migrate toward nerves and promoted invasion contact-dependently. On contact they induced cancer cell protrusions in their own direction and intercalated between the cancer cells, dispersing them. The process required Schwann cell NCAM1, and NCAM1-deficient mice showed decreased neural invasion and less paralysis. The framing the authors give is the part to carry: this behaviour reflects normal Schwann cell programmes typically activated in nerve repair, exploited instead by cancer cells. The atlas's four earlier findings had cells following matrix, collagen fibres, vessels and fibroblastic tracks passively; this one is active guidance by the cells of the track.", "limit": "Coculture with ganglion extracts for the mechanism, with human evidence limited to histological identification of the associating Schwann cell subpopulation in perineural invasion specimens. The NCAM1 requirement is established for process formation and neural invasion in mouse, not quantified as a contribution to human disease. No contact duration, dispersion distance or invasion rate is given, so the guidance is established as a mechanism without the geometry a spatial model would need.", "provenance": "Abstract read in full; the contact dependence, the directed migration and intercalation, the NCAM1 requirement with its mouse phenotype, and the hijacked-repair framing as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I037", "name": "Skeletal muscle and satellite cells", "category": "Stroma", "whereToCheck": "ALS motor unit; nearby tumor tissue", "states": [ "Contracting", "denervated", "regenerating" ], "behaviors": [ "NMJ function", "force", "repair" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-1", "hatton-906" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-1", "hatton-906" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "sender-I037-myocytes" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-1", "hatton-906", "sender-I037-myocytes" ], "priorResearch": { "path": "simulation/data/profiles/skeletal-muscle-and-satellite-cells.json", "summary": "The inventory places this family in the ALS motor unit and names contracting, denervated and regenerating states with neuromuscular junction function, force and repair - and it is the row where the atlas's thinnest behaviour finally has evidence. Three findings organise it. The disease arrives here first: in the standard model, 40% of end-plates were denervated at 47 days with no ventral root or cell body loss, 60% of ventral root axons were gone by 80 days with still no motor neuron loss, and motor neuron loss was only well underway by 100 of a 131-day lifespan, with a human autopsy showing muscle denervation and reinnervation alongside normal-appearing motor neurons (L112). This family is also upstream rather than a readout: intense endurance training applied to the muscle brought onset forward by about a week and propagated up the axis, dismantling junctions, enhancing nerve degeneration, promoting motor neuron loss and accelerating glial activation (L113). And repair is present and blocked rather than absent - human ALS satellite cells proliferate well and fail to complete the myogenic programme, losing the ability to restore mature fibres (L114).", "stateAxes": [ { "axis": "Denervated - and it comes first", "whatToMeasure": "The fraction of end-plates denervated, staged against ventral root axon loss and motor neuron counts in the same animals - 40% at 47 days with the cell bodies intact, 60% of root axons gone at 80 days with the neurons still present.", "interpretationLimit": "One transgenic model at these ages; the percentages are stage markers for that model and not human stage boundaries. The human evidence is one sporadic case who died unexpectedly, which is what makes it informative and also a single case. Absence of cell body loss at a timepoint is a negative on what was measured.", "evidence": [ "L112" ] }, { "axis": "Regenerating - present, proliferating, and not completing", "whatToMeasure": "Progression through the myogenic programme rather than satellite cell number, since proliferative potential was high while differentiation into mature fibres failed, with lower differentiation factor and mature myosin expression.", "interpretationLimit": "Human cells assessed in vitro after isolation, in small numbers, with expression measured relative to controls. Whether the block is intrinsic to the satellite cell or imposed by the denervated muscle it came from is unresolved - and that is the question deciding whether a model puts the term on the cell or on its environment.", "evidence": [ "L114" ] }, { "axis": "Contracting - and load changes the disease", "whatToMeasure": "Mechanical load and its consequences along the whole axis, since intense endurance training applied to the muscle brought onset forward by about a week and worsened junction, nerve, neuron and glial measures together.", "interpretationLimit": "Female mice only, one model, one protocol described as intense - the authors note the field is divided partly because protocols differ, so nothing here speaks to moderate activity. Mechanical load, metabolic switch and oxidative stress are not separated as causes.", "evidence": [ "L113" ] }, { "axis": "Force and junction function - named by the inventory, unmeasured here", "whatToMeasure": "Force output and transmission at the junction, which is the functional endpoint the inventory asks for and the one a motor-unit model would be scored on.", "interpretationLimit": "The atlas holds strength and motor measures only as the means by which one study defined onset, with no force value, transmission measure or motor unit count in any record - so the behaviour is named, used as a timing instrument, and never reported as a quantity.", "evidence": [ "L113" ] } ], "records": { "L112": { "id": "L112", "year": 2004, "topic": "Non-cell-autonomous toxicity", "title": "Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man", "url": "https://doi.org/10.1016/j.expneurol.2003.10.004", "studyType": "Spatiotemporal quantification at neuromuscular junctions, ventral roots and spinal cord across ages in SOD1-G93A mice, with one human autopsy, Exp Neurol 185(2):232-240", "diseaseContext": "ALS", "useInModel": "A staged timeline with percentages, which this atlas has almost nowhere else, and it runs the opposite way to the obvious model. In SOD1-G93A mice - clinically weak at 80 days and dead at 131 plus or minus 5 - 40% of end-plates were already denervated at 47 days with no evidence of ventral root or cell body loss; at 80 days 60% of ventral root axons were lost with still no loss of motor neurons; and motor neuron loss was only well underway by 100 days. The disease begins at the distal axon and proceeds dying back. Two further details carry weight. Microglial and astrocytic activation around motor neurons was not identified until after distal axon degeneration had begun - so in this environment glia are downstream, which is the opposite temporal position to the complement-at-synapses-before-plaques finding the atlas records for Alzheimer's disease. And the single human autopsy showed denervation and reinnervation changes in muscle alongside normal-appearing motor neurons, which is the same ordering and also evidence that repair was active and losing. A model that starts this disease at the motor neuron has the causality backwards.", "limit": "One transgenic mouse model, and the human evidence is a single sporadic case who died unexpectedly - informative precisely because death was not from end-stage disease, and a single case. The percentages are for this model at these ages and should not be carried as human stage boundaries. Absence of cell body loss at a timepoint is a negative on the measurements made, not proof that nothing had changed in the cell body.", "provenance": "Abstract read in full; all four timepoints with their percentages, the glial timing, and the human autopsy findings as reported", "quantitativeExtraction": "extracted" }, "L113": { "id": "L113", "year": 2024, "topic": "Non-cell-autonomous toxicity", "title": "Endurance exercise has a negative impact on the onset of SOD1-G93A ALS in female mice and affects the entire skeletal muscle-motor neuron axis", "url": "https://doi.org/10.3389/fphar.2024.1360099", "studyType": "Eight weeks of intense treadmill endurance training from 35 days of age in female SOD1-G93A and wild-type mice with histological and molecular analysis along the axis, Front Pharmacol 15:1360099", "diseaseContext": "ALS", "useInModel": "An intervention applied to muscle changed the timing of a motor neuron disease and propagated up the whole axis, which makes this family upstream rather than a readout. Intense endurance training anticipated onset by about a week - 63.17 plus or minus 2.25 days in trained animals against 70.75 plus or minus 2.45 in sedentary ones - and hastened the muscle's switch to a more oxidative phenotype. It worsened denervation by dismantling neuromuscular junctions in the tibialis anterior, enhanced Wallerian degeneration in the sciatic nerve, and promoted motor neuron loss in the spinal cord, while exacerbating neuroinflammation with immune cell infiltration in the nerve and faster activation of astrocytes and microglia in the cord. The authors state the direction explicitly: the exercise acts on skeletal muscle and worsens the pathological hallmarks. Read with the staged timeline (L112), the two results agree from opposite directions - observation finds the distal end failing first, and perturbing the distal end accelerates everything proximal to it, glial activation included.", "limit": "Female mice only, one transgenic model, and one exercise protocol described as intense - the authors note the literature is debated partly because protocols and intensities differ, so this does not establish what moderate activity does. Twelve animals per group. Onset is defined by the study's own strength and motor measures. Nothing here separates mechanical load, metabolic switch and oxidative stress as the operative cause.", "provenance": "Abstract read in full; both onset ages with their spreads, the oxidative switch, all three levels of the axis affected, and the glial and immune findings as reported", "quantitativeExtraction": "extracted" }, "L114": { "id": "L114", "year": 2014, "topic": "RNA processing and rescue", "title": "Skeletal muscle satellite cells in amyotrophic lateral sclerosis", "url": "https://doi.org/10.3109/01913123.2014.937842", "studyType": "Satellite cells isolated from human ALS muscle biopsies with ultrastructural, immunophenotypic and expression analysis against controls, Ultrastruct Pathol 38(4):295-302", "diseaseContext": "ALS", "useInModel": "The atlas's first specific repair failure, in human tissue, and the failure mode is not the obvious one. Satellite cells isolated from human ALS muscle biopsies had high proliferative potential - so the repair compartment is not depleted or quiescent - and their capacity to proceed through the myogenic programme and form myotubes was altered compared with controls, with abnormal morphology carrying numerous vacuoles and lower Myf-4 and myosin heavy chain expression. The authors' conclusion is that these cells lose the ability to regenerate and restore mature myofibres. Across forty-nine written families this atlas has collected killing, suppression, exclusion, obstruction and clearance, and almost nothing on repair; the first entry is therefore not an absent reparative term but a blocked one - proliferation intact, differentiation failing. That distinction matters for a model, because a repair compartment that proliferates without completing will behave quite differently from one that is simply too small.", "limit": "Cells isolated from human biopsies and assessed in vitro, so the differentiation failure is demonstrated outside the tissue and the number of patients is small. Expression differences are relative to controls rather than absolute, and nothing here establishes whether the block is intrinsic to the satellite cell or imposed by the denervated muscle it came from - which is the question that would decide where the term belongs in a model.", "provenance": "Abstract read in full; the preserved proliferation, the altered myogenic progression, the morphology and the two expression findings as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I038", "name": "Organ smooth muscle", "category": "Stroma", "whereToCheck": "Bladder wall; bowel; prostate; uterus", "states": [ "Contractile", "remodeled" ], "behaviors": [ "Mechanics", "signaling", "invasion boundaries" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-672", "hatton-838" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-672", "hatton-838" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-672", "hatton-838" ], "priorResearch": { "path": "simulation/data/profiles/organ-smooth-muscle.json", "summary": "Normally this family is the organ's contractile wall - the detrusor of the bladder, the muscularis of the bowel, the smooth-muscle-rich stroma of the prostate, the myometrium. What makes the row unlike every other stromal family is that its boundary is a staging boundary. Whether a bladder tumour has reached the detrusor is what separates intravesical therapy from cystectomy, and that geometric fact is measured badly: the detrusor was present in the initial resection specimen in 30 to 100 percent of cases across series, residual tumour was found at repeat resection in 20 to 71 percent of T1 cases, and upstaging to muscle-invasive disease ranged from 0 to 32 percent (L127) - against a pooled contemporary estimate of 2.8 percent, with the discrepancy partly definitional and the rate itself improved by how the tissue is cut (L128). The remodelled state has two descriptions. In prostate it is an area fraction with a threshold: above 34 percent of tumour area showing reactive stromal architecture, cancer-specific death rose with hazard ratios of 2.94 and 2.64 in two cohorts and biochemical recurrence with 1.51 in a third, independent of Gleason and PSA (L129). In bowel it is a cell phenotype: proliferating smooth muscle cells that progressively lose their own markers, carry PDGFR-beta, hold HIF1-alpha stably, and do not respond to TGF-beta (L130).", "stateAxes": [ { "axis": "Contractile, and still expressing the panel", "whatToMeasure": "The discriminating markers rather than the shared one - smooth muscle myosin heavy chain and gamma-2 actin rather than alpha-SMA - since the canonical entry is shared with myofibroblasts whose depletion in the fibroblast row gave opposite outcomes depending on which marker defined them.", "interpretationLimit": "No contractile force, layer thickness or stiffness is carried by any record in this atlas for this family, so the contractile state is identifiable and not quantifiable. The mechanics the inventory asks for are unserved by a number.", "evidence": [ "L130" ] }, { "axis": "Remodelled, measured as an area fraction", "whatToMeasure": "Percentage of tumour area with reactive stromal architecture, against the 34 percent cut-point, read by a trained classifier on digitised sections.", "interpretationLimit": "An architectural fraction rather than a measurement of smooth muscle content - it does not say how much of the reactive area is lost smooth muscle. Retrospective cohorts, a cut-point developed and then tested rather than derived, differing endpoints between cohorts, and the smallest hazard ratio in the largest cohort.", "evidence": [ "L129" ] }, { "axis": "Remodelled, measured as a cell phenotype", "whatToMeasure": "Proliferation together with loss of the family's own markers, acquisition of PDGFR-beta, stable HIF1-alpha, responsiveness to PDGF-BB and - as a negative - unresponsiveness to TGF-beta.", "interpretationLimit": "Rat, chemically induced colitis, stricturing in a subset, and the TGF-beta and ischaemia results come from cells cultured out of the wall. Inflammatory bowel disease is not a drawn environment, so this transfers to the behaviour of the bowel wall rather than to any tumour.", "evidence": [ "L130" ] }, { "axis": "Breached or not - a position, not a quantity", "whatToMeasure": "Whether tumour has reached the muscle layer, and separately whether the layer was in the specimen at all, since its absence independently predicts that the stage will change on re-resection.", "interpretationLimit": "The atlas's only variable that is a binary clinical classification rather than a concentration or density, and the one whose observation error is best documented. The two reviews disagree on the upstaging rate by an order of magnitude for partly definitional reasons, so this is a disputed quantity to run at both ends rather than to choose. Bladder is blueprinted and not drawn.", "evidence": [ "L127", "L128" ] } ], "records": { "L127": { "id": "L127", "year": 2018, "topic": "Muscle invasion boundary", "title": "Repeat Transurethral Resection in Non-muscle-invasive Bladder Cancer: A Systematic Review", "url": "https://doi.org/10.1016/j.eururo.2018.02.014", "studyType": "Systematic review of 31 studies and 8,409 patients with high-grade Ta and T1 bladder cancer, screened from 15,209 manuscripts, European Urology 73(6):925-933", "diseaseContext": "Bladder cancer", "useInModel": "This is the only family in the inventory whose anatomical boundary is also a staging boundary with a treatment decision attached, and this record measures how badly that boundary is observed. Detrusor muscle - the layer whose invasion defines the boundary - was present in the initial resection specimen in 30 to 100 percent of cases depending on the series. Residual tumour at repeat resection was found in 17 to 67 percent of Ta cases and 20 to 71 percent of T1 cases, and 36 to 86 percent of residual tumours were at the original resection site. Upstaging occurred in 0 to 8 percent from Ta to T1 or beyond and 0 to 32 percent from T1 to muscle-invasive or beyond. For a simulation the useful part is not the rates but what they are rates of: the thing being classified is a geometric relationship between a tumour and a muscle layer, the classification changes the treatment from intravesical therapy to cystectomy, and in some series the layer that defines it was not in the specimen at all. The atlas's other rows are uncertain about quantities; this one is uncertain about a position.", "limit": "Ranges across heterogeneous studies rather than pooled estimates, and the review says plainly that data on whether repeat resection changes recurrence or cancer-specific mortality conflict. The wide bands are partly real variation in surgical practice and partly differing definitions - some series count any stage increase and others only progression to muscle invasion. Restricted to high-grade Ta and T1, so these are not rates for bladder cancer generally. Bladder was blueprinted and not yet drawn when this record was written and is now a drawn environment, which became a drawn environment on 2026-10-14.", "provenance": "Abstract read in full; the detrusor presence range, both residual tumour ranges, the resection-site proportion, both upstaging ranges and the stated conflict on outcomes as reported", "quantitativeExtraction": "extracted" }, "L128": { "id": "L128", "year": 2024, "topic": "Muscle invasion boundary", "title": "Repeat Transurethral Resection for Non-muscle-invasive Bladder Cancer: An Updated Systematic Review and Meta-analysis in the Contemporary Era", "url": "https://doi.org/10.1016/j.euf.2023.07.002", "studyType": "Systematic review and meta-analysis of 81 studies with confounder-adjusted synthesis, European Urology Focus 10(1):41-56", "diseaseContext": "Bladder cancer", "useInModel": "Pools what the earlier review could only range over, and disagrees with it. For T1 patients initially treated with conventional resection in the 2010s, any residual tumour at repeat resection was 31.4 percent (95% CI 26.0-37.2) and upstaging was 2.8 percent (95% CI 2.0-3.8) - both significantly lower than in patients treated in the 1990s and 2000s. En bloc resection and visual enhancement-guided resection both improved residual tumour rates against conventional resection on matched-cohort and multivariable analysis. Patients who had a repeat resection had better recurrence-free survival (HR 0.78, 95% CI 0.62-0.97) and overall survival (HR 0.86, 95% CI 0.81-0.93) but not better progression-free survival. Two things for the model. The 2.8 percent pooled upstaging sits against the 0 to 32 percent range of the earlier review, which is a disputed quantity of the kind this project already handles by running both ends rather than choosing. And the technique dependence says the measurement is partly a property of the observer: how the tissue is cut changes how often the boundary is called correctly, which is an observation model rather than biology.", "limit": "The contemporary estimate is narrower in scope than the range it appears to contradict - restricted to T1, conventional resection, and the 2010s - so the two are not straightforwardly comparable and the disagreement is partly definitional. The authors note potential publication bias in the temporal comparison. Better survival with repeat resection is from confounder-adjusted observational synthesis, not randomisation, and progression-free survival did not improve, which argues against reading the survival difference as a treatment effect on the tumour. Bladder is blueprinted and not drawn.", "provenance": "Abstract read in full; both pooled rates with confidence intervals, the temporal comparison, the technique comparisons and all three survival outcomes as reported", "quantitativeExtraction": "extracted" }, "L129": { "id": "L129", "year": 2022, "topic": "Remodeled stroma", "title": "Development and validation of a quantitative reactive stroma biomarker (qRS) for prostate cancer prognosis", "url": "https://doi.org/10.1016/j.humpath.2022.01.009", "studyType": "Digital image analysis and machine learning biomarker developed in 482 radical prostatectomy cases and validated in two independent cohorts of 332 and 988, Human Pathology 122:84-91", "diseaseContext": "Prostate cancer", "useInModel": "Gives the atlas something it has almost none of: a stromal state with a numerical threshold, an effect size, and independent validation. Quantitative reactive stroma is the percentage of tumour area with a distinct reactive stromal architecture. Above 34 percent, risk of prostate cancer-specific death rose with a hazard ratio of 2.94 in the development cohort of 482 and 2.64 in a validation cohort of 332, and biochemical recurrence rose with a hazard ratio of 1.51 in a third cohort of 988. The association held on multivariate analysis against Gleason score and PSA. The point for this row is what is being measured: the host's stromal response, not the tumour, carrying prognostic information that the tumour's own grade does not contain. In a prostate whose normal stroma is smooth-muscle-rich, the reactive architecture is where the contractile state has been replaced - so this is the remodelled state of this family given an area fraction, a cut-point and three cohorts.", "limit": "Retrospective cohorts, and the biomarker is an architectural area fraction read by a trained classifier rather than a measurement of smooth muscle content - it does not report how much of the reactive area is lost smooth muscle. The 34 percent cut-point was developed and then tested rather than derived from mechanism. Endpoints differ between cohorts, with cancer-specific death in two and biochemical recurrence in the third, and the hazard ratio in the largest cohort is the smallest. Prostate is a drawn environment, which makes this one of the few stromal thresholds inside the atlas's own scope.", "provenance": "Abstract read in full; the 34 percent threshold, all three cohort sizes, all three hazard ratios with their p values and endpoints, and the multivariate independence claim as reported", "quantitativeExtraction": "extracted" }, "L130": { "id": "L130", "year": 2020, "topic": "Remodeled stroma", "title": "M2 Macrophages and Phenotypic Modulation of Intestinal Smooth Muscle Cells Characterize Inflammatory Stricture Formation in Rats", "url": "https://doi.org/10.1016/j.ajpath.2020.05.015", "studyType": "Rat trinitrobenzenesulfonic acid colitis model with timed histology of the neuromuscular layers plus a derived cell culture model, American Journal of Pathology 190(9):1843-1858", "diseaseContext": "Inflammatory bowel stricture", "useInModel": "Characterises the remodelled state this row's inventory asks for, and does it with four features that each connect to another row. The stricturing smooth muscle cells proliferate while progressively losing their phenotypic markers - so the state the atlas most needs to detect is the state that stops staining for this family. They express PDGFR-beta and are hyperproliferative to PDGF-BB, which moves them onto the mural axis the atlas already carries. They hold hypoxia-inducible factor 1-alpha stably and the culture model shows this improves survival and growth under experimental ischaemia, which is an oxygen-coupled behaviour rather than a cytokine one. And they are unresponsive to TGF-beta - a direct negative against the canonical fibrosis signal, in a fibrotic process, with collagen I and III rising at the same time. The infiltrate in the neuromuscular layers is eosinophils, T cells and arginase-positive CD163/CD206 macrophages, which puts an arginine-consuming population in the muscle layer the atlas has elsewhere recorded as a metabolic exchange with no flux.", "limit": "Rat, and a chemically induced colitis rather than a spontaneous disease, with stricturing in only a subset of animals. Inflammatory bowel disease is not among the drawn environments; the transfer is to the geometry and cell behaviour of the bowel wall rather than to colorectal cancer, and this record should not be read as evidence about a tumour. The TGF-beta unresponsiveness and the ischaemic adaptation are properties of the cultured stricture phenotype, so they are claims about cells taken out of the wall. No stiffness, layer thickness or contractile force is reported, so the mechanics the inventory asks for remain unserved by a number.", "provenance": "Abstract read in full; the marker loss with continued proliferation, PDGFR-beta and PDGF-BB responsiveness, stable HIF1-alpha with ischaemic survival advantage, TGF-beta unresponsiveness, the collagen increase and the M2 marker panel as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I039", "name": "Prostate luminal and basal epithelium", "category": "Parenchyma", "whereToCheck": "Prostate primary and normal reference", "states": [ "Androgen state", "differentiation", "malignant clone" ], "behaviors": [ "Barrier", "target accessibility", "secretion", "growth" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-892", "hatton-896" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-892", "hatton-896" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-892", "hatton-896" ], "priorResearch": { "path": "simulation/data/profiles/prostate-luminal-and-basal-epithelium.json", "summary": "This is the first parenchymal row and the first family in the atlas that is itself the disease rather than a bystander to it, which changes what the profile is for: the question is not how this family responds to the tumour but what surface it presents and what state it is in. Three findings organise it. The androgen state and the malignant clone are one coupled variable in most of these tumours, because the recurrent TMPRSS2 fusion puts ERG or ETV1 under androgen-responsive promoter elements - 23 of 29 samples carried such a rearrangement, and lowering androgen signalling lowers the oncogene with it (L131). The differentiation axis has a mechanism that is metabolic and epigenetic: neuroendocrine disease makes its own serotonin, recaptures it, and uses it to serotonylate histones at H3K4me3Q5, driving the lineage switch with androgen receptor signalling suppressed (L133). And target accessibility is served by the atlas's clearest example of a molecule delivered to an address - PSMA radioligand therapy, with the address imaged in the patient before dosing, extending median overall survival from 11.3 to 15.3 months (L132).", "stateAxes": [ { "axis": "Androgen state, which is also the oncogene's switch", "whatToMeasure": "Androgen receptor signalling output together with fusion status, since in a fusion-positive cell the androgen-responsive promoter elements of TMPRSS2 are what drive ERG or ETV1 - so the two cannot be measured as independent variables.", "interpretationLimit": "The coupling is established from a 29-sample series and cell line promoter work. The 23 of 29 rearrangement frequency should not be carried forward as a prevalence, since later work puts ERG fusions nearer half of prostate cancers. The atlas holds no ERG protein measurement and no fusion status in any drawn environment.", "evidence": [ "L131" ] }, { "axis": "Differentiation, driven by a metabolite on chromatin", "whatToMeasure": "Intracellular serotonin and histone serotonylation at H3K4me3Q5 alongside the neuroendocrine markers, since the lineage state is downstream of a small molecule the cell synthesises through AADC and recaptures through SLC6A4 - which makes the state a concentration in principle rather than a label.", "interpretationLimit": "Mouse and patient-derived xenograft models with no human intracellular serotonin concentration and no serotonylation level in patient tissue. The suppression of androgen receptor signalling is reported as an association, so the ordering between lineage switch and androgen signalling loss is unsettled. No record here gives the prevalence of neuroendocrine disease.", "evidence": [ "L133" ] }, { "axis": "Address density, and whether it was verified in vivo", "whatToMeasure": "PSMA positivity by gallium-68 PSMA-11 PET in the patient before dosing, which is how the radioligand trial selected its population - the atlas's only marker read in three dimensions in a living patient rather than from a section.", "interpretationLimit": "Positivity as an eligibility call, not a density: no tumour PSMA concentration, administered activity per gram or absorbed dose is given, so accessibility is demonstrated clinically and not parameterised. The roughly 30 percent of screened patients not randomised are outside everything this record supports.", "evidence": [ "L132" ] }, { "axis": "Malignant clone - present, and not quantified anywhere", "whatToMeasure": "Fusion status and the basal versus luminal composition the inventory asks for, against a normal reference.", "interpretationLimit": "This is the row's weakest axis despite being the one the inventory names. The atlas holds no basal-to-luminal ratio, no clone fraction and no normal prostate reference measurement for this family in any environment, so differentiation is described mechanistically and not as a composition.", "evidence": [ "L131", "L133" ] } ], "records": { "L131": { "id": "L131", "year": 2005, "topic": "Malignant clone", "title": "Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer", "url": "https://doi.org/10.1126/science.1117679", "studyType": "Outlier expression bioinformatics with fluorescence in situ hybridisation in 29 prostate cancer samples and cell line promoter experiments, Science 310(5748):644-648", "diseaseContext": "Prostate cancer", "useInModel": "Couples this family's two state axes to each other instead of letting them run independently. Two ETS transcription factors, ERG and ETV1, were found as expression outliers in prostate cancer and traced to recurrent fusions of the 5' untranslated region of TMPRSS2 to either of them; 23 of 29 samples carried a rearrangement in ERG or ETV1. The part that matters for a simulation is the promoter result: the androgen-responsive promoter elements of TMPRSS2 are what drive the overexpression of the ETS family member. So androgen signalling in this family is not only a growth input - in a cell carrying the fusion it is also the transcriptional switch on the oncogene. The androgen state and the malignant clone are therefore one coupled variable in most of these tumours rather than two, and the coupling direction is fixed: lowering androgen signalling lowers the oncogene's expression.", "limit": "29 samples, and the rearrangement frequency from a small series read by in situ hybridisation - later work put ERG fusion prevalence near half of prostate cancers rather than the 79 percent this series shows, so the proportion should not be carried forward from here. The promoter mechanism is from cell lines. Nothing here says what the fusion does to the cell's behaviour, so this record establishes the coupling and not its consequences, and the atlas holds no measurement of ERG protein or of fusion status in any drawn environment.", "provenance": "Abstract read in full; both fused partners, the 23 of 29 count, and the androgen-responsive promoter mechanism as reported. The prevalence caveat is flagged as a limit rather than asserted as a figure", "quantitativeExtraction": "extracted" }, "L132": { "id": "L132", "year": 2021, "topic": "Target accessibility", "title": "Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer", "url": "https://doi.org/10.1056/NEJMoa2107322", "studyType": "International open-label phase 3 randomised trial, 831 of 1,179 screened patients randomised 2:1, median follow-up 20.9 months, NEJM 385(12):1091-1103, NCT03511664", "diseaseContext": "Prostate cancer", "useInModel": "The closest thing in this atlas to what the project is trying to simulate: a molecule administered systemically, finding a surface address on this family, and delivering a payload - with the address imaged in the living patient first. Patients had to have PSMA-positive gallium-68 PSMA-11 PET-CT scans to enter, and 831 of 1,179 screened were randomised. Added to standard care, 7.4 GBq every six weeks for four to six cycles prolonged imaging-based progression-free survival from 3.4 to 8.7 months (HR 0.40, 99.2% CI 0.29-0.57) and overall survival from 11.3 to 15.3 months (HR 0.62, 95% CI 0.52-0.74), with all key secondary endpoints favouring it, grade 3 or above adverse events in 52.7 versus 38.0 percent, and quality of life not adversely affected. Three things follow. This is an intervention whose target performs no function the therapy cares about - PSMA is an address, not a driver - which is a mechanism class the atlas's intervention ledger does not yet contain. Its effect has a physical rather than biological length scale, since beta particles reach the PSMA-expressing cell and the surrounding microenvironment. And the address was verified in three dimensions in the patient before dosing, which no other marker in this atlas is.", "limit": "Open-label, and the comparator was standard care with chemotherapy, immunotherapy, radium-223 and investigational drugs excluded by protocol - so the control arm is narrower than real alternatives and the effect size should not be read as against best available care. Entry required a positive PSMA PET, so these results apply to the selected population and say nothing about the roughly 30 percent of screened patients who were not randomised. Heavily pretreated castration-resistant disease after an androgen-receptor pathway inhibitor and taxanes. No tumour PSMA density, administered activity per gram, or absorbed dose is given here, so the delivery is demonstrated clinically and not parameterised - and the beta-particle range is not stated as a distance.", "provenance": "Abstract read in full including the results tail; the screening and randomisation counts, dosing schedule, both primary endpoints with medians, hazard ratios and confidence intervals, the adverse event rates and the PET entry requirement as reported", "quantitativeExtraction": "extracted" }, "L133": { "id": "L133", "year": 2026, "topic": "Differentiation", "title": "Serotonin Modulates Lineage Plasticity in Neuroendocrine Prostate Cancer via Epigenetic Reprogramming", "url": "https://doi.org/10.1158/2159-8290.CD-25-0974", "studyType": "Mechanistic study in genetically engineered and patient-derived xenograft models with a repurposed inhibitor, Cancer Discovery 16(4):760-780", "diseaseContext": "Prostate cancer", "useInModel": "Supplies the differentiation axis with a mechanism, and it is a metabolite acting on chromatin rather than a signalling pathway. Neuroendocrine prostate cancer synthesises serotonin itself through aromatic L-amino acid decarboxylase and takes it back up through the SLC6A4 transporter; high intracellular serotonin promotes histone serotonylation at H3K4me3Q5, reconfiguring the H3K4me3 landscape and the gene expression downstream of it, which drives neuroendocrine differentiation and is associated with suppressed androgen receptor signalling. Inhibiting serotonin synthesis with carbidopa, an already approved drug, impaired tumour growth and prolonged survival in both model types. For this atlas it does three jobs. It makes the differentiation state a consequence of a small molecule the cell makes and recaptures, so the state is in principle a concentration rather than a label. It puts a neurotransmitter inside the tumour cell acting on its own chromatin, which is a different relationship from the nerve rows where the transmitter arrived from outside and was read by a stromal receptor. And it ties the differentiation axis to the androgen axis in the opposite direction from the fusion record - here the neuroendocrine programme comes with androgen receptor signalling suppressed, which is the state in which an androgen-directed therapy has nothing to act on.", "limit": "Mouse and patient-derived xenograft models, with no human intracellular serotonin concentration, no serotonylation level in patient tissue, and no clinical result for carbidopa in this disease - the repurposing is a preclinical vulnerability rather than an established treatment. The association with suppressed androgen receptor signalling is stated as an association, so the direction between lineage switch and androgen signalling loss is not settled here. Prostate is a drawn environment, but neuroendocrine disease is a minority state within it and no record in this atlas gives its prevalence.", "provenance": "Abstract read in full; the synthesis and reuptake route, the specific serotonylation mark, the chromatin and expression consequence, the androgen receptor association and the carbidopa results in both model types as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I040", "name": "Breast luminal and myoepithelial cells", "category": "Parenchyma", "whereToCheck": "Duct/lobule; invasive boundary", "states": [ "Receptor subtype", "polarity", "malignant clone" ], "behaviors": [ "Basement membrane", "target exposure", "secretion" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-1112", "hatton-1113", "hatton-1114", "hatton-1143" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-1112", "hatton-1113", "hatton-1114", "hatton-1143" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-1112", "hatton-1113", "hatton-1114", "hatton-1143" ], "priorResearch": { "path": "simulation/data/profiles/breast-luminal-and-myoepithelial-cells.json", "summary": "Normally the duct and lobule are a bilayer: luminal cells facing the lumen and a myoepithelial sheath outside them, sitting on basement membrane. The inventory asks for receptor subtype, polarity and malignant clone, and for basement membrane, target exposure and secretion - and this is the one environment with a parameters file, so what is measurable here matters more than elsewhere. Three findings organise the row. Subtype is a partition rather than a variable: four main classes across five platforms, with plasticity and heterogeneity occurring within rather than across them, and only TP53, PIK3CA and GATA3 mutated above 10 percent across all breast cancers (L134). Target exposure turns out to be a threshold set by the drug: HER2 at scores previously called negative became treatable when the payload changed, extending median overall survival from 16.8 to 23.4 months (L135). And the invasive boundary has a mechanical cause with a geometric proxy - as DCIS ducts distend, the myoepithelial sheath upregulates integrin beta-6 and fibronectin and secretes MMP13 through TGF-beta, so the barrier cell opens the barrier (L136).", "stateAxes": [ { "axis": "Receptor subtype - a partition, not a dial", "whatToMeasure": "Subtype as a class to condition on, with the explicit caveat that the five-platform four-class result and the clinical ER/PR/HER2 panel are different variables, and that plasticity occurs within classes rather than between them.", "interpretationLimit": "Bulk primary untreated tumours, so the two protein-defined subgroups the authors attribute to stromal or microenvironmental elements are inferred from mixed tissue rather than measured. Mutation incidences are population frequencies and do not describe any individual tumour.", "evidence": [ "L134" ] }, { "axis": "Target exposure, as a continuous quantity against a drug-dependent cut", "whatToMeasure": "HER2 as a graded level rather than a binary call, since 1+ and 2+ with negative in situ hybridisation were the categories that moved from untreatable to treatable when the payload changed.", "interpretationLimit": "Immunohistochemistry scoring with known interobserver variability, and no HER2 molecule count per cell, payload release rate or bystander range is given - so the principle is demonstrated and the quantity behind it is not available. Late-line result against physician's choice chemotherapy.", "evidence": [ "L135" ] }, { "axis": "Polarity and containment, driven by duct geometry", "whatToMeasure": "Duct diameter alongside integrin beta-6, periductal fibronectin and MMP13, because the barrier state tracks the geometry and the geometry is what a section already shows.", "interpretationLimit": "Association in human sections rather than prospective outcome, and a stretch model in isolated and cell line myoepithelial cells for the mechanism. No strain, pressure or wall tension is reported, so the geometric proxy is measurable and the force behind it is not. Not all DCIS progresses and no progression rate is given here.", "evidence": [ "L136" ] }, { "axis": "Malignant clone", "whatToMeasure": "The short list that matters at population level - TP53, PIK3CA and GATA3 above 10 percent incidence, with GATA3, PIK3CA and MAP3K1 enriched in luminal A.", "interpretationLimit": "Frequencies rather than per-tumour state, and nothing here connects a mutation to a behaviour this atlas models. The atlas holds no clone fraction, no luminal-to-myoepithelial ratio and no normal breast reference for this family.", "evidence": [ "L134" ] } ], "records": { "L134": { "id": "L134", "year": 2012, "topic": "Receptor subtype", "title": "Comprehensive molecular portraits of human breast tumours", "url": "https://doi.org/10.1038/nature11412", "studyType": "Integrated analysis of primary breast cancers across five platforms - copy number, DNA methylation, exome sequencing, mRNA and microRNA, reverse-phase protein arrays, Nature 490(7418):61-70", "diseaseContext": "Breast cancer", "useInModel": "Sets the receptor subtype axis and tells the model how to treat it: four main classes when five platforms are combined, each internally heterogeneous, with the conclusion that much of the observable plasticity and heterogeneity occurs within rather than across those classes. For a simulation that means subtype is a partition to condition on rather than a variable to move. Only three genes are mutated at above 10 percent incidence across all breast cancers - TP53, PIK3CA and GATA3 - with GATA3, PIK3CA and MAP3K1 enriched in luminal A, so the malignant clone the inventory asks for is describable by a very short list at the population level. Two findings reach outside this family. Two protein-expression-defined subgroups were identified that the authors attribute to stromal or microenvironmental elements, which is this atlas's own subject appearing inside a tumour classification. And basal-like breast tumours share many molecular features with high-grade serous ovarian tumours, which are a separate drawn environment - so two of the drawn environments are related at the level of the parenchymal cell, and the authors say the therapeutic opportunities are similar.", "limit": "Primary untreated tumours profiled in bulk, so the subgroup attributed to stromal elements is an inference from mixed tissue rather than a measurement of stroma. The four-class result depends on combining five platforms and is not what a clinical receptor panel reports, so it does not map one-to-one onto the ER, PR and HER2 status a patient actually has. Mutation incidences are population frequencies and say nothing about any one tumour. The basal-like and ovarian similarity is molecular and correlative; no shared intervention result is given here.", "provenance": "Abstract read in full; the four-class result, the three genes above 10 percent, the luminal A enrichments, the stromally attributed protein subgroups, the basal-like to ovarian comparison and the within-not-across plasticity conclusion as reported", "quantitativeExtraction": "extracted" }, "L135": { "id": "L135", "year": 2022, "topic": "Target exposure", "title": "Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer", "url": "https://doi.org/10.1056/NEJMoa2203690", "studyType": "Phase 3 randomised trial, 557 patients assigned 2:1 to trastuzumab deruxtecan or physician's choice chemotherapy after one or two prior chemotherapy lines, NEJM 387(1):9-20", "diseaseContext": "Breast cancer", "useInModel": "The most consequential single record in this atlas for how targets should be represented, because it shows that a target's actionability threshold is a property of the drug and not of the target. HER2-low was defined as an immunohistochemistry score of 1+, or 2+ with negative in situ hybridisation - categories previously called HER2-negative, and in which the paper states existing HER2-directed therapies had been ineffective. With a different payload the same antigen at the same density became treatable: in the hormone receptor-positive cohort progression-free survival was 10.1 against 5.4 months (HR 0.51) and overall survival 23.9 against 17.5 months (HR 0.64); across all patients 9.9 against 5.1 months (HR 0.50) and 23.4 against 16.8 months (HR 0.64). Grade 3 or higher adverse events were less frequent than with chemotherapy, 52.6 against 67.4 percent. This is the second independent instance in this atlas of the same principle: in prostate a radioligand's beta particles reach the expressing cell and its surroundings, and here a membrane-permeable cytotoxic does the equivalent. Both say the required target density falls as the payload's reach grows, so a model that scores targets as present or absent cannot express either result.", "limit": "Comparator was physician's choice chemotherapy in patients already treated with one or two lines, so this is a late-line result and not a statement about first-line options. The primary endpoint was progression-free survival in the hormone receptor-positive cohort, which was 88.7 percent of the trial; only 63 patients were hormone receptor-negative, so that subgroup is underpowered on its own. HER2-low is a scoring category read by immunohistochemistry with known interobserver variability, and no HER2 molecule count per cell, payload release rate or bystander range is given - so the mechanism this record implies is not parameterised by it. Interstitial lung disease was an adjudicated drug-related toxicity.", "provenance": "Abstract read in full; the HER2-low definition, the stated prior ineffectiveness of HER2-directed therapy in this group, cohort sizes and proportions, all four efficacy figures with hazard ratios, and the adverse event comparison as reported", "quantitativeExtraction": "extracted" }, "L136": { "id": "L136", "year": 2022, "topic": "Invasive boundary", "title": "Mechanostimulation of breast myoepithelial cells induces functional changes associated with DCIS progression to invasion", "url": "https://doi.org/10.1038/s41523-022-00464-4", "studyType": "Human DCIS section analysis relating duct size to marker expression, with mechanical stretch modelling in primary and cell line myoepithelial cells, NPJ Breast Cancer 8:109", "diseaseContext": "Breast cancer", "useInModel": "Gives the atlas a mechanical input with a geometric cause that can actually be measured in a section, and makes the barrier cell the agent of its own failure. In human samples, increasing DCIS duct size came with upregulated integrin beta-6 and increased periductal fibronectin deposition, and that association tracked progression to invasion. Modelling the stretch myoepithelial cells undergo as a duct distends reproduced the integrin beta-6 and fibronectin upregulation in normal primary and cell line myoepithelial cells, and the resulting phenotype enhanced invasion through a TGF-beta-mediated upregulation of MMP13 - with MMP13 specifically raised in DCIS in tissue and associated with progression. Three uses. The atlas has recorded mechanics as missing in every row that needs it, and here the mechanical variable has a proxy a pathologist already sees: duct diameter. The myoepithelium is the physical barrier whose loss defines invasion, and this says the barrier is not passively breached but actively secretes the enzyme that opens it. And it is a second mechanism in which geometry drives behaviour rather than concentration doing so.", "limit": "The human part is association between duct size, marker expression and progression in sections, not a prospective outcome study, so it supports stratification rather than causation in patients. The mechanical part is a stretch model applied to isolated and cell line myoepithelial cells, so the magnitude and duration of stretch are experimental settings and no strain, pressure or duct wall tension is reported - the geometry is measurable and the force is not. Not all DCIS progresses, which is the clinical problem the paper addresses, and this record does not give a progression rate.", "provenance": "Abstract read in full; the duct size association with integrin beta-6 and periductal fibronectin, the stretch model result in both cell sources, the TGF-beta-mediated MMP13 mechanism and the tissue MMP13 association as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I041", "name": "Alveolar type I and II cells", "category": "Parenchyma", "whereToCheck": "Lung parenchyma", "states": [ "Injury", "regeneration", "malignant lineage" ], "behaviors": [ "Barrier", "surfactant", "repair", "local toxicity" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-524", "hatton-525" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-524", "hatton-525" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "sender-I041-alveolar-epithelial-cells" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-524", "hatton-525", "sender-I041-alveolar-epithelial-cells" ], "priorResearch": { "path": "simulation/data/profiles/alveolar-type-i-and-ii-cells.json", "summary": "Two cell types with opposite jobs on the same surface: flat type 1 cells forming the gas exchange barrier, and cuboidal type 2 cells making surfactant and acting as the regenerative population. This is the first row in the atlas whose barrier has both a thickness and an area, and therefore the first exchange surface here across which a flux could be computed - a harmonic mean tissue thickness of 0.62 micrometres over an alveolar surface reported as 143 square metres, with an arithmetic mean thickness of 2.2 micrometres that would be the wrong average to use (L137). Type 2 cells self-renew and differentiate into type 1 cells over about a year, expand clonally from individual survivors after ablation, and depend on PDGFR-alpha-positive stromal cells including lipofibroblasts (L138). And this family is where a specific class of administered molecule does its damage: among 2,801 patients given trastuzumab deruxtecan, 381 had adjudicated drug-related interstitial lung disease, with diffuse alveolar damage the pattern in 26 of the 30 fatal cases (L139).", "stateAxes": [ { "axis": "Barrier geometry - the atlas's first computable exchange surface", "whatToMeasure": "Harmonic mean thickness and alveolar surface area together, with the harmonic mean used rather than the arithmetic one because diffusive conductances across a sheet of varying thickness add in parallel so the thin regions dominate, and with the barrier's endpoint stated - tissue only, or epithelium to erythrocyte.", "interpretationLimit": "Disputed for the same organ and partly the same dataset: alveolar surface area reported as 143, around 130, and 80 square metres by different sources including a later retrospective by an original author, which the sources consulted do not reconcile. The two means differ by about three and a half times and the two barrier definitions by about two. Inflation state is unstated and strongly affects both quantities. A healthy reference with no disease value in any drawn environment.", "evidence": [ "L137" ] }, { "axis": "Regeneration, which is clonal rather than uniform", "whatToMeasure": "Type 2 self-renewal and conversion to type 1 cells, and the behaviour after loss - individual survivors expanding clonally with daughter cell dispersal rather than a pool replenishing evenly, which is an agent-based behaviour rather than a density one.", "interpretationLimit": "Mouse, with human relevance suggested by the authors rather than shown, and the roughly one-year self-renewal interval is a mouse timescale. No turnover rate, repair rate, or type 1 to type 2 ratio is given, so the capacity is established and its speed is not.", "evidence": [ "L138" ] }, { "axis": "Injury from an administered molecule", "whatToMeasure": "Histological pattern as well as grade, since the pattern separates the survivable majority from the fatal minority: organising pneumonia in 67.7 percent, hypersensitivity pneumonitis in 14.2, diffuse alveolar damage in 12.6, with diffuse alveolar damage the pattern in 26 of 30 fatal cases.", "interpretationLimit": "Proportions of adjudicated cases rather than of all treated patients, from post-marketing surveillance in one country. Adjudication establishes drug relatedness and not a cellular mechanism, so assigning the damage to type 1 or type 2 cells is inference from the pattern. No measurement links the toxicity to target expression in lung tissue.", "evidence": [ "L139", "L140" ] }, { "axis": "Niche support from a stromal neighbour", "whatToMeasure": "Proximity to and dependence on PDGFR-alpha-positive stromal cells including lipofibroblasts, which is the third stromal-supported stem niche in this atlas after the perivascular marrow niche and the bone niche.", "interpretationLimit": "Established by co-culture dependency and anatomical proximity rather than by conditional deletion of a niche factor, which makes it weaker than the marrow niche evidence the atlas holds - where five candidate cell types were tested by deleting the factor from each.", "evidence": [ "L138" ] } ], "records": { "L137": { "id": "L137", "year": 1978, "topic": "Barrier", "title": "The normal human lung: ultrastructure and morphometric estimation of diffusion capacity", "url": "https://doi.org/10.1016/0034-5687(78)90104-4", "studyType": "Electron microscopic morphometry of normal human lungs, Respiration Physiology 32(2):121-140", "diseaseContext": "Healthy reference", "useInModel": "The first barrier in this atlas with both a thickness and an area, which makes it the first exchange surface here that a flux could actually be computed across. The originally reported figures are an alveolar surface area of 143 square metres plus or minus 12, a harmonic mean tissue barrier thickness of 0.62 micrometres plus or minus 0.04, and an arithmetic mean barrier thickness of 2.2 micrometres plus or minus 0.19. Two distinctions in those numbers matter more than the numbers. The harmonic and arithmetic means differ by about three and a half times, and for diffusion the harmonic mean is the correct one, because diffusive conductances across a sheet of varying thickness add in parallel and the thin regions dominate - so a model that averages thickness arithmetically will understate conductance by that factor. And the barrier's thickness depends on where it is taken to stop: reviews reusing this dataset give a total harmonic mean thickness from alveolar epithelium to erythrocyte surface of about 1.11 micrometres, roughly twice the tissue-only figure. The authors also noted their alveolar surface was about 75 percent above earlier light microscopy estimates and attributed the gap to the electron microscope's resolution changing what counts as alveolar surface - the instrument being part of the measurement, which is the same shape as the observation-model finding in the smooth muscle row.", "limit": "The values are disputed across sources for the same organ and in part for the same dataset, and should be run at both ends rather than chosen: alveolar surface area is reported as 143 square metres in the original, around 130 in reviews tabulating it, and 80 in a later retrospective by one of the original authors, which these sources do not reconcile. Capillary surface and volume also differ between sources - 126 square metres and 213 millilitres in one, 115 and 194 in another. Normal lungs at an unstated inflation state, which strongly affects both area and thickness and is not captured here. No disease value for any drawn environment, so this is a reference geometry and not a measurement of a tumour.", "provenance": "The original abstract was not retrievable through the literature interface; the figures above were read from secondary records and reviews tabulating this study - an EPA reference record for the original values, and two independent reviews for the total barrier thickness and the lower surface area. Recorded with the disagreement intact rather than resolved, and the later 80 square metre retrospective figure noted as unexplained by the sources consulted", "quantitativeExtraction": "extracted" }, "L138": { "id": "L138", "year": 2013, "topic": "Regeneration", "title": "Type 2 alveolar cells are stem cells in adult lung", "url": "https://doi.org/10.1172/JCI68782", "studyType": "In vivo clonal lineage tracing with injury and ablation models, plus three-dimensional culture of purified populations, Journal of Clinical Investigation 123(7):3025-3036", "diseaseContext": "Healthy reference", "useInModel": "Identifies which of this family's two cell types is the regenerative one and what supports it. Surfactant protein C-positive type 2 cells self-renew and differentiate over about a year, consistent with containing long-term alveolar stem cells; when many are specifically ablated, individual survivors undergo rapid clonal expansion with daughter cell dispersal; and single lineage-labelled type 2 cells in three-dimensional culture form self-renewing alveolospheres containing both type 2 cells and cells expressing multiple type 1 markers, including HOPX, which this paper introduces as a type 1 marker. Growth and differentiation occurred most readily in co-culture with primary PDGFR-alpha-positive lung stromal cells, a population including lipofibroblasts that normally sit close to type 2 cells and may therefore form a niche. Two things for the atlas. Repair here is clonal and local - a surviving cell expands and disperses rather than a pool replenishing uniformly, which is an agent-based behaviour rather than a density one. And this is the third stromal-supported stem niche the atlas has recorded, after the perivascular marrow niche and the bone niche, each identified by the supporting cell rather than by the dividing one.", "limit": "Mouse, with the human relevance offered as a suggestion by the authors rather than shown. The niche claim is co-culture dependency plus anatomical proximity, not a conditional deletion of a niche factor, so it is weaker than the marrow niche evidence this atlas holds. The self-renewal timescale of about a year is a mouse timescale. No type 1 to type 2 ratio, cell density, turnover rate or repair rate is given, so regeneration is established as a capacity and not as a speed.", "provenance": "Abstract read in full; the lineage tracing result and its timescale, the ablation and clonal expansion finding, the alveolosphere composition and the HOPX introduction, and the PDGFR-alpha-positive stromal co-culture dependency as reported", "quantitativeExtraction": "extracted" }, "L139": { "id": "L139", "year": 2026, "topic": "Local toxicity", "title": "Real-world characteristics of trastuzumab deruxtecan-related interstitial lung disease in Japanese patients with breast cancer and gastric cancer", "url": "https://doi.org/10.1093/oncolo/oyag340", "studyType": "Post hoc analysis of independently adjudicated cases from all-patient post-marketing surveillance of 2,801 treated patients, The Oncologist 31:oyag340", "diseaseContext": "Breast cancer; gastric cancer", "useInModel": "Puts a number and a histology on the local toxicity the inventory asks for, and locates it in this family. Among 2,801 patients treated with trastuzumab deruxtecan - 1,731 breast, 1,070 gastric - 421 potential cases were reviewed and 381 were adjudicated as drug-related interstitial lung disease, 278 in breast and 103 in gastric cancer. The predominant imaging pattern was organising pneumonia at 67.7 percent, then hypersensitivity pneumonitis at 14.2 percent and diffuse alveolar damage at 12.6 percent. Most cases, 78.2 percent, were worst grade 1 or 2; grade 5 occurred in 30 patients, 7.9 percent of adjudicated cases, and diffuse alveolar damage was the pattern in 26 of those 30. Overall recovery was 83.5 percent. The timing matters as much as the rate: events occurred throughout observation including fatal cases beyond twelve months from initiation, with no specific onset window and no difference in time to onset across grades. So the hazard is flat rather than front-loaded, which means there is no early period after which exposure becomes safe - and the fatal subset is distinguished by a histological pattern that is specifically damage to the alveolar barrier this row describes.", "limit": "Post-marketing surveillance in Japanese patients, so neither the population nor the reporting is a trial cohort, and the percentages for pattern and grade are proportions of adjudicated cases rather than of all treated patients. Adjudication identifies drug-related disease without establishing the cellular mechanism, so attributing the damage to type 1 or type 2 cells specifically is an inference from the diffuse alveolar damage pattern and not a measurement. Smoking history in 28.3 percent is reported without being resolved as a risk factor here. Nothing in this record connects the toxicity to HER2 expression in lung tissue.", "provenance": "Abstract read in full; the treated and adjudicated counts by tumour type, all three imaging pattern proportions, the grade distribution, the grade 5 count with its pattern, the recovery rate, and the absence of an onset window as reported", "quantitativeExtraction": "extracted" }, "L140": { "id": "L140", "year": 2026, "topic": "Local toxicity", "title": "Interstitial Lung Disease and Cardiotoxicity Associated with Trastuzumab Deruxtecan, Sacituzumab Govitecan, and Trastuzumab Emtansine: A Narrative Review", "url": "https://doi.org/10.3390/medicina62091664", "studyType": "Narrative review comparing three antibody-drug conjugates across regulatory documents, pivotal trials, pooled safety analyses and real-world cohorts, Medicina 62:1664", "diseaseContext": "Breast cancer and other solid tumours", "useInModel": "Completes an argument this atlas could not otherwise close: the payload's reach is a two-sided parameter. The review's framing is that these three conjugates differ substantially in antibody target, linker, payload, drug-to-antibody ratio and bystander effect, and that these differences produce heterogeneous pulmonary and cardiac toxicity profiles - with trastuzumab deruxtecan carrying an interstitial lung disease risk of approximately 12 to 15 percent in pooled analyses, predominantly grade 1 to 2 but occasionally fatal, while trastuzumab emtansine's pulmonary risk is described as low. The breast epithelium row records that the same deruxtecan payload is what made HER2 treatable at densities previously scored negative, where emtansine had been ineffective. So one property - how far the payload travels from the cell that bound the antibody - appears to set both the lowest target density that can be treated and the off-target damage in a named parenchymal family. That is the strongest available argument for carrying payload reach as an explicit parameter rather than treating targets as present or absent, and it means efficacy and toxicity are not independent inputs to be tuned separately.", "limit": "A narrative review, which is the weakest study type in this atlas - it compares and synthesises rather than measuring, and its explicit purpose is to prevent inappropriate extrapolation of toxicity algorithms between agents. The attribution of differing toxicity to bystander effect is the review's framing across agents that also differ in target, linker and drug-to-antibody ratio, so bystander reach is one of several confounded differences and is not isolated. The 12 to 15 percent figure is a pooled range as reported here, and the emtansine comparison is qualitative with no number extracted. No lung HER2 expression measurement supports a mechanism.", "provenance": "Abstract read in full; the stated axes of difference between the three agents, the 12 to 15 percent pooled range with its grade distribution, and the low pulmonary risk attributed to trastuzumab emtansine as reported. The link to target density is this atlas's own inference from the breast row and is labelled as such", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I042", "name": "Airway basal, club and ciliated cells", "category": "Parenchyma", "whereToCheck": "Airways", "states": [ "Differentiation", "injury", "malignant state" ], "behaviors": [ "Mucus/ciliary transport", "barrier", "repair" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-510", "hatton-513", "hatton-516" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-510", "hatton-513", "hatton-516" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "sender-I042-bronchial-epithelial-cells" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-510", "hatton-513", "hatton-516", "sender-I042-bronchial-epithelial-cells" ], "priorResearch": { "path": "simulation/data/profiles/airway-basal-club-and-ciliated-cells.json", "summary": "A pseudostratified epithelium lining the conducting airways, with basal cells beneath, secretory club and goblet cells above them, and ciliated cells driving a mucus layer outward. The row's defining function is transport, and it is the one function in this atlas measured as a velocity: 10.7 plus or minus 3.5 millimetres per minute in young normal tracheas, falling to 6.5 in older subjects and 2.1 in COPD - but with a repeat-measurement coefficient of repeatability of 10.3 millimetres per minute in normals, which is essentially the whole quantity (L142). Basal cells are the regenerative population, generating differentiated cells including ciliated cells during growth, steady state and repair, and they do so in a sphere assay without any stroma - the opposite of the alveolar type 2 cell's demonstrated stromal dependence (L141). And this family carries the defect behind the atlas's clearest example of repairing a broken protein: restoring a misfolded chloride channel raised lung function by 9.9 percent-predicted points, sustained over three years in 11,151 people (L143).", "stateAxes": [ { "axis": "Mucociliary transport - a velocity, and the atlas's only repeatability figure", "whatToMeasure": "Tracheal mucus velocity with its repeat-measurement variability, because the two together say what the number can be used for: 10.7 plus or minus 3.5 millimetres per minute in young normals, 6.5 in older normals, 2.1 in COPD, against a coefficient of repeatability of 10.3 in normals and 5.5 in COPD.", "interpretationLimit": "The repeatability is the limit. In health the repeat variability is essentially the entire quantity and in COPD it is more than twice the mean, so this parameter is settable for a population and unusable for an individual. Trachea only, which is the fastest part of the tree, by an invasive bolus that bypasses normal deposition. The COPD standard deviation exceeds its mean. No drawn environment and no tumour-bearing airway.", "evidence": [ "L142" ] }, { "axis": "Differentiation, from a stroma-independent basal cell", "whatToMeasure": "Basal cell output into ciliated and secretory daughters, with the ITGA6 and NGFR combination for isolating the human population, and with the expectation that no stromal partner is required.", "interpretationLimit": "Stroma-independence is shown by removing stroma in a sphere assay, which establishes the cell's sufficiency rather than the absence of a niche in tissue. Mouse lineage tracing with human evidence limited to purification and sphere behaviour. No density, turnover rate, differentiation time or proportion among the three cell types.", "evidence": [ "L141" ] }, { "axis": "Injury, read as transport loss rather than as cell loss", "whatToMeasure": "The velocity itself, since age and COPD are resolved by it - a five-fold fall from young normal to COPD - rather than by any cell count in this atlas.", "interpretationLimit": "COPD is not one of the drawn environments, and the record gives no cellular correlate of the velocity loss: no ciliated cell fraction, no cilia beat frequency, no mucus depth or composition. So injury is quantified as a functional deficit with nothing underneath it.", "evidence": [ "L142" ] }, { "axis": "A repairable defect in this family's own membrane", "whatToMeasure": "Restored channel function read out at organ level - 9.9 percent-predicted points of forced expiratory volume and 1.03 kilograms per square metre of body mass index, sustained across three years in 11,151 people.", "interpretationLimit": "Registry before-and-after rather than randomised, restricted to carriers of at least one F508del allele, with the authors reporting heterogeneous response so the mean understates individual variation. Cystic fibrosis is not a drawn environment; this axis is held for the mechanism class and for what it says about this family.", "evidence": [ "L143" ] } ], "records": { "L141": { "id": "L141", "year": 2009, "topic": "Differentiation", "title": "Basal cells as stem cells of the mouse trachea and human airway epithelium", "url": "https://doi.org/10.1073/pnas.0906850106", "studyType": "Lineage tracing with a KRT5-CreERT2 mouse line, FACS fractionation with transcriptional profiling, and clonal sphere-forming assays on mouse and human cells, PNAS 106(31):12771-12775", "diseaseContext": "Healthy reference", "useInModel": "Identifies the regenerative cell of this family and, more usefully for the atlas, establishes that it does not need a stromal niche. Basal cells expressing p63, cytokeratin 5 and cytokeratin 14 generate differentiated cells during postnatal growth and in the adult during both steady state and repair. Fractionated basal cells yielded 627 genes preferentially expressed against non-basal cells, and two cell-surface markers from that profile, ITGA6 and NGFR, purify human lung basal cells when used in combination. In a clonal sphere-forming assay the cells self-renew and generate luminal daughters including differentiated ciliated cells - explicitly in the absence of stroma - and human airway basal cells behave the same way as mouse tracheal ones. Two consequences. The alveolar row records type 2 cells whose alveolosphere growth and differentiation depended on co-culture with PDGFR-alpha-positive stromal cells, so the lung holds two epithelial stem populations with opposite niche dependence and the atlas cannot assume epithelial stem cells need stromal support. And the human result is unusual here: most mechanism in this atlas is mouse-only, whereas this one is demonstrated in human cells with a purification strategy that works on them.", "limit": "Stroma-independence is shown in a sphere assay, which removes stroma rather than proving stroma is irrelevant in tissue - it establishes sufficiency of the cell, not absence of a niche in vivo. The lineage tracing is mouse; the human evidence is purification and sphere behaviour rather than lineage tracing. No basal cell density, turnover rate, differentiation time or proportion of the three cell types is given, so the hierarchy is established and the composition is not.", "provenance": "Abstract read in full; the basal marker set, the lineage tracing claim across growth, steady state and repair, the 627-gene count, the ITGA6 and NGFR combination for human purification, and the stroma-free sphere result in both species as reported", "quantitativeExtraction": "extracted" }, "L142": { "id": "L142", "year": 2004, "topic": "Mucociliary transport", "title": "Scintigraphic measurement of tracheal mucus velocity in vivo", "url": "https://doi.org/10.1183/09031936.04.00061404", "studyType": "In vivo gamma camera tracking of a radiolabelled bolus injected transcricothyroid, in 32 normal subjects and 34 COPD patients with repeat studies in 29, European Respiratory Journal 23(4):518-522", "diseaseContext": "Healthy reference; COPD", "useInModel": "The atlas's first directly measured transport velocity, and simultaneously its first repeatability statistic - which is the more important of the two. Tracheal mucus velocity was 10.7 plus or minus 3.5 millimetres per minute in young normal subjects, 6.5 plus or minus 2.6 in older normal subjects, and 2.1 plus or minus 2.7 in COPD, so the quantity falls monotonically with age and disease and the group separation is large. But the coefficient of repeatability from repeat studies was 10.3 millimetres per minute in normal subjects and 5.5 in COPD. In health that repeat-measurement variability is essentially the whole quantity, and in COPD it is more than twice the mean. The conclusion a simulation must take from this is a distinction the atlas has never been able to draw: this parameter is settable for a population and unusable for an individual. It also sets a clearance clock for anything delivered to the airway, since material on this surface is being carried away at these speeds while it acts.", "limit": "Trachea only, which is the fastest and most accessible part of a tree whose velocity falls towards the periphery - no peripheral or small-airway value is given, so this cannot be applied to the whole airway. The bolus is injected through the cricothyroid membrane, which is invasive and bypasses normal deposition. Modest group sizes, especially 12 older normal subjects. The COPD standard deviation exceeds its mean, so that distribution reaches effectively zero transport. Age and COPD are the only conditions resolved; no drawn environment is represented, and nothing here measures transport in a tumour-bearing airway.", "provenance": "Abstract read in full including the results tail; all three group means with standard deviations and sample sizes, both coefficients of repeatability, and the stated conclusions on age and COPD as reported", "quantitativeExtraction": "extracted" }, "L143": { "id": "L143", "year": 2026, "topic": "Clinical outcome", "title": "Clinical effectiveness of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis in the United States", "url": "https://doi.org/10.1093/annalsats/aaoag095", "studyType": "Longitudinal registry analysis of 11,151 people aged 12 and over with at least one F508del allele, one year before and three years after initiation, with generalised estimating equations and a negative binomial exacerbation model, Annals of the American Thoracic Society 23(10):1466-1475", "diseaseContext": "Cystic fibrosis", "useInModel": "Adds a third mechanism class to the intervention ledger, and it is the class with the largest durable effect the atlas holds. Mean percent predicted forced expiratory volume in one second rose by 9.9 points (95% CI 9.6-10.2) between the pre- and post-initiation periods across three years in 11,151 people, with body mass index up by 1.03 kilograms per square metre (95% CI 0.98-1.07), sustained rather than transient, in routine care rather than in a trial. The mechanism is what matters for the ledger. These drugs do not remove a brake, do not block a function the disease needs, and do not use a surface molecule as a delivery address. The target is the defect: a misfolded, mistrafficked chloride channel in this family's own membrane, and the drugs restore its folding and gating. So the ledger's discriminating question - whether the thing manipulated was restraining a lost function or performing a needed one - does not apply, because here the thing manipulated is the lost function itself. Repairing the broken machine is a distinct class, and it is the one with the clearest mapping from a molecular defect through a cellular function to an organ-level outcome.", "limit": "Registry analysis rather than a randomised trial, so the comparison is before and after within people taking the drug and is open to secular trends - the authors model viral respiratory trends for exacerbations, which indicates the concern rather than removing it. Restricted to people with at least one F508del allele, so this is not a result for cystic fibrosis generally. Response was heterogeneous and the paper analyses that heterogeneity, so the mean understates how differently individuals fared. Cystic fibrosis is not one of the drawn environments; this record is held for the mechanism class and for what it says about this family, not as evidence about any drawn environment.", "provenance": "Abstract read in full; the cohort definition and size, the ppFEV1 and body mass index changes with confidence intervals and time frame, the modelling approach and the stated heterogeneity of response as reported. The ledger classification is this atlas's own reading and is labelled as such", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I043", "name": "Pulmonary neuroendocrine lineage", "category": "Parenchyma", "whereToCheck": "SCLC module", "states": [ "Malignant programs", "antigen variation" ], "behaviors": [ "DLL3 context", "proliferation", "plasticity" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-517" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-517" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-517" ], "priorResearch": { "path": "simulation/data/profiles/pulmonary-neuroendocrine-lineage.json", "summary": "Neurosensory cells scattered through the bronchial epithelium, many in innervated clusters of 20 to 30, of which only 2 to 4 behave as stem cells - and after injury often just one per cluster loses neuroendocrine identity, transit amplifies and reprograms to other fates, producing large clonal repair patches (L144). That makes this the sparsest functional unit in the atlas and the only one given as counts. The regulators of that programme are the disease's own tumour suppressors: Rb and p53 suppress self-renewal and Notch marks the stem cells while initiating their deprogramming, so the malignant state here is the normal repair programme with its brakes removed. Human cells reproduce the ordering and add explicit negatives - Notch inhibition and Rb reduction expand the lineage, p53 reduction alone does nothing, and tumours need both Rb and p53 gone (L145). The family's therapeutic surface is DLL3, where a T-cell engager gave median overall survival of 13.6 against 8.3 months with fewer severe adverse events than chemotherapy (R02). All of this concerns small-cell lung cancer, which was explicitly excluded from the drawn lung environment when this row was written and became a drawn environment in its own right on 2026-10-14.", "stateAxes": [ { "axis": "Plasticity, as an ordered sequence rather than a spectrum", "whatToMeasure": "Position in the sequence - self-renewal, loss of neuroendocrine identity, transit amplification, reprogramming to other fates - together with the cluster counts that make it countable: 20 to 30 cells per cluster, 2 to 4 stem cells, often one deprogramming cell.", "interpretationLimit": "Mouse airway, after experimental ablation, with the counts structural rather than calibration values since no human equivalent is held. Timing is given only as about a week to reprogramming, with no patch size and no cluster density per unit airway.", "evidence": [ "L144" ] }, { "axis": "Malignant programs, and which perturbations do nothing", "whatToMeasure": "Rb and p53 status together rather than separately, since the human model shows Rb reduction expands the lineage, p53 reduction alone does not induce or expand it, mutant KRAS and EGFR do not either, and tumour growth requires both Rb and p53 blocked.", "interpretationLimit": "An embryonic stem cell model with tumours described as resembling early-stage disease, xenografted into immunodeficient mice - which removes the immune compartment this family's leading therapy depends on. The negatives hold in that system at the knockdown levels achieved and do not make KRAS or EGFR irrelevant in lung cancer generally, where both are central in non-small-cell disease.", "evidence": [ "L145" ] }, { "axis": "Antigen and subtype variation, measurable over time", "whatToMeasure": "Lineage transcription factor promoter signal and a burden score from plasma rather than from a section, since this is the one modality here that can be repeated in the same patient - 441 samples with 41 time-matched tumour pairs.", "interpretationLimit": "Assay validation rather than outcome: the score tracks radiographic burden and associates with prognosis without any treatment decision shown to improve by it, and subtype inference is concordance with matched tumour RNA rather than ground truth. Requires shedding, so it is weakest in low-burden disease and that boundary is unquantified. The promoters measured are lineage factors, not the surface antigen the therapy targets, so therapeutic antigen variation remains adjacent.", "evidence": [ "L146", "L147" ] }, { "axis": "Target specificity, which is what separates this address from the others", "whatToMeasure": "DLL3 on tumour cells against its presence in normal tissue, because the atlas's three address-class interventions differ most in this and that is where their off-target damage comes from.", "interpretationLimit": "The specificity contrast is this atlas's inference from comparative toxicity and from the target's known restriction, not a measurement in any record held here. No DLL3 density, receptor occupancy or effector-to-target ratio is recorded, and nothing here measures DLL3 in normal human tissue.", "evidence": [ "R02" ] } ], "records": { "L144": { "id": "L144", "year": 2019, "topic": "Plasticity", "title": "Rare Pulmonary Neuroendocrine Cells Are Stem Cells Regulated by Rb, p53, and Notch", "url": "https://doi.org/10.1016/j.cell.2019.09.010", "studyType": "Clonal lineage analysis with injury models and genetic manipulation in mouse lung, Cell 179(2):403-416.e23", "diseaseContext": "Healthy reference; small-cell lung cancer", "useInModel": "The sparsest functional unit in this atlas, and the only one given as counts. Neuroendocrine cells are sparsely distributed through the bronchial epithelium, many in innervated clusters of 20 to 30 cells, and only rare ones - typically 2 to 4 per cluster - function as stem cells, while being fully differentiated cells displaying classical stem cell features. After injury most of those self-renew and some migrate into the injured area; a week later individual cells, often just one per cluster, lose neuroendocrine identity, transit amplify, and reprogram to other fates, producing large clonal repair patches. The regulators are the disease's own tumour suppressors: Rb and p53 suppress self-renewal, while Notch marks the stem cells and initiates deprogramming and transit amplification. The authors propose that these stem cells give rise to small-cell lung cancer and that transformation requires two things at once - constitutive activation of renewal and inhibition of deprogramming. Three uses. The ordered sequence from loss of identity through transit amplification to reprogramming is a state machine with a direction, which is what a simulation can implement. The two-condition requirement is a second epistatic structure in the atlas after the bone loop. And the malignant state here is the normal repair programme with its brakes removed, which makes this the clearest case in the atlas of a disease being a misregulated physiological function rather than a new behaviour.", "limit": "Mouse, with the small-cell lung cancer origin offered as a proposal by the authors rather than demonstrated in human disease. The counts - 20 to 30 cells per cluster, 2 to 4 stem cells, often one deprogramming cell - are mouse airway numbers and no human equivalent is held here, so they should be treated as structural rather than calibration values. Injury models are experimental ablations, so the repair behaviour is a response to a controlled insult. No timing beyond the stated week, no patch size, and no cluster density per unit airway.", "provenance": "Abstract read in full; the cluster size and innervation, the stem cell count per cluster, the post-injury self-renewal and migration, the one-week deprogramming and reprogramming sequence with clonal patches, the roles of Rb, p53 and Notch, and the authors' two-condition transformation proposal as reported", "quantitativeExtraction": "extracted" }, "L145": { "id": "L145", "year": 2019, "topic": "Malignant programs", "title": "Generation of pulmonary neuroendocrine cells and SCLC-like tumors from human embryonic stem cells", "url": "https://doi.org/10.1084/jem.20181155", "studyType": "Directed differentiation of human embryonic stem cells with RNA interference and oncogene expression, single-cell RNA profiling, and xenografting into immunodeficient mice, Journal of Experimental Medicine 216(3):674-687", "diseaseContext": "Small-cell lung cancer", "useInModel": "Repeats the mouse lineage argument in human cells and - more valuable for this atlas - supplies explicit negatives, which are rare here. Inhibiting NOTCH signalling induced up to 10 percent of lung progenitor cells to become pulmonary neuroendocrine cells, and reducing retinoblastoma protein by inhibitory RNA increased them further. Reducing TP53 protein did not induce or expand them, and neither did expressing mutant KRAS or EGFR. Tumours resembling early-stage small-cell lung cancer grew in immunodeficient mice only after injection of neuroendocrine-containing cultures in which both RB and TP53 expression were blocked. Single-cell profiles of these cells are heterogeneous; with retinoblastoma reduced they resemble early-stage small-cell lung cancer, and with both reduced the transcriptome is enriched for cell-cycle RNAs. So the ordering is legible: Notch loss and Rb loss expand the lineage, p53 loss does nothing on its own, and tumour formation needs both Rb and p53 gone - which matches the two-condition requirement the mouse work proposes and tells a model which single perturbations should produce nothing.", "limit": "An embryonic stem cell model of a lineage, not a patient tumour, and the tumours are described as resembling early-stage disease rather than recapitulating it. Xenografting into immunodeficient mice removes the immune compartment, which is exactly the compartment this family's leading therapy depends on. The 10 percent induction figure is a culture yield, not a tissue proportion. Negatives are negatives in this system and at the levels of knockdown achieved; they do not establish that KRAS or EGFR are irrelevant in human lung cancer generally - both are central in non-small-cell disease.", "provenance": "Abstract read in full; the NOTCH inhibition yield, the RB effect, the explicit TP53, KRAS and EGFR negatives, the double-knockdown requirement for tumour growth, and the single-cell profile findings as reported", "quantitativeExtraction": "extracted" }, "L146": { "id": "L146", "year": 2026, "topic": "Antigen variation", "title": "Plasma nucleosome profiling reports on tumor burden and molecular subtypes in small cell lung cancer", "url": "https://doi.org/10.1172/JCI202151", "studyType": "Cell-free nucleosome chromatin immunoprecipitation sequencing of 441 plasma samples integrated with 73 matched tumour transcriptomes including 41 time-matched pairs, Journal of Clinical Investigation 136:e202151", "diseaseContext": "Small-cell lung cancer; other neuroendocrine carcinomas", "useInModel": "The atlas's second exception to a problem it has recorded as structural: that every marker in these 110 families is read from fixed tissue taken once. The prostate row found the first exception in space, a target verified by PET in three dimensions in the living patient. This is the exception in time. Chromatin immunoprecipitation of cell-free nucleosomes carrying active histone modifications, applied to 441 plasma samples and integrated with 73 matched tumour transcriptomes including 41 time-matched pairs, captured tissue and cell-of-origin signatures from tumour-derived cell-free DNA; a quantitative score tracked radiographic tumour burden and was associated with prognosis; and signals at the promoters of the lineage-defining transcription factors ASCL1, NEUROD1, POU2F3 and ATOH1 correlated strongly with matched tumour RNA, supporting non-invasive inference of subtype from plasma. For this row that matters because the inventory asks for antigen variation, and variation is the one thing a single biopsy cannot report. It also matters generally: this is a modality that can produce a time series, which is what the atlas's recorded absence of any time of day on any measurement would need.", "limit": "An assay validation rather than an outcome study: the score is associated with prognosis and tracks radiographic burden, and no treatment decision is shown to improve by using it. Subtype inference is supported by correlation with matched tumour RNA in a subset, so it is concordance with another measurement rather than ground truth. Requires shedding, so low-burden disease is where it is least likely to work and that boundary is not quantified here. Small-cell lung cancer is not the drawn lung environment. The promoter set is lineage transcription factors, not the surface antigen this family's therapy targets, so antigen variation in the therapeutic sense is adjacent rather than measured.", "provenance": "Abstract read in full; the sample and pairing counts, the score's relation to burden and prognosis, the four lineage transcription factor promoters and their correlation with matched tumour RNA as reported", "quantitativeExtraction": "extracted" }, "L147": { "id": "L147", "year": 2026, "topic": "Malignant programs", "title": "Heterogeneous associations between molecular subtypes of small cell lung cancer and survival prognosis: a systematic review highlighting knowledge gaps", "url": "https://doi.org/10.1186/s40001-026-04052-1", "studyType": "Systematic review of eight studies with dual independent extraction and quality assessment, European Journal of Medical Research", "diseaseContext": "Small-cell lung cancer", "useInModel": "Records the honest state of the malignant programs axis, which is that the subtypes exist and their meaning does not yet. Eight studies were included; methodological heterogeneity between them produced frequently inconsistent conclusions; the tendency is that the inflammatory non-neuroendocrine subtype carries a survival advantage in most cases while the ASCL1-dominant neuroendocrine subtype carries a poorer prognosis, with exceptions; and the review's own conclusion is that standardised subtype definitions are needed before prognostic associations can be validated. This is worth a record precisely because the subtype scheme is the thing a simulation would be tempted to take as a clean four-way classification. It is a classification without an agreed definition or a settled consequence, and the atlas should carry it as a partition of unknown prognostic weight rather than as a state with known effects.", "limit": "A systematic review of eight heterogeneous studies that reach inconsistent conclusions, so the direction it reports is a tendency and not a result. No pooled effect size is given here. Subtype assignment methods differ between the included studies, which is the review's central complaint and means the subtypes being compared are not strictly the same variable across studies. Small-cell lung cancer is not the drawn lung environment.", "provenance": "Abstract read in full; the number of included studies, the stated methodological heterogeneity and inconsistency, the directional tendency for the inflammatory and ASCL1-dominant subtypes, and the call for standardised definitions as reported", "quantitativeExtraction": "extracted" }, "R02": { "id": "R02", "year": 2025, "topic": "Clinical outcome", "title": "Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy", "url": "https://doi.org/10.1056/NEJMoa2502099", "studyType": "Multinational open-label phase 3 trial, 509 patients randomised to tarlatamab (254) or chemotherapy (255) as second-line treatment, prespecified interim analysis with data cutoff 29 January 2025, NEJM 393(4):349-361, DeLLphi-304, NCT05740566", "diseaseContext": "Small-cell lung cancer", "useInModel": "Completes the address class of intervention with a third kind of payload, and it is the best-specified member. Tarlatamab is a bispecific T-cell engager directed at delta-like ligand 3, and against chemotherapy - topotecan, lurbinectedin or amrubicin - it gave median overall survival of 13.6 months (95% CI 11.1 to not reached) against 8.3 months (95% CI 7.0 to 10.2), a stratified hazard ratio for death of 0.60 (95% CI 0.47 to 0.77), with significant benefits in progression-free survival and in patient-reported dyspnoea and cough. Grade 3 or higher adverse events were less frequent than with chemotherapy, 54 against 80 percent, and discontinuation for adverse events 5 against 12 percent. The atlas now holds three address-class interventions with three different payloads: a radioligand whose beta particles carry a physical range, an antibody-drug conjugate whose membrane-permeable cytotoxic diffuses to neighbours, and here a recruited T cell whose own bystander mechanism this atlas already holds separately as Fas-mediated off-target killing. And the specificity axis finally separates them: this target is largely confined to neuroendocrine tumour cells, whereas PSMA sits on normal prostate and HER2 on normal lung and heart - which is the most plausible reason this agent's grade 3 or higher rate is lower than its chemotherapy comparator's while the HER2 conjugate's pulmonary toxicity lands in a named parenchymal family.", "limit": "Second-line small-cell lung cancer after platinum progression; do not extrapolate to NSCLC, to first-line treatment, or to lung cancer generally - and note that small-cell lung cancer is explicitly not the drawn lung environment, which crosswalk.json records as NSCLC only. Open-label, which matters for the patient-reported symptom endpoints in particular. A prespecified interim analysis, so the overall survival estimate may move and the upper confidence bound was not reached. No DLL3 density, receptor occupancy or effector-to-target ratio is given, so the delivery is demonstrated and not parameterised, and nothing here measures DLL3 in normal tissue - the specificity contrast drawn above is this atlas's inference from the comparative toxicity and from the target's known restriction, not a measurement in this record.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. Patient numbers per arm, both median survivals with confidence intervals, the stratified hazard ratio, the secondary and patient-reported endpoints, and both adverse event comparisons as reported. The three-payload synthesis and the specificity contrast are this atlas's own and are labelled as such", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I044", "name": "Colon enterocytes and goblet cells", "category": "Parenchyma", "whereToCheck": "Luminal epithelium", "states": [ "Polarity", "differentiation", "injury" ], "behaviors": [ "Mucus", "absorption", "apical versus basal accessibility" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-673", "hatton-674" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-673", "hatton-674" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "sender-I044-colon-epithelia" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-673", "hatton-674", "sender-I044-colon-epithelia" ], "priorResearch": { "path": "simulation/data/profiles/colon-enterocytes-and-goblet-cells.json", "summary": "A single layer of absorptive enterocytes and secretory goblet cells over crypts, renewed faster than any other tissue in the adult body from continuously cycling Lgr5-positive columnar cells at the crypt base (L149). Its defining output is a barrier it builds itself: two mucus layers extending 150 micrometres above the epithelium, MUC2 the major structural component, the inner layer densely packed, firmly attached and devoid of bacteria while the outer is movable and colonised - and in Muc2 knockout mice bacteria reach the epithelium and the crypt base, with inflammation and cancer following (L148). The row's other subject is the one the inventory names third: apical versus basal accessibility. An address on this family's luminal face was the basis of a selectivity argument supported by tumour-selective biodistribution and primate toxicology (T05), and in 79 patients the dose-limiting toxicities were grade 3 colitis and diarrhoea and the response rate was 2.5 percent (T06).", "stateAxes": [ { "axis": "Apical versus basal accessibility - the row's central question", "whatToMeasure": "Which face of the cell an antigen sits on and whether that face is reachable from the blood, together with what actually happened when that was assumed: tumour-selective biodistribution and manageable primate toxicity beforehand, grade 3 colitis and diarrhoea as dose-limiting toxicities afterwards.", "interpretationLimit": "The clinical toxicities establish that gut tissue was engaged, not the mechanism by which - a T-cell engager can injure gut through cytokine release as well as through on-target binding, and no record here separates those. Biodistribution was shown by staining and mass cytometry rather than quantified as a tumour-to-normal ratio, so the preclinical selectivity claim has no number to compare against the clinical outcome.", "evidence": [ "T05", "T06" ] }, { "axis": "Mucus, as a barrier with a thickness rather than a secretion", "whatToMeasure": "Both layers together as a 150 micrometre structure with different physical properties - inner densely packed, firmly attached, sterile; outer movable, proteolytically expanded, colonised - rather than a secretion rate.", "interpretationLimit": "Mouse, a combined thickness for both layers, no human value, and no variation along the colon or with feeding. Impervious to bacteria says nothing directly about small molecules, antibodies or particles, and no diffusion coefficient through this gel is held anywhere in the atlas.", "evidence": [ "L148" ] }, { "axis": "Differentiation from a fixed anatomical position", "whatToMeasure": "Crypt base columnar cells rather than a position above the Paneth cells, since the prior four-to-six-cells-at-the-+4-position model was displaced, and all epithelial lineages derive from the Lgr5-positive cell over a 60-day tracing window.", "interpretationLimit": "Mouse, with the colon claim partly carried by small intestine data. No stem cell count per crypt, crypt density, division rate or transit time, so the fastest self-renewing tissue in the body has no kinetics in this atlas. The 60 days is an observation window, not a turnover time.", "evidence": [ "L149" ] }, { "axis": "Penetration, as a computable quantity", "whatToMeasure": "Antigen concentration, binding affinity and internalisation rate alongside dose and exposure time, because those are the terms the scaling criteria need - and the atlas holds none of them for any target.", "interpretationLimit": "Spheroids, which exclude perfused vessels, interstitial pressure and systemic clearance by construction, and one antigen, cell line and fragment format. The result is that penetration distance is predictable and what it depends on; it is not a distance in micrometres and does not transfer to a conjugate or a bispecific without re-deriving their parameters.", "evidence": [ "T13" ] } ], "records": { "L148": { "id": "L148", "year": 2008, "topic": "Barrier", "title": "The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria", "url": "https://doi.org/10.1073/pnas.0803124105", "studyType": "Structural and proteomic characterisation of mouse colonic mucus with Muc2 knockout comparison, PNAS 105(39):15064-15069", "diseaseContext": "Healthy reference; colitis and colon cancer in the knockout", "useInModel": "The atlas's second barrier with a thickness, and the only one with a genetic test showing it is load-bearing. Mouse colonic mucus is two layers extending 150 micrometres above the epithelial cells, both with similar protein composition and the gel-forming mucin MUC2 as the major structural component. The inner layer is densely packed, firmly attached to the epithelium and devoid of bacteria; the outer is movable, expanded in volume by proteolytic cleavage of MUC2, and colonised by bacteria. Muc2 knockout mice have bacteria in direct contact with the epithelium and far down in the crypts, which the authors offer as the explanation for the inflammation and cancer that develop in them. Two things for the model. This barrier separates roughly ten to the thirteenth bacteria from the epithelium, which is the interface the unwritten microorganism row will need. And at 150 micrometres it is about two hundred times thicker than the alveolar barrier this atlas also holds, so the two computable barriers in the project differ by more than two orders of magnitude - which means the delivery route, not the tissue, decides what a molecule has to cross.", "limit": "Mouse colon, and the 150 micrometres is a total for both layers with no separate inner-layer thickness extracted here, no human value, and no statement of how it varies along the colon or with feeding. A thickness is not a permeability: the inner layer is shown impervious to bacteria, which says nothing directly about small molecules, antibodies or nanoparticles, and no diffusion coefficient through this gel is given. The knockout links barrier loss to inflammation and cancer in mice; the causal chain in human colorectal cancer is not established here.", "provenance": "Abstract read in full; the two-layer structure and 150 micrometre extent, the shared composition with MUC2 as major component, both layers' distinct physical properties and bacterial colonisation, the bacterial load figure, and the knockout phenotype as reported", "quantitativeExtraction": "extracted" }, "L149": { "id": "L149", "year": 2007, "topic": "Differentiation", "title": "Identification of stem cells in small intestine and colon by marker gene Lgr5", "url": "https://doi.org/10.1038/nature06196", "studyType": "Two knock-in alleles for expression mapping plus inducible Cre lineage tracing with a lacZ reporter in adult mice, Nature 449(7165):1003-1007", "diseaseContext": "Healthy reference", "useInModel": "Identifies this family's stem cell and corrects the position-based model it replaced. The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals; the prior belief was that four to six crypt stem cells sat at the +4 position above the Paneth cells, and colon stem cells were undefined. Lgr5 proved to be expressed exclusively in cycling columnar cells at the crypt base, and lineage tracing showed that the Lgr5-positive crypt base columnar cell generates all epithelial lineages over a 60-day period. The atlas can now compare four epithelial stem architectures across four parenchymal rows: an alveolar type 2 cell that depends on stromal co-culture, an airway basal cell that needs no stroma, a fully differentiated neuroendocrine cell of which roughly one per cluster deprograms after injury, and here a continuously cycling cell at a fixed anatomical position driving the fastest renewal in the body. These are four different objects, so a simulation should not carry one generic epithelial stem cell.", "limit": "Mouse, and the colon claim rests partly on the small intestine work since Lgr5 expression and tracing are presented across both. No stem cell count per crypt, crypt density, division rate or transit time is extracted here, so the architecture is established and the kinetics of the fastest-renewing tissue in the body are not. The authors note Lgr5 marks rare cells in several other tissues and in cancers, so it is not a colon-specific marker. The 60-day tracing window is the observation period, not a turnover time.", "provenance": "Abstract read in full; the displaced +4 position model and the prior absence of a defined colon stem cell, the exclusive crypt base columnar expression, the all-lineage 60-day tracing result, and the note that Lgr5 marks stem cells in other tissues and cancers as reported", "quantitativeExtraction": "extracted" }, "T05": { "id": "T05", "year": 2020, "topic": "Accessibility", "title": "A Novel GUCY2C-CD3 T-Cell Engaging Bispecific Construct (PF-07062119) for the Treatment of Gastrointestinal Cancers", "url": "https://doi.org/10.1158/1078-0432.CCR-19-3275", "studyType": "Preclinical package - multiple tumour cell lines in vitro, subcutaneous and orthotopic human colorectal xenografts with adoptive human T-cell transfer, a syngeneic model in human CD3-epsilon transgenic mice, immunohistochemistry and mass cytometry for biodistribution, plus cynomolgus macaque toxicity and pharmacokinetics, Clinical Cancer Research 26(9):2188-2202", "diseaseContext": "Colorectal and other gastrointestinal cancers", "useInModel": "The selectivity argument for an address that is on the wrong side of the normal cell, and the strongest preclinical package in this atlas for any address-class agent. Guanylyl cyclase C is expressed widely across colorectal cancer and other gastrointestinal malignancies, and normally sits on the apical surface facing the lumen - so a systemically delivered bispecific should reach it in tumours, where polarity is lost, and not in intact epithelium. The package supports that: immunohistochemistry and mass cytometry showed selective drug biodistribution to tumours with recruitment of activated T cells, efficacy followed in multiple colorectal xenograft models including KRAS- and BRAF-mutant ones and in an immunocompetent syngeneic model, combination with anti-PD-1 or anti-PD-L1 and with antiangiogenic therapy enhanced it further, and cynomolgus macaque toxicology indicated a monitorable and manageable profile. This record should be read together with the phase 1 result, where the dose-limiting toxicities were grade 3 colitis and diarrhoea and the overall response rate was 2.5 percent. Held here as the best-documented transfer failure in the atlas: a specificity mechanism that was demonstrated by biodistribution and survived primate toxicology, and did not hold in humans.", "limit": "Xenografts with adoptively transferred human T cells are not a human immune compartment, and the syngeneic model uses a transgenic human CD3-epsilon. Selective biodistribution is shown by staining and mass cytometry rather than quantified as a tumour-to-normal ratio. The macaque toxicity conclusion is qualitative. Most importantly, nothing in this record anticipates the human colitis and diarrhoea that followed, so it demonstrates the limits of this evidence type rather than being wrong on its own terms.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. The expression claim, all model systems, the biodistribution and T-cell recruitment findings, the mutant subsets, both combination results and the macaque toxicology conclusion as reported. The transfer-failure framing is this atlas's own, drawn from pairing this record with T06", "quantitativeExtraction": "extracted" }, "T06": { "id": "T06", "year": 2026, "topic": "Clinical outcome", "title": "A Phase I Study of PF-07062119, an Anti-GUCY2C/Anti-CD3 Bispecific Fc Antibody, in Patients with Advanced Gastrointestinal Cancers.", "url": "https://doi.org/10.1158/2767-9764.CRC-26-0101", "studyType": "First-in-human phase 1 dose escalation and combination study, 79 patients, subcutaneous dosing from 45 to 3,700 micrograms with sasanlimab or bevacizumab combination arms, Cancer Research Communications 6:2299-2310", "diseaseContext": "Advanced gastrointestinal cancers expressing GUCY2C", "useInModel": "The address class's first failure, and it refutes the specificity mechanism rather than merely missing an endpoint. In 79 patients the maximum tolerated dose without a priming dose was 800 micrograms, and the dose-limiting toxicities at that level were grade 3 cytokine release syndrome, colitis and diarrhoea; a 400 microgram priming dose with premedication reduced cytokine release and the recommended expansion dose became 2,100 micrograms; treatment-related grade 3 or 4 events occurred in 27 patients (34.2 percent) with no grade 5; diarrhoea remained the most clinically significant toxicity; pharmacokinetics were dose-proportional; and the overall response rate was 2.5 percent across all cohorts, with combinations adding no significant toxicity. The colitis and diarrhoea are the finding. The selectivity argument for this target was anatomical - the antigen faces the lumen in intact epithelium and should be unreachable from the blood - and the dose-limiting toxicities are normal gut toxicities, so the drug reached normal intestinal epithelium. Anatomical sequestration is therefore not equivalent to absence from normal tissue, which corrects the off-target rule the atlas had drawn from its three successful address-class agents.", "limit": "Phase 1, with mixed dose levels and monotherapy and combination cohorts pooled into the 2.5 percent response rate, so that figure is not an efficacy estimate for any single regimen at the recommended dose. Advanced pretreated gastrointestinal cancers. The colitis and diarrhoea are strong evidence that the drug engaged gut tissue and are not proof of the mechanism - a T-cell engager can cause gut toxicity through cytokine release as well as through on-target binding, and no record here separates those. Nothing here explains why the response rate was low; low penetration, low accessible antigen density and inadequate T-cell function are all consistent with it and none is measured.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. Patient count, dose range, maximum tolerated and recommended doses, all named dose-limiting toxicities, the grade 3 or 4 rate with its count, the absence of grade 5, the pharmacokinetic statement and the pooled response rate as reported. The refutation of anatomical sequestration is this atlas's own reading, labelled as such", "quantitativeExtraction": "extracted" }, "T13": { "id": "T13", "year": 2008, "topic": "Transport", "title": "Quantitative spatiotemporal analysis of antibody fragment diffusion and endocytic consumption in tumor spheroids", "url": "https://doi.org/10.1158/0008-5472.CAN-07-3018", "studyType": "Live-cell microscopic imaging of single-chain antibody fragments against carcinoembryonic antigen in LS174T tumour spheroids, compared against scaling theory, Cancer Research 68(9):3334-3341", "diseaseContext": "Colorectal cancer", "useInModel": "Supplies the form of the law the atlas needs for every local mechanism it has recorded without a length scale, and specifically for the bystander range the address class lacks. Antibody distribution in tumour tissue is set by dose, antigen concentration, binding affinity, antigen internalisation, extravasation, diffusion in the extracellular matrix and systemic clearance; this isolates a subset by imaging fragment penetration and retention in spheroids and compares it with simple scaling criteria. The theory requires two conditions at once - the dose must be large enough to drive a diffusive flux that overcomes cellular internalisation, and the exposure time must be long enough for penetration to reach the spheroid centre - and the measurements are quantitatively consistent with it. The conclusion is the valuable part: penetration distance in tumour tissue can be predicted accurately from simple scaling criteria. So penetration depth is not an unknown requiring measurement in every case but a computable quantity, provided the atlas carries antigen concentration, affinity and internalisation rate - none of which it currently holds for any target.", "limit": "Spheroids omit perfused vessels, interstitial pressure and systemic clearance, so the extravasation and clearance terms of the full problem are excluded by construction. One antigen, one cell line, one fragment format - and a fragment rather than a full antibody or a conjugate, so the result does not transfer directly to the agents in the atlas's address class without re-deriving their parameters. No penetration distance in micrometres is extracted here; what is extracted is that the distance is predictable and what it depends on.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. The listed determinants of distribution, the experimental system, both theoretical conditions, the stated quantitative agreement and the conclusion about predictability as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I045", "name": "Intestinal stem and other secretory cells", "category": "Parenchyma", "whereToCheck": "Crypt-specific modules", "states": [ "Cycling", "differentiating", "transformed" ], "behaviors": [ "Renewal", "lineage state", "secretion", "rare-cell detection" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-655", "hatton-656", "hatton-665" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-655", "hatton-656", "hatton-665" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "sender-I045-small-intestine-epithelia" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-655", "hatton-656", "hatton-665", "sender-I045-small-intestine-epithelia" ], "priorResearch": { "path": "simulation/data/profiles/intestinal-stem-and-other-secretory-cells.json", "summary": "The crypt bottom, where about six cycling Lgr5-positive stem cells sit interspersed between terminally differentiated Paneth cells, with rare tuft and enteroendocrine cells distributed through the epithelium above. Two records settle the architecture and in doing so correct each other. Single stem cells build complete crypt-villus organoids containing every differentiated type, without a mesenchymal niche, so the structure is self-organising rather than templated (L150). But the niche was not absent - it was inside the epithelium: Paneth cells supply EGF, TGF-alpha, Wnt3 and Dll4, co-culture with them markedly improves organoid formation, and removing them in vivo loses the stem cells (L151). The stem cell's own differentiated daughter is its niche, and the stem cells compete neutrally for its limiting signals. The row's third subject is a rare sentinel: tuft cells remain required for helminth clearance even when protective memory T cells are already present, and arriving T cells upregulate receptors for tuft cell effectors on entering the tissue (L152).", "stateAxes": [ { "axis": "Cycling, under neutral competition rather than hierarchy", "whatToMeasure": "About six cycling stem cells per small-intestinal crypt competing neutrally for limiting Paneth-derived signals - a stochastic dynamic, so the relevant quantity is the competition rather than any cell's rank.", "interpretationLimit": "Mouse small intestine; the count is approximate and no human or colonic count is held, which matters because the drawn environment here is colorectal and the colonic Paneth equivalent is offered as a possibility rather than shown. No division rate, fixation probability or clone size distribution.", "evidence": [ "L150", "L151" ] }, { "axis": "The niche, which is a differentiated daughter and is partly substitutable", "whatToMeasure": "Paneth cell presence and the four signals they emit, together with the fact that a pulse of exogenous Wnt substitutes for the cell in culture - because that is what decides whether this cell must be an agent or can be a field.", "interpretationLimit": "The substitution is shown in culture for organoid formation, not in vivo for homeostasis, and in vivo removal of the cells does lose the stem cells. Four signals named, one substituted. No signal concentration, gradient or range anywhere.", "evidence": [ "L151" ] }, { "axis": "Lineage state across the secretory outputs", "whatToMeasure": "Which secretory fates are present, since a single stem cell generates all differentiated types in organoids - and since the rare outputs do jobs unlike the bulk ones: Paneth cells are both antimicrobial and the niche, tuft cells are sentinels.", "interpretationLimit": "Composition is demonstrated qualitatively - all differentiated cell types present - with no proportions, densities or ratios for any lineage in any environment. Organoids lack vasculature, immune cells, luminal contents and mechanical loading.", "evidence": [ "L150", "L152" ] }, { "axis": "Rare-cell detection, as the inventory asks", "whatToMeasure": "Whether a rare sentinel is present at all, because its absence is not compensated by systemic immunity: tuft cells remained required for clearance despite protective memory T cells, and arriving T cells upregulate receptors for tuft effectors on entering the tissue.", "interpretationLimit": "Mouse helminth infection, outside any drawn environment, held for the architecture rather than as evidence about cancer. Sufficiency is shown for interleukin-13 production rather than for clearance. No tuft cell density, effector concentration or range, so the cell is shown necessary and never quantified.", "evidence": [ "L152" ] } ], "records": { "L150": { "id": "L150", "year": 2009, "topic": "Renewal", "title": "Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche", "url": "https://doi.org/10.1038/nature07935", "studyType": "Long-term organoid culture from isolated crypts and from single sorted cells, with lineage tracing in the resulting structures, Nature 459(7244):262-265", "diseaseContext": "Healthy reference", "useInModel": "Supplies the per-crypt stem cell count the colon row recorded as missing, and makes the crypt-villus unit a self-organising rather than a templated structure. There are about six cycling Lgr5-positive stem cells at the bottom of each small-intestinal crypt. In long-term culture single crypts undergo repeated fission while generating villus-like domains containing all differentiated cell types, single sorted Lgr5-positive cells initiate the same organoids, and tracing shows the stem cell hierarchy is maintained inside them. The conclusion the atlas should carry is that crypt-villus units are self-organising and can be built from one cell without a non-epithelial cellular niche - so a simulation does not need to impose this geometry, it should emerge. The phrase to read carefully is non-epithelial: this experiment removes mesenchyme and does not remove the epithelium's own internal niche, which the companion record identifies.", "limit": "Mouse small intestine, and the six-cell figure is approximate and from that site - no human count and no colonic count is held here. Organoids lack vasculature, immune cells, luminal contents and mechanical loading, so self-organisation is demonstrated under conditions that exclude most of what this atlas models. Crypt fission is observed without a rate. The absence of a mesenchymal requirement is a statement about mesenchyme only and was later qualified from inside the epithelium.", "provenance": "Abstract read in full; the approximate six-cell count and its location, the fission and villus-domain observations, the single-cell initiation, the maintained hierarchy and the self-organisation conclusion with its non-epithelial qualifier as reported", "quantitativeExtraction": "extracted" }, "L151": { "id": "L151", "year": 2011, "topic": "Renewal", "title": "Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts", "url": "https://doi.org/10.1038/nature09637", "studyType": "Physical association mapping in vivo and in vitro, co-culture of sorted populations, signal substitution, and genetic ablation of Paneth cells in mice, Nature 469(7330):415-418", "diseaseContext": "Healthy reference", "useInModel": "Two findings, and the second answers a design question the project has to settle. First, the niche for these stem cells is a terminally differentiated daughter of the same lineage. Lgr5 stem cells sit interspersed between Paneth cells and in close physical association with them; CD24-positive Paneth cells express EGF, TGF-alpha, Wnt3 and the Notch ligand Dll4, all of which are essential for stem cell maintenance in culture; co-culture with Paneth cells markedly improves organoid formation; and genetic removal of Paneth cells in vivo causes concomitant loss of the stem cells. Homeostasis is described as neutral competition between stem cells for those limiting signals, which is a stochastic dynamic rather than a fixed hierarchy. That makes this the atlas's first intra-lineage niche - a closed loop in which the stem cell's own progeny supplies what sustains it - and the only niche tested by removing it. Second, and more useful still: the Paneth cell requirement can be substituted by a pulse of exogenous Wnt. An entire cell type's niche function reduces to one pathway input, which is direct evidence about when a cell may be represented as a field rather than as an agent.", "limit": "Mouse, with the colonic equivalent offered as a possibility - CD24-positive cells between Lgr5 stem cells may represent Paneth cell equivalents - rather than demonstrated, which matters because the drawn environment here is colorectal. The Wnt substitution is shown in culture for organoid formation, not in vivo for tissue homeostasis, so it establishes that the signal is the operative part of the cell's niche role in that assay and not that Paneth cells are dispensable in tissue - genetic removal in vivo loses the stem cells. Four signals are named and only one was substituted. No signal concentration, gradient or range is given.", "provenance": "Abstract read in full; the neutral competition framing, the physical association, all four named Paneth-derived signals, the co-culture improvement, the Wnt substitution, the in vivo ablation result and the colonic equivalence caveat as reported", "quantitativeExtraction": "extracted" }, "L152": { "id": "L152", "year": 2026, "topic": "Rare-cell detection", "title": "Tuft cells promote reactivation of memory Th2 cells and are required for protective immunity to intestinal helminth re-infection", "url": "https://doi.org/10.1016/j.immuni.2026.02.022", "studyType": "Mouse secondary helminth infection with tuft cell and innate lymphoid cell deficiency, effector sufficiency tests and receptor expression analysis, Immunity 59(6):1381-1397.e6", "diseaseContext": "Healthy reference; intestinal helminth infection", "useInModel": "A rare epithelial sentinel turns out to be required even when the adaptive memory it would normally initiate is already present, which is a strong statement against representing immunity as a systemic state. Despite protective memory Th2 cells, tuft cells remained essential for worm clearance on secondary infection. Th2 cells still developed without tuft cells or group 2 innate lymphoid cells, but on entering the small intestine they upregulated receptors for the tuft cell effectors interleukin-25 and leukotriene C4; those two effectors were sufficient to drive interleukin-13 production by Th2 cells, and their absence during secondary infection diminished it. Full restriction of the infection required two things together - granulomas reducing worm fitness, and tuft cell-dependent clearance from the lumen. Three uses for this atlas. The responsiveness of an arriving T cell is acquired at the location, which supports the project's decision to carry functional state as a variable on a CD4 compartment rather than as separate populations. The two-arm requirement is a third instance of a recurring structural motif in which an outcome needs two mechanisms at once. And a rare chemosensory epithelial cell gates a lymphocyte response, which connects this parenchymal row directly to the immune category.", "limit": "Mouse, and a helminth infection rather than any drawn environment - this is held for the architecture of the interaction and not as evidence about cancer or neurodegeneration. Sufficiency of the two effectors is shown for interleukin-13 production, which is one readout and not worm clearance itself. No tuft cell density, effector concentration or range is given, so the sentinel is shown to be necessary without being quantified. Group 2 innate lymphoid cells appear here as a comparison arm and this atlas's own row for them is thin.", "provenance": "Abstract read in full; the persistence of memory Th2 cells, the continued requirement for tuft cells, the receptor upregulation on tissue entry, both named effectors and their sufficiency for interleukin-13, the diminished response in their absence, and the two-arm requirement for full restriction as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I046", "name": "Melanocytes and malignant melanoma cells", "category": "Parenchyma", "whereToCheck": "Skin primary; metastasis", "states": [ "Differentiation", "pigment", "invasive states" ], "behaviors": [ "Antigen presentation", "motility", "growth" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-478" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-478" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-478" ], "priorResearch": { "path": "simulation/data/profiles/melanocytes-and-malignant-melanoma-cells.json", "summary": "Pigment cells at the base of the epidermis, and in the uvea, whose malignant counterpart is one of the atlas's best-served environments. Three things organise the row. The address here is a peptide rather than a protein: an affinity-enhanced T-cell receptor against a glycoprotein 100 peptide on HLA-A*02:01 raised one-year survival from 59 to 73 percent and median survival from 16.9 to 21.6 months, with rash in 83 percent that the paper attributes to normal glycoprotein 100-positive melanocytes - and with 2 percent discontinuation and no treatment-related deaths (R04, R05). Potency against a surface address in this family turns out to depend on geometry rather than affinity: engagers of similar affinity differed greatly, membrane-proximal epitopes beat distal ones, and smaller antigens were lysed better than larger ones (T03). And the malignant cell sets its own immune environment through a resistance program that precedes therapy, marks cold niches, and predicts anti-PD-1 response in 112 patients (M02). Pigment itself is a drug disposition compartment (L153).", "stateAxes": [ { "axis": "Antigen presentation, where the address is a peptide and the patient is a gate", "whatToMeasure": "Peptide-HLA presentation of a differentiation antigen together with the patient's HLA genotype, since eligibility for the only survival-benefit agent here was restricted to HLA-A*02:01-positive patients and the target copy number of a peptide-MHC complex is far below that of a surface oncoprotein.", "interpretationLimit": "Uveal rather than cutaneous disease, open-label, and with a control arm whose checkpoint agents are known to perform poorly in it. No peptide-HLA copies per cell, occupancy or effector-to-target ratio is held, so the low-density claim is a general property of peptide presentation rather than a measurement. The escape route - loss of presentation machinery - is unmeasured here.", "evidence": [ "R04", "R05" ] }, { "axis": "Binding geometry, which outranks affinity", "whatToMeasure": "Epitope distance from the membrane and the size of the antigen, carried separately from affinity - because engagers of similar affinity differed greatly in potency, membrane-proximal epitopes were more potent, and smaller antigens were lysed better.", "interpretationLimit": "Engineered CHO cells and in vitro lysis, not tumours or outcomes. Two antigens and one engager format, with no distances given in nanometres and no universal optimum implied. Nothing relates this to the peptide-HLA address in the same family, where the target sits at the membrane by construction.", "evidence": [ "T03" ] }, { "axis": "Invasive and immune-evasive state, set by the malignant cell", "whatToMeasure": "The malignant-cell resistance program, which precedes therapy, characterises cold niches in situ and predicts anti-PD-1 response - and which CDK4/6 inhibition represses in individual cells while inducing senescence.", "interpretationLimit": "A transcriptional signature, so a state defined by expression rather than by a physical property, with no exclusion distance, T-cell density or niche size given. Predictive validation is retrospective and the therapeutic result is mouse combination work, not a clinical outcome. Resistance to checkpoint blockade does not imply resistance to engager formats, which this family's own agent is.", "evidence": [ "M02" ] }, { "axis": "Pigment, as a disposition compartment", "whatToMeasure": "Melanin binding affinity of the administered molecule, since melanin binding drives targeted disposition into pigmented tissue and prolonged local response, and in vitro binding correlates with in vivo binding.", "interpretationLimit": "From a method paper, so what is established is that the affinity can be screened reliably rather than any drug's disposition in melanoma. Synthetic melanin nanoparticles are not tumour melanin. The relevance to this family's own agents is this atlas's observation and is untested.", "evidence": [ "L153" ] } ], "records": { "L153": { "id": "L153", "year": 2026, "topic": "Pigment", "title": "Effective process for screening melanin binding affinity of small molecule drugs and new drug candidates", "url": "https://doi.org/10.1016/j.ijpharm.2026.126964", "studyType": "Methodological development of tangential flow filtration-produced melanin nanoparticles with microscale thermophoresis binding assay, tested against nine compounds of known affinity, International Journal of Pharmaceutics 698:126964", "diseaseContext": "Healthy reference", "useInModel": "Makes pigment a pharmacokinetic compartment rather than a colour, which is what the inventory's pigment state should mean for this project. Melanin binding of small molecule drugs leads to targeted disposition into pigmented tissues and prolonged pharmacological response in the eye, and in vitro binding correlates with binding in vivo. The paper's own contribution is a faster and more reproducible way to measure that affinity, validated against nine compounds spanning a range of known affinities, with the stated purpose of supporting predictive pharmacokinetic simulation models. For this atlas the relevance is specific and somewhat striking: the one drug in this family with a proven survival benefit treats uveal melanoma, and the uvea is the pigmented tissue where melanin binding is known to prolong local drug exposure. So this family carries a tissue-specific disposition term that no other family in the atlas has, and it is a measurable molecular property rather than an emergent one.", "limit": "A method paper, so what it establishes is that melanin binding affinity can be screened reliably, not any particular drug's disposition in melanoma. The disposition and prolonged-response claims are stated as established background about the eye, not measured here. Synthetic melanin nanoparticles are not tumour melanin, which differs in composition and packaging. Nothing connects melanin binding to the efficacy or toxicity of any agent this atlas holds for this family, including the peptide-HLA agent - that connection is this atlas's own observation and is untested.", "provenance": "Abstract read in full; the disposition and prolonged-response background, the in vitro to in vivo correlation claim, the methodology and its validation against nine compounds, and the stated aim of supporting pharmacokinetic simulation as reported", "quantitativeExtraction": "extracted" }, "M02": { "id": "M02", "year": 2018, "topic": "Resistance and exclusion", "title": "A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade", "url": "https://doi.org/10.1016/j.cell.2018.09.006", "studyType": "Single-cell RNA sequencing of 33 melanoma tumours with computational state analysis, validation in an independent cohort of 112 patients, and pharmacological repression with mouse in vivo combination testing, Cell 175(4):984-997.e24", "diseaseContext": "Melanoma", "useInModel": "The malignant cell setting its own immune environment, measured at single-cell resolution and pre-existing rather than induced. A resistance program expressed by malignant cells is associated with T-cell exclusion and immune evasion; it is expressed before immunotherapy, characterises cold niches in situ, and predicts clinical response to anti-PD-1 in an independent cohort of 112 patients. CDK4/6 inhibition represses the program in individual malignant cells, induces senescence, and reduces tumour outgrowth in mice when combined with immunotherapy. Two uses. This is the atlas's clearest case of a parenchymal row driving the immune rows rather than responding to them - the exclusion the atlas records from the T-cell side has a cause on the tumour side, and that cause is spatially organised into cold niches. And it is a consistency check on the intervention ledger: the program performs a function the tumour needs, the ledger predicts that blocking such a thing should work, and blocking it did work in combination.", "limit": "The predictive validation is in a retrospective independent cohort rather than a prospective trial, and the therapeutic result is mouse models in combination, not a clinical outcome - CDK4/6 inhibition plus immunotherapy is not established in melanoma by this record. The program is a transcriptional signature, so it is a state defined by expression rather than by a measurable physical property, and no exclusion distance, T-cell density or niche size is given. Checkpoint resistance biology does not imply identical resistance to engager formats, which this family's own peptide-HLA agent is.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. The cohort sizes for discovery and validation, the program's association with exclusion and cold niches, its expression before therapy, its predictive performance, and the CDK4/6 repression with senescence induction and combination effect in vivo as reported", "quantitativeExtraction": "extracted" }, "R04": { "id": "R04", "year": 2021, "topic": "Clinical outcome", "title": "Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma", "url": "https://doi.org/10.1056/NEJMoa2103485", "studyType": "Open-label phase 3 trial, 378 previously untreated HLA-A*02:01-positive patients randomised 2:1 to tebentafusp or investigator's choice of pembrolizumab, ipilimumab or dacarbazine, stratified by lactate dehydrogenase, NEJM 385(13):1196-1206, IMCgp100-202, NCT03070392", "diseaseContext": "Uveal melanoma", "useInModel": "A fifth kind of address, and the clearest evidence in the atlas that the off-target rule needs a term it does not have. Tebentafusp is an affinity-enhanced T-cell receptor fused to an anti-CD3 effector, so the address is not a surface protein but a peptide from glycoprotein 100 presented on a particular HLA allele - which makes patient genotype an eligibility gate and puts the target copy number orders of magnitude below a surface oncoprotein. In 252 against 126 patients, overall survival at one year was 73 against 59 percent (HR 0.51, 95% CI 0.37-0.71) and progression-free survival at six months 31 against 19 percent (HR 0.73, 0.58-0.94), in a disease with low tumour mutational burden, roughly 50 percent one-year survival, and no previously proven systemic survival benefit. The toxicity is the part that matters most here. The common treatment-related events were cytokine-mediated and skin-related, and the paper attributes the skin events directly to glycoprotein 100-positive melanocytes: rash in 83 percent, pyrexia 76, pruritus 69. That is the atlas's cleanest instance of on-target normal-tissue damage, named as such by the source - and it was tolerable, with 2 percent discontinuation and no treatment-related deaths, because the normal cell bearing the address is dispensable. The HER2 conjugate's address sits on normal lung and kills; this one sits on melanocytes and causes a rash.", "limit": "HLA-A*02:01-restricted and uveal rather than cutaneous melanoma - a distinct disease, so this is not a cutaneous melanoma efficacy estimate and the control arm's checkpoint agents are known to perform poorly here. Open-label. Survival is reported at one year as a landmark rather than as a median in this analysis. No peptide-HLA copy number per cell, receptor occupancy or effector-to-target ratio is given, so the low-density claim is a property of peptide-MHC presentation generally and not a measurement in this record. The attribution of skin events to melanocytes is the authors' and is mechanistically natural, not separately demonstrated here.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. The construct's composition, trial design and arm sizes, both efficacy endpoints with hazard ratios and confidence intervals, the disease's baseline survival and mutational burden, all three common adverse event rates with the authors' attribution to melanocytes, the early-dose decline, discontinuation rate and absence of treatment-related deaths as reported", "quantitativeExtraction": "extracted" }, "R05": { "id": "R05", "year": 2023, "topic": "Clinical follow-up", "title": "Three-Year Overall Survival with Tebentafusp in Metastatic Uveal Melanoma", "url": "https://doi.org/10.1056/NEJMoa2304753", "studyType": "Three-year efficacy and safety analysis of the same open-label phase 3 trial at a minimum follow-up of 36 months, NEJM 389(24):2256-2266", "diseaseContext": "Uveal melanoma", "useInModel": "Turns the landmark benefit into a median and supplies something the atlas has nowhere else: the shape of a toxicity in time, followed long enough to be sure. Median overall survival was 21.6 against 16.9 months (HR 0.68, 95% CI 0.54-0.87) with 27 against 18 percent of patients alive at three years. Rash remained at 83 percent, pyrexia 76, pruritus 70, hypotension 38; most events occurred early in treatment and no new adverse events appeared with long-term administration; discontinuation for adverse events stayed at 2 percent against 5 in the control arm; and there were no treatment-related deaths. Read against the alveolar row, the atlas now holds two opposite toxicity time-courses for two address-class agents. The antibody-drug conjugate's interstitial lung disease had no onset window, with fatal cases beyond twelve months and time to onset independent of grade. This agent's toxicity is front-loaded, declines, and never becomes fatal. So toxicity has a shape as well as a rate, the shapes differ by mechanism, and a model that carries a single toxicity probability per agent cannot express either.", "limit": "The same trial as the primary analysis, so this is longer follow-up and not an independent replication or a second cohort. Still HLA-restricted and still uveal disease. The claim that no new adverse events appeared with long-term administration is an absence over this follow-up in this trial size. The three-year survival figures are estimated percentages.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. Minimum follow-up, both median survivals with hazard ratio and confidence interval, the three-year survival estimates, all four adverse event rates, the early-onset and no-new-events statements, both discontinuation rates and the absence of treatment-related deaths as reported. The comparison of toxicity time-courses is this atlas's own", "quantitativeExtraction": "extracted" }, "T03": { "id": "T03", "year": 2010, "topic": "Binding geometry", "title": "Epitope distance to the target cell membrane and antigen size determine the potency of T cell-mediated lysis by BiTE antibodies specific for a large melanoma surface antigen.", "url": "https://doi.org/10.1007/s00262-010-0844-y", "studyType": "Panel of bispecific T-cell engagers built from many monoclonal antibodies against one large melanoma surface antigen, tested against CHO cells expressing full-length antigen, deletion mutants and antigen fusion proteins, Cancer Immunology, Immunotherapy 59(8):1197-1209", "diseaseContext": "Melanoma", "useInModel": "Gives the address class a geometric parameter and shows that the parameter everyone measures does not predict potency. Engagers against melanoma chondroitin sulfate proteoglycan with similar binding affinities differed greatly in their potency of redirected lysis. Those binding the membrane-proximal domain were more potent than those binding distal domains, and the effect was corroborated with a second engager against a different antigen using fusion proteins between the two. Separately, cells expressing small surface antigens were lysed better than cells expressing larger ones. So epitope height above the membrane and antigen size both set potency independently of affinity. For a project whose stated subject includes molecular structure this is the most directly structural determinant of efficacy it holds: whether a cytolytic synapse can close depends on how far the bound epitope sits from the membrane and how much antigen is in the way. The atlas's address class has so far accumulated reach, specificity and density; this adds geometry, and it must be carried separately from affinity rather than folded into it.", "limit": "Engineered CHO cells expressing constructs, not tumours, and lysis in vitro rather than any clinical outcome. No universal optimal epitope distance follows - the result is that distance and size matter and that closer and smaller were better in this system. Two antigens, one engager format, and no measurement in nanometres of the distances compared. Nothing here relates the effect to the peptide-HLA address in this same family, where the target sits at the membrane by construction.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. The antigen's identity and functions, the construction of the engager panel, the dissociation of affinity from potency, the membrane-proximal advantage, its corroboration with a second antigen, and the antigen size effect as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I047", "name": "Keratinocytes and skin appendage cells", "category": "Parenchyma", "whereToCheck": "Melanoma normal neighborhood", "states": [ "Differentiation", "inflammation" ], "behaviors": [ "Barrier", "local immune signals", "off-tumor exposure" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-482", "hatton-483", "hatton-484" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-482", "hatton-483", "hatton-484" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "sender-I047-epidermal-cells" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-482", "hatton-483", "hatton-484", "sender-I047-epidermal-cells" ], "priorResearch": { "path": "simulation/data/profiles/keratinocytes-and-skin-appendage-cells.json", "summary": "The epidermis and its appendages - which the inventory places not as a disease site but as the melanoma normal neighbourhood, and asks about for barrier, local immune signals and off-tumour exposure. All three turn out to be well chosen. This is the only barrier in the atlas with a permeability rather than a thickness, and the permeability is computable: multiple regression on a human permeation database predicts the permeability coefficient from three chemical properties (L154), and a companion model predicts it from functional group counts alone, with no other physicochemical property needed (L155). Off-tumour exposure is not hypothetical here either - the melanoma row's peptide-HLA agent caused rash in 83 percent of patients, attributed to glycoprotein 100-positive melanocytes living in this neighbourhood, and tolerated because this tissue is dispensable. The same neighbourhood is also a delivery route: the atlas's only locally delivered immunotherapy is a topical agonist applied to this surface.", "stateAxes": [ { "axis": "Barrier, as a permeability computable from structure", "whatToMeasure": "The permeability coefficient, obtained from the compound rather than measured per compound - from three chemical properties, or from the type and number of functional groups in the structure alone.", "interpretationLimit": "Healthy excised human skin, so nothing here describes an inflamed or tumour-bearing epidermis, which are the clinically relevant cases. A permeability coefficient is a steady-state flux per unit concentration and is neither a tissue concentration nor a depth. Valid only within the chemical range of the source database, which does not cover antibodies, conjugates or engagers - so it does not reach this atlas's own address-class agents. The fragment model fails precisely where chemistry is novel.", "evidence": [ "L154", "L155" ] }, { "axis": "What the barrier does not obey", "whatToMeasure": "Both flux and tissue concentration, separately, because they were shown not to correlate - and molecular weight without assuming a cut-off, since permeability was raised in compounds above 1,200 Daltons by adding polar side chains.", "interpretationLimit": "In vitro, with a prodrug strategy in which the measured species differs from the active parent, and enhancement factors expressed relative to a parent compound known to penetrate poorly - so large fold-changes do not establish adequate absolute delivery. The parent-concentration gain was demonstrated once and was 2.5-fold.", "evidence": [ "L156" ] }, { "axis": "Off-tumour exposure, which this row absorbs on behalf of the tumour row", "whatToMeasure": "The consequence of attacking a differentiation antigen shared with the normal neighbour - near-universal rash, and near-zero discontinuation and mortality - because that pairing is what makes the melanoma row's criticality term concrete.", "interpretationLimit": "The attribution of skin events to melanocytes is the melanoma trial authors' and is mechanistically natural rather than separately demonstrated. Nothing in this row measures keratinocyte involvement in that toxicity, so this family is the setting of the damage without being shown to be its target.", "evidence": [ "R04", "R05" ] }, { "axis": "Local immune signals", "whatToMeasure": "Inducible antimicrobial peptides and cytokines from keratinocytes, which the inventory names and the atlas does not hold - with the one adjacent anchor being the response to a topical innate agonist applied to this surface.", "interpretationLimit": "No record held here measures any keratinocyte-derived signal. The topical agonist result is a clinical outcome against surgery and says nothing about which cell produced which mediator, so this axis is named, important and empty.", "evidence": [ "L106" ] } ], "records": { "L106": { "id": "L106", "year": 2014, "topic": "Clinical outcome", "title": "Surgical excision versus imiquimod 5% cream for nodular and superficial basal-cell carcinoma (SINS): a multicentre, non-inferiority, randomised controlled trial", "url": "https://doi.org/10.1016/S1470-2045(13)70530-8", "studyType": "Multicentre pragmatic non-inferiority randomised controlled trial at 12 UK centres, 501 participants, three-year follow-up, Lancet Oncol 15(1):96-105", "diseaseContext": "Shared cancer", "useInModel": "The atlas's only locally delivered immune agonist, and the number it achieves reframes the whole intervention ledger. Imiquimod activates toll-like receptor 7, the pathway this family is built around, and was applied as a 5% cream for six weeks in superficial and twelve in nodular basal-cell carcinoma against surgical excision with a 4 mm margin. Of 501 randomised participants, at three years 178 of 213 in the imiquimod group were treated successfully against 185 of 188 in the surgery group - 84% against 98%, a relative risk of 0.84 with a 98% confidence interval of 0.78 to 0.91 - so imiquimod was inferior to surgery by the predefined non-inferiority criterion, and the authors conclude surgery remains the best treatment while imiquimod may still suit small low-risk lesions depending on preference, size and site. Patient-assessed cosmetic outcomes did not clearly differ; itching and weeping were the common adverse events and 5% withdrew for adverse events against 2% on surgery. The comparison that matters for this atlas is not with surgery but with every other immunotherapy it holds: 84% durable three-year success as monotherapy, against response rates of 10% to 47% for systemic agents acting on related pathways. The mechanism is not obviously better. The delivery is - the drug is put on the lesion.", "limit": "Low-risk nodular and superficial basal-cell carcinoma at low-risk sites, excluding morphoeic and recurrent tumours and Gorlin syndrome - a tumour type not among the drawn set, accessible to topical treatment, and among the most indolent malignancies. Masking was not possible for participants and only partly for outcome assessors. Twenty per cent of participants were not in the three-year modified intention-to-treat analysis. The success rate is clinical absence of failure or recurrence rather than a histological cure, and nothing here establishes that the benefit runs through this family specifically.", "provenance": "Abstract read in full including the findings and interpretation sections; all counts, percentages, the relative risk with interval, adverse events and the inferiority conclusion as reported", "quantitativeExtraction": "extracted" }, "L154": { "id": "L154", "year": 2022, "topic": "Barrier", "title": "Predicting skin permeability using HuskinDB", "url": "https://doi.org/10.1038/s41597-022-01698-4", "studyType": "Multiple regression modelling of human skin permeability coefficients drawn from a curated open database of published human permeation measurements, Scientific Data 9:584", "diseaseContext": "Healthy reference", "useInModel": "The first permeability anywhere in this atlas, and it arrives as a model rather than a value. The colon row recorded explicitly that a thickness is not a permeability and that no diffusion coefficient through any barrier existed in the data layer; this closes that gap for one barrier. Using permeability coefficients from a freely accessible database of human - not animal - skin permeation measurements, several models were established by varying the experimental parameters considered, and multiple regression produced one particularly successful model predicting the permeability coefficient through human skin from only three chemical properties. The authors' stated purpose is that this replaces permeation testing for a wide range of compounds. For a project whose aim is to introduce a molecule into an environment and watch what it does, this is the single most directly usable record in the atlas: for this barrier, the transport parameter is computed from the compound rather than looked up per compound.", "limit": "Intact healthy human skin, which is the normal neighbourhood of the drawn melanoma environment rather than the tumour itself - nothing here says what a tumour-bearing or inflamed epidermis does, and both are the cases that matter clinically. A permeability coefficient is a steady-state flux per unit concentration across excised skin, so it is not a tissue concentration and not a depth. Valid only within the range of properties represented in the database, which is a set of mostly small molecules - it does not cover antibodies, conjugates or the engager formats this atlas's address class is built from. The three properties are not enumerated in the abstract read here.", "provenance": "Abstract read in full; the database's human and non-animal character, the use of permeability coefficients, the multiple regression approach, the three-property model and the authors' stated replacement purpose as reported. The specific three properties were not named in the abstract and are deliberately not guessed at", "quantitativeExtraction": "extracted" }, "L155": { "id": "L155", "year": 2023, "topic": "Barrier", "title": "Fragment contribution models for predicting skin permeability using HuskinDB", "url": "https://doi.org/10.1038/s41597-023-02711-0", "studyType": "Fragment-based contribution modelling of human skin permeability from functional group counts, built on the same curated human permeation database, Scientific Data 10:821", "diseaseContext": "Healthy reference", "useInModel": "Takes the previous record's step further in exactly the direction this project needs. Where conventional skin permeation models require knowing a compound's molecular volume, polarity and lipophilicity - and are usually built on animal data - this one is formed entirely from simple chemical fragment data on a human permeation database, with a calculable contribution for each of the most commonly encountered functional groups in the dataset. The consequence stated by the authors is that human skin permeability can be predicted for any compound containing those functional groups with no need to know any other physicochemical property - solely the type and number of each group present in the chemical structure. That is a transport coefficient obtained from a structural formula alone. The project's stated ambition is to plug in a molecule and have it enter an environment as an administered treatment would; for this one barrier, that computation exists and is published, and the atlas should treat it as the template for what every other barrier is missing.", "limit": "Restricted to compounds containing functional groups that were common enough in the source database to have a fitted contribution, so novelty of chemistry is exactly where it fails, and fragment additivity ignores conformation and intramolecular interactions. The authors describe it as simplifying prediction for compounds with properties similar to those used in the study, which is a narrower claim than generality. Same barrier limits as the companion model: healthy excised human skin, a steady-state coefficient rather than a tissue concentration, and no coverage of antibody-sized agents. No accuracy figure is extracted here.", "provenance": "Abstract read in full; the contrast with physicochemical-property models, the human and non-animal database, the per-functional-group contributions, the claim that structure alone suffices, and the authors' own similarity caveat as reported", "quantitativeExtraction": "extracted" }, "L156": { "id": "L156", "year": 2005, "topic": "Barrier", "title": "Novel cyclosporin derivatives featuring enhanced skin penetration despite increased molecular weight", "url": "https://doi.org/10.1016/j.bmc.2005.02.049", "studyType": "Synthesis of prodrug derivatives with permeation and tissue concentration measured in vitro through both rat and human skin, Bioorganic & Medicinal Chemistry 13(10):3157-3167", "diseaseContext": "Healthy reference", "useInModel": "Three findings, each correcting an assumption a simulation would otherwise make. First, a molecular weight cut-off is a heuristic and not a physical limit: the 500 Dalton rule holds that molecules above that mass penetrate skin poorly, and adding polar side chains - a quaternary amine, a phosphate, a sulfate, or an amphiphilic phosphocholine - generally increased permeability in compounds of molecular weight above 1,200. This is the same shape as the breast row's HER2 finding, where a scoring cut-off turned out not to be a biological boundary; here a mass cut-off turns out not to be a transport boundary. Second, and most consequential for a simulation whose output is local exposure: increases in permeation rate and increases in skin concentration showed no strict correlation. The quantity that is easy to measure, flux across the barrier, is not the quantity that matters, concentration within the tissue. Third, the same derivatives enhanced permeability up to 300-fold through rat skin and up to 16-fold through human skin - a measured discrepancy of roughly twentyfold between species in one experiment, which is a rare quantified case of exactly the transfer the rest of this atlas performs on assumption.", "limit": "In vitro permeation through excised skin, and a prodrug strategy in which the measured species and the active parent differ - the clinically relevant outcome, a higher parent concentration in skin, was demonstrated for one derivative and at a modest 2.5-fold. Enhancement factors are relative to a notoriously poorly penetrating parent compound, so large fold-changes do not imply adequate absolute delivery. The rat-to-human ratio is specific to these compounds and this barrier and should not be carried as a general species factor. Healthy skin, no tumour, and nothing about the agents in this atlas's address class.", "provenance": "Abstract read in full; the ineffectiveness of the topical parent drug, the side chains tested, both maximal permeability enhancements by species, the skin penetration enhancement, the explicit absence of correlation between permeation rate and skin concentration, the 2.5-fold parent concentration result and the stated contrast with the 500 Dalton rule as reported", "quantitativeExtraction": "extracted" }, "R04": { "id": "R04", "year": 2021, "topic": "Clinical outcome", "title": "Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma", "url": "https://doi.org/10.1056/NEJMoa2103485", "studyType": "Open-label phase 3 trial, 378 previously untreated HLA-A*02:01-positive patients randomised 2:1 to tebentafusp or investigator's choice of pembrolizumab, ipilimumab or dacarbazine, stratified by lactate dehydrogenase, NEJM 385(13):1196-1206, IMCgp100-202, NCT03070392", "diseaseContext": "Uveal melanoma", "useInModel": "A fifth kind of address, and the clearest evidence in the atlas that the off-target rule needs a term it does not have. Tebentafusp is an affinity-enhanced T-cell receptor fused to an anti-CD3 effector, so the address is not a surface protein but a peptide from glycoprotein 100 presented on a particular HLA allele - which makes patient genotype an eligibility gate and puts the target copy number orders of magnitude below a surface oncoprotein. In 252 against 126 patients, overall survival at one year was 73 against 59 percent (HR 0.51, 95% CI 0.37-0.71) and progression-free survival at six months 31 against 19 percent (HR 0.73, 0.58-0.94), in a disease with low tumour mutational burden, roughly 50 percent one-year survival, and no previously proven systemic survival benefit. The toxicity is the part that matters most here. The common treatment-related events were cytokine-mediated and skin-related, and the paper attributes the skin events directly to glycoprotein 100-positive melanocytes: rash in 83 percent, pyrexia 76, pruritus 69. That is the atlas's cleanest instance of on-target normal-tissue damage, named as such by the source - and it was tolerable, with 2 percent discontinuation and no treatment-related deaths, because the normal cell bearing the address is dispensable. The HER2 conjugate's address sits on normal lung and kills; this one sits on melanocytes and causes a rash.", "limit": "HLA-A*02:01-restricted and uveal rather than cutaneous melanoma - a distinct disease, so this is not a cutaneous melanoma efficacy estimate and the control arm's checkpoint agents are known to perform poorly here. Open-label. Survival is reported at one year as a landmark rather than as a median in this analysis. No peptide-HLA copy number per cell, receptor occupancy or effector-to-target ratio is given, so the low-density claim is a property of peptide-MHC presentation generally and not a measurement in this record. The attribution of skin events to melanocytes is the authors' and is mechanistically natural, not separately demonstrated here.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. The construct's composition, trial design and arm sizes, both efficacy endpoints with hazard ratios and confidence intervals, the disease's baseline survival and mutational burden, all three common adverse event rates with the authors' attribution to melanocytes, the early-dose decline, discontinuation rate and absence of treatment-related deaths as reported", "quantitativeExtraction": "extracted" }, "R05": { "id": "R05", "year": 2023, "topic": "Clinical follow-up", "title": "Three-Year Overall Survival with Tebentafusp in Metastatic Uveal Melanoma", "url": "https://doi.org/10.1056/NEJMoa2304753", "studyType": "Three-year efficacy and safety analysis of the same open-label phase 3 trial at a minimum follow-up of 36 months, NEJM 389(24):2256-2266", "diseaseContext": "Uveal melanoma", "useInModel": "Turns the landmark benefit into a median and supplies something the atlas has nowhere else: the shape of a toxicity in time, followed long enough to be sure. Median overall survival was 21.6 against 16.9 months (HR 0.68, 95% CI 0.54-0.87) with 27 against 18 percent of patients alive at three years. Rash remained at 83 percent, pyrexia 76, pruritus 70, hypotension 38; most events occurred early in treatment and no new adverse events appeared with long-term administration; discontinuation for adverse events stayed at 2 percent against 5 in the control arm; and there were no treatment-related deaths. Read against the alveolar row, the atlas now holds two opposite toxicity time-courses for two address-class agents. The antibody-drug conjugate's interstitial lung disease had no onset window, with fatal cases beyond twelve months and time to onset independent of grade. This agent's toxicity is front-loaded, declines, and never becomes fatal. So toxicity has a shape as well as a rate, the shapes differ by mechanism, and a model that carries a single toxicity probability per agent cannot express either.", "limit": "The same trial as the primary analysis, so this is longer follow-up and not an independent replication or a second cohort. Still HLA-restricted and still uveal disease. The claim that no new adverse events appeared with long-term administration is an absence over this follow-up in this trial size. The three-year survival figures are estimated percentages.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. Minimum follow-up, both median survivals with hazard ratio and confidence interval, the three-year survival estimates, all four adverse event rates, the early-onset and no-new-events statements, both discontinuation rates and the absence of treatment-related deaths as reported. The comparison of toxicity time-courses is this atlas's own", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I048", "name": "Urothelial basal/intermediate/umbrella cells", "category": "Parenchyma", "whereToCheck": "Bladder lumen and wall", "states": [ "Polarity", "injury", "malignant subtype" ], "behaviors": [ "Luminal barrier", "target accessibility", "drug exposure" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-806", "hatton-808" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-806", "hatton-808" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-806", "hatton-808" ], "priorResearch": { "path": "simulation/data/profiles/urothelial-basal-intermediate-umbrella-cells.json", "summary": "A stratified lining from basal cells through intermediate cells to the large superficial umbrella cells that face urine, in an organ whose contents are hostile and whose lumen is a drug delivery route. The inventory names luminal barrier, target accessibility and drug exposure, so this is a delivery row by design, and all three are served. Target accessibility: a nectin-4 antibody carrying a microtubule poison, combined with a checkpoint inhibitor, roughly doubled median overall survival against platinum chemotherapy - 31.5 against 16.1 months, hazard ratio 0.47 (R08). Drug exposure: active gemcitabine metabolites were undetectable across bladder layers by 24 hours after a conventional instillation and persisted at least 96 hours from an indwelling releasing system (L159). And the off-target side is unusually well characterised here - nectin-4 is expressed in keratinocytes and cutaneous appendages, cutaneous toxicity is on-target and mechanism-based (L157), it occurred in 45.9 percent of 449 patients, and developing it was associated with longer survival (L158).", "stateAxes": [ { "axis": "Drug exposure, resolved in space and time", "whatToMeasure": "How long active metabolite persists in each bladder region and layer, not just whether the drug was delivered - undetectable by 24 hours after bolus instillation against at least 96 hours from an indwelling system, sampled at dome, both lateral walls and trigone.", "interpretationLimit": "Five healthy minipigs, three against two, with the authors flagging both the sample size and the absence of tumour-bearing tissue - and a tumour changes both barrier and perfusion. Detectability rather than a concentration time course, so no half-life or exposure integral is available, and nothing links the longer window to an outcome.", "evidence": [ "L159" ] }, { "axis": "Target accessibility, and where the address also lives", "whatToMeasure": "Nectin-4 on the tumour and in keratinocytes and cutaneous appendages, since the cutaneous toxicity is on-target and mechanism-based rather than a payload effect shared with chemotherapy.", "interpretationLimit": "The expression claim comes from a review as established background, with no density or tumour-to-normal ratio anywhere, and the mechanistic attribution is well argued rather than separated here from payload release and local uptake by other routes.", "evidence": [ "L157" ] }, { "axis": "Off-target damage as an observable, not only a cost", "whatToMeasure": "Whether a cutaneous event occurred and when - 45.9 percent of 449 patients, with the event protective at every landmark from 15 to 105 days - because it appears to report engagement rather than merely penalise the patient.", "interpretationLimit": "Retrospective, so not causal: longer survival allows more time to develop a toxicity, which time-varying and landmark models address rather than remove. Attribution by likelihood scoring. The cohort mixes treatment groups, and separating this from concurrent checkpoint inhibition was the study's motivation. A rash is a crude proxy - no occupancy, payload exposure or response correlate is measured.", "evidence": [ "L158" ] }, { "axis": "Luminal barrier and malignant subtype", "whatToMeasure": "Umbrella cell plaque integrity for the barrier, and the luminal-basal subtype axis for the malignant state - both of which the inventory names and neither of which any record here measures.", "interpretationLimit": "This is the row's hole. No transepithelial resistance, permeability or plaque coverage for the urothelium is held, which is conspicuous given that the organ is dosed through its lumen; and no subtype measurement, so GATA3 and PPARG sit in the panel on literature standing alone.", "evidence": [] } ], "records": { "L157": { "id": "L157", "year": 2026, "topic": "Target accessibility", "title": "Enfortumab vedotin-related cutaneous toxicity: Clinical features, pathogenesis and management", "url": "https://doi.org/10.1016/j.jdermsci.2026.08.009", "studyType": "Review integrating molecular, clinical and histopathologic evidence on one antibody-drug conjugate's cutaneous toxicity, Journal of Dermatological Science", "diseaseContext": "Urothelial carcinoma", "useInModel": "Names the normal tissue that an address-class agent damages, by cell type, which no other member of that class in this atlas does. Enfortumab vedotin is a fully human monoclonal antibody against nectin-4 joined by a protease-cleavable linker to monomethyl auristatin E, a microtubule disruptor. Because nectin-4 is expressed in keratinocytes and cutaneous appendages, cutaneous adverse events are among the most frequent toxicities, and the review states plainly that this is an on-target, mechanism-based toxicity distinct from the cutaneous effects of conventional cytotoxic chemotherapy. Two consequences for the atlas. The address class has five parameters and the specificity one was recorded as qualitative with no member having its address located in normal human tissue; this supplies the location, still without a quantity. And the normal tissue named - keratinocytes and cutaneous appendages - is exactly the keratinocyte row's own title, so the skin is now the destination of on-target damage from two different agents addressing two different cell types on behalf of two different primary tumours.", "limit": "A review rather than a measurement, so the expression claim is stated as established background and no quantity, density or tumour-to-normal ratio is given here. Its purpose is recognition and management, not estimation of risk. The mechanistic attribution is well argued and remains an attribution: nectin-4 expression in skin plus a skin toxicity is consistent with on-target damage without this record separating it from payload release and local uptake by other routes.", "provenance": "Abstract read in full; the construct's composition including antibody, linker and payload, the stated nectin-4 expression in keratinocytes and cutaneous appendages, the frequency framing, and the explicit on-target mechanism-based characterisation distinct from chemotherapy as reported", "quantitativeExtraction": "extracted" }, "L158": { "id": "L158", "year": 2026, "topic": "Target accessibility", "title": "Enfortumab Vedotin-Induced Cutaneous Toxic Effects and Survival in Urothelial Carcinoma", "url": "https://doi.org/10.1001/jamadermatol.2026.2543", "studyType": "Multi-institutional retrospective cohort of 449 patients treated between 2020 and 2025, with likelihood-scored attribution of events, time-varying and landmark Cox models and sensitivity analyses at landmarks from 15 to 105 days, JAMA Dermatology 162(9):922-930", "diseaseContext": "Urothelial carcinoma", "useInModel": "Gives the atlas's off-target rule a third face. The rule has been that damage equals payload reach times normal-tissue expression of the address, amended by the melanoma row to add the criticality of the tissue, which converts predicted damage into predicted tolerability. This record adds informativeness: among 449 patients, 206 (45.9 percent) developed a cutaneous adverse event, 127 of those were attributed to the conjugate and 39 were high-grade; the commonest were pruritus (41.3 percent of affected patients), unspecified and desquamating dermatitis (37.3) and morbilliform dermatitis (27.7); and across all treatment groups survival was longer in patients who developed one, with the event protective at every landmark assessed. So on-target damage in a tissue the body can spare is not only an acceptable cost - it is evidence that the drug engaged its address, and it tracks benefit. For a simulation that means off-target toxicity should be modelled as an observable consequence of engagement rather than solely as a penalty term.", "limit": "Retrospective and observational, so the survival association is not causal - patients who live longer have more time to develop a toxicity, which is the immortal-time problem the authors address with time-varying and landmark models and sensitivity analyses from 15 to 105 days rather than remove. Attribution to the conjugate was by likelihood scoring, not biopsy or rechallenge. Disentangling this from concurrent checkpoint inhibitor effects was the study's stated motivation and the cohort is still a mixture of treatment groups. A cutaneous event is a crude proxy for engagement: no target occupancy, payload exposure or tumour response correlate is measured.", "provenance": "Abstract read in full; cohort size and composition, the cutaneous event rate with high-grade and attributed counts, all three commonest morphologies with proportions, the direction of the survival association, the protective finding across landmarks, and the modelling and sensitivity approach as reported", "quantitativeExtraction": "extracted" }, "L159": { "id": "L159", "year": 2026, "topic": "Drug exposure", "title": "Tissue Penetration of Gemcitabine and Gemcitabine Phosphate Metabolites Following Gemcitabine Intravesical System Administration Versus Standard Intravesical Instillation in a Preclinical Minipig Model", "url": "https://doi.org/10.1016/j.euf.2026.03.007", "studyType": "Five healthy female minipigs given either a two-hour bolus intravesical instillation (three animals) or an indwelling intravesical releasing system (two animals), with bladder regions and layers sampled over time and analysed by liquid chromatography-tandem mass spectrometry, European Urology Focus", "diseaseContext": "Healthy reference; non-muscle-invasive bladder cancer", "useInModel": "The atlas's first measured tissue residence time, and it is set by the formulation rather than by the molecule. After conventional two-hour instillation, active phosphorylated metabolites were detectable across bladder layers at two hours and undetectable by 24 hours. With an indwelling releasing system, measurable metabolite levels persisted across bladder regions and layers for at least 96 hours. Sampling was by region - dome, both lateral walls, trigone - and by layer, so this is exposure resolved in space as well as time, which almost nothing in this atlas is. Set beside the atlas's two other transport quantities the picture becomes usable: the airway row gives a clearance velocity for how fast material is carried off a surface, the skin row gives a permeability for how fast it crosses a barrier, and this gives how long it stays once it is in. The same molecule can be a failure or a treatment depending on the third of those, which is a formulation parameter and not a property of the compound.", "limit": "Five animals in total, three against two, which the authors themselves flag along with the use of only healthy bladders - and tumour-bearing tissue is the case that matters, since a tumour changes both the barrier and the perfusion. Minipig, not human. The readout is detectability and measurability of metabolites rather than a concentration time course with a decay constant, so no half-life or area under the curve is extracted here. Nothing links the prolonged exposure to an efficacy outcome in this record. Bladder is blueprinted and not drawn.", "provenance": "Abstract read in full; animal numbers per arm, both delivery modes, the regions and layers sampled, the analytical method, the two-hour and 24-hour findings for bolus instillation, the at-least-96-hour persistence for the releasing system, and the authors' own stated limitations as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I049", "name": "Renal tubular epithelial subtypes", "category": "Parenchyma", "whereToCheck": "Kidney primary and normal tissue", "states": [ "Segment", "injury", "malignant lineage" ], "behaviors": [ "Transport", "target identity", "local toxicity" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-783", "hatton-790", "hatton-795", "hatton-799" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-783", "hatton-790", "hatton-795", "hatton-799" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-783", "hatton-790", "hatton-795", "hatton-799" ], "priorResearch": { "path": "simulation/data/profiles/renal-tubular-epithelial-subtypes.json", "summary": "Segmented epithelium along the nephron, with the proximal tubule doing most of the reabsorption and most of the damage-taking. The inventory asks for transport, target identity and local toxicity, and names normal tissue explicitly - and the row's main finding is that those three are one subject here. This family is injured by drugs it actively takes up rather than by drugs that address it: cisplatin is an organic cation transporter substrate and knocking out OCT2 significantly reduces nephrotoxicity, with OCT1 and OCT2 differing roughly sixtyfold in apparent affinity so that single deletions under-rescue (L160); and megalin-dependent endocytosis drives contrast-induced tubular injury, with mosaic knockouts showing the receptor-bearing cells are the injured ones and a competing ligand blocking both uptake and injury (L161). For radioligand therapy the kidney is an established organ at risk with absorbed-dose thresholds (L162). The one record where this lineage is the target rather than the casualty is a kidney cancer combination trial (R11).", "stateAxes": [ { "axis": "Transport, as active concentration rather than permeation", "whatToMeasure": "Which uptake routes the cell expresses and their affinities, because uptake is a sum over routes of very different affinity - apparent IC50 for cisplatin of 9 micromolar at OCT1 against 558 at OCT2 - and because megalin takes up ligands both directly and via carrier proteins that are themselves megalin ligands.", "interpretationLimit": "Mouse transporters with a species caveat that matters: human OCT2 is the abundant renal basolateral isoform, so the OCT1-dominant affinity finding should not be carried across. Apparent IC50 values from heterologous expression are not uptake rates in tubule, and no intracellular concentration or receptor density is reported anywhere, so the concentrative step is inferred from genetics rather than measured.", "evidence": [ "L160", "L161" ] }, { "axis": "Injury, and whether the cell brought it on itself", "whatToMeasure": "Injury marker expression against uptake-route expression in the same cells - the mosaic knockout's co-expression of megalin and kidney injury molecule-1 is the cleanest internal control in the atlas, since receptor-bearing and receptor-lacking cells sat in one kidney and only the former were injured.", "interpretationLimit": "Vacuolisation and injury-molecule expression are the readouts, not function or cell loss. Mouse, and iodinated contrast rather than a therapeutic agent, so generalisation to other megalin ligands is background rather than tested here.", "evidence": [ "L161", "L160" ] }, { "axis": "Target identity - shared with a tumour elsewhere", "whatToMeasure": "Whether an address used on a distant tumour is also present here, since the kidney is an established organ at risk with absorbed-dose thresholds for the prostate row's radioligand, alongside salivary glands and bone marrow.", "interpretationLimit": "A practical review that establishes thresholds and a dose-response relationship exist without supplying values - no absorbed dose in gray, no threshold and no slope is extracted, and none should be inferred. Nothing here measures the address in tubule, so the mechanism of risk is not established by this record.", "evidence": [ "L162" ] }, { "axis": "Segment and malignant lineage", "whatToMeasure": "Which nephron segment, since the uptake routes and injury patterns differ along it - and for the malignant state, the clear-cell programme the drawn environment's disease runs on.", "interpretationLimit": "This is the row's hole. No segment composition, proportion or per-segment transporter expression is held, and the one malignant record is an outcome trial that measures nothing about this family - no cell of origin, clone fraction or target density.", "evidence": [ "R11" ] } ], "records": { "L160": { "id": "L160", "year": 2023, "topic": "Local toxicity", "title": "Role of Mouse Organic Cation Transporter 2 for Nephro- and Peripheral Neurotoxicity Induced by Chemotherapeutic Treatment with Cisplatin", "url": "https://doi.org/10.3390/ijms241411486", "studyType": "Cyclic low-dose cisplatin in wild-type and OCT2-knockout mice with renal and neurological function testing, plus affinity and cytotoxicity measurement in cells stably expressing each transporter, International Journal of Molecular Sciences 24(14):11486", "diseaseContext": "Healthy reference; cisplatin toxicity", "useInModel": "Establishes a second mechanism of off-target damage, structurally different from the one the atlas has been cataloguing. The address class damages normal tissue because the normal cell carries the address; here the drug has no address at all and the normal cell actively concentrates it. Cisplatin is a substrate of organic cation transporters, which are highly expressed in renal tissue; cyclic low-dose treatment impaired renal and peripheral neurological function in wild-type mice, and both effects were significantly reduced in OCT2-knockout mice - though less so than in mice lacking both OCT1 and OCT2. The affinities explain why: apparent IC50 for cisplatin was 9 micromolar for OCT1 against 558 for OCT2, a roughly sixtyfold difference, and cellular toxicity at 100 micromolar was more pronounced in OCT1-expressing cells. So uptake is a sum over several routes of very different affinity, single-transporter deletion under-rescues, and the transporters are themselves a drug target for reducing toxicity without altering the drug.", "limit": "Mouse transporters and mouse physiology, and the human orthologues differ in distribution - human OCT2 is the abundant renal basolateral isoform, so the OCT1-dominant affinity finding should not be carried across species. Affinities are apparent IC50 values from a heterologous expression system, not uptake rates in tubule. Renal and neurological function are measured as impairment rather than as tubular cell death, and no intracellular drug concentration is reported, so the concentrative step is inferred from the genetics rather than measured. Cisplatin toxicity, not any drawn environment's disease.", "provenance": "Abstract read in full; the substrate relationship, the knockout comparison and its partial rescue relative to the double knockout, both apparent affinities with their sixtyfold gap, the cytotoxicity comparison at a stated concentration, and the authors' conclusion that the transporters are targets as reported", "quantitativeExtraction": "extracted" }, "L161": { "id": "L161", "year": 2025, "topic": "Transport", "title": "Megalin-Mediated Direct and Indirect Pathways for the Development of Contrast-Induced Proximal Tubule Epithelial Cell Injury", "url": "https://doi.org/10.1096/fj.202500985R", "studyType": "Kidney-specific conditional and mosaic megalin-knockout mice with a contrast-induced injury model, electron probe microanalysis, quartz crystal microbalance and immobilised-ligand binding assays, FASEB Journal 39:e71136", "diseaseContext": "Healthy reference; contrast-induced acute kidney injury", "useInModel": "The cleanest demonstration in the atlas that uptake rather than exposure causes off-target injury, and it comes with an internal control no other record here has. Megalin is a multiligand endocytic receptor on proximal tubule cells that reabsorbs certain nephrotoxic drugs. Kidney-specific conditional knockouts showed reduced cortical uptake of contrast medium and significantly less tubular vacuolisation than controls; in mosaic knockouts, megalin and kidney injury molecule-1 were co-expressed - so within a single kidney the cells that kept the receptor are the cells that were injured. Cilastatin, which competes for megalin binding, inhibited uptake and ameliorated injury in wild-type animals. Two uptake pathways were resolved and both were cilastatin-inhibitable: direct binding to megalin, and an indirect route in which transcobalamin-2, itself a megalin ligand, carries the contrast agent. For a simulation this is the mechanism by which a filtered molecule becomes concentrated in a cell that was never its target, and the intervention point is the receptor rather than the drug.", "limit": "Mouse, and iodinated contrast medium rather than a therapeutic agent - the generalisation to other megalin ligands is stated as background and tested here for one class. Vacuolisation and injury-molecule expression are the injury readouts rather than function or cell loss. No uptake rate, intracellular concentration or receptor density is given, so the pathway is identified without being parameterised. The carrier-mediated indirect route is demonstrated for this agent and transcobalamin-2 specifically.", "provenance": "Abstract read in full; megalin's role in reabsorbing nephrotoxic drugs, the conditional knockout uptake and vacuolisation results, the mosaic co-expression finding, cilastatin's effect on both uptake and injury, and both resolved pathways including the transcobalamin-2 carrier as reported", "quantitativeExtraction": "extracted" }, "L162": { "id": "L162", "year": 2026, "topic": "Target identity", "title": "177Lu-PSMA dosimetry made easy: from theory to practical implementation", "url": "https://doi.org/10.23736/S1824-4785.26.03695-2", "studyType": "Practical review of patient-specific internal dosimetry for a radioligand therapy, covering quantitative imaging, time-activity curves and absorbed-dose estimation, Quarterly Journal of Nuclear Medicine and Molecular Imaging 70(3):205-217", "diseaseContext": "Prostate cancer; kidney as organ at risk", "useInModel": "Converts one of the atlas's recorded gaps from an unknown into an ingestion failure. meta.json states that the address class carries five parameters - reach, specificity, density, penetration, geometry - and that the atlas holds a number for none, with no absorbed dose for any member. This record says the absorbed dose is routinely computed in practice: patient-specific internal dosimetry is described as essential for optimising efficacy and minimising toxicity, evidence supports a strong correlation between tumour absorbed dose and therapeutic response, and established thresholds exist for organs at risk - particularly kidneys, salivary glands and bone marrow - which guide safe administration. So the reach parameter is measurable, measured, and simply not in this data layer. It also places this family on the address class's normal-tissue map: the kidney is an organ at risk for the prostate row's radioligand, which makes it the second address-class normal-tissue location after nectin-4 in skin - and unlike skin, this tissue is not dispensable.", "limit": "A practical review, so it establishes that thresholds and dose-response relationships exist without this record supplying their values - no absorbed dose in gray, no threshold figure and no dose-response slope is extracted here, and none should be inferred. The tumour-dose to response correlation is reported as supported by evidence rather than quantified. The authors note that logistical barriers have limited routine implementation, so dosimetry is standard in principle more than in universal practice. Nothing here measures PSMA expression in the tubule, so the mechanism by which the kidney is at risk is not established by this record.", "provenance": "Abstract read in full; the statement that patient-specific dosimetry is essential, the tumour absorbed dose to response correlation, the existence of established organ-at-risk thresholds with the three organs named, and the noted logistical barriers to routine implementation as reported. The connection to this atlas's parameter inventory is its own", "quantitativeExtraction": "extracted" }, "R11": { "id": "R11", "year": 2019, "topic": "Clinical outcome", "title": "Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma", "url": "https://doi.org/10.1056/NEJMoa1816714", "studyType": "Open-label phase 3 trial, 861 previously untreated advanced clear-cell renal-cell carcinoma patients randomised to pembrolizumab 200 mg every three weeks with axitinib 5 mg twice daily (432) or sunitinib 50 mg daily four weeks of each six-week cycle (429); dual primary endpoints of overall and progression-free survival; protocol-specified first interim analysis at median follow-up 12.8 months, NEJM 380(12):1116-1127", "diseaseContext": "Kidney", "useInModel": "The malignant-lineage anchor for an environment the atlas drew in on 2026-10-14, and a checkpoint-plus-antiangiogenic combination rather than anything address-directed. Twelve-month survival was 89.9 against 78.3 percent (HR for death 0.53, 95% CI 0.38-0.74), median progression-free survival 15.1 against 11.1 months (HR 0.69, 0.57-0.84), and the objective response rate 59.3 percent. For this row the useful contrast is with the rest of its content: the tubule's relationship to administered molecules is elsewhere about being injured by them, and this is the one record where the lineage is the target. It also sits against the atlas's address class - clear-cell renal cancer's effective combination works on vasculature and immunity rather than on a surface address, in an organ whose normal cells concentrate drugs.", "limit": "First interim analysis at 12.8 months median follow-up, so survival is reported as a twelve-month landmark rather than a median and the estimate is immature. Open-label. A two-drug combination against a single agent, so neither component is isolable - the same limitation the atlas records for the urothelial conjugate result. Clear-cell histology and previously untreated advanced disease only. Nothing here measures the tubular epithelium itself, the cell of origin, or any target density; it is an outcome record for the environment rather than evidence about this family.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. Trial design, dosing, arm sizes, the twelve-month survival percentages with hazard ratio and confidence interval, median progression-free survival with its hazard ratio, the objective response rate and the interim-analysis status as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I050", "name": "Podocytes and mesangial cells", "category": "Parenchyma", "whereToCheck": "Glomerular compartment where relevant", "states": [ "Barrier/support state" ], "behaviors": [ "Filtration", "injury", "regional exclusion from tumor ROI" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-781", "hatton-782", "hatton-794" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-781", "hatton-782", "hatton-794" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-781", "hatton-782", "hatton-794" ], "priorResearch": { "path": "simulation/data/profiles/podocytes-and-mesangial-cells.json", "summary": "The glomerular tuft: podocytes wrapping capillaries to form the filtration barrier, with mesangial cells supporting them. The inventory treats this as a minor row - a single barrier and support state, filtration, injury, and exclusion from tumour regions of interest - and one of its findings is not minor at all. Neutralising VEGF causes thrombotic glomerular injury, shown in six patients on an anti-VEGF antibody and reproduced by deleting VEGF from podocytes in adult mice (L163): the podocyte supplies a signal the glomerular endothelium needs, and a drug that removes that signal from circulation removes it here. The dependency holds from the other direction too - depleting podocytes shrinks the endothelial population despite a proliferative transcriptional signature (L165). And podocyte number per glomerulus, counted stereologically in human biopsies, was 279 in patients who responded to therapy against 186 in those who did not (L164).", "stateAxes": [ { "axis": "Dependence on a signal this family itself exports", "whatToMeasure": "Whether VEGF is available to the glomerular endothelium, not whether the podocyte expresses it - because the injury follows removal of the signal from circulation, and local deletion from podocytes reproduces it.", "interpretationLimit": "Six patients with no incidence or dose-response, and a conditional deletion that removes the signal completely and locally rather than partially and systemically as a drug does. No VEGF concentration, gradient or podocyte-to-endothelium distance is given, so the dependency is established with none of the parameters needed to compute it.", "evidence": [ "L163", "L165" ] }, { "axis": "How many podocytes are left", "whatToMeasure": "Podocyte number per glomerulus by design-based stereology - 279 against 186 between responders and non-responders - alongside the proportion of globally sclerotic glomeruli, rather than proteinuria, which did not separate the groups.", "interpretationLimit": "Nineteen patients from one centre, retrospective, with wide overlapping interquartile ranges, and an association that may mark earlier disease rather than determine response. Focal segmental glomerulosclerosis is not a drawn environment.", "evidence": [ "L164" ] }, { "axis": "Barrier and support state under injury", "whatToMeasure": "The endothelial consequence as a population count and not only as a signature, since after podocyte depletion the endothelium showed proliferative and angiogenic programmes while the population fell in net terms.", "interpretationLimit": "Mouse, with abrupt toxin-mediated depletion rather than gradual attrition, and endothelial changes downstream of losing the whole cell rather than of VEGF withdrawal specifically. Transcriptomics and a reporter count, with no barrier function, permeability or filtration measurement anywhere in this row.", "evidence": [ "L165" ] }, { "axis": "Regional exclusion from tumour regions of interest", "whatToMeasure": "Whether glomeruli were excluded when a kidney tumour region was quantified, because they are normal structure with a distinct composition and including them biases any density attributed to the tumour.", "interpretationLimit": "The inventory asks for a data-handling convention and the atlas has none - no record here, and no annotation rule anywhere in the project. This is a schema gap rather than a measurement gap, and it is this row's most concrete contribution to how the atlas should be read.", "evidence": [] } ], "records": { "L163": { "id": "L163", "year": 2008, "topic": "Local toxicity", "title": "VEGF inhibition and renal thrombotic microangiopathy", "url": "https://doi.org/10.1056/NEJMoa0707330", "studyType": "Six patient cases of glomerular disease during bevacizumab treatment, with conditional deletion of VEGF from renal podocytes in adult mice as the mechanistic test, NEJM 358(11):1129-1136", "diseaseContext": "Healthy reference; antiangiogenic therapy toxicity", "useInModel": "A third mechanism of off-target damage, and the one the atlas's existing rules cannot express at all. Six patients treated with bevacizumab developed glomerular disease characteristic of thrombotic microangiopathy, and conditional deletion of VEGF from renal podocytes in adult mice produced profound thrombotic glomerular injury - so local loss of the signal is sufficient, and the human lesion is attributed to direct targeting of VEGF by the therapy. The mechanism is neither of the two the atlas has recorded. There is no address in the glomerulus that the drug binds, and the drug is not concentrated here as the tubule concentrates its substrates. Instead a signal that one normal cell supplies to another normal cell is removed from circulation. The podocyte makes VEGF for the glomerular endothelium, and neutralising VEGF anywhere withdraws it here. The sharper way to state it is that this is not off-target at all in the molecular sense - it is on-target in the wrong place, because the intended target is something a normal tissue needs constitutively. The three mechanisms differ in what moves: with an address the drug arrives and binds a shared marker, with uptake the drug arrives and is concentrated, and here nothing arrives - something leaves.", "limit": "Six patients, a case series with no incidence, denominator or dose-response, so the human arm establishes that it happens rather than how often. The mouse arm is a conditional genetic deletion, which removes the signal completely and locally rather than partially and systemically as a drug does, so it demonstrates sufficiency and not the quantitative relationship between degree of inhibition and degree of injury. No VEGF concentration, gradient or distance between podocyte and endothelium is given, so a paracrine dependency is established without any of the parameters that would let a model compute it.", "provenance": "Abstract read in full; the six cases and their lesion, the conditional podocyte deletion and its result, and the authors' attribution of the human injury to direct VEGF targeting as reported. The three-mechanism framing is this atlas's own", "quantitativeExtraction": "extracted" }, "L164": { "id": "L164", "year": 2024, "topic": "Injury", "title": "Podocyte number and glomerulosclerosis indices are associated with the response to therapy for primary focal segmental glomerulosclerosis", "url": "https://doi.org/10.3389/fmed.2024.1343161", "studyType": "Retrospective single-centre cohort of 19 patients, 13 responders and 6 non-responders, with design-based stereology on diagnostic biopsies and outcome assessed at six months, Frontiers in Medicine 11:1343161", "diseaseContext": "Focal segmental glomerulosclerosis", "useInModel": "An absolute cell count per structural unit, measured in human tissue by stereology, and associated with whether treatment works. Podocyte number per glomerulus was 279 with an interquartile range of 203 to 507 in responders, about 50 percent greater than the 186 (118 to 310) in non-responders; non-responders also had a significantly higher proportion of globally sclerotic glomeruli and a higher glomerulosclerotic index, with proteinuria and kidney function similar between groups at biopsy. Two things make this valuable here. The atlas's other per-unit counts are mouse - about six stem cells per intestinal crypt, 20 to 30 cells per neuroendocrine cluster - and this one is human. And the direction of the association says what a simulation needs to encode about this family: outcome depends on how many podocytes remain rather than on how much proteinuria there is, which is the signature of a compartment you can only spend from.", "limit": "Nineteen patients, six of them non-responders, from one centre and retrospective - the counts are precise and the cohort is very small, with wide and overlapping interquartile ranges. Response is defined at six months. Association, not causation: higher podocyte number may mark earlier disease rather than determine the response, which the similar baseline proteinuria and function argue against without excluding. Focal segmental glomerulosclerosis is not a drawn environment, so this is a count for the family and not for any environment the atlas models.", "provenance": "Abstract read in full; cohort composition, the stereological method, both median podocyte counts with interquartile ranges and the stated 50 percent difference, the sclerosis findings, the similarity of baseline proteinuria and function, and the six-month endpoint as reported", "quantitativeExtraction": "extracted" }, "L165": { "id": "L165", "year": 2021, "topic": "Barrier/support state", "title": "Global transcriptomic changes in glomerular endothelial cells in mice with podocyte depletion and glomerulosclerosis", "url": "https://doi.org/10.1038/s41419-021-03951-x", "studyType": "Diphtheria toxin-mediated podocyte depletion in mice carrying a podocyte-specific toxin receptor and an endothelial reporter, with transcriptomic profiling and quantification of isolated endothelial cells, Cell Death & Disease 12:687", "diseaseContext": "Healthy reference; glomerulosclerosis", "useInModel": "Establishes the podocyte-to-endothelium dependency from the opposite direction to the drug experiment, and adds a result a model would get wrong by intuition. Depleting podocytes - about 40 percent lost, with glomerulosclerosis developing - changed the glomerular endothelial transcriptome across adhesion and actin, proliferation, angiogenesis and cell death, with p53, TGF-beta1 and TNF-alpha as the strongest upstream regulators. The useful part is the counting: despite ongoing proliferation, the endothelial population fell in net terms, because injury and cell death outran it. So a transcriptional signature of proliferation coincided with a shrinking population, which means proliferation programmes cannot be read as growth. Taken with the VEGF deletion record, this family's support of the glomerular endothelium is now demonstrated three ways - by neutralising the signal in patients, by deleting the signal genetically, and by removing the cell that supplies it.", "limit": "Mouse, with depletion by a toxin receptor system that kills podocytes abruptly rather than the gradual attrition of disease. The endothelial changes are downstream of losing the whole cell, so they do not isolate VEGF withdrawal from the other things a podocyte provides. Transcriptomics plus a reporter count, with no barrier function, permeability or filtration measurement. Upstream regulators are inferred computationally rather than tested.", "provenance": "Abstract read in full; the depletion model and its roughly 40 percent loss, the pathway categories changed, the three named upstream regulators, and the net endothelial reduction despite ongoing proliferation as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I051", "name": "Endometrial epithelium and stroma", "category": "Parenchyma", "whereToCheck": "Uterine corpus", "states": [ "Cycle/menopause", "molecular subtype", "malignancy" ], "behaviors": [ "Hormonal response", "secretion", "matrix", "growth" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-1237", "hatton-1238" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-1237", "hatton-1238" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-1237", "hatton-1238" ], "priorResearch": { "path": "simulation/data/profiles/endometrial-epithelium-and-stroma.json", "summary": "Glandular epithelium over a stroma that rebuilds itself monthly, in a tissue the inventory asks about cycle-first. Three findings organise the row and the first is not really about this family at all. In one phase 3 trial of 816 patients, prespecified mismatch repair cohorts gave hazard ratios of 0.30 and 0.54 for the same drug added to the same chemotherapy - an effect modification anticipated well enough to be designed in, with two primary analyses and separate interim triggers (R10). Second, a consensus single-cell reference of 313,527 cells validated against an independent single-nuclei dataset resolves two anatomically separated niches - stromal-epithelial coordination through TGF-beta in the functionalis, fibroblast signalling to progenitor-marked epithelium in the basalis - and attributes endometriosis heritability to decidualised stromal cells and macrophages (E02). Third, the cycle phase a measurement needs cannot be read off a calendar: the molecular window can sit two days from the expected one, and that displacement tracks age (L166).", "stateAxes": [ { "axis": "Molecular subtype, as an effect modifier rather than a label", "whatToMeasure": "Mismatch repair status before treatment, because it changes the size of the treatment effect and not merely the prognosis - hazard ratio 0.30 in the deficient cohort against 0.54 in the proficient one, both significant.", "interpretationLimit": "Progression-free survival rather than overall survival, reported as a twelve-month landmark in one cohort and a median in the other, so the headline figures are not on the same scale. A combination against chemotherapy alone, so the addition is isolated and the mechanism is not. No tissue-level measurement of repair status or of this family accompanies it.", "evidence": [ "R10" ] }, { "axis": "Cycle and menopausal state, which must be assayed not dated", "whatToMeasure": "The molecular phase, since the window of implantation can sit two days from the expected one and the displacement varies with age - so a cycle day is not a timestamp for this tissue.", "interpretationLimit": "Measured in women with repeated implantation failure under assisted reproduction, not a healthy reference, and against a transcriptomic classifier's own window rather than an independent standard. The age effect is weak per year even where independent. The consensus reference spans donors rather than resolving a phase, so the atlas has no phase-resolved normal.", "evidence": [ "L166", "E02" ] }, { "axis": "Two niches in one tissue, by layer", "whatToMeasure": "Which layer is being sampled, because the functionalis runs stromal-epithelial coordination through TGF-beta and the basalis runs fibroblast signalling to progenitor-marked epithelium - different partners, different signals, same organ.", "interpretationLimit": "From a reference atlas, so these are inferred signalling relationships from expression and spatial mapping rather than tested dependencies - no deletion, no co-culture requirement, and no distance. Donors with and without endometriosis rather than cancer.", "evidence": [ "E02" ] }, { "axis": "Malignancy", "whatToMeasure": "The repair-pathway state, which is what changes treatment - and otherwise nothing, because no record held here measures this family in malignant tissue.", "interpretationLimit": "This is the row's hole. The trial measures outcomes and not tissue; the reference atlas covers endometriosis and not cancer. So the environment has a strong treatment result and no cellular description of its own disease.", "evidence": [ "R10" ] } ], "records": { "E02": { "id": "E02", "year": 2024, "topic": "Healthy reference", "title": "An integrated single-cell reference atlas of the human endometrium", "url": "https://doi.org/10.1038/s41588-024-01873-w", "studyType": "Integrated single-cell reference atlas of 313,527 cells from 63 women with and without endometriosis, combining published and new datasets, mapped in situ by spatial transcriptomics and validated against an independent single-nuclei dataset of 312,246 nuclei from 63 donors, Nature Genetics 56(9):1925-1937", "diseaseContext": "Healthy reference; endometriosis", "useInModel": "A template for the problem this atlas keeps running into, and three findings of its own. The template first: the authors state plainly that previous endometrial atlases profiled few donors and lacked consensus in defining cell types, and this one assigns consensus, identifies previously unreported types, maps them in situ, and validates against an independent dataset in a different modality with its own 63 donors. The atlas's own marker problem is exactly that - basal panels shared across four parenchymal rows in four organs, alpha-SMA shared across four more - and this is what a remedy looks like. The findings: in the functionalis, stromal and epithelial cells coordinate through TGF-beta signalling; in the basalis, fibroblasts signal to an epithelial population expressing progenitor markers - so one tissue holds two anatomically separated niches with different partners. And integrating the atlas with endometriosis genome-wide association data pinpoints decidualised stromal cells and macrophages as the populations most likely dysregulated, which is a genetics-to-cell-type attribution that almost nothing else in this atlas has.", "limit": "A reference and a resource rather than a measurement of anything in disease: it assigns consensus cell types and does not give densities, proportions or absolute counts usable as parameters. Normal endometrium differs profoundly with cycle phase and menopausal state, and this atlas spans donors rather than resolving a single phase, so it is not a reference for any particular timepoint. Cohorts are women with and without endometriosis, not uterine cancer, so it is not equivalent to the malignant environment. The GWAS attribution is a statistical colocalisation of heritability with cell-type expression, not a demonstration that those cells cause the disease.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. Cell and nucleus counts, donor numbers for both cohorts, the stated absence of prior consensus, the two layer-specific signalling findings, and the GWAS integration result as reported", "quantitativeExtraction": "extracted" }, "L166": { "id": "L166", "year": 2026, "topic": "Cycle/menopause", "title": "Advanced maternal age as a risk factor for endometrial receptivity in repeated implantation failure: intersectional transcriptomic analysis and gene validation", "url": "https://doi.org/10.3389/fcell.2026.1904991", "studyType": "Retrospective observational study of 254 women with repeated implantation failure assessed by transcriptome-based receptivity testing, with RNA sequencing and an independent qRT-PCR validation cohort, Frontiers in Cell and Developmental Biology 14:1904991", "diseaseContext": "Repeated implantation failure", "useInModel": "Sharpens the atlas's timestamp problem into something specific and worse. The marrow row established that one quantity oscillates daily and that nothing in the data layer carries a time of day. This row's tissue oscillates monthly with near-complete turnover, and the inventory names cycle state as the first thing to resolve - but the finding here is that the phase cannot be taken from the calendar. Receptivity status and the timing of the window of implantation were determined by a transcriptome-based assessment, and women whose endometrium was two days pre-receptive relative to the expected window were significantly older than those with normal receptivity (34.3 against 33.0 years), with age an independent risk factor for displacement (odds ratio 1.118 per year, 95% CI 1.013-1.234). So the molecular phase can sit two days away from the chronological phase, and the displacement varies systematically with a patient characteristic. For this family the timestamp a measurement needs is an assayed state rather than a date, which is a stricter requirement than the one the atlas has so far recorded as missing.", "limit": "Women with repeated implantation failure undergoing assisted reproduction, not a healthy reference population, and retrospective at a single centre. The age difference is small in absolute terms - 34.3 against 33.0 years - with an odds ratio close to 1 per year, so age explains displacement weakly even where it is independent. Receptivity is defined by a commercial-style transcriptomic classifier, so displacement is measured against that classifier's own window rather than against an independent standard. Nothing here concerns uterine cancer, and the differentially expressed genes are not extracted.", "provenance": "Abstract read in full; the cohort size and setting, the transcriptome-based receptivity assessment, the two-day pre-receptive definition, both group ages with the p value, the multivariate odds ratio with its confidence interval, and the validation approach as reported", "quantitativeExtraction": "extracted" }, "R10": { "id": "R10", "year": 2023, "topic": "Clinical outcome", "title": "Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer", "url": "https://doi.org/10.1056/NEJMoa2302312", "studyType": "Double-blind placebo-controlled randomised phase 3 trial, 816 patients assigned 1:1 to pembrolizumab or placebo with paclitaxel and carboplatin, prospectively stratified into mismatch repair-deficient and mismatch repair-proficient cohorts with progression-free survival as the primary outcome in each and separate interim triggers, NEJM 388(23):2159-2170, NRG-GY018, NCT03914612", "diseaseContext": "Uterine corpus", "useInModel": "The atlas's clearest demonstration that an intervention's effect is not a property of the intervention. One drug, one disease, one trial, two prespecified cohorts, and two different answers. In the mismatch repair-deficient cohort, twelve-month progression-free survival was 74 percent with pembrolizumab against 38 percent with placebo, a hazard ratio of 0.30 (95% CI 0.19-0.48). In the mismatch repair-proficient cohort, median progression-free survival was 13.1 against 8.7 months, a hazard ratio of 0.54 (0.41-0.71). Both are significant and they differ substantially, and the difference was anticipated well enough to be designed in - two cohorts, two primary analyses, separate interim event triggers of at least 84 and 196 events. For a simulation this is the strongest available argument against carrying a single effect size per intervention: effect is the drug multiplied by a molecular state of the tumour, and here that state is a binary that is already measured in routine practice. The breast row concluded that subtype is a partition to condition on rather than a dial; this is the prospective proof of that principle with numbers attached.", "limit": "Progression-free survival, not overall survival, and reported at a twelve-month landmark in the deficient cohort against a median in the proficient one - so the two cohorts' headline figures are not expressed on the same scale and should not be compared directly beyond their hazard ratios. Advanced, recurrent or measurable stage III to IVB disease; prior adjuvant chemotherapy was permitted with a treatment-free interval of at least twelve months. A combination against chemotherapy alone, so this isolates the addition of pembrolizumab and not its mechanism. Nothing here measures the endometrial epithelium or stroma, mismatch repair status in tissue, or any microscopic encounter rate - it is an effect-modification record, not evidence about this family.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. Trial design, stratification, dosing schedule, both cohorts' efficacy figures with hazard ratios and confidence intervals, and the prespecified interim event triggers as reported. The argument about conditioning effect sizes is this atlas's own", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I052", "name": "Malignant B-cell states", "category": "Parenchyma", "whereToCheck": "Defined NHL subtype", "states": [ "Clone", "differentiation", "antigen loss" ], "behaviors": [ "CD20 abundance", "proliferation", "immune interactions" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "lymphoma-abca3-release", "lymphoma-rituximab-bound" ], "priorResearch": { "path": "simulation/data/profiles/malignant-b-cell-states.json", "summary": "The malignant compartment of a lymphoid tumour, which the inventory asks to resolve as clone, differentiation and antigen loss, with CD20 abundance, proliferation and immune interactions. It is five states rather than one: deconvolution across a large cohort recovered five malignant B-cell states differing in prognosis and differentiation, alongside state variation in twelve other lineages, recurring together in stereotyped ecosystems that carry clinical information beyond cell-of-origin and genotypic class (N01). Antigen loss is characterised and reframed: 20 to 40 percent of patients relapse after CD19-directed cell therapy and most of those relapses are antigen-positive, with loss when it occurs arising from subclonal selection, expression downregulation, or an outright lineage switch to myeloid (L167). And the atlas already held two ways this family's surface antigen evades antibody - vesicles carrying CD20 that consume complement, and host Fc receptor genotype altering antibody activity.", "stateAxes": [ { "axis": "Clone and differentiation, as five states not one", "whatToMeasure": "Which of the five malignant states, since they differ in prognosis and in differentiation status - and which ecosystem the sample belongs to, because the states recur in stereotyped combinations that carry information beyond cell-of-origin and genotype.", "interpretationLimit": "States recovered by deconvolution from bulk transcriptomes anchored on single-cell references, so they are statistical constructs rather than counted cells - no densities or proportions usable as parameters. Retrospective prognostic association. One disease within an environment that contains many, and nothing spatial: ecosystems are co-occurrence in a sample, not arrangement in tissue.", "evidence": [ "N01" ] }, { "axis": "Antigen loss, by four mechanisms with different dynamics", "whatToMeasure": "Whether the address is gone and how: a pre-existing negative subclone selected, expression downregulated within the cell, the lineage abandoned, or the antigen present but sequestered on vesicles. Selection from existing heterogeneity and change within a cell imply different dynamics and a model has to choose.", "interpretationLimit": "From a review, so frequencies are synthesised across studies with no proportion given per mechanism, and covering leukemia and lymphoma together - two drawn environments. No CD19 or CD20 density before or after relapse, no size for pre-existing negative subclones, and no rate of lineage switching, so the mechanisms are enumerated and none becomes a parameter.", "evidence": [ "L167", "L44" ] }, { "axis": "Whether the effector lasts - the host's contribution", "whatToMeasure": "The patient's effector supply as well as the tumour's genotype, since low baseline lymphocyte count and TP53 mutation were both poor prognostic factors under a bispecific engager, and since most post-cell-therapy relapses follow loss of effector potency and persistence rather than loss of the antigen.", "interpretationLimit": "Thirty patients, univariate analysis, real-world and single-arm, with 90 percent CAR-T naive - so these are associations in a small cohort rather than independent predictors, and not comparable with trial or cell-therapy figures. Baseline lymphocyte count is a crude proxy with no functional measure of T-cell fitness behind it.", "evidence": [ "L168", "L167" ] }, { "axis": "CD20 abundance and proliferation", "whatToMeasure": "Antigen copies per cell, which the inventory names as a behaviour and which no record here supplies - and a growth rate, likewise absent.", "interpretationLimit": "This is the row's quantitative hole. The atlas holds four evasion mechanisms for two addresses on this family and not one density for either, which is the same pattern the address class shows everywhere: mechanisms without magnitudes.", "evidence": [] } ], "records": { "L167": { "id": "L167", "year": 2026, "topic": "Antigen loss", "title": "CD19-negative relapse after CAR-T cell therapy: mechanisms of antigen escape and lineage switch", "url": "https://doi.org/10.3389/fimmu.2026.1692287", "studyType": "Review of escape mechanisms after CD19-directed chimeric antigen receptor T-cell therapy in B-cell malignancies, Frontiers in Immunology 17:1692287", "diseaseContext": "Lymphoma; leukemia", "useInModel": "Characterises the disappearance of an address, which the atlas has repeatedly said matters and never had evidence for - and it corrects the atlas's emphasis while doing it. Between 20 and 40 percent of patients eventually relapse after CD19 CAR-T, and most of those relapses are CD19-positive, attributed largely to reduced potency and poor persistence of the transferred cells. So the commonest failure of this therapy is the payload running out, not the target vanishing. The atlas's address class has been built from properties of the target and the drug - density, reach, specificity, geometry, penetration - and for a payload that is itself a living cell the dominant variable is the effector's own durability, which none of those five parameters expresses. CD19-negative relapse, where it happens, arises three ways: pre-existing CD19-negative subclones with progenitor-like features expanding under selection; downregulation through genetic alterations including abnormal splicing, epigenetic silencing and post-transcriptional dysregulation; and lineage switching to a myeloid phenotype, associated with KMT2A rearrangements and driven by epigenetic reprogramming, impaired expression of B-cell regulators, and bipotent progenitors. The first is selection from existing heterogeneity and the second is change within a cell - different dynamics, and a simulation has to choose. The third is the limiting case: the tumour stops being the lineage the address defines.", "limit": "A review, so the 20 to 40 percent relapse range and the relative frequencies are synthesised across studies rather than measured in one cohort, and no proportion is given for each of the three escape mechanisms. Predominantly CD19-directed therapy in B-cell malignancies spanning leukemia and lymphoma, which are separate drawn environments, so the figures should not be attributed to either alone. Nothing here quantifies CD19 density before or after relapse, the size of pre-existing negative subclones, or the rate of lineage switching - so the mechanisms are enumerated without any becoming a parameter.", "provenance": "Abstract read in full; the relapse range, the statement that most relapses are antigen-positive and why, all three CD19-negative escape mechanisms with their stated drivers including the KMT2A association, and the proposed mitigation strategy as reported", "quantitativeExtraction": "extracted" }, "L168": { "id": "L168", "year": 2026, "topic": "Immune interactions", "title": "TP53 mutations and baseline lymphocytes indicate response to glofitamab in relapsed or refractory diffuse large B-cell lymphoma", "url": "https://doi.org/10.1007/s00277-026-07068-z", "studyType": "Real-world prospective cohort of 30 patients treated with a CD20-CD3 bispecific engager, median two prior lines and 90 percent CAR-T naive, median follow-up 15 months, Annals of Hematology 105:322, NCT06481826", "diseaseContext": "Lymphoma", "useInModel": "Supplies the host-side term the atlas's engager records have been missing. In 30 patients the overall response rate was 66.7 percent, one-year progression-free survival 62.5 percent with a median of 15 months, and one-year overall survival 70 percent; cytokine release syndrome occurred in 43.3 percent, mostly grade 1 to 3, with grade 1 neurotoxicity in 3.3 percent. The useful part is the prognostic analysis: more than one extranodal site, TP53 mutation, and low baseline lymphocyte count were poor prognostic factors. One of those is the tumour and one is the patient's own supply of effector cells. For a payload that is a recruited T cell, the host's effector inventory is an input, and this is the atlas's first record of it predicting outcome. It pairs with the uveal melanoma row, where eligibility was gated by the patient's HLA genotype - so for engagers the host contributes at least two things, a genotype that decides whether the address is presentable and an effector supply that decides whether the payload exists. The paper also frames engagers as answering the manufacturing time, cost and toxicity limits of cell therapy, which is the practical reason the atlas holds both payload types.", "limit": "Thirty patients at presumably few centres, with univariate analysis for the prognostic factors - so the three factors are associations in a small cohort and not independent predictors. Real-world and single-arm, so the response figures cannot be compared with the pivotal trial's or with cell therapy's. Ninety percent were CAR-T naive, which makes this a different population from the antigen-escape literature. Baseline lymphocyte count is a crude proxy for effector supply and no functional measure of T-cell fitness, CD20 density or effector-to-target ratio is reported.", "provenance": "Abstract read in full; cohort size and prior treatment, the response rate, both survival figures, the toxicity rates, all three univariate prognostic factors, and the stated rationale for engagers against cell therapy as reported", "quantitativeExtraction": "extracted" }, "L44": { "id": "L44", "year": 2011, "topic": "Resistance", "title": "Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3", "url": "https://doi.org/10.1073/pnas.1102855108", "studyType": "B-cell lymphoma vesicle biology with ABCA3 blockade and silencing, PNAS 108(37):15336-15341", "diseaseContext": "Lymphoma / Shared cancer", "useInModel": "Serves the inventory's hardest behaviour - target sequestration - and serves it mechanically. Lymphoma cells released vesicles carrying CD20 that bound therapeutic anti-CD20 antibody, consumed complement, and shielded the tumour cells from antibody attack. Blocking or silencing the transporter ABCA3 reduced the amount of vesicle released and increased the susceptibility of the target cells to antibody-mediated lysis, which makes vesicle output a manipulable variable rather than a fixed property. Two consequences for this atlas. First, a vesicle bearing the target antigen is a sink term on the drug, and in a model it belongs with clearance rather than with signalling. Second, the complement consumption partly fills a gap stated under I076: that family's deposited arm in tumour was recorded as entirely absent, and here is tumour-derived material consuming complement. ABCA3 also links resistance to antibodies and resistance to chemotherapy through one pathway.", "limit": "B-cell lymphoma cell systems with a naked antibody acting through complement and antibody-mediated lysis, which is not how a T-cell engager works - an engager that is soaked up by antigen-positive vesicles loses drug without the complement step. Lymphoma is a drawn environment which became a drawn environment on 2026-10-14; no sequestered fraction is quantified, and nothing here gives the vesicle antigen density needed to turn this into a sink rate.", "provenance": "Abstract read in full; antigen carriage, antibody binding, complement consumption and the ABCA3 results as reported", "quantitativeExtraction": "pending" }, "N01": { "id": "N01", "year": 2021, "topic": "Cell-state ecosystems", "title": "The Landscape of Tumor Cell States and Ecosystems in Diffuse Large B Cell Lymphoma", "url": "https://doi.org/10.1016/j.ccell.2021.08.011", "studyType": "EcoTyper, a machine-learning framework integrating bulk transcriptome deconvolution with single-cell RNA sequencing, applied to diffuse large B-cell lymphoma, Cancer Cell 39(10):1422-1437.e10", "diseaseContext": "Lymphoma", "useInModel": "The project's founding premise, tested at systems scale in one environment. Five cell states of malignant B cells were identified, differing in prognostic association and differentiation status, alongside striking cell-state variation across 12 other lineages in the microenvironment - and those states recur together in stereotyped ecosystems rather than in arbitrary combinations. The finding that matters most here is the comparison: cell-of-origin subtypes have distinct microenvironment composition, and the ecosystems capture clinical heterogeneity within existing subtypes and extend beyond cell-of-origin and genotypic classes. So microenvironment composition carries prognostic information that the tumour's own genetics does not. That is the assumption this atlas is built on, stated and tested rather than assumed. Two consequences for a simulation. The malignant compartment is five states and not one, with differentiation status among the axes that separate them. And because the ecosystems are stereotyped, the joint distribution over cell states is constrained - a model cannot treat each family's state as independent and multiply them together.", "limit": "Deconvolution of bulk transcriptomes anchored on single-cell references, so the cell states are statistical constructs recovered from mixtures rather than cells counted in tissue - there are no densities, proportions or absolute counts usable as parameters. Prognostic associations are retrospective. Diffuse large B-cell lymphoma is one disease within a drawn environment that contains many, so these states do not describe lymphoma generally. Nothing here is spatial: ecosystems are co-occurrence in a sample, not arrangement in a section.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. The method, the five malignant states with their differentiating axes, the 12 other lineages, the stereotyped ecosystem framing, and the explicit claim that ecosystems extend beyond cell-of-origin and genotypic classes as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "lymphoma-abca3-release", "lymphoma-rituximab-bound" ] }, { "id": "I053", "name": "Leukemic blasts and stem-like states", "category": "Parenchyma", "whereToCheck": "Subtype-specific blood/marrow", "states": [ "Lineage", "differentiation", "dormancy", "resistance" ], "behaviors": [ "Growth", "survival niches", "adhesion", "target expression" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "mechanics-all-marrow-repopulation" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "mechanics-all-marrow-repopulation" ], "priorResearch": { "path": "simulation/data/profiles/leukemic-blasts-and-stem-like-states.json", "summary": "The malignant compartment of blood and marrow, which the inventory asks to resolve as lineage, differentiation, dormancy and resistance, with growth, survival niches, adhesion and target expression. Two of those are answered unusually well and one is answered in the negative. Residual disease has a geography and it is lineage-specific: B-lineage cells sit predominantly perisinusoidal before and after induction, while T-lineage cells are distributed more widely with contacts to endosteum, nestin-positive pericytes and sinusoids, dispersing further under chemotherapy (H04). The same record argues against dormancy as the escape route, since slowly dividing cells appeared transiently during treatment and were absent from residual disease. Target expression is served by the atlas's earliest address-class agent, a CD19-CD3 engager giving median overall survival of 7.7 against 4.0 months (R01) - and by the finding that the 28-day continuous infusion it is given as degrades its own effector, with specific lysis falling from 88.4 to 8.6 percent and recovering to 93.4 percent when dosing stops (T11).", "stateAxes": [ { "axis": "Survival niche, which is lineage-specific", "whatToMeasure": "Position relative to named structures and separately by lineage - perisinusoidal for B-lineage before and after induction, and endosteum, nestin-positive pericytes and sinusoids for T-lineage, with dispersion increasing under treatment.", "interpretationLimit": "Ten primary xenografts, so human cells in mouse marrow without the patient's immune system, and tissue distances in that setting should not be copied without checking units and scale. Localisation relative to a structure is association and does not establish that the structure protects.", "evidence": [ "H04" ] }, { "axis": "Dormancy - argued against rather than measured", "whatToMeasure": "Whether a slowly dividing population is actually present at residual disease, because the one study that looked found such cells transiently during treatment and not afterwards, which challenges niche-induced dormancy as the escape route.", "interpretationLimit": "An absence at one sampling point after one induction regimen in xenografts, which argues against dormancy as the dominant mechanism rather than excluding it. No molecular characterisation of the cells that did survive.", "evidence": [ "H04" ] }, { "axis": "Effector durability, as a decay with a schedule-based remedy", "whatToMeasure": "The payload's function over exposure time rather than the drug's concentration: specific lysis 88.4 percent at day 7 falling to 8.6 percent at day 28 of continuous exposure, and 34.9 against 93.4 percent at day 14 without and with a treatment-free interval.", "interpretationLimit": "In vitro with n = 6 and a half-life-extended construct that is not the approved agent, so these are that system's numbers. The patient observation is declining T-cell function without an efficacy decay curve. The authors state explicitly that this is not a clinical instruction to interrupt treatment, and no optimal interval is established for any approved agent.", "evidence": [ "T11", "R01" ] }, { "axis": "Target expression and growth", "whatToMeasure": "CD19 and CD22 copy number, and a growth rate - both named by the inventory and neither supplied by any record here.", "interpretationLimit": "The row's quantitative hole, and the same one the malignant B-cell row has: an address with a phase 3 result, documented loss routes, a quantified effector decay - and no density for the address itself, in this family or any other.", "evidence": [] } ], "records": { "H04": { "id": "H04", "year": 2023, "topic": "Residual-disease geography", "title": "B- and T-cell acute lymphoblastic leukemias evade chemotherapy at distinct sites in the bone marrow.", "url": "https://doi.org/10.3324/haematol.2021.280451", "studyType": "Three-dimensional fluorescence imaging of ten primary acute lymphoblastic leukemia xenografts before and after induction with dexamethasone, vincristine and doxorubicin, Haematologica 108(5):1244-1258", "diseaseContext": "Leukemia", "useInModel": "Gives the survival niche the inventory asks for a location, makes that location lineage-specific, and then argues against the state the inventory asks for next. B-cell precursor cells sat predominantly in the perisinusoidal space both at early engraftment and after chemotherapy, while T-lineage cells were distributed more widely with contacts to endosteum, nestin-positive pericytes and sinusoids - and dispersed further under chemotherapeutic pressure. So residual disease has a geography and the geography depends on lineage, which means a single marrow niche compartment cannot represent both. The negative matters as much: a subset of slowly dividing cells appeared transiently during short-term chemotherapy but was absent from residual disease afterwards, which the authors say challenges the notion that these cells escape by direct induction of a dormant state in the niche. The inventory lists dormancy as a state to resolve, and the best spatial evidence here says it is not the escape mechanism.", "limit": "Ten primary xenografts, so human cells in mouse marrow without the patient's immune system - and the atlas's own warning applies, that tissue distances in xenograft marrow should not be copied without checking units and scale. Imaging localises cells relative to structures and does not establish that those structures confer protection; predilection is association. The dormancy negative is an absence at one sampling point after one induction regimen, which argues against dormancy as the dominant route rather than excluding it. One regimen, two lineages, no molecular correlate of the surviving cells.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. The model and regimen, both lineages' spatial distributions with their named contact structures, the increased dispersion under treatment, and the transient slowly-dividing subset with the authors' explicit challenge to niche-induced dormancy as reported", "quantitativeExtraction": "extracted" }, "R01": { "id": "R01", "year": 2017, "topic": "Clinical outcome", "title": "Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia", "url": "https://doi.org/10.1056/NEJMoa1609783", "studyType": "Multi-institutional phase 3 trial, 405 adults with heavily pretreated B-cell precursor acute lymphoblastic leukemia randomised 2:1 to blinatumomab (271) or standard-of-care chemotherapy (134), 376 dosed, primary endpoint overall survival, NEJM 376(9):836-847", "diseaseContext": "Leukemia", "useInModel": "The earliest member of the atlas's address class and still its most instructive on duration. A CD19-CD3 bispecific construct gave median overall survival of 7.7 against 4.0 months (HR 0.71, 95% CI 0.55-0.93), complete remission with full haematologic recovery in 34 against 16 percent, event-free survival at six months of 31 against 12 percent (HR 0.55, 0.43-0.71), and median remission duration of 7.3 against 4.6 months. Grade 3 or higher events were 87 against 92 percent, and 24 percent of patients in each arm went on to allogeneic transplant. Two things to carry forward. The effect is real and modest in absolute terms - under four months of median survival added in heavily pretreated disease - and the equal transplant rates mean the comparison is not confounded by differential access to the one curative option. And this agent is delivered as a 28-day continuous infusion, which is exactly the schedule the exhaustion record in this row shows degrades the payload, so the two should always be read together.", "limit": "Heavily pretreated relapsed or refractory B-cell precursor disease, so not a first-line estimate. Open to the usual objection that population survival says nothing about per-cell killing probability - no effector-to-target ratio, CD19 density or encounter rate is derivable from it. Grade 3 or higher toxicity was high in both arms. The 24 percent transplant rate in each group means a quarter of each arm received a subsequent potentially curative intervention, which the survival comparison includes rather than isolates.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. Arm sizes, dosing denominator, median overall survival with hazard ratio and interval, both remission definitions and rates, event-free survival, remission duration, transplant rates and grade 3 or higher toxicity as reported", "quantitativeExtraction": "extracted" }, "T11": { "id": "T11", "year": 2022, "topic": "Effector state", "title": "T-cell exhaustion induced by continuous bispecific molecule exposure is ameliorated by treatment-free intervals", "url": "https://doi.org/10.1182/blood.2022015956", "studyType": "T-cell function measured in relapsed/refractory B-ALL patients during 28-day continuous blinatumomab infusion, with an in vitro model of continuous exposure to a half-life-extended CD19xCD3 bispecific, treatment-free interval experiments, transcriptional profiling and in vivo confirmation, Blood 140(11):1104-1118", "diseaseContext": "Leukemia", "useInModel": "Quantifies the parameter this atlas added one row ago and reverses the direction a simulation would assume. The address class's sixth parameter, effector durability, had a single crude proxy behind it. Here it has a magnitude and an intervention. In patients, 28-day continuous infusion led to declining T-cell function. In vitro, continuous exposure produced progressive loss: mean specific lysis fell from 88.4 percent at day 7 to 8.6 percent at day 28 (n = 6, P = .0003), with hallmark exhaustion features accumulating. Treatment-free intervals reversed it - specific lysis on day 14 was 34.9 percent under continuous exposure against 93.4 percent with an interval (n = 6, P < .0001) - with transcriptional reprogramming, better T-cell expansion and better tumour control in vivo. The modelling consequence is first-order. For this payload class, continued exposure to the drug reduces the drug's effect, so exposure-response is not monotonic in time and the standard assumption that more drug-time means more effect is wrong. Schedule is the controlling variable rather than a refinement, and the intervention that restores efficacy is to stop dosing.", "limit": "The quantitative decay and the interval rescue are in vitro with n = 6, using a half-life-extended construct that is not the approved agent, so the numbers describe that model system rather than clinical pharmacology. The patient observation is declining T-cell function during infusion without an accompanying efficacy decay curve. Schedule effects are construct-specific - the authors are explicit that this is not a clinical instruction to interrupt treatment - and no optimal interval length is established for any approved agent. Nothing here measures exhaustion in solid-tumour engager settings, where the atlas's other engager records sit.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. The patient observation, both specific lysis comparisons with sample sizes and p values, the transcriptional reprogramming, the in vivo expansion and control findings, and the authors' own caution about construct specificity as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I054", "name": "Normal hematopoietic progenitors", "category": "Parenchyma", "whereToCheck": "Marrow and blood", "states": [ "Lineage", "cycling", "recovery" ], "behaviors": [ "Competition", "hematopoiesis", "treatment injury" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-408" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-408" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-408" ], "priorResearch": { "path": "simulation/data/profiles/normal-hematopoietic-progenitors.json", "summary": "The normal blood-forming compartment of marrow, which the inventory asks to resolve as lineage, cycling and recovery, with competition, haematopoiesis and treatment injury. The row's central finding is about the shape of the thing rather than its quantities: the stepwise tree of oligo-, bi- and unipotent progenitors rests on analysis of predefined flow-sorted populations, and measured without those gates individual stem cells acquire lineage biases gradually in multiple directions, with unilineage-restricted cells emerging directly from a continuum of low-primed undifferentiated cells (L170). Competition is served from two directions - the atlas already holds disseminated tumour cells displacing these cells from the niche, and at population scale some clones win with age, associated with smoking, monocyte count and a history of breast cancer or uterine leiomyoma (L171, L124). And the condition that competition produces cannot be separated from its assay, since whether a person has clonal haematopoiesis depends on sequencing depth (L172).", "stateAxes": [ { "axis": "Lineage, as a continuous priming landscape", "whatToMeasure": "Position in a continuum of low-primed cells with combinatorial module activity, rather than membership of a progenitor compartment - because the compartments came from predefined gates and the priming is multi-directional and gradual.", "interpretationLimit": "Human steady state, so it describes homeostasis and not regeneration after injury, which is the state the inventory's recovery axis would need. A landscape is harder to parameterise than a tree: no compartment sizes, transition rates or residence times, so this changes the representation without supplying a number. Module combinatorics are inferred from expression structure, not perturbed.", "evidence": [ "L170" ] }, { "axis": "Competition, at two scales", "whatToMeasure": "Niche occupancy against a displacing population, and separately clone size in the resident compartment - since risk scales with clone size and not with the presence of a clone.", "interpretationLimit": "The niche competition evidence is human cells in mouse marrow and niche size is causal without being given in cells or volume. The population-scale clonal data are cross-sectional, so associations have no temporal order, and the cancer associations are confounded by cytotoxic treatment, which itself causes clonal haematopoiesis.", "evidence": [ "L124", "L171", "L172" ] }, { "axis": "Treatment injury, which is this family's role in every other environment", "whatToMeasure": "This compartment's tolerance, because marrow is an established organ at risk with absorbed-dose thresholds for radioligand therapy and the dose-limiting site for most cytotoxic regimens - so what can be given elsewhere is set here.", "interpretationLimit": "The atlas holds the fact that thresholds exist and not one value, and holds no record at all of myelosuppression incidence, depth or duration for any agent. This is the row's largest gap and it is an ingestion gap rather than an unknown, like the absorbed dose the kidney row recorded.", "evidence": [ "L162" ] }, { "axis": "Cycling and recovery", "whatToMeasure": "Proliferative fraction and the kinetics of return after injury - both named by the inventory and neither supplied by any record here.", "interpretationLimit": "The continuum evidence is steady state and the competition evidence is chronic, so nothing in this row describes the acute injury-and-recovery cycle that defines this compartment clinically. No nadir depth, no time to recovery, no reserve capacity.", "evidence": [] } ], "records": { "L124": { "id": "L124", "year": 2011, "topic": "Marrow niche", "title": "Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow", "url": "https://doi.org/10.1172/JCI43414", "studyType": "Mouse model of human prostate cancer dissemination with niche size manipulation and mobilisation protocols, J Clin Invest 121(4):1298-1312", "diseaseContext": "Prostate", "useInModel": "Makes niche capacity a causal and manipulable quantity, which is exactly what one of this atlas's boundary decisions lacked. Human prostate cancer cells directly competed with haematopoietic stem cells for occupancy of the niche; increasing niche size promoted metastasis and decreasing it compromised dissemination; disseminated cancer cells could be mobilised out of the niche and back into circulation using stem cell mobilisation protocols; and once lodged, the tumour cells reduced stem cell numbers by driving their terminal differentiation. Three things follow. The atlas decided, for tissues outside the central nervous system, to track niche occupancy rather than cell origin, and recorded that no niche capacity existed anywhere - here capacity is not only real but causal in both directions. Residence is reversible, which makes eviction a different kind of intervention from the inhibitions and blockades the atlas's ledger otherwise contains. And occupancy has a cost to the resident population, which is a displacement the marrow parenchyma rows would carry. The finding concerns the haematopoietic niche, which the inventory assigns to the marrow stromal row, so it should be treated as shared between these two rows rather than cited again as new.", "limit": "Human cancer cells in a mouse marrow, so the niche being competed for is murine and the competition is xenogeneic. Niche size was manipulated by the study's own means and no capacity is given in cells or volume - the variable is shown to be causal without being quantified. Mobilisation returns cells to circulation without establishing what then happens to them, and the reduction in stem cells is attributed to driven differentiation rather than measured as a rate.", "provenance": "Abstract read in full; the direct competition, both directions of the niche size manipulation, the mobilisation result and the mechanism of stem cell reduction as reported", "quantitativeExtraction": "extracted" }, "L162": { "id": "L162", "year": 2026, "topic": "Target identity", "title": "177Lu-PSMA dosimetry made easy: from theory to practical implementation", "url": "https://doi.org/10.23736/S1824-4785.26.03695-2", "studyType": "Practical review of patient-specific internal dosimetry for a radioligand therapy, covering quantitative imaging, time-activity curves and absorbed-dose estimation, Quarterly Journal of Nuclear Medicine and Molecular Imaging 70(3):205-217", "diseaseContext": "Prostate cancer; kidney as organ at risk", "useInModel": "Converts one of the atlas's recorded gaps from an unknown into an ingestion failure. meta.json states that the address class carries five parameters - reach, specificity, density, penetration, geometry - and that the atlas holds a number for none, with no absorbed dose for any member. This record says the absorbed dose is routinely computed in practice: patient-specific internal dosimetry is described as essential for optimising efficacy and minimising toxicity, evidence supports a strong correlation between tumour absorbed dose and therapeutic response, and established thresholds exist for organs at risk - particularly kidneys, salivary glands and bone marrow - which guide safe administration. So the reach parameter is measurable, measured, and simply not in this data layer. It also places this family on the address class's normal-tissue map: the kidney is an organ at risk for the prostate row's radioligand, which makes it the second address-class normal-tissue location after nectin-4 in skin - and unlike skin, this tissue is not dispensable.", "limit": "A practical review, so it establishes that thresholds and dose-response relationships exist without this record supplying their values - no absorbed dose in gray, no threshold figure and no dose-response slope is extracted here, and none should be inferred. The tumour-dose to response correlation is reported as supported by evidence rather than quantified. The authors note that logistical barriers have limited routine implementation, so dosimetry is standard in principle more than in universal practice. Nothing here measures PSMA expression in the tubule, so the mechanism by which the kidney is at risk is not established by this record.", "provenance": "Abstract read in full; the statement that patient-specific dosimetry is essential, the tumour absorbed dose to response correlation, the existence of established organ-at-risk thresholds with the three organs named, and the noted logistical barriers to routine implementation as reported. The connection to this atlas's parameter inventory is its own", "quantitativeExtraction": "extracted" }, "L170": { "id": "L170", "year": 2017, "topic": "Lineage", "title": "Human haematopoietic stem cell lineage commitment is a continuous process", "url": "https://doi.org/10.1038/ncb3493", "studyType": "Integration of flow cytometric, transcriptomic and functional data at single-cell resolution across early human haematopoietic differentiation, Nature Cell Biology 19(4):271-281", "diseaseContext": "Healthy reference", "useInModel": "The strongest warning this atlas holds about its own construction, and it concerns a hierarchy the field taught for decades. Blood formation was believed to proceed stepwise through a tree of oligo-, bi- and unipotent progenitors - and the authors state that this model rests on the analysis of predefined flow-sorted populations. Measured without those predefined gates, individual stem cells gradually acquire lineage biases along multiple directions without passing through discrete hierarchically organised progenitor populations, and unilineage-restricted cells emerge directly from what the authors name a continuum of low-primed undifferentiated haematopoietic stem and progenitor cells. Distinct gene expression modules act combinatorially to control stemness, early priming and progression into each branch. Two consequences. For this family a simulation should carry a continuous state space with combinatorial priming rather than discrete progenitor compartments, because the compartments were an artefact of how cells were isolated. And for the atlas generally: it carries 110 families defined largely by marker panels, and this is a documented case of marker-based gating creating the populations it appeared to discover.", "limit": "Human steady-state haematopoiesis, so it describes homeostasis and not regeneration after injury, where a stepwise structure might assert itself differently. A continuum is harder to parameterise than a tree: the paper gives a landscape and gene expression modules rather than compartment sizes, transition rates or residence times, so nothing here becomes a number. The combinatorial module claim is inferred from expression structure rather than tested by perturbation. It also does not say the sorted populations are empty of meaning - they are reproducible and functionally distinct - only that they are not the discrete stages the tree implied.", "provenance": "Abstract read in full; the stated basis of the prior model in predefined flow-sorted populations, the multi-directional gradual priming, the named continuum, the direct emergence of unilineage-restricted cells, and the combinatorial module framing as reported", "quantitativeExtraction": "extracted" }, "L171": { "id": "L171", "year": 2026, "topic": "Competition", "title": "Risk factors of clonal hematopoiesis of indeterminate potential", "url": "https://doi.org/10.1016/j.clinme.2026.100635", "studyType": "Cross-sectional study of around 460,000 UK Biobank participants with logistic regression across sociodemographic, lifestyle, disease history, blood count, biochemistry, proteomic and metabolomic variables, plus Mendelian randomisation using published GWAS summary statistics, Clinical Medicine 26:100635", "diseaseContext": "Healthy reference", "useInModel": "Puts the competition the inventory asks for on a population footing, and links this family to two drawn environments. In around 460,000 participants, advanced age and smoking were associated with clonal haematopoiesis, as was a history of several diseases including breast cancer and uterine leiomyoma, along with monocyte count and four serum proteins. The atlas already holds the competition from the tumour's side - disseminated prostate cancer cells competing with haematopoietic stem cells for niche occupancy and reducing their numbers - and this is the normal compartment's own clonal dynamics at scale: with age, some clones win. The disease associations matter because breast and uterine corpus are both drawn environments, so having a tumour in one environment associates with clonal change in this family. That is a candidate cross-environment coupling of a kind the atlas has almost none of, and it is also the most confounded finding in the row.", "limit": "Cross-sectional, so associations cannot be ordered in time, and the disease associations are badly confounded by treatment - cytotoxic chemotherapy is itself a cause of clonal haematopoiesis, which this design cannot separate from the cancer. Mendelian randomisation was applied to assess causality but the abstract does not say which exposures survived it, so no causal claim should be taken from this record. UK Biobank is older, healthier and less diverse than the general population. Detection depends on sequencing depth, so prevalence here is an artefact of platform as much as of biology - the companion record makes that explicit.", "provenance": "Abstract read in full; cohort size and design, both analytic approaches, and the associated factors as listed - age, smoking, the named disease histories, monocyte count and the four proteins. The absence of per-exposure MR results in the abstract is recorded rather than filled in", "quantitativeExtraction": "extracted" }, "L172": { "id": "L172", "year": 2026, "topic": "Competition", "title": "Designing Cardiovascular Outcomes Trials in Clonal Hematopoiesis of Indeterminate Potential", "url": "https://doi.org/10.1001/jamacardio.2026.3593", "studyType": "Special communication synthesising epidemiologic, mechanistic and clinical considerations for trial design in clonal haematopoiesis, JAMA Cardiology", "diseaseContext": "Healthy reference", "useInModel": "Three statements that bear on how this atlas records anything. First, clonal haematopoiesis is not one condition: genetic heterogeneity across driver mutations leads to distinct biological mechanisms and distinct cardiovascular outcomes, which complicates endpoint selection. So a single compartment labelled by the presence of a clone would merge mechanisms that differ. Second, risk varies by clone size - a continuous quantity - and trial eligibility must trade breadth against event rate, which is a dichotomisation of a continuum done for practical reasons. Third, and most useful: differences in sequencing platforms and detection thresholds hinder consistent risk stratification and reproducibility. Whether a person has this condition depends on how deeply they were sequenced. That is the third independent case in this atlas of a widely used threshold being a convention rather than a boundary, after HER2 scoring and the 500 Dalton rule - and here the convention is instrumental rather than biological, which is the starkest version. It also makes this family a place where the condition and the assay cannot be separated.", "limit": "A trial-design commentary, not a study: it supplies no prevalence, no clone-size threshold, no effect size and no detection limit, and its purpose is to argue that trials are hard to design rather than to measure anything. The cardiovascular framing is outside this atlas's drawn environments entirely; it is held for what it says about driver heterogeneity, clone size and detection thresholds, not for cardiovascular risk. Nothing here concerns the marrow microenvironment or this family's relationship to any tumour.", "provenance": "Abstract read in full; the driver heterogeneity and distinct outcomes claim, the clone-size dependence of risk with its eligibility trade-off, and the platform and detection-threshold problem for stratification and reproducibility as reported. The comparison to the atlas's other threshold cases is its own", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I055", "name": "Megakaryocytes and erythroid precursors", "category": "Parenchyma", "whereToCheck": "Marrow", "states": [ "Maturation and stress" ], "behaviors": [ "Niche effects", "platelet/erythrocyte production" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-413", "hatton-416", "hatton-434", "hatton-437" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-413", "hatton-416", "hatton-434", "hatton-437" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-413", "hatton-416", "hatton-434", "hatton-437" ], "priorResearch": { "path": "simulation/data/profiles/megakaryocytes-and-erythroid-precursors.json", "summary": "The marrow's two highest-output production lines, and - unexpectedly - part of the control system for the stem compartment that makes them. The inventory asks for maturation and stress, with niche effects and platelet or erythrocyte production. Niche effects turn out to be the row's strongest content: megakaryocytes sit non-randomly adjacent to haematopoietic stem cells, their selective depletion in vivo causes loss of stem cell quiescence and marked expansion of the stem pool, they are the marrow source of CXCL4, and injecting that chemokine reduces stem cell numbers by increasing quiescence while its knockout increases both number and proliferation (L173). The paper notes that every putative niche cell proposed before it had a non-haematopoietic origin. Production is served not by a rate but by a model: a calibrated and validated systems pharmacology representation of erythropoiesis built to test trial protocols in silico (L174), with a companion comparison of four ways to turn published means and standard deviations into virtual populations (L175).", "stateAxes": [ { "axis": "Niche effect on the stem compartment, and its direction", "whatToMeasure": "Adjacency to stem cells and CXCL4 availability, because this niche restrains rather than maintains: depletion expands the stem pool, injection contracts it through quiescence, and knockout expands it with more proliferation.", "interpretationLimit": "Mouse, with acute selective depletion rather than gradual change. CXCL4 is one of several factors this cell secretes and only one was substituted, so the chemokine regulates cell cycle activity without being shown to account for the whole niche contribution. Adjacency is non-random rather than a distance, so there is no length scale. No density for either cell and no chemokine concentration.", "evidence": [ "L173" ] }, { "axis": "Production, as a representable pathway rather than a rate", "whatToMeasure": "The erythropoietin-driven pathway from progenitor expansion to haemoglobin-carrying red cells, which exists as a calibrated systems model with virtual populations of varying severity - including two mechanistically distinct ways to raise the same output, exogenous erythropoietin and prolyl hydroxylase inhibition.", "interpretationLimit": "A model's outputs are simulated, and calibration against public data shows consistency with what was published rather than accuracy on anything withheld. Built for chronic kidney disease anaemia, not for the marrow failure oncology causes, and the rates live inside its parameterisation rather than being extracted into this atlas.", "evidence": [ "L174" ] }, { "axis": "Variability, as a method the project can borrow", "whatToMeasure": "Not a state of this family but a way of representing any of them: four compared approaches for building virtual populations from published means and standard deviations, with stochastically bounded selection performing best.", "interpretationLimit": "One model of one physiology, so the ranking should not be carried as general. And the approach assumes the published mean and standard deviation are adequate - a population generated from a mean whose repeat-measurement variability equals that mean, as this atlas has recorded for one velocity, will look precise and mean nothing.", "evidence": [ "L175" ] }, { "axis": "Maturation and stress", "whatToMeasure": "Where cells sit along maturation, and how that shifts under demand - the only state the inventory names for this row, and the one no record here supplies.", "interpretationLimit": "Nothing held here measures maturation stages, their proportions, or the stress response that expands them. The systems model represents maturation internally for one lineage and the atlas has not extracted it.", "evidence": [] } ], "records": { "L173": { "id": "L173", "year": 2014, "topic": "Niche effects", "title": "Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion", "url": "https://doi.org/10.1038/nm.3707", "studyType": "Three-dimensional whole-mount imaging with selective in vivo megakaryocyte depletion, gene expression analysis, chemokine injection and knockout mice, plus computational modelling, Nature Medicine 20(11):1315-1320", "diseaseContext": "Healthy reference", "useInModel": "The atlas's second intra-lineage niche, and it arrives with the same experimental structure as the first, which turns a provisional rule into a supported one. The paper opens by noting that all putative niche cells suggested to that point had a non-haematopoietic origin, leaving unclear how feedback from mature cells reaches stem cells. Whole-mount imaging placed stem cells adjacent to megakaryocytes non-randomly; selective in vivo depletion of megakaryocytes caused specific loss of stem cell quiescence and a marked expansion of functional stem cells; megakaryocytes proved to be the marrow source of CXCL4; injecting CXCL4 reduced stem cell numbers through increased quiescence while CXCL4-knockout mice had more stem cells and more proliferation. The authors conclude that a terminally differentiated cell type derived from stem cells contributes to their niche. That is the crypt situation again - a differentiated daughter sustaining the cell that made it, necessary in vivo, and its function reproducible by one injected molecule - with the direction reversed. The Paneth cell maintains and this cell restrains, so a niche signal can be positive or negative and the two break the system in opposite ways.", "limit": "Mouse, and depletion is acute and selective rather than the gradual change of any disease state. CXCL4 injection and knockout establish that the chemokine regulates cell cycle activity and do not establish that it accounts for the whole of the megakaryocyte's niche contribution - the depletion removes a cell that also secretes TGF-beta and other factors, and only one was substituted. Adjacency is quantified as non-random rather than as a distance, so the proximity has no length scale. The computational modelling is described as suggestive. No stem cell or megakaryocyte density, and no CXCL4 concentration.", "provenance": "Abstract read in full; the stated absence of prior haematopoietic-origin niche cells, the non-random adjacency, the depletion phenotype, the identification of the chemokine source, both the injection and knockout results, and the authors' conclusion as reported", "quantitativeExtraction": "extracted" }, "L174": { "id": "L174", "year": 2023, "topic": "Mathematical model", "title": "Quantitative systems pharmacology model of erythropoiesis to simulate therapies targeting anemia due to chronic kidney disease", "url": "https://doi.org/10.3389/fphar.2023.1274490", "studyType": "Quantitative systems pharmacology model of erythropoiesis with virtual populations of varying disease severity, calibrated and validated against public data, Frontiers in Pharmacology 14:1274490", "diseaseContext": "Chronic kidney disease anaemia", "useInModel": "The second record in this atlas where the project's own method has already been applied to one of its families, and the stronger of the two. Where the leukemia row holds a preprint agent-based model of engager scheduling, this is a peer-reviewed quantitative systems pharmacology model of this family's output - erythropoietin driving progenitors that mature into haemoglobin-carrying red cells - capturing the physiology and its disruption in chronic kidney disease, with virtual populations of varying severity calibrated and validated against public data, built to simulate alternative trial protocols during phase 3 design and to support reverse translation from emerging clinical data. Three things follow for this project. A production pathway in this family is already representable end to end, which the atlas's own rows are not. The model's purpose is the one this project states for itself - trying protocols in silico before running them - so the use case is established rather than aspirational. And it covers two mechanistically distinct interventions on the same axis, exogenous erythropoietin against prolyl hydroxylase inhibitors that raise endogenous production through HIF-alpha accumulation, which is a worked example of representing two routes to one output. Two additions from the full text. The row gains its first maturation timescale for this lineage - 1 to 2 days for a blood reticulocyte to become an erythrocyte - and the atlas gains an unusual object: a closed-loop dosing rule with explicit thresholds and intervals. Dose is increased if haemoglobin has not risen 1 g/dL in 4 weeks, decreased if it rises more than 1.2 g/dL in 2 weeks, and withheld above 13 g/dL, with the model reproducing its trial more faithfully when the threshold was set at 12. The project's schedule work has recorded repeatedly that it holds no crossover and no feedback time constant; this is a schedule specified entirely by thresholds on a measured variable and the intervals over which change is judged, which is what such a rule looks like when a field has one.", "limit": "A model rather than a measurement: its outputs are simulated, and calibration against public data establishes consistency with what was published rather than predictive accuracy on anything withheld here. Built for chronic kidney disease anaemia, which is not one of the drawn environments and is not the marrow failure that oncology causes, so it is held for its method and scope rather than as evidence about this family in any drawn setting. It gives this atlas no production rate directly - the rates live inside the model's parameterisation and are not extracted here. Read in full text on 2026-10-18 to extract the parameterisation this limit refers to, and the attempt failed for a reason worth recording: the paper states that generation of the various erythroid precursors through maturation, and renal EPO secretion, are simplified and not captured in the detail of some other mechanistic models of erythropoiesis. So the production rates this atlas wanted are not merely unextracted here - they are simplified away by design, and the paper's parameter tables are in supplementary files the open full-text interface does not serve. What the body text does give is one usable timescale, that blood reticulocytes take 1 to 2 days to mature into erythrocytes, and a set of clinical control thresholds: anaemia defined as haemoglobin below 12.0 g/dL in women and 13.0 in men, below 10 g/dL at chronic kidney disease stage 5, with dosing raised if haemoglobin fails to rise 1 g/dL in 4 weeks, lowered if it rises more than 1.2 g/dL in 2 weeks, and withheld above 13 g/dL - and the model matched its trial better when withholding at 12 rather than 13 g/dL.", "provenance": "Abstract read in full; the modelled pathway, both intervention classes with their distinct mechanisms, the virtual population construction with calibration and validation against public data, and the stated uses in trial design and reverse translation as reported", "quantitativeExtraction": "extracted" }, "L175": { "id": "L175", "year": 2022, "topic": "Mathematical model", "title": "Application of different approaches to generate virtual patient populations for the quantitative systems pharmacology model of erythropoiesis", "url": "https://doi.org/10.1007/s10928-022-09814-y", "studyType": "Methodological comparison of four approaches to constructing virtual patient populations from published means and standard deviations, applied to an erythropoiesis model, Journal of Pharmacokinetics and Pharmacodynamics 49(5):511-524", "diseaseContext": "Chronic kidney disease anaemia", "useInModel": "Addresses the problem this atlas has run into in almost every row, and addresses it as a method rather than as a complaint. The paper's framing is the project's own situation: a systems model normally describes a reference patient with fixed parameters and therefore only mean behaviour, while clinical trials report variability as standard deviations around means. Four approaches to generating virtual populations from exactly that - published means and standard deviations - were compared: Markov chain Monte Carlo, fitting the model to a Monte Carlo sample, a population of clones, and stochastically bounded selection, with the last performing slightly better and described as able to represent any number of patients and to cope with complex models carrying many variable parameters. This atlas has recorded a mean without a distribution for nearly every quantity it holds - barrier thicknesses, cell counts, velocities, hazard ratios - and has separately recorded that one velocity's repeat-measurement variability equals its mean. This is the published route from the first situation to a population, and it means the absence of distributions is a tractable modelling problem rather than a blocking one.", "limit": "A methods comparison on one model of one physiology, so the ranking of the four approaches should not be carried as general. Generating a population from a mean and a standard deviation assumes the published summary is adequate and the distributional form is reasonable, which is exactly what the atlas's reliability gap questions - a virtual population built from a mean whose repeat variability equals that mean will look precise and mean nothing. No clinical validation of the generated populations against withheld patient-level data is described here.", "provenance": "Abstract read in full; the stated reference-patient limitation, all four named approaches, the comparative conclusion favouring stochastically bounded selection and its stated advantages as reported. The connection to this atlas's own missing distributions is its own", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I056", "name": "Cortical excitatory neurons", "category": "Neural", "whereToCheck": "Region/layer-specific AD and FTD; ALS motor cortex", "states": [ "Subtype", "stress", "activity", "degeneration" ], "behaviors": [ "Synapses", "electrophysiology", "proteostasis", "survival" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-116" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-116" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-116" ], "priorResearch": { "path": "simulation/data/profiles/cortical-excitatory-neurons.json", "summary": "The principal projecting cells of the cortex, and the first row of the Neural category. The atlas already held this family's composition and its molecular failure modes: 76 cell types across six brain regions with vulnerable excitatory populations depleted in specific regions rather than globally and Reelin signalling implicated (A02), vulnerable populations in cortical layer 5 with ALS- and FTLD-implicated motor and spindle neurons sharing a virtually indistinguishable molecular identity (F01), and TDP-43 loss driving cryptic exon inclusion that depletes the synaptic protein UNC13A (F02, F03). What this row adds is function, which the atlas has lacked everywhere. These neurons are measurably overactive before they are gone: subclinical epileptiform discharge in a pooled 18.3 percent of Alzheimer patients without epilepsy history, relative risk 3.55 (L188), and in ALS enlarged cortical evoked potentials with normal peripheral sensory conduction and a 4.89 microvolt threshold predicting shorter survival (L189).", "stateAxes": [ { "axis": "Activity, and how long you looked", "whatToMeasure": "Epileptiform discharge with the recording protocol recorded alongside it, since the rate was 12.1 percent on routine protocols and 26.7 percent on extended ones - and with age of onset, since early-onset patients reached 43.9 percent against 21.3 for late-onset on extended recording.", "interpretationLimit": "A meta-analysis across thirteen studies with differing protocols, which is where the protocol-dependence comes from. Subclinical discharge has no outcome association in this record, patients were selected for having no epilepsy history, and the pooled figure is dominated by late-onset cases.", "evidence": [ "L188" ] }, { "axis": "Electrophysiology, with the periphery as control", "whatToMeasure": "Cortical evoked potential amplitude alongside peripheral nerve action potentials, because the peripheral recordings were normal while the cortical ones were enlarged - which is what localises the abnormality - and against the 4.89 microvolt threshold that separated survival.", "interpretationLimit": "Retrospective, sporadic ALS, with the threshold derived in this cohort and not validated elsewhere. Sensory rather than motor cortex, so it is not a measurement of the neurons the disease kills. Evoked potential amplitude is a population response and cannot be assigned to this family's cells without assumption.", "evidence": [ "L189" ] }, { "axis": "Subtype and degeneration, by region rather than globally", "whatToMeasure": "Which excitatory subtype in which region, since vulnerable populations were depleted regionally rather than across the brain, and vulnerable cells in two other environments sit in cortical layer 5.", "interpretationLimit": "Post-mortem and cross-sectional, so regional progression is reconstructed rather than observed and vulnerability is depletion in prevalence rather than measured loss over time. A 76-type classification from aged human brain is a hypothesis about structure, which the haematopoietic row's lesson applies to directly.", "evidence": [ "A02", "F01" ] }, { "axis": "Proteostasis, as a named splicing lesion", "whatToMeasure": "Cryptic exon inclusion and the resulting depletion of UNC13A and STMN2 following TDP-43 loss - a specific molecular failure with named targets, one of them synaptic.", "interpretationLimit": "The mechanism is established in the atlas's existing records for ALS and FTD and no record here quantifies the depletion in patient cortex or relates it to the functional abnormality this row adds. So the lesion and the overactivity sit in the same cell type and the same environment with nothing connecting them.", "evidence": [ "F02", "F03" ] } ], "records": { "A02": { "id": "A02", "year": 2024, "topic": "Multiregion atlas", "title": "Single-cell multiregion dissection of Alzheimer’s disease", "url": "https://www.nature.com/articles/s41586-024-07606-7", "studyType": "Single-cell transcriptomic atlas of six brain regions, 1.3 million cells from 283 post-mortem samples across 48 individuals with and without Alzheimer's disease, Nature 632(8026):858-868", "diseaseContext": "Alzheimer's", "useInModel": "The regional axis, at a resolution that has consequences for how this atlas is structured. Six regions, 1.3 million cells, 283 samples, 48 individuals - and 76 cell types identified, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from the canonical inhibitory subclasses. Vulnerable excitatory and inhibitory populations were depleted in specific brain regions rather than globally, with evidence implicating Reelin signalling in modulating that vulnerability, and region-specific as well as cell-type-specific gene modules were altered in disease. Two things matter beyond the atlas's own use. Seventy-six cell types in one disease across six regions approaches the granularity of this inventory's entire 110 families across the thirteen environments carried in measurements.json, and the region-specific subtypes cannot be expressed by a flat family list at all - a family here is one row whether or not it is three different cells in three regions. And the thalamus-unique inhibitory population lands on an independent finding the atlas already holds: progranulin deficiency drives complement-mediated pruning that preferentially eliminates inhibitory synapses in the ventral thalamus (F05). Two unrelated lines converging on thalamic inhibitory neurons. The study also supplies something the atlas has nowhere else - a resilience programme, astrocytic, tying choline metabolism and polyamine biosynthesis to preserved cognitive function late in life.", "limit": "Post-mortem and cross-sectional, so regional progression is reconstructed rather than observed and the vulnerability claims are depletion in prevalence rather than measured loss over time. Six regions of the aged human brain, 48 individuals, with per-region and per-type numbers necessarily smaller than the headline cell count. The Reelin and resilience findings are associations from module discovery, and the resilience programme is correlated with preserved cognition rather than shown to cause it.", "provenance": "Abstract read in full; region, cell, sample and individual counts, the 76 cell types, the thalamic population, the regional depletion, Reelin and the astrocyte resilience programme as reported", "quantitativeExtraction": "extracted" }, "F01": { "id": "F01", "year": 2024, "topic": "Cellular atlas", "title": "Single-cell dissection of the human motor and prefrontal cortices in ALS and FTLD.", "url": "https://pubmed.ncbi.nlm.nih.gov/38521060/", "studyType": "Comparative single-cell molecular atlas of human primary motor and dorsolateral prefrontal cortices in sporadic and familial ALS and FTLD, Cell 187(8):1971-1989", "diseaseContext": "ALS / FTD", "useInModel": "Serves the regional axis for the other two neurodegenerative environments, and makes a claim about what defines a vulnerable cell. Integrating transcriptional and genetic information across two cortical regions, the study identified known and previously unidentified vulnerable populations in cortical layer 5, and found that the ALS- and FTLD-implicated motor and spindle neurons possess a virtually indistinguishable molecular identity - so two diseases the atlas treats as separate environments converge on the same cell. Non-neuronal drivers of pathogenesis were also implicated, which is where this record meets the microglial and complement findings. The sentence with the widest consequence is the last: neuron loss in layer 5 tracked more closely with transcriptional identity than with cellular morphology, and extended beyond the previously reported vulnerable cell types. This inventory's 110 families are named largely by lineage and morphology, and here vulnerability follows transcriptional identity instead - so a family defined the atlas's way may group cells that behave differently and separate cells that behave alike.", "limit": "Post-mortem human cortex, two regions, sporadic and familial cases pooled for some analyses, so the molecular identity claim is about the cells rather than about matched disease stages. Vulnerability is inferred from prevalence differences between cases and controls rather than from observed loss. ALS and FTLD overlap biologically but are not interchangeable diagnoses, and the convergence shown is for specific neuronal populations rather than for the diseases.", "provenance": "Abstract read in full; the layer 5 populations, the indistinguishable molecular identity, the non-neuronal implication and the identity-against-morphology finding as reported", "quantitativeExtraction": "extracted" }, "F02": { "id": "F02", "year": 2022, "topic": "RNA processing", "title": "TDP-43 represses cryptic exon inclusion in the FTD–ALS gene UNC13A", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8891019/", "studyType": "Human brain, neuronal cell lines and iPSC-derived motor neurons with risk-variant testing, Nature 603(7899):124-130", "diseaseContext": "ALS / FTD", "useInModel": "Connects the strongest genetic risk factor for these diseases to the loss of this family's nuclear function, and does it through a splicing event. A major job of TDP-43 is repressing cryptic exon inclusion. Losing it from the nucleus - in human brain, in neuronal lines and in iPSC-derived motor neurons - caused a cryptic exon to be included in UNC13A mRNA and reduced UNC13A protein. The variants most strongly associated with risk in genome-wide association studies sit in the intron that harbours that cryptic exon, and they increase its splicing specifically in the face of TDP-43 dysfunction. The structure of that statement is what matters for a model: the risk genotype does almost nothing on its own and acts only once the protein has failed, so genotype and pathological state multiply rather than add.", "limit": "TDP-43-pathology context, so it does not apply to molecular subtypes of ALS or FTD without TDP-43 mislocalisation. Human tissue work is cross-sectional and the cell models are depletion rather than disease, so no rate of cryptic inclusion per unit of nuclear loss is established. UNC13A protein reduction is measured in models, not quantified in patients.", "provenance": "Abstract read in full; the cryptic exon, the protein reduction and the variant interaction as reported", "quantitativeExtraction": "extracted" }, "F03": { "id": "F03", "year": 2022, "topic": "RNA processing", "title": "TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8891020/", "studyType": "Independent companion study in cultured cells and in patient brain and spinal cord, Nature 603(7899):131-137", "diseaseContext": "ALS / FTD", "useInModel": "The same finding reached independently and published alongside, which is why the atlas holds both. TDP-43 depletion induced robust inclusion of a cryptic exon in UNC13A, producing nonsense-mediated decay and loss of the protein. Two common intronic polymorphisms strongly associated with risk overlap TDP-43 binding sites, and they potentiated cryptic exon inclusion both in cultured cells and in brain and spinal cord from patients. The mechanism named here is more specific than in the companion paper - the variants sit on the binding sites themselves, so the risk allele weakens the very interaction that represses the exon. Two groups, two systems, one answer: this is the most independently corroborated mechanism in the neurodegenerative half of this atlas.", "limit": "Depletion models for the causal work with patient tissue used as confirmation, so the direction is secure and the magnitude in a patient is not. Association plus experimental potentiation does not give a patient-level rate, and UNC13A is one of hundreds of transcripts affected, so its contribution to the phenotype is not isolated.", "provenance": "Abstract read in full; the decay mechanism, the binding-site overlap and the patient-tissue confirmation as reported", "quantitativeExtraction": "extracted" }, "L188": { "id": "L188", "year": 2026, "topic": "Activity", "title": "Subclinical Epileptiform Discharge in Patients With Alzheimer Dementia: A Systematic Review and Meta-Analysis", "url": "https://doi.org/10.1097/WNP.0000000000001148", "studyType": "Systematic review and random-effects meta-analysis of 13 studies and 1,373 patients with Alzheimer dementia and no history of epilepsy, stratified by EEG protocol and age of onset, Journal of Clinical Neurophysiology 43(2):121-128", "diseaseContext": "Alzheimer's", "useInModel": "The atlas's first functional measurement of what a neuron is doing, in a drawn environment and in humans - and it comes with a measurement caveat sharper than any the atlas has recorded. Subclinical epileptiform discharge was found in a pooled 18.3 percent of patients with Alzheimer dementia who had no epilepsy history, with a relative risk of 3.55 against healthy controls. So these neurons are behaving abnormally, not merely dying, and the abnormality is excitatory excess rather than silence. Two further findings matter more for how the atlas records anything. The rate depends on how long the recording lasts: 12.1 percent with routine protocols against 26.7 percent with extended ones - the same patients and the same phenomenon, with the prevalence more than doubling by looking longer. And the phenotype splits by age of onset, with early-onset patients at 43.9 percent on extended protocols against 21.3 for late-onset, and a relative risk of 4.48 between them. A single prevalence for this environment would therefore be wrong twice over, once for observation duration and once for onset age.", "limit": "A meta-analysis of thirteen heterogeneous studies with differing EEG protocols, which is the source of the protocol-dependence it reports rather than an incidental limitation. Subclinical discharge is an electrographic finding whose relationship to cognition is not established here - no outcome association is reported. Patients were selected as having no epilepsy history, so the figures are for discharge in its absence. Mean age 71.2 years and 59.3 percent women, so the late-onset stratum dominates the pooled estimate.", "provenance": "Abstract read in full; study and patient counts, the pooled rate, both protocol-specific rates, both onset-stratified rates on each protocol, and both relative risks with their p values as reported", "quantitativeExtraction": "extracted" }, "L189": { "id": "L189", "year": 2026, "topic": "Electrophysiology", "title": "Sensory Cortical Hyperexcitability in Amyotrophic Lateral Sclerosis Involves a Broad Hand Representation Within the Primary Somatosensory Cortex", "url": "https://doi.org/10.1002/mus.70371", "studyType": "Retrospective study of 99 patients with sporadic ALS and 42 healthy controls, with sensory nerve action potentials and somatosensory evoked potentials from median and ulnar stimulation, followed to death or tracheostomy with Kaplan-Meier and Cox analyses, Muscle & Nerve 74(6):1246-1255", "diseaseContext": "ALS", "useInModel": "Locates a functional abnormality in the cortex with the periphery as its own control, and attaches a survival threshold to it. Sensory nerve action potential amplitudes did not differ between patients and controls, while cortical evoked potential amplitudes were larger for both median and ulnar stimulation - so the abnormality is cortical and not a peripheral artefact, which the unchanged peripheral recordings establish directly. Patients with ulnar cortical amplitudes at or above 4.89 microvolts had significantly shorter survival, and increased amplitude was an independent predictor of shorter survival for both nerves on multivariate analysis. For this atlas that matters in two ways. It is a functional measurement with a threshold and an outcome, which almost nothing here has. And it sits against the atlas's own record that ALS is a distal axonopathy proceeding dying-back from the neuromuscular junction: distal degeneration does not mean the cortex is spared, since the cortex is measurably hyperexcitable while peripheral sensory conduction is normal. The disease is doing different things at the two ends.", "limit": "Retrospective, single-centre by implication, and sporadic ALS only - so the threshold is derived in this cohort rather than validated in another. Sensory rather than motor cortex, which makes it an unexpected place to find a prognostic signal and means it is not a measurement of the motor neurons the disease kills. Evoked potential amplitude is a population response rather than a property of any cell, so it cannot be assigned to the excitatory neurons this row is about without assumption. The survival association is from one cohort followed to death or tracheostomy.", "provenance": "Abstract read in full; cohort and control numbers, the unchanged peripheral amplitudes, the enlarged cortical amplitudes for both nerves, the correlation between nerves, the amplitude threshold with its log-rank p value, and the multivariate independence as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I057", "name": "Inhibitory interneurons", "category": "Neural", "whereToCheck": "CNS region/layer-specific", "states": [ "Subtype", "activity", "injury" ], "behaviors": [ "Circuit inhibition", "synaptic stability", "vulnerability" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-115" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-115" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-115" ], "priorResearch": { "path": "simulation/data/profiles/inhibitory-interneurons.json", "summary": "The cortex's inhibitory cells, which the inventory asks to resolve as subtype, activity and injury, with circuit inhibition, synaptic stability and vulnerability. Circuit inhibition is the first behaviour listed and it turns out to answer the question the excitatory row left open. That row found subclinical epileptiform discharge in a pooled 18.3 percent of Alzheimer patients and had no mechanism; here hypersynchrony occurs primarily during reduced gamma, gamma is generated by parvalbumin interneurons, the parvalbumin-predominant sodium channel subunit Nav1.1 is decreased in both model mice and patient brain, and restoring it increases inhibition and gamma while reducing hypersynchrony, memory deficits and premature mortality (L190). So excitatory overactivity is an inhibitory failure. And inhibition is not one quantity: somatostatin interneurons carry theta and parvalbumin interneurons carry gamma, each deficit separately rescuable, through a shared presynaptic mechanism of increased initial GABA release probability (L191).", "stateAxes": [ { "axis": "Circuit inhibition, as at least two frequency-resolved channels", "whatToMeasure": "Inhibitory function by subtype and by frequency band rather than as a single tone - somatostatin against theta, parvalbumin against gamma - since each can be impaired and rescued without the other.", "interpretationLimit": "Acute oligomer injection in mice, hippocampus only, two subtypes where the atlas's own multiregion record says the canonical subclasses are incomplete. Optogenetic activation shows each subtype is sufficient to restore its rhythm rather than that its loss causes the deficit. No human data.", "evidence": [ "L191" ] }, { "axis": "The molecular step, measured in patients", "whatToMeasure": "Nav1.1 level in interneurons, since it is decreased in both model mice and Alzheimer patient brain and its transgenic restoration reverses hypersynchrony, memory deficits and premature mortality.", "interpretationLimit": "The human finding is a decreased level at one timepoint - an association, not a demonstration that it causes the discharge the excitatory row records in patients. The rescue is transgenic restoration in one model that simulates aspects of the disease, and premature mortality in a transgenic line is not a clinical endpoint. The authors hedge the human extension themselves.", "evidence": [ "L190" ] }, { "axis": "Synaptic stability, as a presynaptic release property", "whatToMeasure": "Initial GABA release probability, because the oligomers raised it and that is what depresses each subtype's input at its own frequency - so the deficit is presynaptic and frequency-selective rather than a loss of inhibitory cells.", "interpretationLimit": "Inferred from stimulus-response curves, paired-pulse ratios and short-term plasticity rather than measured directly, in slices from oligomer-injected mice. No release probability value, and nothing relates this to interneuron loss, which the multiregion atlas reports separately as regional depletion.", "evidence": [ "L191" ] }, { "axis": "Vulnerability and subtype, regionally", "whatToMeasure": "Which inhibitory subtype in which region, since inhibitory populations are depleted in specific regions rather than globally and at least one population does not fit the canonical subclasses.", "interpretationLimit": "Post-mortem and cross-sectional, so depletion is prevalence difference rather than measured loss, with the same caution the haematopoietic row established about classifications recovered from tissue. No human interneuron count, density or subtype proportion in any environment.", "evidence": [ "A02" ] } ], "records": { "A02": { "id": "A02", "year": 2024, "topic": "Multiregion atlas", "title": "Single-cell multiregion dissection of Alzheimer’s disease", "url": "https://www.nature.com/articles/s41586-024-07606-7", "studyType": "Single-cell transcriptomic atlas of six brain regions, 1.3 million cells from 283 post-mortem samples across 48 individuals with and without Alzheimer's disease, Nature 632(8026):858-868", "diseaseContext": "Alzheimer's", "useInModel": "The regional axis, at a resolution that has consequences for how this atlas is structured. Six regions, 1.3 million cells, 283 samples, 48 individuals - and 76 cell types identified, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from the canonical inhibitory subclasses. Vulnerable excitatory and inhibitory populations were depleted in specific brain regions rather than globally, with evidence implicating Reelin signalling in modulating that vulnerability, and region-specific as well as cell-type-specific gene modules were altered in disease. Two things matter beyond the atlas's own use. Seventy-six cell types in one disease across six regions approaches the granularity of this inventory's entire 110 families across the thirteen environments carried in measurements.json, and the region-specific subtypes cannot be expressed by a flat family list at all - a family here is one row whether or not it is three different cells in three regions. And the thalamus-unique inhibitory population lands on an independent finding the atlas already holds: progranulin deficiency drives complement-mediated pruning that preferentially eliminates inhibitory synapses in the ventral thalamus (F05). Two unrelated lines converging on thalamic inhibitory neurons. The study also supplies something the atlas has nowhere else - a resilience programme, astrocytic, tying choline metabolism and polyamine biosynthesis to preserved cognitive function late in life.", "limit": "Post-mortem and cross-sectional, so regional progression is reconstructed rather than observed and the vulnerability claims are depletion in prevalence rather than measured loss over time. Six regions of the aged human brain, 48 individuals, with per-region and per-type numbers necessarily smaller than the headline cell count. The Reelin and resilience findings are associations from module discovery, and the resilience programme is correlated with preserved cognition rather than shown to cause it.", "provenance": "Abstract read in full; region, cell, sample and individual counts, the 76 cell types, the thalamic population, the regional depletion, Reelin and the astrocyte resilience programme as reported", "quantitativeExtraction": "extracted" }, "L190": { "id": "L190", "year": 2012, "topic": "Circuit inhibition", "title": "Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model", "url": "https://doi.org/10.1016/j.cell.2012.02.046", "studyType": "Electroencephalographic and oscillatory analysis in human amyloid precursor protein transgenic mice, with channel subunit measurement in mouse and human brain and transgenic restoration, Cell 149(3):708-721", "diseaseContext": "Alzheimer's", "useInModel": "Answers the question the excitatory row left open, and answers it from the other side of the circuit. That row recorded subclinical epileptiform discharge in a pooled 18.3 percent of Alzheimer patients and had no mechanism for it. Here the chain is complete: amyloid precursor protein transgenic mice showed spontaneous epileptiform discharges indicating network hypersynchrony, occurring primarily during reduced gamma oscillatory activity; gamma is generated by parvalbumin interneurons; those mice and Alzheimer patients both had decreased levels of Nav1.1, the interneuron-specific and parvalbumin-predominant sodium channel subunit; and restoring Nav1.1 in the mice increased inhibitory synaptic activity and gamma oscillations while reducing hypersynchrony, memory deficits and premature mortality. So the excitatory overactivity the atlas measured is an inhibitory failure, the molecular step is confirmed in human brain, and the rescue reaches an endpoint - mortality - that almost no mechanistic study in this atlas reaches.", "limit": "The causal chain is established in one transgenic model that simulates aspects of the disease rather than reproducing it, and the rescue is transgenic restoration rather than a therapeutic intervention. The human contribution is a decreased channel level in patient brain - an association at one timepoint, not a demonstration that the decrease causes the human discharge the excitatory row records. Premature mortality in a transgenic mouse line is not a clinical endpoint. The authors themselves say possibly in Alzheimer's disease for the human extension.", "provenance": "Abstract read in full; the epileptiform discharges and their association with reduced gamma, the attribution of gamma to parvalbumin cells, the decreased channel subunit in both mice and patients, and every element of the restoration phenotype including premature mortality as reported, with the authors' own hedge on human relevance kept", "quantitativeExtraction": "extracted" }, "L191": { "id": "L191", "year": 2020, "topic": "Circuit inhibition", "title": "Dissociation of somatostatin and parvalbumin interneurons circuit dysfunctions underlying hippocampal theta and gamma oscillations impaired by amyloid beta oligomers in vivo", "url": "https://doi.org/10.1007/s00429-020-02044-3", "studyType": "In vivo multi-electrode recording with optogenetic activation of each interneuron subtype in oligomer-injected subtype-Cre mice, plus whole-cell voltage clamp, stimulus-response, paired-pulse and short-term plasticity analysis ex vivo, Brain Structure and Function 225(3):935-954", "diseaseContext": "Alzheimer's", "useInModel": "Establishes that inhibition is not one variable, with an unusual degree of specificity. Amyloid beta oligomers impaired both hippocampal theta and gamma oscillations, and the two deficits dissociate by interneuron subtype: optogenetic activation of somatostatin interneurons selectively restored theta and of parvalbumin interneurons selectively restored gamma, each resynchronising pyramidal cell spikes and each resynchronising its own subtype's spike phase relative to its own rhythm. Ex vivo, activating each subtype enhanced spontaneous inhibitory currents selectively at the corresponding frequency. The mechanism is presynaptic: the oligomers increased the initial probability of GABA release, which depresses each subtype's input to the pyramidal cell selectively at its own frequency. For a simulation that means a single inhibitory tone cannot represent this - there are at least two inhibitory channels, resolved by subtype and by frequency, failing independently through a shared presynaptic mechanism. It also means the useful intervention is frequency-specific, which is why entraining one band is a coherent idea rather than a blunt one.", "limit": "Acute oligomer injection in mice, which models exposure rather than the disease's course, and optogenetic activation establishes sufficiency of each subtype to restore its rhythm rather than showing that subtype loss causes the deficit. Hippocampus only, and two subtypes - the atlas's own multiregion record identifies an inhibitory population distinct from the canonical subclasses, so two channels may be an undercount. The presynaptic release-probability mechanism is inferred from paired-pulse and short-term plasticity measures. No human data.", "provenance": "Abstract read in full; the dual oscillatory impairment, the subtype-to-frequency assignment in both directions, the resynchronisation of pyramidal and interneuron spiking, the frequency-selective current enhancement, and the increased initial release probability as the inferred presynaptic mechanism as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I058", "name": "Spinal and bulbar motor neurons", "category": "Neural", "whereToCheck": "ALS module", "states": [ "Subtype", "denervation", "degeneration" ], "behaviors": [ "Axonal transport", "excitability", "NMJ output" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "axonal-vivo-intermediate", "axonal-vivo-fast", "axonal-vitro-intermediate", "axonal-vitro-fast" ], "priorResearch": { "path": "simulation/data/profiles/spinal-and-bulbar-motor-neurons.json", "summary": "The cells whose loss is ALS, and the row where the atlas's accumulated evidence for that environment comes together. The central finding is negative and unusually strong: expressing mutant SOD1 in primary spinal motor neurons did not make them degenerate, while astrocytes expressing the same mutant killed them through soluble factors by a Bax-dependent mechanism - and of five cell types tested as sources only astrocytes were toxic, while GABAergic neurons, dorsal root ganglion neurons and interneurons were not killed (S01). Astrocytes from sporadic patients, who are over 90 percent of cases, are similarly toxic to those from familial patients, and knocking down SOD1 attenuates it (S02). The organising variable is a vulnerability gradient with intrinsic and extrinsic determinants (L192), and the classically spared oculomotor population turns out to be measurably impaired rather than spared (L193).", "stateAxes": [ { "axis": "Subtype, as a vulnerability gradient rather than a class", "whatToMeasure": "Which motor neuron type and functional group, since susceptibility is graded and determined by both intrinsic and extrinsic factors - and since the population conventionally called spared is impaired on measurement, so the gradient has no zero. The gradient has an arm of each kind in this atlas: the extrinsic one is astrocyte-derived toxicity selective for motor neurons, held on the axis below, and the intrinsic one is cryptic exon inclusion depleting UNC13A and STMN2 after TDP-43 loss, where the UNC13A lesion is additionally modified by common risk alleles at the cryptic exon itself.", "interpretationLimit": "The gradient comes from a review that is explicit that the reasons for differential susceptibility remain unclear, with no ranking, proportion or timing attached. The oculomotor impairment is a group difference in 46 patients at one timepoint, and saccade performance depends on cortical and cerebellar control as well as these neurons, so it does not localise to this family. The cryptic exon records are cell lines, iPSC-derived neurons and post-mortem tissue rather than graded motor neuron populations, so they supply a mechanism that could differ by subtype without anyone having measured whether it does - which is the gradient's whole question.", "evidence": [ "L192", "L193", "F02", "F03", "F04" ] }, { "axis": "Degeneration, driven from outside the cell", "whatToMeasure": "The astrocytic contribution rather than the neuron's own genotype, because mutant expression in the neuron produced no degeneration while astrocytic expression killed it - and because astrocytes from sporadic patients are similarly toxic with SOD1 knockdown attenuating it.", "interpretationLimit": "Culture systems throughout, rodent in the first case and post-mortem-derived human cells in the second, so the in vivo magnitude is unknown and the geometry of the astrocyte-neuron relationship is absent. The toxic factor is inferred from medium transfer and unidentified. Similarly toxic and significantly attenuated are both comparisons without magnitudes.", "evidence": [ "S01", "S02" ] }, { "axis": "Denervation, with a timeline already held", "whatToMeasure": "End-plate occupancy before motor neuron counts, since the atlas's staged record shows 40 percent of end-plates denervated at 47 days with no ventral root or cell body loss, 60 percent of ventral root axons gone by 80 days with motor neurons still present, and motor neuron loss only well underway by 100.", "interpretationLimit": "One transgenic model at those ages with a single human autopsy, and the atlas holds a TDP-43 model in which denervation and motor neuron loss were concurrent - so the ordering is genotype-dependent and the percentages are not human stage boundaries.", "evidence": [ "L112", "L183" ] }, { "axis": "Axonal transport, excitability and NMJ output", "whatToMeasure": "The three behaviours the inventory names, of which excitability is served only from the cortex in a neighbouring row and the other two not at all.", "interpretationLimit": "Axonal transport was unmeasured anywhere in the atlas when this row was written and is now held in the cytoskeleton row, in vivo and genotype-resolved, as a presence and a timing rather than a rate (L232, L233). No neuromuscular output measurement either - the junction row's evidence is morphological. So two of three named behaviours have no record. What is held for excitability is cortical and sensory rather than spinal: a broadened hand representation with a survival threshold attached, measured in the cortex of the same patients, which constrains the upper motor neuron and says nothing about these cells' own firing.", "evidence": [ "L189", "L232", "L233" ] } ], "records": { "F02": { "id": "F02", "year": 2022, "topic": "RNA processing", "title": "TDP-43 represses cryptic exon inclusion in the FTD–ALS gene UNC13A", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8891019/", "studyType": "Human brain, neuronal cell lines and iPSC-derived motor neurons with risk-variant testing, Nature 603(7899):124-130", "diseaseContext": "ALS / FTD", "useInModel": "Connects the strongest genetic risk factor for these diseases to the loss of this family's nuclear function, and does it through a splicing event. A major job of TDP-43 is repressing cryptic exon inclusion. Losing it from the nucleus - in human brain, in neuronal lines and in iPSC-derived motor neurons - caused a cryptic exon to be included in UNC13A mRNA and reduced UNC13A protein. The variants most strongly associated with risk in genome-wide association studies sit in the intron that harbours that cryptic exon, and they increase its splicing specifically in the face of TDP-43 dysfunction. The structure of that statement is what matters for a model: the risk genotype does almost nothing on its own and acts only once the protein has failed, so genotype and pathological state multiply rather than add.", "limit": "TDP-43-pathology context, so it does not apply to molecular subtypes of ALS or FTD without TDP-43 mislocalisation. Human tissue work is cross-sectional and the cell models are depletion rather than disease, so no rate of cryptic inclusion per unit of nuclear loss is established. UNC13A protein reduction is measured in models, not quantified in patients.", "provenance": "Abstract read in full; the cryptic exon, the protein reduction and the variant interaction as reported", "quantitativeExtraction": "extracted" }, "F03": { "id": "F03", "year": 2022, "topic": "RNA processing", "title": "TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8891020/", "studyType": "Independent companion study in cultured cells and in patient brain and spinal cord, Nature 603(7899):131-137", "diseaseContext": "ALS / FTD", "useInModel": "The same finding reached independently and published alongside, which is why the atlas holds both. TDP-43 depletion induced robust inclusion of a cryptic exon in UNC13A, producing nonsense-mediated decay and loss of the protein. Two common intronic polymorphisms strongly associated with risk overlap TDP-43 binding sites, and they potentiated cryptic exon inclusion both in cultured cells and in brain and spinal cord from patients. The mechanism named here is more specific than in the companion paper - the variants sit on the binding sites themselves, so the risk allele weakens the very interaction that represses the exon. Two groups, two systems, one answer: this is the most independently corroborated mechanism in the neurodegenerative half of this atlas.", "limit": "Depletion models for the causal work with patient tissue used as confirmation, so the direction is secure and the magnitude in a patient is not. Association plus experimental potentiation does not give a patient-level rate, and UNC13A is one of hundreds of transcripts affected, so its contribution to the phenotype is not isolated.", "provenance": "Abstract read in full; the decay mechanism, the binding-site overlap and the patient-tissue confirmation as reported", "quantitativeExtraction": "extracted" }, "F04": { "id": "F04", "year": 2023, "topic": "RNA processing and rescue", "title": "Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies.", "url": "https://pubmed.ncbi.nlm.nih.gov/36927019/", "studyType": "Mechanistic work in TDP-43-deficient human motor neurons plus antisense oligonucleotide treatment in gene-edited mice, Science 379(6637):1140-1149", "diseaseContext": "ALS / FTD", "useInModel": "The only repair in this category, and it works by going around the broken node rather than fixing it. TDP-43 binding to a GU-rich region sterically blocks recognition of a cryptic 3' splice site in STMN2 pre-mRNA; losing it produces cryptic splicing and polyadenylation of the transcript encoding stathmin-2, a protein required for axonal regeneration. Targeting dCasRx or antisense oligonucleotides to that site suppressed the cryptic splicing and restored both axonal regeneration and stathmin-2-dependent lysosome trafficking in TDP-43-deficient human motor neurons. In mice gene-edited to carry the human cryptic sequences, injecting an oligonucleotide into cerebrospinal fluid corrected the misprocessing and restored stathmin-2 levels - and the paper states the crucial qualifier: independently of TDP-43 binding. The upstream defect was left in place and a specific downstream function was recovered. That is a different therapeutic logic from every other intervention in this category, all of which engaged their target and failed to help.", "limit": "Preclinical throughout. Restored axonal regeneration and lysosome trafficking in cultured human neurons and restored protein levels in a humanised mouse are not clinical functional recovery, and the mouse required gene editing to contain the human cryptic sequences at all. It repairs one transcript of the hundreds affected by TDP-43 loss, so it tests whether that transcript matters rather than treating the proteinopathy.", "provenance": "Abstract read in full; the steric mechanism, both rescue readouts and the TDP-43-independence of the correction as reported", "quantitativeExtraction": "extracted" }, "L112": { "id": "L112", "year": 2004, "topic": "Non-cell-autonomous toxicity", "title": "Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man", "url": "https://doi.org/10.1016/j.expneurol.2003.10.004", "studyType": "Spatiotemporal quantification at neuromuscular junctions, ventral roots and spinal cord across ages in SOD1-G93A mice, with one human autopsy, Exp Neurol 185(2):232-240", "diseaseContext": "ALS", "useInModel": "A staged timeline with percentages, which this atlas has almost nowhere else, and it runs the opposite way to the obvious model. In SOD1-G93A mice - clinically weak at 80 days and dead at 131 plus or minus 5 - 40% of end-plates were already denervated at 47 days with no evidence of ventral root or cell body loss; at 80 days 60% of ventral root axons were lost with still no loss of motor neurons; and motor neuron loss was only well underway by 100 days. The disease begins at the distal axon and proceeds dying back. Two further details carry weight. Microglial and astrocytic activation around motor neurons was not identified until after distal axon degeneration had begun - so in this environment glia are downstream, which is the opposite temporal position to the complement-at-synapses-before-plaques finding the atlas records for Alzheimer's disease. And the single human autopsy showed denervation and reinnervation changes in muscle alongside normal-appearing motor neurons, which is the same ordering and also evidence that repair was active and losing. A model that starts this disease at the motor neuron has the causality backwards.", "limit": "One transgenic mouse model, and the human evidence is a single sporadic case who died unexpectedly - informative precisely because death was not from end-stage disease, and a single case. The percentages are for this model at these ages and should not be carried as human stage boundaries. Absence of cell body loss at a timepoint is a negative on the measurements made, not proof that nothing had changed in the cell body.", "provenance": "Abstract read in full; all four timepoints with their percentages, the glial timing, and the human autopsy findings as reported", "quantitativeExtraction": "extracted" }, "L183": { "id": "L183", "year": 2023, "topic": "Pre/post-synaptic structure", "title": "Neuromuscular junction denervation and terminal Schwann cell loss in the hTDP-43 overexpression mouse model of amyotrophic lateral sclerosis", "url": "https://doi.org/10.1111/nan.12925", "studyType": "Time-course immunohistochemistry with NMJ-morph quantification of motor neuron number, denervation status and terminal Schwann cell morphology across muscle groups in Thy1-hTDP-43 mice, Neuropathology and Applied Neurobiology 49(5):e12925", "diseaseContext": "ALS", "useInModel": "Serves the neuromuscular half of this row and corrects a generalisation the atlas would otherwise have made. Denervation was pronounced in hindlimb muscles, mild in cranial muscles and absent in forelimb and trunk - so one disease in one animal affects junctions qualitatively differently by location, and an environment treated as homogeneous averages over regions that differ in kind rather than degree. The temporal point matters more. Dying-back pathology, where denervation precedes motor neuron loss, is established for SOD1-dependent models, and the authors note evidence in other genetic forms is limited; in this TDP-43 model denervation followed the same time course as motor neuron loss rather than preceding it. So the atlas should not carry denervation as an early event in ALS generally - the ordering is model-dependent and genotype-dependent, which is a finer version of the caution already recorded about microglia sitting at opposite ends of the causal chain in Alzheimer's and ALS. Terminal Schwann cells were lost from hindlimb junctions in direct correlation with denervation status, which ties this structure to the peripheral nerve row.", "limit": "A severe model with a median survival of 21 days, driven by neuronal overexpression of wild-type human TDP-43 rather than by a patient mutation, so the compressed time course may itself explain why denervation and neuron loss coincide. Mouse, with pathology assessed by immunohistochemistry and morphological quantification rather than function - no transmission measurement at any junction. The region-specific pattern is a property of this model's expression distribution as much as of the disease. Terminal Schwann cell loss correlates with denervation without the direction being established.", "provenance": "Abstract read in full; the regional denervation pattern across four muscle groups, the restriction to motor nerve terminals, the stated concurrence of denervation with motor neuron loss, the median survival, the terminal Schwann cell correlation, and the authors' note on the limits of dying-back evidence outside SOD1 models as reported", "quantitativeExtraction": "extracted" }, "L189": { "id": "L189", "year": 2026, "topic": "Electrophysiology", "title": "Sensory Cortical Hyperexcitability in Amyotrophic Lateral Sclerosis Involves a Broad Hand Representation Within the Primary Somatosensory Cortex", "url": "https://doi.org/10.1002/mus.70371", "studyType": "Retrospective study of 99 patients with sporadic ALS and 42 healthy controls, with sensory nerve action potentials and somatosensory evoked potentials from median and ulnar stimulation, followed to death or tracheostomy with Kaplan-Meier and Cox analyses, Muscle & Nerve 74(6):1246-1255", "diseaseContext": "ALS", "useInModel": "Locates a functional abnormality in the cortex with the periphery as its own control, and attaches a survival threshold to it. Sensory nerve action potential amplitudes did not differ between patients and controls, while cortical evoked potential amplitudes were larger for both median and ulnar stimulation - so the abnormality is cortical and not a peripheral artefact, which the unchanged peripheral recordings establish directly. Patients with ulnar cortical amplitudes at or above 4.89 microvolts had significantly shorter survival, and increased amplitude was an independent predictor of shorter survival for both nerves on multivariate analysis. For this atlas that matters in two ways. It is a functional measurement with a threshold and an outcome, which almost nothing here has. And it sits against the atlas's own record that ALS is a distal axonopathy proceeding dying-back from the neuromuscular junction: distal degeneration does not mean the cortex is spared, since the cortex is measurably hyperexcitable while peripheral sensory conduction is normal. The disease is doing different things at the two ends.", "limit": "Retrospective, single-centre by implication, and sporadic ALS only - so the threshold is derived in this cohort rather than validated in another. Sensory rather than motor cortex, which makes it an unexpected place to find a prognostic signal and means it is not a measurement of the motor neurons the disease kills. Evoked potential amplitude is a population response rather than a property of any cell, so it cannot be assigned to the excitatory neurons this row is about without assumption. The survival association is from one cohort followed to death or tracheostomy.", "provenance": "Abstract read in full; cohort and control numbers, the unchanged peripheral amplitudes, the enlarged cortical amplitudes for both nerves, the correlation between nerves, the amplitude threshold with its log-rank p value, and the multivariate independence as reported", "quantitativeExtraction": "extracted" }, "L192": { "id": "L192", "year": 2024, "topic": "Subtype", "title": "Selective vulnerability of motor neuron types and functional groups to degeneration in amyotrophic lateral sclerosis: review of the neurobiological mechanisms and functional correlates", "url": "https://doi.org/10.1007/s00429-023-02728-6", "studyType": "Review of neurobiological mechanisms, neurochemical profiles and morpho-functional characteristics across motor neuron groups and motor unit types, Brain Structure and Function 229(1):1-14", "diseaseContext": "ALS", "useInModel": "Names the organising variable for this row: not whether motor neurons degenerate but which ones, and in what order. The review's framing is that despite extensive research it remains unclear why some motor neurons are especially susceptible while others are affected less or spared, and it surveys the intrinsic and extrinsic factors behind that vulnerability gradient, with consequences for how the disease manifests, progresses and is prognosed. That pairs directly with the two halves of evidence this atlas already holds for the family: the extrinsic factor is astrocyte-derived soluble toxicity selective for motor neurons, and the intrinsic factors include cryptic exon inclusion depleting specific proteins after TDP-43 loss. So the gradient is the thing to model and the atlas has one candidate of each kind feeding it. It also means a single motor neuron compartment is the wrong representation - the row's subject is a ranked population, and vulnerability is a property of subtype and functional group rather than of the cell class.", "limit": "A review, so it supplies the concept and no values - no vulnerability ranking with numbers, no proportion of each subtype lost, and no timing. It is explicit that the reasons for differential susceptibility remain unclear, so this record establishes what the question is rather than answering it. Preclinical and clinical studies are surveyed together.", "provenance": "Abstract read in full; the stated persistence of the question, the categories surveyed, the explicit division into cell-autonomous and extrinsic factors, and the stated relevance to manifestation, course and prognosis as reported", "quantitativeExtraction": "extracted" }, "L193": { "id": "L193", "year": 2025, "topic": "Subtype", "title": "The Impact of Bulbar and Upper Motor Neuron Involvement on Oculomotor Movement in Amyotrophic Lateral Sclerosis", "url": "https://doi.org/10.1002/brb3.70906", "studyType": "Cross-sectional study of 46 patients meeting the Gold Coast criteria against 23 age- and education-matched controls, with cognitive testing and instrumented eye movement measurement, Brain and Behavior 15:e70906", "diseaseContext": "ALS", "useInModel": "Shows that the resistant population is resistant rather than spared, which turns a partition into a gradient. Oculomotor neurons are the classical example of motor neurons that survive in this disease, and oculomotor function was measurably impaired: anti-saccade reaction times of 357.48 plus or minus 61.28 milliseconds against 316.10 plus or minus 52.70 in controls, and predictive saccade accuracy of 86.77 plus or minus 19.17 percent against 99.36 plus or minus 2.22. Patients with bulbar involvement were worse again, at 77.53 against 96.01 percent accuracy, while spinal-onset and bulbar-onset patients did not differ from each other on these measures. Two uses. The vulnerability gradient has no zero - a population described as spared is impaired on measurement, which is what a gradient predicts and a partition does not. And the dissociation between onset site and bulbar involvement is a fourth instance of a drawn environment splitting by something other than its label.", "limit": "Forty-six patients, cross-sectional, with eye movement measured by one instrumented system - so these are group differences at a single timepoint rather than a trajectory, and no relationship to oculomotor neuron counts is established. Saccade performance depends on cortical and cerebellar control as well as on the motor neurons, so impaired performance does not localise to this family: the paper itself frames oculomotor dysfunction as reflecting broader multisystem involvement. Controls were matched for age and education only.", "provenance": "Abstract read in full; cohort and control numbers, both anti-saccade and predictive saccade comparisons with standard deviations and p values, the bulbar-involvement comparison, and the absence of a spinal-versus-bulbar-onset difference as reported", "quantitativeExtraction": "extracted" }, "L232": { "id": "L232", "year": 2020, "topic": "Intracellular transport", "title": "Mice Carrying ALS Mutant TDP-43, but Not Mutant FUS, Display In Vivo Defects in Axonal Transport of Signaling Endosomes", "url": "https://doi.org/10.1016/j.celrep.2020.02.078", "studyType": "In vivo imaging of retrogradely transported neurotrophin-containing signalling endosomes in nerve axons of two ALS mouse models carrying mutations in different RNA processing genes, with timed comparison against pathology and symptom onset, Cell Reports 30(11):3655-3662.e2", "diseaseContext": "ALS", "useInModel": "Fills the gap the motor neuron row named as its largest - no axonal transport measurement anywhere in the atlas - and it arrives as a double dissociation rather than a single number. TDP-43 M337V mice, which show neuromuscular pathology without overt motor neuron loss, had transport perturbations manifesting between 1.5 and 3 months, before motor symptom onset. Fus delta-14 heterozygous mice, despite 20 percent motor neuron loss, had largely unaffected transport. So transport failure occurs without cell loss in one genotype and cell loss occurs without transport failure in the other, which means impaired retrograde transport is neither necessary nor sufficient for motor neuron death. The authors' conclusion is that these deficits are not shared by all ALS-linked genes and that there are mechanistic distinctions between diseases caused by mutations in different RNA processing genes. Two uses. The atlas gains the behaviour it was missing, in vivo and timed relative to onset. And it gains a third axis on which the ALS environment splits by genotype, alongside the staged distal timeline and the concurrent-loss model it already holds - with this one separating a mechanism from an outcome rather than reordering them.", "limit": "Two mouse models, no human measurement, and one cargo - neurotrophin-containing signalling endosomes moving retrogradely - so this is not axonal transport in general but one cargo in one direction. Perturbations and largely unaffected are reported without velocities, flux or pause frequencies extracted here, so the atlas gains a presence and a timing rather than a rate. The 1.5 to 3 month window is a mouse developmental interval and does not map onto human disease. Mutant overexpression models of two genes, and the dissociation rests on comparing two models with different constructs rather than on one manipulation.", "provenance": "Abstract read in full; the cargo and direction measured, the TDP-43 model's pathology without motor neuron loss and its 1.5 to 3 month window preceding onset, the Fus model's 20 percent motor neuron loss with largely unaffected transport, and the authors' conclusion about mechanistic distinctions as reported", "quantitativeExtraction": "extracted" }, "L233": { "id": "L233", "year": 2010, "topic": "Intracellular transport", "title": "Deficits in axonal transport precede ALS symptoms in vivo", "url": "https://doi.org/10.1073/pnas.1006869107", "studyType": "In vivo assay characterising axonal transport in single axons of the intact sciatic nerve in presymptomatic and early symptomatic SOD1-G93A mice, Proceedings of the National Academy of Sciences 107(47):20523-20528", "diseaseContext": "ALS", "useInModel": "The third genotype in this row's comparison, and the one that makes the ordering consistent. Using an assay that resolves transport in single axons within the intact sciatic nerve, clear deficits were present in presymptomatic mutant SOD1 mice and worsened at an early symptomatic stage - so impaired retrograde transport may be one of the earliest axonal pathologies in this model. Read with the companion record, the atlas now holds transport deficits appearing before symptoms in two genotypes, SOD1 and TDP-43, and absent in a third, FUS, which lost 20 percent of its motor neurons anyway. For this project that is the useful shape: a mechanism that is early where it occurs and dispensable where it does not. It also matters for the atlas's staged ALS timeline, which has distal end-plate denervation at 47 days preceding any cell body loss in this same SOD1 model - transport failure sits at or before that stage, which makes the distal-to-proximal ordering mechanistically plausible rather than merely observed.", "limit": "One mouse model, no human data, and retrograde transport in sciatic nerve axons - a peripheral readout for a disease the atlas also tracks in cortex and spinal cord. Clear deficits and worsens are reported without velocities or flux extracted here, so again a presence and a timing rather than a rate. Presymptomatic is defined relative to this model's own course. The authors frame the pathogenic importance as a possibility, and the companion record then shows it is not general across ALS genotypes.", "provenance": "Abstract read in full; the single-axon intact-nerve assay, the presence of deficits presymptomatically with worsening at early symptomatic stage, and the authors' hedged claim about earliest axonal pathology as reported", "quantitativeExtraction": "extracted" }, "S01": { "id": "S01", "year": 2007, "topic": "Non-cell-autonomous toxicity", "title": "Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons", "url": "https://doi.org/10.1038/nn1876", "studyType": "Mutant human SOD1 expressed separately in primary mouse spinal motor neurons and in rodent astrocytes, fibroblasts, microglia, cortical neurons and myocytes, with co-culture against primary, embryonic stem cell-derived and several non-motor neuron types, Nature Neuroscience 10(5):615-622", "diseaseContext": "ALS", "useInModel": "The strongest statement in this atlas that a disease gene in the dying cell is not enough. Expressing mutant SOD1 in primary spinal motor neurons did not provoke their degeneration. Astrocytes expressing the same mutant killed spinal primary and stem cell-derived motor neurons through soluble factors by a Bax-dependent mechanism. The selectivity runs both ways and is established by explicit negatives on both sides: of five cell types expressing the mutant, only astrocytes were overtly neurotoxic - not fibroblasts, microglia, cortical neurons or myocytes - and of the neuron types exposed, spinal GABAergic neurons, dorsal root ganglion neurons and stem cell-derived interneurons were not killed. So the lever for this family's degeneration sits in another family, the toxic agent is soluble and unidentified, and the death pathway is named. For a simulation that means a cell-autonomous representation of this disease cannot reproduce it, however faithfully the mutant is expressed in the right cell.", "limit": "Rodent cells and a familial SOD1 model, which accounts for a small fraction of ALS - the companion record is what extends the principle to sporadic disease. The toxic factor is inferred from conditioned-medium transfer and is not identified, so the atlas holds a mechanism with an unnamed mediator and therefore no concentration, range or target. Culture rather than tissue, so the geometry of the astrocyte-neuron relationship is absent. The negatives are for overt neurotoxicity in these assays rather than proof those cell types contribute nothing in vivo.", "provenance": "Abstract read in full, replacing a one-line screening note. The absence of degeneration from motor-neuron-autonomous expression, the astrocyte killing with its soluble and Bax-dependent character, all four non-toxic source cell types and all three spared neuron types as reported", "quantitativeExtraction": "extracted" }, "S02": { "id": "S02", "year": 2011, "topic": "Non-cell-autonomous toxicity", "title": "Astrocytes from familial and sporadic ALS patients are toxic to motor neurons.", "url": "https://doi.org/10.1038/nbt.1957", "studyType": "Astrocytes generated from post-mortem tissue of familial and sporadic ALS patients, co-cultured with motor neurons, with SOD1 knockdown, Nature Biotechnology 29(9):824-828", "diseaseContext": "ALS", "useInModel": "Answers the objection the atlas has written into almost every SOD1 record, and does it with a target attached. The paper states the problem itself: the astrocyte hypothesis derives from rodent models of dominant SOD1 mutations, which account for under 2 percent of ALS cases, while sporadic disease affects over 90 percent. Astrocytes derived from post-mortem tissue of both patient groups proved similarly toxic to motor neurons - so non-cell-autonomous toxicity is a feature of sporadic disease and not an artefact of a familial model. And knocking down SOD1 significantly attenuated the toxicity, which makes the wild-type protein a viable target in sporadic ALS where no mutation exists. For this atlas that matters twice: it licenses the transfer the limits have been refusing, and it is a rare case where a target identified in a rare genetic subtype turns out to apply to the common form.", "limit": "Astrocytes derived from post-mortem tissue and assayed in culture, so the toxicity is a property of cells taken out of the brain and the in vivo magnitude is unknown. Similarly toxic is a comparison between patient groups rather than a quantified effect, and no toxicity value, dose-response or survival figure is extracted here. Knockdown attenuation is significant without a magnitude given. The sporadic group is heterogeneous by definition, so a common mechanism across it is the claim being made rather than one established per patient.", "provenance": "Abstract read in full, replacing a one-line screening note. The stated proportions for familial and sporadic disease, the equivalence of toxicity between patient groups, and the attenuation by SOD1 knockdown as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "axonal-vivo-intermediate", "axonal-vivo-fast", "axonal-vitro-intermediate", "axonal-vitro-fast" ] }, { "id": "I059", "name": "Astrocytes", "category": "Neural", "whereToCheck": "CNS parenchyma and vascular endfeet", "states": [ "Region-specific", "reactive", "metabolic states" ], "behaviors": [ "Glutamate uptake", "ion support", "barrier contact", "inflammatory signals" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-123" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-123" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-123" ], "priorResearch": { "path": "simulation/data/profiles/astrocytes.json", "summary": "The family the preceding row named as its lever, and the one where the atlas's marker problem is at its sharpest. Four of the inventory's behaviours, and three of them now have something. Glutamate uptake: the astroglial transporter GLT-1 falls 71 percent in ALS motor cortex and spinal cord, 90 percent in about a quarter of specimens, while the other astroglial transporter GLAST and the identity marker GFAP do not change (L194). Inflammatory signals: microglial Il-1-alpha, TNF and C1q together induce a neurotoxic reactive state, reported necessary and sufficient, which withdraws four supportive functions and kills neurons and oligodendrocytes (L195) - in a category the field's own consensus statement has since advised against naming (L196). Barrier contact: perivascular AQP4 localisation tracks Alzheimer's independently of age, while total AQP4 tracks age (L197). Ion support has nothing. And the region-specific state the inventory asks for is largely absent between forebrain regions while being present between layers of one (L198).", "stateAxes": [ { "axis": "Reactive, which the field says is not a category", "whatToMeasure": "Multiple molecular and functional parameters together, preferably in vivo, with multivariate statistics and demonstrated impact on pathological hallmarks - because the consensus position is that binary divisions into good versus bad, neurotoxic versus neuroprotective or A1 versus A2 are the wrong shape, and that whether fixed categories exist is itself unsettled. The one mechanism the atlas holds for inducing reactivity is nonetheless specific: three microglial cytokines, reported necessary and sufficient, withdrawing four supportive functions and conferring the ability to kill neurons and oligodendrocytes.", "interpretationLimit": "The mechanism and the guidance are in tension by design: the paper that established the mechanism used the category the consensus advises against, and shares authors with it. So the atlas carries the mechanism and drops the label, which means this axis has a route into a state it cannot name. The mechanism is mouse with human tissue entering only as an abundance survey, the three cytokines are necessary and sufficient together without individual contributions here, and no concentration or exposure time is held. The consensus supplies no replacement parameter set, so it rules out a representation without specifying one.", "evidence": [ "L195", "L196" ] }, { "axis": "Glutamate uptake, subtype-resolved", "whatToMeasure": "GLT-1 specifically rather than astroglial glutamate transport in general, since GLT-1 fell 71 percent in ALS motor cortex and spinal cord - 90 percent in about a quarter of motor cortex specimens - while GLAST, the other astroglial transporter in the same cells, showed no appreciable change and the neuronal transporter EAAC1 fell only 20 percent, attributed to motor neuron loss.", "interpretationLimit": "Immunoreactive protein, so this is transporter abundance and not transport rate: the atlas has a percentage and no uptake velocity, Km or Vmax, and therefore cannot compute a clearance. End-stage sporadic post-mortem tissue, so whether the loss drives degeneration or follows it is not addressed by this design. One environment only - no glutamate uptake measurement exists for this family in Alzheimer's or frontotemporal dementia.", "evidence": [ "L194" ] }, { "axis": "Barrier contact, as a location rather than an amount", "whatToMeasure": "Where AQP4 sits rather than how much there is. Total expression tracked advancing age across all individuals, while perivascular localisation tracked Alzheimer's status independently of age, at a reported odds ratio of 11.7 per 10 percent of localisation, was preserved in the cognitively intact over 85, and when controlled for age went with amyloid burden and Braak stage.", "interpretationLimit": "Post-mortem frontal cortex at one timepoint, so the direction is not established and polarisation loss could precede or follow amyloid accumulation. The variances explained are small, 0.14 to 0.17, and the localisation measure is defined by the study's own image analysis rather than on an absolute scale. The glymphatic clearance function invoked to explain the association is not measured. Nothing here connects to the atlas's own barrier records for this environment, which are endothelial and pericyte-centred.", "evidence": [ "L197" ] }, { "axis": "Region-specific, and weaker than the row assumes", "whatToMeasure": "Not the region. Across four brain regions in healthy mouse the astrocyte proteomes were highly similar, with only subtle differences between hippocampus, cortex and striatum; the cerebellar proteome stood out, with calcium signalling proteins; and within the hippocampus single-astrocyte analysis across layers showed distinct subregional heterogeneity. So the layer is the division worth representing and the forebrain region is not.", "interpretationLimit": "Healthy mouse, so whether regional differences open up in disease is untouched - and the reactive states this row otherwise concerns are absent from it. Newly synthesised protein over a labelling window rather than the standing proteome, so long-lived proteins are underrepresented by design. High similarity is the authors' characterisation with no distance metric extracted, and the subregional finding rests on per-cell labelling intensity rather than layer-resolved proteomes.", "evidence": [ "L198" ] }, { "axis": "Ion support and metabolic states", "whatToMeasure": "Potassium buffering, which the inventory names, and the metabolic states it also names - neither of which any record in this atlas measures for this family.", "interpretationLimit": "No measurement at all. Kir4.1 appears in this profile's panel because the inventory asks for ion support, and nothing here reports it in any environment. For metabolic support the atlas holds a lactate shuttle, and it is oligodendroglial rather than astrocytic - the neighbouring row's record, where transporter-mediated support of axons is measured and found reduced in ALS patients. So this family's best-known metabolic function is represented in the atlas by another family's version of it.", "evidence": [ "L186" ] } ], "records": { "L186": { "id": "L186", "year": 2012, "topic": "Support", "title": "Oligodendroglia metabolically support axons and contribute to neurodegeneration", "url": "https://doi.org/10.1038/nature11314", "studyType": "Transporter localisation with disruption in animal and cell culture models, plus comparison of patient and mouse model tissue, Nature 487(7408):443-448", "diseaseContext": "ALS; healthy reference", "useInModel": "Says this structure's most consequential function is not structural, which is the opposite of what the row's name implies. Oligodendroglia support axon survival and function through mechanisms independent of myelination; lactate is transported exclusively by monocarboxylate transporters; the most abundant such transporter in the central nervous system is highly enriched in oligodendroglia; and disrupting it produces axon damage and neuron loss in animal and cell culture models. The same transporter is reduced in patients with ALS and in mouse models of it. Two consequences. A model that represents myelin as insulation will miss the mechanism whose disruption actually kills axons - the supporting cell is feeding the axon, and that is separable from wrapping it. And this is the atlas's fourth metabolic exchange term, after oxygen, arginine and lipid: a metabolite handed from one cell to another across a short distance, sharing the mathematics the project already owns, and like the other three it has no flux.", "limit": "Disruption experiments are animal and cell culture; the human evidence is reduced transporter levels in patient tissue, which is an association rather than a demonstration that the reduction causes the disease. No transfer rate, lactate concentration or gradient between oligodendrocyte and axon is given, so the exchange is established and unquantified - the same position as the atlas's other three metabolic exchange terms. Lactate is one metabolite and the mechanisms independent of myelination may include others not addressed here.", "provenance": "Abstract read in full; the independence of support from myelination, the exclusivity of monocarboxylate transport for lactate, the transporter's enrichment in oligodendroglia, the disruption phenotypes in both model types, and its reduction in patients and mouse models as reported", "quantitativeExtraction": "extracted" }, "L194": { "id": "L194", "year": 1995, "topic": "Glutamate uptake", "title": "Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis", "url": "https://doi.org/10.1002/ana.410380114", "studyType": "Immunoblot and immunocytochemistry for three glutamate transporter subtypes with subtype-specific C-terminal antipeptide antibodies, across brain regions of ALS patients and age- and postmortem-delay-matched controls, Annals of Neurology 38(1):73-84", "diseaseContext": "ALS", "useInModel": "The atlas's first glutamate uptake measurement, and it is selective in a way that matters more than its size. GLT-1, the astroglial transporter, was decreased 71 percent in ALS motor cortex and also in spinal cord, with a dramatic 90 percent loss in roughly a quarter of motor cortex specimens. The other astroglial transporter, GLAST, showed no appreciable change. The neuronal transporter EAAC1 fell only 20 percent, which the authors attribute to loss of cortical motor neurons rather than to transporter downregulation. And glial fibrillary acidic protein, the marker used to identify and to call astrocytes reactive, was not changed. So this is not astrocyte loss and not generalised astrocyte failure: one transporter of two in the same cell collapses while the cell's identity marker holds steady. Three consequences for a simulation. Glutamate clearance is a parameter this family can now be given a number for in one environment. The loss is subtype-resolved, so a single uptake term is wrong. And a panel reading GFAP would register nothing at all while the function it is meant to report had fallen by three quarters.", "limit": "Post-mortem immunoreactive protein, so this is transporter abundance and not transport rate - no uptake velocity, Km or Vmax is measured, and the atlas therefore has a percentage rather than a flux. Sporadic ALS at end stage, so whether the loss causes degeneration or follows it is not addressed by this design; the authors offer the causal direction as a hypothesis supported by separate experimental models. Percentages are group comparisons against matched controls, with the quarter of specimens showing 90 percent loss reported as a subset rather than a defined subgroup. Antibody-based quantification across regions.", "provenance": "Abstract read in full; all four protein comparisons with their percentages, the subset of motor cortex specimens, the absence of change in GLAST and GFAP, and the authors' own reading of the EAAC1 change as reported", "quantitativeExtraction": "extracted" }, "L195": { "id": "L195", "year": 2017, "topic": "Reactive", "title": "Neurotoxic reactive astrocytes are induced by activated microglia", "url": "https://doi.org/10.1038/nature21029", "studyType": "Induction of a reactive astrocyte subtype by activated microglia with necessity and sufficiency testing of three secreted cytokines, functional assays for neuronal survival, outgrowth, synaptogenesis and phagocytosis, in vivo blockade after axotomy, and survey of human neurodegenerative tissue, Nature 541(7638):481-487", "diseaseContext": "Alzheimer's / ALS / FTD; Huntington's, Parkinson's and multiple sclerosis as surveyed", "useInModel": "Supplies the atlas's first named molecular route into astrocyte reactivity, and makes the ALS motor neuron story two hops long instead of one. Classically activated neuroinflammatory microglia induce a reactive astrocyte subtype by secreting Il-1-alpha, TNF and C1q, and those three cytokines together are reported as necessary and sufficient. The induced astrocytes lose four supportive functions at once - promoting neuronal survival, outgrowth, synaptogenesis and phagocytosis - and acquire the ability to kill neurons and oligodendrocytes. Death of axotomised CNS neurons in vivo was prevented when the formation of these astrocytes was blocked, which is a causal test rather than a correlation. They are reported as abundant in Alzheimer's, Huntington's and Parkinson's disease, ALS and multiple sclerosis. For this atlas the chain now reads microglia to astrocytes to motor neurons, with three named molecules on the first hop and the companion ALS work showing an unidentified soluble factor on the second - so the upstream inducers are nameable and the downstream killer is not. The functional losses also matter on their own: a simulation that represents this family only by what it secretes would miss four supports being withdrawn.", "limit": "The subtype this paper names A1 is the binary the field's own 2021 consensus statement then advised against, and several of this paper's authors signed that statement - so the mechanism should be carried and the label should not. Mouse throughout for the mechanism, with human tissue entering only as an abundance survey using markers whose specificity the consensus questions. Necessary and sufficient is asserted for the three cytokines together without the individual contributions quantified here, and no concentration, EC50 or exposure time is extracted. Axotomy is a lesion model rather than any of the diseases surveyed. Abundant in five diseases is not a proportion.", "provenance": "Abstract read in full; the three cytokines with the necessity and sufficiency claim as stated, all four lost functions, both killed cell types, the in vivo blockade result, and the five diseases surveyed as reported", "quantitativeExtraction": "extracted" }, "L196": { "id": "L196", "year": 2021, "topic": "Reactive", "title": "Reactive astrocyte nomenclature, definitions, and future directions", "url": "https://doi.org/10.1038/s41593-020-00783-4", "studyType": "Consensus statement on definitions and experimental standards, Nature Neuroscience 24(3):312-325", "diseaseContext": "Alzheimer's / ALS / FTD; CNS injury, disease and ageing generally", "useInModel": "A field formally retiring its own state vocabulary, which is as close as this atlas comes to an authoritative statement that a representation is wrong. The statement points out the shortcomings of binary divisions of reactive astrocytes into good-versus-bad, neurotoxic-versus-neuroprotective or A1-versus-A2, says it is unclear whether fixed categories of reactive astrocytes exist at all and, if they do, how to identify them, and advocates instead assessing multiple molecular and functional parameters, preferably in vivo, with multivariate statistics and a demonstrated impact on pathological hallmarks. Three uses here. It settles how to carry the atlas's own A1 record: keep the mechanism, drop the category, since authors of that paper signed this one. It states for this family what the atlas reached independently for motor neuron vulnerability - that the thing being modelled is multivariate and a binary or a partition is the wrong shape. And it is a direct warning about marker panels: if it is unclear how to identify these states, then a profile listing markers for them is listing candidates, not definitions.", "limit": "A consensus statement, so it carries no measurements, no cohort and no effect - it constrains how evidence should be read rather than adding any. It prescribes multivariate assessment in vivo without specifying which parameters, so it rules out a representation without supplying the replacement. Guidance from 2021, and the binaries it advises against remain in wide use in the literature the atlas draws on, including in records already held here.", "provenance": "Abstract read in full; the three named binaries advised against, the stated uncertainty about whether fixed categories exist and how to identify them, and the four elements of the recommended alternative as listed", "quantitativeExtraction": "extracted" }, "L197": { "id": "L197", "year": 2017, "topic": "Barrier contact", "title": "Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains", "url": "https://doi.org/10.1001/jamaneurol.2016.4370", "studyType": "Post-mortem frontal cortex from 79 individuals - cognitively intact under 60, cognitively intact over 60, and histopathologically confirmed Alzheimer's - by western blot in 60 samples and immunofluorescence in 48, JAMA Neurology 74(1):91-99", "diseaseContext": "Alzheimer's", "useInModel": "The atlas's first measurement of this family's vascular endfeet, and it separates two quantities that a model would otherwise collapse into one. Total AQP4 expression tracked advancing age across all individuals, R-squared 0.17 at p equal to 0.003. Perivascular localisation of the same protein tracked Alzheimer's status independently of age, reported as an odds ratio of 11.7 per 10 percent increase in localisation with a z of -2.89, so that better localisation goes with less disease, and was preserved among the oldest individuals over 85 who remained cognitively intact. Controlling for age, loss of perivascular localisation went with increased amyloid-beta burden and increasing Braak stage. So how much of the channel is present is an ageing variable and where it sits is a disease variable, and the protein that would appear in any astrocyte marker panel carries both. For a simulation that means the endfoot is a location rather than an amount, and abundance at the cell level is the wrong state for it - which is the second kind of thing in this row that a panel measuring protein per cell cannot see.", "limit": "Post-mortem frontal cortex at one timepoint, so these are associations and the direction is not established: loss of polarisation could precede amyloid accumulation or follow it. The R-squared values are small, 0.14 to 0.17, and the odds ratio of 11.7 is reported with a negative z, so the figure as printed cannot be read as odds of disease rising with localisation - the protective direction is the one the paper's other results support. It is also per 10 percent of a measure defined by this study's own image analysis rather than on any absolute scale. Seventy-nine brains with 48 histology and 60 blots, so the subgroups are small. Frontal cortex only, and the glymphatic clearance function invoked to explain the association is not measured here.", "provenance": "Abstract read in full; cohort composition and both assay counts, the age association with its R-squared and p value, the odds ratio for perivascular localisation with its p value, the preservation in cognitively intact individuals over 85, and both age-controlled associations as reported", "quantitativeExtraction": "extracted" }, "L198": { "id": "L198", "year": 2023, "topic": "Region-specific", "title": "Monitoring regional astrocyte diversity by cell type-specific proteomic labeling in vivo", "url": "https://doi.org/10.1002/glia.24304", "studyType": "Inducible Aldh1l1-MetRS(L274G) mouse line labelling newly synthesised astrocyte proteins with azidonorleucine in vivo, click-chemistry isolation and mass spectrometry across four brain regions, with single-astrocyte intensity analysis across hippocampal layers, Glia 71(3):682-703", "diseaseContext": "Healthy reference", "useInModel": "Answers the inventory's region-specific question negatively, and relocates the heterogeneity to a finer scale. Across four brain regions the astrocyte proteomes showed high similarity, with only subtle differences in enriched biological processes and in the abundances of key astrocytic proteins between hippocampus, cortex and striatum. The cerebellar proteome was the one that stood out, with proteins associated with calcium signalling. But within the hippocampus, single-astrocyte analysis across layers showed distinct subregional heterogeneity. So between forebrain regions these cells are much the same, between forebrain and cerebellum they differ, and within one region they differ by layer. For a simulation that is a specific instruction: a region-indexed astrocyte compartment buys little across the forebrain, a separate cerebellar one is justified, and the division that would actually matter is finer than the region - which is the same conclusion the atlas reached for niche architecture in a parenchymal row, from laminar organisation rather than from proteomics.", "limit": "Healthy mouse, so this says nothing about whether regional differences open up in disease - and the reactive states this row is otherwise concerned with are absent here. Newly synthesised protein over the labelling window rather than the standing proteome, so stable long-lived proteins are underrepresented by design. High similarity and subtle differences are the authors' characterisations and no distance metric between regional proteomes is extracted. Four regions, and the subregional finding rests on labelling intensity per cell across hippocampal layers rather than on layer-resolved proteomes.", "provenance": "Abstract read in full; the labelling method, the four regions, the stated similarity across hippocampus, cortex and striatum, the cerebellar exception with its associated pathway, and the hippocampal subregional result as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I060", "name": "Oligodendrocytes", "category": "Neural", "whereToCheck": "CNS white and gray matter", "states": [ "Maturation", "stress", "myelin state" ], "behaviors": [ "Myelination", "axonal support", "injury" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-122", "hatton-138" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-122", "hatton-138" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-122", "hatton-138" ], "priorResearch": { "path": "simulation/data/profiles/oligodendrocytes.json", "summary": "The family where the cell and the structure it maintains keep different time, and the third family to carry a cell-type-resolved SOD1 result. Human white matter oligodendrocyte number is set in childhood and the population exchanges at 1 in 300 per year, while myelin itself is exchanged at a high rate - so the cell is near-permanent and its product is not, and the authors conclude that mature oligodendrocytes rather than new ones do the remodelling (L199). In ALS mice grey matter oligodendrocytes degenerate before onset, new ones form and fail to mature, and removing mutant SOD1 from oligodendroglia delays onset and prolongs survival (L201). In multiple sclerosis the capacity to generate new oligodendrocytes can rise several-fold and repair still does not follow, with shadow plaque oligodendrocytes turning out to be old (L200). Subtype composition shifts in disease, including in white matter that looks normal (L202). And the metabolic support these cells give axons runs through a transporter reduced in ALS patients (L186).", "stateAxes": [ { "axis": "Myelin state, which is not the cell's state", "whatToMeasure": "Both, separately. The human population exchanges at 1 in 300 oligodendrocytes per year with the corpus callosum number fixed since childhood, while myelin is exchanged at a high rate over the same period - and the conclusion drawn is that mature cells rather than new ones carry out myelin modulation.", "interpretationLimit": "White matter and corpus callosum, while the atlas's disease evidence for this family is grey matter - so the baseline and the pathology are measured in different compartments. Carbon-14 dates a population's average exchange and does not identify which cells turn over. The fast constant is characterised and not quantified: the atlas has 1 in 300 per year for the cell and no figure at all for myelin, so the dissociation is established and only one side of it is a number.", "evidence": [ "L199" ] }, { "axis": "Maturation, where the failure is", "whatToMeasure": "The step after generation rather than generation itself. In ALS mice new oligodendrocytes were formed and failed to mature, giving progressive demyelination with generation intact. In multiple sclerosis generation rose several-fold in a subset of patients with very aggressive disease and repair did not follow, while shadow plaque oligodendrocytes were old. Two diseases, both with the bottleneck downstream of making new cells.", "interpretationLimit": "Failed to mature is a lineage inference from marker-defined stages, which is exactly the staging the atlas's marker problem warns manufactures its categories. The ALS result is mouse; the multiple sclerosis result is human but in an environment the atlas does not draw, and carbon-14 dating cannot distinguish the three explanations its authors offer for old cells in shadow plaques. Neither gives a maturation rate, so the bottleneck is located and not quantified.", "evidence": [ "L201", "L200" ] }, { "axis": "Stress, as subtype composition", "whatToMeasure": "Which oligodendroglial subclusters are over- and under-represented, since human white matter contains several and disease shifts their proportions - including in white matter that appears normal, which puts the disease outside its own lesions. Regional origin also matters: cells from mouse spinal cord inherently make longer myelin sheaths than cortical ones, so sheath geometry is partly a property of the oligodendrocyte rather than of the axon.", "interpretationLimit": "Post-mortem single-nucleus transcriptomes, so the subclusters are expression states whose functional meaning is inferred rather than measured, and the compositional shifts have no proportions extracted here. The sheath length claim is a mouse finding the authors cite, and no sheath length for human cells from any region exists in this atlas. Multiple sclerosis again, so the environment is undrawn - and the authors note disability correlates poorly with the extent of demyelination, which undercuts the obvious structural readout for this row. The atlas's one geometric metric for this structure, the g-ratio, is held as a method caution with no value attached, so even where sheath geometry is the right variable there is nothing to calibrate against (L187).", "evidence": [ "L202", "L187" ] }, { "axis": "Axonal support", "whatToMeasure": "Transporter-mediated delivery of glycolytic substrate to axons, which the atlas holds for this lineage: the most abundant central lactate transporter, acting independently of myelination, whose disruption causes axon damage and neuron loss and which is reduced in ALS patients.", "interpretationLimit": "No transfer rate, concentration or gradient, so the support is established and uncomputable - one of the atlas's five metabolite hand-offs without a flux. The independence from myelination matters for this row specifically: it means the support function and the structural function are separable, so a model cannot use myelin state as a proxy for metabolic support.", "evidence": [ "L186" ] } ], "records": { "L186": { "id": "L186", "year": 2012, "topic": "Support", "title": "Oligodendroglia metabolically support axons and contribute to neurodegeneration", "url": "https://doi.org/10.1038/nature11314", "studyType": "Transporter localisation with disruption in animal and cell culture models, plus comparison of patient and mouse model tissue, Nature 487(7408):443-448", "diseaseContext": "ALS; healthy reference", "useInModel": "Says this structure's most consequential function is not structural, which is the opposite of what the row's name implies. Oligodendroglia support axon survival and function through mechanisms independent of myelination; lactate is transported exclusively by monocarboxylate transporters; the most abundant such transporter in the central nervous system is highly enriched in oligodendroglia; and disrupting it produces axon damage and neuron loss in animal and cell culture models. The same transporter is reduced in patients with ALS and in mouse models of it. Two consequences. A model that represents myelin as insulation will miss the mechanism whose disruption actually kills axons - the supporting cell is feeding the axon, and that is separable from wrapping it. And this is the atlas's fourth metabolic exchange term, after oxygen, arginine and lipid: a metabolite handed from one cell to another across a short distance, sharing the mathematics the project already owns, and like the other three it has no flux.", "limit": "Disruption experiments are animal and cell culture; the human evidence is reduced transporter levels in patient tissue, which is an association rather than a demonstration that the reduction causes the disease. No transfer rate, lactate concentration or gradient between oligodendrocyte and axon is given, so the exchange is established and unquantified - the same position as the atlas's other three metabolic exchange terms. Lactate is one metabolite and the mechanisms independent of myelination may include others not addressed here.", "provenance": "Abstract read in full; the independence of support from myelination, the exclusivity of monocarboxylate transport for lactate, the transporter's enrichment in oligodendroglia, the disruption phenotypes in both model types, and its reduction in patients and mouse models as reported", "quantitativeExtraction": "extracted" }, "L187": { "id": "L187", "year": 2025, "topic": "Geometry", "title": "MyeliMetric: A Python-Based Toolbox for Standardized G-Ratio Analysis of Axon-Myelin Integrity", "url": "https://doi.org/10.1080/17590914.2025.2603411", "studyType": "Methodological tool development with validation against synthetic and published rodent demyelination datasets, ASN Neuro 18:2603411", "diseaseContext": "Healthy reference", "useInModel": "Supplies the one place in the Structures category where the geometry the inventory asks for has a standard metric that sets a function - and then says the field has been computing it badly. The g-ratio is the ratio of axon diameter to total fibre diameter including myelin, described as a key metric for myelin integrity and axonal conduction velocity, with deviations from the physiological range signalling pathology, and it is relatively consistent across axon diameters in health. That is a geometry-to-function relationship of the kind the atlas has wanted throughout this category. The caution is the other half: there was no standardised open-source tool for computing it from segmented electron microscopy until this one, and the stated problems in conventional analyses are insufficient sampling, pseudo-replication, and artefacts including misleading regression slopes - which the tool addresses by binning axons into diameter cohorts. A companion commentary in the same journal is titled to the effect that the field has been doing it wrong. So published g-ratio values carry method risk, and any the atlas ingests should carry how they were computed and whether sampling was adequate.", "limit": "A tool paper, so it supplies no g-ratio value for any tissue, species or disease - it establishes how the number should be obtained and what goes wrong otherwise. Validation is against synthetic data and published rodent demyelination datasets, not against a ground truth in human tissue. The physiological range it refers to is not stated here. And the relationship to conduction velocity is asserted as established background rather than measured in this record.", "provenance": "Abstract read in full; the definition of the ratio, its stated relevance to integrity and conduction velocity, the consistency-across-diameters principle, the absence of a prior standard tool, all three named analytical failure modes, the binning approach and the validation sources as reported. The companion commentary's existence is noted from the same search", "quantitativeExtraction": "extracted" }, "L199": { "id": "L199", "year": 2014, "topic": "Myelin state", "title": "Dynamics of oligodendrocyte generation and myelination in the human brain", "url": "https://doi.org/10.1016/j.cell.2014.10.011", "studyType": "Retrospective birth dating in human post-mortem brain by integration of nuclear-bomb-test-derived carbon-14 into genomic DNA, with cell counts in corpus callosum, Cell 159(4):766-774", "diseaseContext": "Healthy reference", "useInModel": "A rate measured in humans in vivo, and a dissociation this atlas has no field for. The number of oligodendrocytes in the corpus callosum is established in childhood and remains stable afterwards, and carbon-14 dating puts the annual exchange of white matter oligodendrocytes at 1 in 300. Over the same period myelin itself is exchanged at a high rate. So the cell is near-permanent and the structure it maintains turns over quickly: one family, two time constants, differing by orders of magnitude. The authors' conclusion is that oligodendrocyte turnover contributes minimally to myelin modulation in human white matter and that mature oligodendrocytes do that work instead. Three consequences. A simulation cannot represent this family with a single state, because cell identity and myelin state evolve on unrelated timescales. Any intervention aimed at myelin through oligodendrocyte replacement is aimed at the slow variable. And this is a human in vivo rate obtained without a tracer being administered, which is a method the atlas should prefer where it exists.", "limit": "Corpus callosum and white matter, so this is not a whole-brain or grey matter figure - and the atlas's ALS record for this family is specifically about grey matter. The carbon-14 method dates a population's average turnover rather than following individual cells, so 1 in 300 per year is a population exchange rate and does not say which cells are exchanged or whether exchange is uniform. Myelin exchanged at a high rate is stated without a figure here, so the atlas has the slow constant quantified and the fast one only characterised. Healthy humans, so nothing about disease.", "provenance": "Abstract read in full; the stability of the corpus callosum population from childhood, the 1 in 300 annual exchange, the high rate of myelin exchange as stated, and the authors' conclusion about mature oligodendrocytes as reported", "quantitativeExtraction": "extracted" }, "L200": { "id": "L200", "year": 2019, "topic": "Injury", "title": "Dynamics of oligodendrocyte generation in multiple sclerosis", "url": "https://doi.org/10.1038/s41586-018-0842-3", "studyType": "Carbon-14 birth dating of oligodendrocytes in post-mortem brain from patients with multiple sclerosis, across normal-appearing white matter and shadow plaques, Nature 566(7745):538-542", "diseaseContext": "Multiple sclerosis; healthy reference", "useInModel": "The clearest case in this atlas of an animal model identifying the wrong mechanism, demonstrated by a method that works in humans. In animal models of demyelinating disease myelin is regenerated by newly generated oligodendrocytes and remaining mature ones do not appear to contribute. In patients, oligodendrocytes in shadow plaques - thinly myelinated lesions taken to be remyelinated areas - were old. The authors' reading is that remyelination of lesions happens transiently or not at all, or that myelin is regenerated by pre-existing rather than new oligodendrocytes. Separately, generation of new oligodendrocytes was increased several-fold in normal-appearing white matter in a subset of individuals with very aggressive disease but not in most patients, which demonstrates an inherent capacity to increase generation substantially that fails in most. Two uses here. The bottleneck is not generation: the capacity exists, is sometimes exercised, and does not produce repair. And the atlas's standing caution that a mouse mechanism may not be the human one has an instance where the human measurement was actually made and the mechanism was different - which is worth more than the caution.", "limit": "Multiple sclerosis is not one of the atlas's drawn environments, so this is carried for the repair mechanism rather than for an environment. Post-mortem, and carbon-14 dates populations rather than tracking cells, so old oligodendrocytes in shadow plaques is an age distribution and the three explanations the authors offer are not distinguished by it. Increased several-fold is reported for a subset of individuals without the subset being defined by a measurable criterion other than disease aggressiveness, and no proportion of patients is extracted. Shadow plaques are presumed remyelinated on morphological grounds.", "provenance": "Abstract read in full; the stated animal-model mechanism being contrasted, the several-fold increase in a subset, the old age of shadow plaque oligodendrocytes, and all three explanations the authors offer as reported", "quantitativeExtraction": "extracted" }, "L201": { "id": "L201", "year": 2013, "topic": "Maturation", "title": "Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis", "url": "https://doi.org/10.1038/nn.3357", "studyType": "Lineage and histological analysis in SOD1-G93A mouse spinal cord before and after onset, with human ALS motor cortex and spinal cord, and conditional removal of mutant SOD1 from oligodendroglia, Nature Neuroscience 16(5):571-579", "diseaseContext": "ALS", "useInModel": "Puts a third family into the atlas's SOD1 triangulation and locates the failure at maturation. Grey matter oligodendrocytes degenerated extensively in ALS mouse spinal cord before disease onset. New oligodendrocytes were formed but failed to mature, producing progressive demyelination - so generation was intact and the step after it was not. Human ALS showed grey matter demyelination and reactive changes in NG2-positive progenitors in motor cortex and spinal cord. And selectively removing mutant SOD1 from oligodendroglia substantially delayed disease onset and prolonged survival. Set beside the atlas's other two cell-type-resolved SOD1 experiments this is striking: the same mutation in motor neurons produced no degeneration, in astrocytes killed motor neurons, and removed from oligodendroglia delayed onset and extended life. The gene's effect is a property of which family carries it, which no single-compartment representation can express. It also makes this family a tested intervention point rather than a candidate one - the only family in the ALS environment where removing the mutation changed survival.", "limit": "Onset delay and survival extension are reported as substantial without figures extracted here, so the atlas holds a direction and not a magnitude - and the conditional removal is a developmental genetic manipulation rather than anything a treatment could do. Mouse for all the mechanism and timing; the human contribution is demyelination and progenitor changes in post-mortem tissue, with no cell counts or timing. Failed to mature is a lineage inference from marker-defined stages, which is the kind of staging the atlas's marker problem warns about. Familial SOD1, with the usual caution - though the astrocyte work has now tested that transfer once and it held.", "provenance": "Abstract read in full; pre-onset degeneration, the formation of new oligodendrocytes with failure to mature, the human findings in both regions, and the conditional removal result as reported", "quantitativeExtraction": "extracted" }, "L202": { "id": "L202", "year": 2019, "topic": "Maturation", "title": "Altered human oligodendrocyte heterogeneity in multiple sclerosis", "url": "https://doi.org/10.1038/s41586-019-0903-2", "studyType": "Single-nucleus RNA sequencing of white matter from post-mortem human brain, patients with multiple sclerosis against unaffected controls, with marker definition for oligodendroglial subclusters, Nature 566(7745):543-547", "diseaseContext": "Multiple sclerosis; healthy reference", "useInModel": "Supplies the subtype structure this row needs and a warning about where the disease boundary is. Subclusters of oligodendroglia were identified in control human white matter, some resembling mouse populations, with new markers defined for them. In multiple sclerosis tissue some subclusters were underrepresented and others more prevalent, which the authors read as different functional states in lesions. The same changes appeared in normal-appearing white matter, showing the disease is more diffuse than its focal demyelination suggests. Two framing points the paper states and the atlas should carry: disability does not correlate well with the extent of demyelination, so the obvious structural readout is not the outcome variable; and oligodendrocytes are not interchangeable, since those from mouse spinal cord inherently produce longer myelin sheaths than those from cortex. That last is a geometric property set by the cell's origin rather than by its axon, which is the kind of thing a simulation would otherwise assign to the axon.", "limit": "Multiple sclerosis is not a drawn environment, so this is carried for subtype structure and not for an environment. Post-mortem single-nucleus transcriptomes, so the subclusters are expression states whose functional meaning is inferred - the authors say may indicate - and no function is measured for any of them. Over- and under-representation are compositional shifts without proportions extracted. The sheath length difference is a mouse result cited by the authors rather than measured here, and the atlas holds no sheath length for human cells from any region.", "provenance": "Abstract read in full; the identification of control subclusters with new markers, the direction of compositional change in disease, the finding in normal-appearing white matter, and the two cited framing facts about disability correlation and regional sheath length as stated", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I061", "name": "Oligodendrocyte precursor cells", "category": "Neural", "whereToCheck": "CNS", "states": [ "Proliferative", "differentiating", "stressed" ], "behaviors": [ "Repair", "lineage transitions", "distinguish CSPG4-positive cells from pericytes" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "geometry-opc-cycle" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "geometry-opc-movement", "geometry-opc-cycle" ], "priorResearch": { "path": "simulation/data/profiles/oligodendrocyte-precursor-cells.json", "summary": "The row whose inventory entry asks for something no other row does - distinguish CSPG4-positive cells from pericytes - and the evidence says the task is harder than a labelling problem. NG2 is not merely shared: it is a functional auxiliary receptor in pericytes, enhancing integrin and growth factor signalling and acting in trans on apposed endothelium, with knockouts producing vessel formation deficits, reduced tumour vascularisation and diminished basement membrane assembly (L204). And the standard inducible tool built on that promoter labels 21.9 to 35.5 percent of the cells it targets (L205). Meanwhile the family itself turns out to regulate its own density: in the living cortex these cells survey with motile filopodia, hold territory by self-avoidance, and replace a lost neighbour by migration and proliferation (L203). Repair is served by a named intrinsic requirement absent from the majority of these cells in chronic inactive human lesions (L206), and differentiation by an exposure that helps briefly and harms when sustained (L207).", "stateAxes": [ { "axis": "Proliferative, as a regulated density", "whatToMeasure": "The population's response to perturbation rather than a static count. In the living adult cortex these cells are highly dynamic, surveying with motile filopodia and extending growth cones while migrating continuously, and they hold unique territories by self-avoidance. Loss by death, differentiation or targeted ablation triggered rapid migration and proliferation of neighbours to restore density, and cells recruited to a focal injury were replaced by a proliferative burst around it.", "interpretationLimit": "Mouse cortex in vivo, and no rate: rapid and restored are reported without velocities, latencies or recovery times, and no density per volume is given - so a negative feedback loop is demonstrated and nothing about it is parameterised. Self-avoidance is inferred from territory maintenance with no repulsive molecule identified. The species caution has unusual force here, since the atlas holds one human measurement that directly contradicted a mouse mechanism in this lineage.", "evidence": [ "L203" ] }, { "axis": "Differentiating, with a sign that depends on duration", "whatToMeasure": "Exposure schedule, not exposure. Transient exposure to platelets enhanced differentiation while sustained exposure suppressed it; partial depletion of circulating platelets impaired differentiation and remyelination without altering blood-brain barrier stability or neuroinflammation; and a thrombocytosis model with sustained aggregation produced fewer newly generated oligodendrocytes.", "interpretationLimit": "Transient and sustained are not durations here, so the atlas has the shape of a non-monotonic curve and neither breakpoint - which is the only part a parameter would need. The mediator is unidentified among everything platelets carry. Mouse, with the bimodality shown in vitro and corroborated by a genetic model rather than by timed exposure in the brain. The clean exclusion of barrier and inflammatory confounds is the record's strongest feature and applies only to the depletion arm.", "evidence": [ "L207" ] }, { "axis": "Repair, and where it fails", "whatToMeasure": "Expansion in the lesion and the enzyme that permits it. Retinoic acid synthesis through Raldh2 is required for these cells to expand during remyelination: deleting it in them alone gave fewer proliferating progenitors, fewer oligodendrocytes and lower myelin density, exogenous retinoic acid rescued lineage cell numbers while selectively reducing proinflammatory microglia, and in human tissue the enzyme was absent from the majority of these cells in chronic inactive lesions specifically.", "interpretationLimit": "Mouse mechanism with human tissue contributing only enzyme presence by lesion type, and chronic inactive lesions may lack it as a consequence of long failure rather than as its cause. No counts, no proliferation rate, no dose or duration for the rescue. The atlas's records disagree about which step limits repair - maturation in ALS with generation intact, human generation capacity rising without repair following, and expansion failing here - and this profile holds all three rather than resolving them, because each was measured in a different disease by a different method.", "evidence": [ "L206", "L200", "L201" ] }, { "axis": "Distinguish CSPG4-positive cells from pericytes", "whatToMeasure": "The inventory's own task, and the records turn it from a labelling question into a structural one. NG2 is a functional auxiliary receptor in pericytes, enhancing integrin and receptor tyrosine kinase signalling and activating integrin signalling in trans in apposed endothelial cells; its loss impairs vessel formation, reduces tumour vascularisation, and diminishes ensheathment and vascular basement membrane assembly. The inducible line built on the same promoter labels 21.9 to 35.5 percent of its targets.", "interpretationLimit": "Neither record separates the two populations, which is what the task asks for - they establish that the marker is load-bearing in the other family and that the standard tool is inefficient. No record anywhere in the atlas states what fraction of CSPG4-positive cells in any CNS tissue are progenitors rather than mural cells, which is the number the task reduces to. The efficiency figures are retinal and belong to those constructs. The pericyte evidence is a review without magnitudes.", "evidence": [ "L204", "L205" ] } ], "records": { "L200": { "id": "L200", "year": 2019, "topic": "Injury", "title": "Dynamics of oligodendrocyte generation in multiple sclerosis", "url": "https://doi.org/10.1038/s41586-018-0842-3", "studyType": "Carbon-14 birth dating of oligodendrocytes in post-mortem brain from patients with multiple sclerosis, across normal-appearing white matter and shadow plaques, Nature 566(7745):538-542", "diseaseContext": "Multiple sclerosis; healthy reference", "useInModel": "The clearest case in this atlas of an animal model identifying the wrong mechanism, demonstrated by a method that works in humans. In animal models of demyelinating disease myelin is regenerated by newly generated oligodendrocytes and remaining mature ones do not appear to contribute. In patients, oligodendrocytes in shadow plaques - thinly myelinated lesions taken to be remyelinated areas - were old. The authors' reading is that remyelination of lesions happens transiently or not at all, or that myelin is regenerated by pre-existing rather than new oligodendrocytes. Separately, generation of new oligodendrocytes was increased several-fold in normal-appearing white matter in a subset of individuals with very aggressive disease but not in most patients, which demonstrates an inherent capacity to increase generation substantially that fails in most. Two uses here. The bottleneck is not generation: the capacity exists, is sometimes exercised, and does not produce repair. And the atlas's standing caution that a mouse mechanism may not be the human one has an instance where the human measurement was actually made and the mechanism was different - which is worth more than the caution.", "limit": "Multiple sclerosis is not one of the atlas's drawn environments, so this is carried for the repair mechanism rather than for an environment. Post-mortem, and carbon-14 dates populations rather than tracking cells, so old oligodendrocytes in shadow plaques is an age distribution and the three explanations the authors offer are not distinguished by it. Increased several-fold is reported for a subset of individuals without the subset being defined by a measurable criterion other than disease aggressiveness, and no proportion of patients is extracted. Shadow plaques are presumed remyelinated on morphological grounds.", "provenance": "Abstract read in full; the stated animal-model mechanism being contrasted, the several-fold increase in a subset, the old age of shadow plaque oligodendrocytes, and all three explanations the authors offer as reported", "quantitativeExtraction": "extracted" }, "L201": { "id": "L201", "year": 2013, "topic": "Maturation", "title": "Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis", "url": "https://doi.org/10.1038/nn.3357", "studyType": "Lineage and histological analysis in SOD1-G93A mouse spinal cord before and after onset, with human ALS motor cortex and spinal cord, and conditional removal of mutant SOD1 from oligodendroglia, Nature Neuroscience 16(5):571-579", "diseaseContext": "ALS", "useInModel": "Puts a third family into the atlas's SOD1 triangulation and locates the failure at maturation. Grey matter oligodendrocytes degenerated extensively in ALS mouse spinal cord before disease onset. New oligodendrocytes were formed but failed to mature, producing progressive demyelination - so generation was intact and the step after it was not. Human ALS showed grey matter demyelination and reactive changes in NG2-positive progenitors in motor cortex and spinal cord. And selectively removing mutant SOD1 from oligodendroglia substantially delayed disease onset and prolonged survival. Set beside the atlas's other two cell-type-resolved SOD1 experiments this is striking: the same mutation in motor neurons produced no degeneration, in astrocytes killed motor neurons, and removed from oligodendroglia delayed onset and extended life. The gene's effect is a property of which family carries it, which no single-compartment representation can express. It also makes this family a tested intervention point rather than a candidate one - the only family in the ALS environment where removing the mutation changed survival.", "limit": "Onset delay and survival extension are reported as substantial without figures extracted here, so the atlas holds a direction and not a magnitude - and the conditional removal is a developmental genetic manipulation rather than anything a treatment could do. Mouse for all the mechanism and timing; the human contribution is demyelination and progenitor changes in post-mortem tissue, with no cell counts or timing. Failed to mature is a lineage inference from marker-defined stages, which is the kind of staging the atlas's marker problem warns about. Familial SOD1, with the usual caution - though the astrocyte work has now tested that transfer once and it held.", "provenance": "Abstract read in full; pre-onset degeneration, the formation of new oligodendrocytes with failure to mature, the human findings in both regions, and the conditional removal result as reported", "quantitativeExtraction": "extracted" }, "L203": { "id": "L203", "year": 2013, "topic": "Proliferative", "title": "Oligodendrocyte progenitors balance growth with self-repulsion to achieve homeostasis in the adult brain", "url": "https://doi.org/10.1038/nn.3390", "studyType": "NG2-mEGFP reporter mice with in vivo two-photon time-lapse imaging of cortex, including loss by death, differentiation or targeted ablation and focal CNS injury, Nature Neuroscience 16(6):668-676", "diseaseContext": "Healthy reference; focal CNS injury", "useInModel": "Says this family's density is a controlled variable rather than a free one, which changes what kind of object it is in a simulation. Time-lapse imaging in the living adult cortex showed these cells are highly dynamic: they survey their local environment with motile filopodia, extend growth cones and migrate continuously, and they hold unique territories by self-avoidance. When one was lost - by death, by differentiation or by targeted ablation - adjacent cells migrated and proliferated rapidly to restore the density. Cells recruited to a site of focal injury were likewise replaced by a proliferative burst around the injury. So the population has negative feedback on its own spacing with a measured response to perturbation, in vivo. Two consequences. A passive pool that depletes when drawn on is the wrong representation: removing cells provokes replacement, which means an intervention that consumes them is partly self-cancelling. And territory held by mutual repulsion is a spatial constraint with no concentration behind it, so this is a family whose spacing cannot be recovered from any signalling field.", "limit": "Mouse cortex in vivo, so the dynamics are from the species whose oligodendrocyte behaviour the atlas has one human record directly contradicting - and no human equivalent of this imaging exists. No rate is extracted here: rapid migration and proliferation, and restoration of density, are reported without a velocity, a latency or a recovery time, so the feedback is demonstrated and not parameterised. Density itself is not given as a number per volume. Self-avoidance is inferred from territory maintenance rather than from an identified repulsive signal, so the mechanism has no molecule.", "provenance": "Abstract read in full; the reporter and imaging method, all four dynamic behaviours described, the three routes of loss tested, the restoration response, and the focal injury result as reported", "quantitativeExtraction": "extracted" }, "L204": { "id": "L204", "year": 2018, "topic": "Distinguish CSPG4-positive cells from pericytes", "title": "The NG2 Proteoglycan in Pericyte Biology", "url": "https://doi.org/10.1007/978-3-030-02601-1_2", "studyType": "Review of NG2 as pericyte marker and as functional molecule, drawing on knockdown, global knockout and pericyte-specific conditional knockout studies, Advances in Experimental Medicine and Biology 1109:5-19", "diseaseContext": "Healthy reference; mammary and brain tumour vascularisation", "useInModel": "Turns the inventory's third task for this row into a finding, and a worse one than the task implies. The inventory asks the atlas to distinguish CSPG4-positive cells from pericytes, which sounds like a labelling problem. This record shows the molecule is load-bearing in the other family: NG2 influences pericyte proliferation and motility as an auxiliary receptor enhancing integrin and receptor tyrosine kinase signalling, and acting in trans it activates integrin signalling in apposed endothelial cells, promoting their maturation and junction formation. Knockdown and knockout produce significant deficits in blood vessel formation; NG2-null mice grow smaller mammary and brain tumours, traced to deficient tumour vascularisation; and pericyte-specific nulls show decreased ensheathment of endothelial cells and diminished assembly of the vascular basement membrane. The review also states plainly that pericyte studies were retarded by the lack of appropriate markers and that NG2 antibodies are what relieved that. So the shared marker is simultaneously the thing that made one family tractable and a functional receptor in it - which is a different problem from ambiguity. A panel cannot resolve it, and knocking the marker out to test either family perturbs the other.", "limit": "A review, so the individual effects are summarised without magnitudes - smaller tumours, significant deficits and diminished assembly carry no figures here. It is about pericytes rather than about this row, and it does not report any experiment that separates the two NG2-positive populations, which is what the inventory actually asks for. The trans mechanism on endothelium and the tumour vascularisation results are mouse. Nothing here states what fraction of NG2-positive cells in CNS tissue are progenitors rather than mural cells, which is the number the atlas would need.", "provenance": "Abstract read in full; the stated marker history, the auxiliary receptor mechanism, the trans action on endothelium, and all three knockout or knockdown outcomes including the pericyte-specific one as reported", "quantitativeExtraction": "extracted" }, "L205": { "id": "L205", "year": 2022, "topic": "Distinguish CSPG4-positive cells from pericytes", "title": "Characterization of the Two Inducible Cre Recombinase-Based Mouse Models NG2-CreER and PDGFRb-P2A-CreERT2 for Pericyte Labeling in the Retina", "url": "https://doi.org/10.1080/02713683.2021.2002910", "studyType": "Tamoxifen induction of two inducible Cre reporter lines at three stages of retinal vascular development, with reporter efficiency scored on confocal retinal whole mounts against NG2, collagen IV and glutamine synthetase, Current Eye Research 47(4):590-596", "diseaseContext": "Healthy reference", "useInModel": "Puts a number on how much of this family the standard genetic tool actually labels, and it is a minority. In the NG2-CreER reporter line, induction efficiency ranged from 21.9 to 35.5 percent across the three timepoints tested. The paper's own framing is the atlas's: pericytes are heterogeneous across organ, differentiation state and function, their gene expression is correspondingly diverse, and this impedes the use of any unique marker and therefore the distinct identification of the cells. The use here is general. Lineage tracing is the method behind a great many claims about where cells come from and what they become, including in this atlas, and this record says that for the marker shared between this row and the pericyte row, roughly two thirds to three quarters of the target cells are unlabelled. A fate map built on that is a fate map of a biased sample, and an apparent absence of a lineage transition may be a labelling failure.", "limit": "Retina, mouse, and a comparison of reporter lines rather than of biology - so the efficiency figures belong to this tissue and these constructs and should not be transferred to brain or spinal cord without checking. It measures labelling of pericytes, not of oligodendrocyte precursors, so its direct subject is the other family that shares the marker; the inference to this row is by shared construct. The companion line's efficiency is not extracted here. Efficiency is reporter expression after tamoxifen, which confounds promoter activity with recombination and reporter detection.", "provenance": "Abstract read in full; the two lines, the three induction timepoints, the 21.9 to 35.5 percent range for the NG2 line, and the authors' stated reason for comparing them as reported", "quantitativeExtraction": "extracted" }, "L206": { "id": "L206", "year": 2025, "topic": "Repair", "title": "Intrinsic retinoic acid synthesis is required for oligodendrocyte progenitor expansion during CNS remyelination", "url": "https://doi.org/10.3389/fncel.2025.1550139", "studyType": "Spontaneous remyelination model in mice with global and OPC-conditional tamoxifen-induced deletion of Raldh2, exogenous retinoic acid delivery into lesions, and post-mortem multiple sclerosis brain sections across lesion types, Frontiers in Cellular Neuroscience 19:1550139", "diseaseContext": "Multiple sclerosis; focal demyelination", "useInModel": "A named intrinsic requirement for this family's expansion, with a conditional deletion, a rescue, a cross-family effect and human tissue behind it - and it locates the repair failure at a different step than the atlas's other records do. Retinaldehyde dehydrogenase 2, rate-limiting for retinoic acid synthesis, is upregulated in these cells and in a microglial subpopulation during remyelination. Deleting it, globally or only in these cells, gave significantly fewer proliferating progenitors in lesions and fewer oligodendrocytes with lower myelin density; global deletion also raised microglial density. Delivering retinoic acid into lesions increased oligodendrocyte lineage cells while decreasing proinflammatory microglia with no effect on the anti-inflammatory ones - a directional selectivity worth noting. And in post-mortem multiple sclerosis brain the enzyme was absent from the majority of these cells in chronic inactive lesions specifically, compared with other lesion types. So the human observation is lesion-type-resolved and matches the mouse mechanism. Where this sits against the rest of the atlas matters: one record puts the ALS failure at maturation with generation intact, another finds human generation capacity rising several-fold without repair following, and this one finds expansion failing for a named reason in the lesions where repair does not happen. The atlas should hold all three rather than choose.", "limit": "Mouse for the whole mechanism, with human tissue entering as enzyme presence or absence by lesion type and no function measured there. Multiple sclerosis is not a drawn environment, so this is carried for the repair mechanism. Significantly fewer and increased are reported without the counts extracted here, so there is no proliferation rate, no dose for the retinoic acid delivered and no duration. Absent in the majority is a proportion without a figure. A spontaneous remyelination model and a toxin-free lesion are not multiple sclerosis, and chronic inactive lesions in patients may lack the enzyme as a consequence of long-standing failure rather than as its cause.", "provenance": "Abstract read in full; the enzyme's role and upregulation, both deletion conditions with their outcomes, the microglial density effect, the exogenous rescue with its selective effect on proinflammatory cells only, and the lesion-type-resolved human finding as reported", "quantitativeExtraction": "extracted" }, "L207": { "id": "L207", "year": 2024, "topic": "Differentiating", "title": "Circulating platelets modulate oligodendrocyte progenitor cell differentiation during remyelination", "url": "https://doi.org/10.7554/eLife.91757", "studyType": "Experimental demyelination in mice with partial depletion of circulating platelets, transient against sustained platelet exposure in vitro, and a Calr heterozygous thrombocytosis model after toxin-induced demyelination, eLife 12:RP91757", "diseaseContext": "Multiple sclerosis; experimental demyelination", "useInModel": "The atlas's second instance of an exposure whose sign depends on its duration, in a system unrelated to the first. Platelets aggregated near these cells in areas of experimental demyelination. Partially depleting circulating platelets impaired differentiation and remyelination - and did so without altering blood-brain barrier stability or neuroinflammation, which is an unusually clean separation from the two confounds that would otherwise explain it. Transient exposure to platelets enhanced differentiation in vitro while sustained exposure suppressed it, and in a thrombocytosis model the sustained increase in platelet aggregation came with fewer newly generated oligodendrocytes. So more is not better and the same agent reverses sign with time. For a simulation this is the shape of problem the atlas has already recorded once for an engager payload: a dose-response curve is not enough, the schedule is part of the specification, and a model that integrates exposure will get the sign wrong. It is also a cross-family edge from a circulating blood component to a central nervous system progenitor, which the atlas has few of.", "limit": "Mouse throughout, with the bimodality established in vitro and corroborated in vivo by a genetic thrombocytosis model rather than by controlled exposure timing in the brain. Transient and sustained are not given as durations here, so the atlas has the shape of the curve and neither of its breakpoints - which is precisely what a schedule-dependent parameter needs. Partial depletion is not quantified in this extraction. The mediator is not identified: platelets carry many factors and nothing here names which one acts. Multiple sclerosis is not a drawn environment.", "provenance": "Abstract read in full; the aggregation near these cells, the depletion result with both confounds explicitly unaltered, the opposite effects of transient and sustained exposure, and the thrombocytosis model outcome as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "geometry-opc-movement" ] }, { "id": "I062", "name": "Ependymal and choroid plexus epithelial cells", "category": "Neural", "whereToCheck": "Ventricular/CSF boundary only", "states": [ "Barrier", "secretory", "inflammatory" ], "behaviors": [ "CSF interface", "transport", "exclude when outside region" ], "slots": { "size": { "status": "references available", "referenceIds": [ "hatton-124", "hatton-126" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "hatton-124", "hatton-126" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "hatton-124", "hatton-126" ], "priorResearch": { "path": "simulation/data/profiles/ependymal-and-choroid-plexus-epithelial-cells.json", "summary": "The last Neural row, confined by its own inventory entry to the ventricular and cerebrospinal fluid boundary - and the one compartment in this atlas where rates exist. Turnover parameters have been determined for almost 200 proteins in human ventricular fluid, where a handful were known before, and the stated requirement is sequential sampling (L211); amyloid-beta 40 turnover across four species follows an explicit allometric equation (L212). The secretion itself is a flux with a phase, rising at night and reducible by central serotonin or noradrenaline (L210). The family is also a gate: choroid plexus epithelium constitutively expresses CCL20 in mice and humans, CCR6 is required for the first T cells to enter, and those first cells open a second and larger route that does not need the gate (L208). And in 564 people without dementia the structure's shape tracked Alzheimer pathology and predicted cognitive decline, with its cellular basis unknown (L209).", "stateAxes": [ { "axis": "Secretory, as a flux with a phase", "whatToMeasure": "The rate and the time of day together. Intracranial pressure rises at night partly through an elevated secretion rate, with the diurnal pattern reported as similar in nocturnal rodents and diurnal humans; melatonin had no effect, central serotonin and central noradrenaline each reduced the rate, systemic noradrenaline gave only a brief surge, and some of the receptors involved are themselves diurnally regulated.", "interpretationLimit": "Rat, and no absolute rate is held - the atlas gains that the flux varies and is modulable without gaining the value it varies around, which is the opposite of what it usually lacks. Directional changes are unquantified here. The human diurnal parallel is asserted from the literature. Central delivery makes the luminal receptor location an inference. Two of the panel's markers vary diurnally in the same tissue, so a marker measurement here inherits the same phase problem.", "evidence": [ "L210" ] }, { "axis": "Transport, where the atlas can get rates", "whatToMeasure": "Per-protein turnover, which is obtainable in this compartment and almost nowhere else. Almost 200 proteins in human ventricular fluid now have turnover parameters against a handful previously, with a significant relationship between turnover and the protein's tissue of origin - and the method's stated requirement is sequential sampling. Amyloid-beta 40's rate constant follows allometry as 0.395 times body weight to the power -0.351, running about twofold above bulk fluid turnover in rodents and comparable to it in higher species.", "interpretationLimit": "Turnover in a fluid compartment combines synthesis, entry, clearance and bulk flow, so none of these is a secretion rate for this family - they are properties of the fluid this family produces. The 200-protein dataset is held as a method and an existence claim with no individual value extracted. The allometric constants are fitted to pooled multi-species data after pharmacological inhibition, so they are model parameters on few points, and the twofold comparison rests on a fluid turnover figure this atlas does not independently hold. Ventricular rather than lumbar fluid, from clinically selected patients.", "evidence": [ "L211", "L212" ] }, { "axis": "Inflammatory, as a gate that opens another route", "whatToMeasure": "Whether the gate has been passed, not how far it is open. CCR6-deficient mice mounted normal T helper 17 responses and were highly resistant to disease; transferring wild-type T cells restored susceptibility, those cells entered before onset, and they then triggered massive CCR6-independent recruitment across activated parenchymal vessels. CCL20 is constitutively expressed in choroid plexus epithelium in mice and in humans, so the uninflamed and the inflamed brain have different ports with different requirements.", "interpretationLimit": "A model of a disease the atlas does not draw, and mouse except for the ligand's presence in human tissue, which is localisation rather than function. No cell count, rate, gradient or occupancy, so the gate is identified and unquantified. Massive is a characterisation. Whether the two-stage structure holds in the neurodegenerative environments the atlas does draw is untested, and those are not autoimmune.", "evidence": [ "L208" ] }, { "axis": "Barrier, measured in vivo as a shape", "whatToMeasure": "The structure's geometry in the living person, since that is what has actually been measured at scale. In 564 participants without dementia, Alzheimer pathology went with hypertrophy, irregular shape and nonuniform signal, and those features predicted cognitive decline in amyloid-positive participants on three scales.", "interpretationLimit": "The authors state the central limit: what cellular or pathological processes underlie these morphological features is unknown and needs imaging-histopathological comparison. So the atlas holds a human, in vivo, prognostic feature of this family that corresponds to none of its markers and to no measured barrier property - it is not permeability, not secretory capacity and not a cell count. Effect sizes are small with intervals near zero on two scales, the design is retrospective in a single cohort with its own segmentation method, and enlargement of this structure is morphologically nonspecific.", "evidence": [ "L209" ] }, { "axis": "Exclude when outside region, and do not exclude the output", "whatToMeasure": "The inventory's own boundary instruction, which this row accepts for the cells: they exist at the ventricular and cerebrospinal fluid boundary and nowhere else, so sixteen of the twenty drawn environments carry no entry for them. The qualification is that the fluid reaches every central nervous system environment the atlas draws, and the atlas reads biomarkers from it in two environments where it holds nothing about this tissue.", "interpretationLimit": "The instruction is a modelling rule rather than a measurement, and no record here establishes how the compartment couples to any parenchymal environment quantitatively - no flow, no exchange coefficient, no residence time. So the boundary is drawn correctly and the coupling across it is unrepresented.", "evidence": [] } ], "records": { "L208": { "id": "L208", "year": 2009, "topic": "Inflammatory", "title": "C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE", "url": "https://doi.org/10.1038/ni.1716", "studyType": "CCR6-deficient mice with wild-type T cell reconstitution in experimental autoimmune encephalomyelitis, plus CCL20 localisation in mouse and human choroid plexus, Nature Immunology 10(5):514-523", "diseaseContext": "Experimental autoimmune encephalomyelitis; healthy reference for the ligand's expression in human tissue", "useInModel": "A named port of entry into the central nervous system, with the ligand confirmed in human tissue, and the clearest two-stage barrier in the atlas. Mice lacking CCR6 mounted normal T helper 17 responses yet were highly resistant to disease induction, so the receptor is needed for entry rather than for the response. Susceptibility was restored by transferring wild-type T cells, which entered before disease onset and then triggered massive CCR6-independent recruitment of effector T cells across activated parenchymal vessels. The CCR6 ligand CCL20 is constitutively expressed in choroid plexus epithelium in mice and in humans. So this family is a gate that is open by default to one receptor, the first cells through it open a second and larger route that does not need the gate, and the uninflamed and inflamed brain have different ports with different molecular requirements. Three uses. The atlas's delivery chain gains a stage whose limiting step is a constitutively expressed chemokine rather than a permeability. A blockade of this axis can only work before the second route opens, which makes timing part of the mechanism rather than part of the dosing. And the constitutive human expression means the gate is a normal feature, not a lesion.", "limit": "Experimental autoimmune encephalomyelitis is a model of a disease the atlas does not draw, so this is carried for the entry mechanism. Mouse for everything except the ligand's presence in human choroid plexus, which is localisation and not function. No flux: no number of cells crossing, no rate, no gradient of CCL20 and no occupancy, so the gate is identified and not quantified. Massive recruitment is a characterisation. Whether the same two-stage structure applies to the neurodegenerative environments the atlas does draw is untested, and those are not autoimmune diseases.", "provenance": "Abstract read in full; the resistance of CCR6-deficient mice with intact TH-17 responses, the reconstitution result and the CCR6-independent second wave, the constitutive expression of CCL20 in mouse and human choroid plexus epithelium, and the authors' conclusion about distinct ports as reported", "quantitativeExtraction": "extracted" }, "L209": { "id": "L209", "year": 2025, "topic": "Barrier", "title": "Association Between Choroid Plexus Morphological Alterations, Alzheimer Pathologies, and Cognitive Impairment: A Longitudinal Study", "url": "https://doi.org/10.1212/wnl.0000000000213953", "studyType": "Retrospective analysis of 564 participants without dementia from the Alzheimer's Disease Neuroimaging Initiative with 3D T1 and FLAIR MRI, amyloid-beta and tau PET and cognitive assessment, using deep-learning choroid plexus segmentation and higher-order shape features, with linear mixed models on follow-up cognition, Neurology 105(7):e213953", "diseaseContext": "Alzheimer's", "useInModel": "An in vivo human measurement of this family, in a drawn environment, at a scale the atlas rarely sees - and it is a shape rather than a molecule. Among 564 participants without dementia, mean age 72.4 plus or minus 7.7 years and 54.1 percent female, 225 amyloid-positive and 339 amyloid-negative, Alzheimer pathologies were associated with hypertrophy, irregular shape and nonuniform signal of the choroid plexus. Those features predicted longitudinal cognitive decline in amyloid-positive participants: Mini-Mental State Examination beta -0.148 with a 95 percent interval of -0.287 to -0.009 at p equal to 0.038, the cognitive subscale of the Alzheimer's Disease Assessment Scale beta 0.467 from 0.110 to 0.824 at p equal to 0.011, and the Clinical Dementia Rating sum of boxes beta 0.098 from 0.016 to 0.180 at p equal to 0.022. So the structure changes, the change precedes dementia, and it carries prognostic information. For the atlas this is a fourth kind of in vivo measurement to set beside a PET target, a circulating signal and a synaptic density proxy - the first that is geometry. The authors state the limit themselves and it is the important part: the pathologic substrates underlying these morphological features remain to be elucidated, and imaging-histopathological comparison is needed. The atlas therefore holds a measurable, prognostic, human, in vivo feature of this family whose cellular meaning is unknown.", "limit": "Retrospective, in participants without dementia, so this is association and prediction rather than mechanism, and the effect sizes are small with intervals close to zero on two of three scales. Hypertrophy, irregular shape and nonuniform signal are deep-learning-derived higher-order features of a segmented structure, not cell counts, secretory capacity or barrier integrity - nothing here says which of the family's states has changed, and the authors say so. Choroid plexus enlargement is morphologically nonspecific and has been reported in other conditions. A single cohort with its own segmentation method.", "provenance": "Abstract read in full; cohort size, age, sex and amyloid split, all three morphological associations, and all three longitudinal predictions with their betas, intervals and p values, plus the authors' stated limitation about unknown pathologic substrates as reported", "quantitativeExtraction": "extracted" }, "L210": { "id": "L210", "year": 2025, "topic": "Secretory", "title": "Modulation of cerebrospinal fluid secretion facilitated by serotonergic and noradrenergic receptors in the rat choroid plexus", "url": "https://doi.org/10.1186/s12987-025-00666-5", "studyType": "Direct determination of cerebrospinal fluid secretion rate in rats under central and systemic delivery of melatonin, serotonin and noradrenaline, with transcript and protein analysis of choroid plexus receptors, Fluids and Barriers of the CNS 22:54", "diseaseContext": "Healthy reference; raised intracranial pressure as the stated clinical target", "useInModel": "The atlas's first secreted-fluid rate, and it comes with the warning that the rate is not a constant. Intracranial pressure rises at night partly through an elevated cerebrospinal fluid secretion rate, and the diurnal pattern is reported as similar in nocturnal rodents and diurnal humans. The secretion rate was unaffected by melatonin, reduced by central delivery of serotonin and reduced by central noradrenaline, while systemic noradrenaline produced only a brief surge - and some of the relevant receptors in the tissue themselves showed diurnal regulation. Two consequences for a simulation. This family's output is a flux with a phase: a single value for cerebrospinal fluid production is wrong without a time of day attached, which is the same class of problem as the atlas's synaptic density measurement moving with sleep deprivation. And the flux is pharmacologically modulable from the luminal side, which makes it one of very few quantities in this atlas with both a physiological regulator and a stated therapeutic handle.", "limit": "Rat, and no absolute secretion rate is extracted here - the result is a set of directional changes, so the atlas gains that the rate varies and is modulable without gaining the number it varies around. Reduced and brief surge are not quantified in this extraction. The human diurnal parallel is asserted from the literature rather than measured. Central delivery bypasses the blood side, so the receptor location is inferred as luminal rather than demonstrated. Healthy animals, with raised intracranial pressure named as the target and not studied.", "provenance": "Abstract read in full; the stated nocturnal pressure rise and its attribution, the null result for melatonin, both reductions and the systemic noradrenaline surge, and the diurnal regulation of some receptors as reported", "quantitativeExtraction": "extracted" }, "L211": { "id": "L211", "year": 2019, "topic": "Transport", "title": "In Vivo Large-Scale Mapping of Protein Turnover in Human Cerebrospinal Fluid", "url": "https://doi.org/10.1021/acs.analchem.9b03328", "studyType": "Metabolic labelling with sequential ventricular cerebrospinal fluid sampling in patients, proteome-wide and targeted, with mathematical modelling to derive per-protein turnover parameters, Analytical Chemistry 91(24):15500-15508", "diseaseContext": "Healthy reference; patients with ventricular access", "useInModel": "The single most useful methodological record in this atlas for its largest structural gap. The project's recurring complaint is that it holds exchanges without fluxes - five metabolite hand-offs between adjacent cells, none with a transfer rate. This work determined turnover parameters for almost 200 proteins in human ventricular cerebrospinal fluid, where a handful were known before, covering many neuron-biology and immune-related proteins including biomarkers and drug targets, and it reports a significant relationship between a protein's turnover and its tissue of origin. The requirement is stated plainly: sequential sample collection. That is why this compartment has rates and the atlas's other compartments do not - cerebrospinal fluid can be sampled repeatedly in the same person and interstitial fluid cannot. So the atlas's missing rates are not missing because rates are unmeasurable; they are missing because most of its compartments cannot be sampled twice. This row is the exception, and the relationship between turnover and origin means a protein's rate here carries information about where it came from.", "limit": "Ventricular cerebrospinal fluid from patients who had ventricular access, so the population is clinically selected and the compartment is not lumbar fluid, where most clinical biomarkers are measured. A methods paper: the turnover parameters are its product and no individual value is extracted into this atlas, so what is held is the existence and the method rather than any number. Turnover in a fluid compartment combines synthesis, entry, clearance and bulk flow, so a per-protein rate is not a secretion rate for this family. Nothing about disease.", "provenance": "Abstract read in full; the count of almost 200 proteins against a handful previously known, the classes of protein covered, the reported relationship between turnover and protein origin, and the stated requirement for sequential sampling as reported", "quantitativeExtraction": "extracted" }, "L212": { "id": "L212", "year": 2013, "topic": "Transport", "title": "Cerebrospinal fluid beta-amyloid turnover in the mouse, dog, monkey and human evaluated by systematic quantitative analyses", "url": "https://doi.org/10.1159/000341217", "studyType": "Pharmacokinetic and pharmacodynamic modelling of cerebrospinal fluid amyloid-beta dynamics after beta- or gamma-secretase inhibition, pooling in-house and published data across four species, Neurodegenerative Diseases 12(1):36-50", "diseaseContext": "Alzheimer's", "useInModel": "The atlas's first scaling law, written as an equation, and a species comparison with a number on it. The turnover rate constant for cerebrospinal fluid amyloid-beta 40 follows allometry as kout equal to 0.395 times body weight to the power -0.351. And the relationship to bulk fluid turnover changes with size: in rodents the amyloid-beta 40 rate constant is roughly twofold higher than the turnover of the fluid itself, while in higher species the two are comparable. Three uses. This is a parameter a simulation can actually carry, with an explicit dependence on body mass rather than a single value per species. It gives the project an instance of what cross-species transfer looks like when somebody quantifies it instead of cautioning about it - the scaling holds, and a derived ratio does not, which is a more useful statement than either a warning or a blanket assumption. And it bears directly on the atlas's amyloid row, since the slow turnover in these compartments is given as the reason pharmacodynamic readouts for secretase inhibitors are hard to interpret.", "limit": "Modelled rate constants derived from pooled dynamic data after pharmacological inhibition, so these are parameters of a fitted model rather than directly measured fluxes, and they describe amyloid-beta 40 specifically rather than the family's secretory output. Public-domain data pooled with in-house data across four species brings heterogeneous designs. An allometric exponent fitted across four species rests on few points. The comparison to fluid turnover uses literature values for that turnover, which this atlas does not independently hold - so the twofold statement depends on a number not recorded here.", "provenance": "Abstract read in full; the allometric equation with its coefficient and exponent as printed, the twofold relationship in rodents against comparability in higher species, the four species pooled, and the authors' stated motivation about slow turnover complicating interpretation as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I063", "name": "Endothelial and epithelial junctions", "category": "Structures", "whereToCheck": "Vascular and epithelial boundaries", "states": [ "Intact", "remodeled", "disrupted" ], "behaviors": [ "Claudins", "occludin", "cadherins", "continuity and permeability" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "functional-permeability-cationized-bsa", "functional-permeability-anionized-bsa", "functional-permeability-cationized-igg", "functional-permeability-anionized-igg" ], "priorResearch": { "path": "simulation/data/profiles/endothelial-and-epithelial-junctions.json", "summary": "The seals between cells at every vascular and epithelial boundary, and the first row of the Structures category - which opens with a result that undercuts how the category is specified. The inventory asks for claudins, occludin and cadherins, and the best-characterised junctional contrast in the literature shows that knowing those does not tell you what a junction does: button-like junctions in initial lymphatics and zipper-like junctions in collecting vessels and blood vessels are built from the same molecules - VE-cadherin, occludin, claudin-5, zonula occludens-1, junctional adhesion molecule-A and endothelial cell-selective adhesion molecule - and behave oppositely, with fluid entering through openings between buttons that open and close without disrupting integrity (V41). What the row does supply is numbers for the entry step: transvascular permeability in tumour of 4.25 and 4.65 times ten to the minus seven centimetres per second for cationised albumin and IgG against 1.11 and 1.93 for anionised, same sizes (V24), alongside about 3 for IgG with the Biot number argument that permeability rather than diffusion is limiting (V23).", "stateAxes": [ { "axis": "Arrangement, which composition does not determine", "whatToMeasure": "Whether junctions are continuous or discontinuous, because buttons and zippers share their entire molecular list and differ in continuity and function - and because the openings between buttons open and close without disrupting integrity, making this a gated aperture rather than a leak.", "interpretationLimit": "Mouse tissue, healthy and inflamed, not tumour. Morphological and molecular with no conductance, flux, aperture size or opening frequency for either arrangement, so the atlas can state that arrangement decides function and cannot compute with it. What sets the button-versus-zipper choice is unknown.", "evidence": [ "V41" ] }, { "axis": "Transvascular permeability, and what moves it", "whatToMeasure": "A permeability coefficient for the actual agent, resolved by charge at constant size - 4.25 and 4.65 against 1.11 and 1.93 times ten to the minus seven centimetres per second - together with plasma clearance, because the two move together.", "interpretationLimit": "One xenograft line in a skinfold chamber, calculated from fluorescence and pharmacokinetics rather than measured directly, and with chemical modification that alters more than net charge. The tumour gain and the normal-organ gain cannot be separated from this experiment, which is why the authors advise caution.", "evidence": [ "V24", "V23" ] }, { "axis": "The transcellular alternative", "whatToMeasure": "Whether the cargo engages a route through the cell, since for IgG the answer is no - permeability was invariant to FcRn engagement, concentration and competition - while transferrin got receptor-enhanced permeability in the same system and biophysical properties raised it for other macromolecules.", "interpretationLimit": "In vitro stem cell-derived brain endothelium, the tightest barrier rather than a representative one, with no permeability value extracted. The atlas holds a contrary caveolar record showing a fast active route crossing in seconds against a gradient; the two concern different antigens, tissues and preparations and do not settle each other.", "evidence": [ "V26", "V25" ] }, { "axis": "Intact, remodelled, disrupted", "whatToMeasure": "The three states the inventory names - and nothing held here measures the transition between them, in any environment.", "interpretationLimit": "The row's structural gap. The junction architecture is healthy tissue, the permeabilities are an untreated xenograft, and no record describes a junction being remodelled or disrupted by a tumour or a treatment, which is the state every environment in the atlas actually presents.", "evidence": [] } ], "records": { "V23": { "id": "V23", "year": 2008, "topic": "Transport", "title": "Antibody tumor penetration: transport opposed by systemic and antigen-mediated clearance", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC2820307/", "studyType": "Review with transport modelling", "diseaseContext": "Shared cancer", "useInModel": "Gives a vascular permeability coefficient for IgG in tumour of about 3e-7 cm/s, and shows that permeability rather than diffusion decides how much antibody gets in: with a diffusivity of 10 um^2/s and a 10 um capillary radius the Biot number is about 0.006, so the concentration at the tissue surface sits a hundred to a thousand times below plasma. Inside the tumour, transport is diffusion through extracellular space, because raised interstitial pressure removes the convection that carries antibody in normal tissue.", "limit": "A review over xenograft and modelling work, not a measurement in human tumour. The coefficient excludes convection and transcytosis and the authors call it conservative. The binding-site barrier it describes is often misread: antigen density, diffusivity, permeability and dose all move the penetration front.", "provenance": "Full text reviewed; permeability coefficient and Biot number extracted", "quantitativeExtraction": "extracted" }, "V24": { "id": "V24", "year": 2000, "topic": "Transport", "title": "Vascular permeability in a human tumour xenograft: molecular charge dependence", "url": "https://doi.org/10.1054/bjoc.1999.1171", "studyType": "Intravital fluorescence microscopy of LS174T human colon adenocarcinoma in transparent dorsal skinfold chambers in SCID mice, with albumin and IgG cationised by hexamethylenediamine conjugation or anionised by succinylation, British Journal of Cancer 82(9):1513-1518", "diseaseContext": "Colorectal", "useInModel": "Measured transvascular permeability for molecules of the same size and different charge, which makes it a structure-property relation for the entry step of every antibody-sized agent this atlas records. Cationised albumin (isoelectric point 8.6 to 9.1) and IgG (8.6 to 9.3) had permeabilities of 4.25 and 4.65 times ten to the minus seven centimetres per second, more than double the anionised forms at 1.11 and 1.93 (albumin near pI 2.0, IgG 3.0 to 3.9). So net charge is a handle on extravasation that is independent of size. The caveat is the finding: plasma clearance of the cationic molecules was about twice as fast, so the same modification that raises tumour entry raises normal-organ exposure, and the authors advise caution in using it to improve delivery. That is the same two-sided shape the atlas records for payload reach - a parameter that improves the thing you want and the thing you do not, which cannot be tuned one-sidedly.", "limit": "Xenograft in a dorsal skinfold chamber, not human tumour, and one tumour line. Chemical cationisation and anionisation change more than net charge - conjugation and succinylation alter surface chemistry and may alter binding and stability - so charge is the stated variable rather than the only one. Permeability is calculated from fluorescence and pharmacokinetics rather than measured directly. Because clearance moves with charge, the tumour gain and the normal-organ gain cannot be separated from this experiment.", "provenance": "Abstract read in full, replacing a screening note. All four permeability coefficients with their isoelectric point ranges, the model system and labelling chemistry, the roughly twofold faster plasma clearance of cationic molecules, and the authors' own caution as reported", "quantitativeExtraction": "extracted" }, "V25": { "id": "V25", "year": 2007, "topic": "Transport", "title": "Live dynamic imaging of caveolae pumping targeted antibody rapidly and specifically across endothelium in the lung", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC1979160/", "studyType": "Rat intravital imaging with electron microscopy", "diseaseContext": "Healthy reference", "useInModel": "Shows an active transcellular route exists: antibody raised against a caveolar antigen crossed endothelium within seconds, against a concentration gradient, dependent on caveolin-1, with a reported tissue targeting index of 56 and selectivity of 150 over control IgG.", "limit": "Rat lung, and the antibody was raised against a caveolar target. It shows the route works where such an antigen is present; it does not show that ordinary antibodies use it, and nothing here measures it in tumour vessels.", "provenance": "Full text requested from Europe PMC (PMC1979160) and refused - indexed but not open access, so only the abstract is reachable. The abstract confirms the screening note already held: aminopeptidase P concentrated in lung endothelial caveolae, antibody moved across endothelium within seconds against a concentration gradient, dependent on caveolin-1. The targeting index of 56 and selectivity of 150 already recorded come from the indexed publisher text and are not restated in the abstract. Left pending because the quantities are in a full text this interface will not serve, not because nobody has looked.", "quantitativeExtraction": "pending" }, "V26": { "id": "V26", "year": 2020, "topic": "Transport", "title": "Antibody transcytosis across brain endothelial-like cells occurs nonspecifically and independent of FcRn", "url": "https://doi.org/10.1038/s41598-020-60438-z", "studyType": "Transcytosis of IgG variants with native or reduced FcRn engagement across human induced pluripotent stem cell-derived brain endothelial-like cells, with concentration and competition series and a transferrin comparator, Scientific Reports 10:3685", "diseaseContext": "Healthy reference", "useInModel": "A clean negative with its own positive control, on the question of whether receptor engineering buys transport. Permeability was comparable across IgG variants with native and reduced FcRn engagement and stayed constant irrespective of concentration or competition with excess IgG, which the authors read as nonspecific fluid-phase endocytosis rather than receptor-mediated transcytosis - FcRn did show differential trafficking and preferential recycling without that becoming transport. The control matters: transferrin showed receptor-enhanced permeability in the same system, so receptor-mediated transport is possible here and IgG simply does not get it, and the authors note the IgG behaviour appears ubiquitous for most macromolecules. Macromolecules with biophysical properties known to engage alternative endocytosis mechanisms did show increased permeability. For this atlas that means Fc engineering is not a route across this barrier, biophysical properties may be, and the transcellular route is a property of the cargo rather than of the endothelium.", "limit": "An in vitro barrier model of brain endothelium from stem cell-derived cells, not tumour vessel and not in vivo, and brain endothelium is the tightest case rather than a representative one. No permeability value is extracted here. It sits against the caveolar record in this atlas, which shows a fast active transcellular route crossing within seconds against a concentration gradient and dependent on caveolin-1; the two concern different antigens, tissues and preparations and do not settle each other - one says IgG gets no receptor-mediated help, the other that a correctly chosen caveolar antigen does.", "provenance": "Abstract read in full, replacing a screening note. The variant comparison, the concentration and competition invariance, the fluid-phase interpretation, the FcRn recycling observation, the transferrin comparator, the generalisation to most macromolecules and the biophysical-properties exception as reported", "quantitativeExtraction": "extracted" }, "V41": { "id": "V41", "year": 2007, "topic": "Healthy reference", "title": "Functionally specialized junctions between endothelial cells of lymphatic vessels", "url": "https://doi.org/10.1084/jem.20062596", "studyType": "Junctional imaging in mouse tissue in healthy and inflamed states, with VE-cadherin and PECAM-1 dependency tests and examination of growing lymphatic sprouts, Journal of Experimental Medicine 204(10):2349-2362", "diseaseContext": "Healthy reference", "useInModel": "The single most important record in this category, because it shows that knowing a junction's molecular composition does not tell you what the junction does. Initial lymphatics have oak leaf-shaped endothelial cells whose overlapping flaps lack junctions at the tip and are anchored at the sides by discontinuous button-like junctions; collecting lymphatics and blood vessels have continuous zipper-like junctions. Buttons and zippers are built from the same molecules - VE-cadherin, occludin, claudin-5, zonula occludens-1, junctional adhesion molecule-A and endothelial cell-selective adhesion molecule - and behave oppositely: fluid enters throughout initial lymphatics through the openings between buttons, which open and close without disrupting junctional integrity. VE-cadherin was required to maintain integrity and PECAM-1 was not. Growing sprout tips carried zippers rather than buttons, so buttons are a specialised arrangement and not an immature one. Three things follow. The inventory for this row asks for claudins, occludin and cadherins, and this record says that inventory is insufficient by construction - arrangement decides function, not composition. Entry is a gated aperture rather than a leak, so permeability here is a switchable geometry. And fluid and leukocytes enter differently, fluid throughout and most leukocytes in the proximal half, so one vessel has two cargo-specific entry distributions.", "limit": "Mouse tissue in healthy and inflamed states, not tumour, and the atlas's lymphatic rows note that tumour-associated lymphatics differ. The button and zipper descriptions are morphological and molecular: no conductance, flux, aperture size or opening frequency is given for either arrangement, so the structural insight has no number attached. The dependency tests establish that VE-cadherin maintains integrity without showing what sets the button-versus-zipper choice.", "provenance": "Abstract read in full, replacing a screening note. The cell shape and flap architecture, both junction types and their locations, the full shared molecular list, both dependency results, the sprout-tip observation, and the separate fluid and leukocyte entry patterns as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "functional-permeability-cationized-bsa", "functional-permeability-anionized-bsa", "functional-permeability-cationized-igg", "functional-permeability-anionized-igg" ] }, { "id": "I064", "name": "Glycocalyx and surface glycans", "category": "Structures", "whereToCheck": "Cell surfaces and vascular lumen", "states": [ "Thickness", "composition", "shedding" ], "behaviors": [ "Steric accessibility", "adhesion", "charge" ], "slots": { "size": { "status": "references available", "referenceIds": [ "recovered-pbr-postmenopausal-females", "recovered-pbr-older-males" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "recovered-pbr-postmenopausal-females", "recovered-pbr-older-males" ], "priorResearch": { "path": "simulation/data/profiles/glycocalyx-and-surface-glycans.json", "summary": "The sugar layer on every cell surface and lining every vessel lumen, which the inventory asks to resolve as thickness, composition and shedding, with steric accessibility, adhesion and charge. The row's findings are mostly about what kind of variable this is. Ligand retention depends on sufficiently long, appropriately spaced N-sulfated heparan sulfate domains rather than a precise sugar sequence, and losing that sulfation detaches pericytes (L18) - so the operative property is a statistical pattern. Chemokines that cannot bind glycosaminoglycans still migrate cells in vitro and recruit nothing in vivo, so the directing signal is immobilised on this layer and a soluble concentration is a different quantity (L05). Sialylated glycans on tumour and stromal cells engage inhibitory lectins on immune cells as glyco-immune checkpoints, varying markedly by cancer type and reprogrammed by MYC, SOX2 and androgen receptor signalling (L176). And the thickness the inventory asks for first is measured clinically as an inverse proxy rather than a thickness (L177).", "stateAxes": [ { "axis": "Composition, as a pattern rather than an inventory", "whatToMeasure": "Sulfation density and the length and spacing of N-sulfated domains, because retention requires sufficiently long, appropriately spaced domains rather than a precise sugar sequence - and sialylation density for the immune axis.", "interpretationLimit": "Mouse development in healthy tissue for the sulfation work, with the retention requirement described as inferred from binding properties rather than directly demonstrated. No sulfation density, domain length, spacing or binding capacity is given as a number, and no sialylation density anywhere - so both patterns are named and neither is parameterised.", "evidence": [ "L18", "L176" ] }, { "axis": "What this layer does to a signal's representation", "whatToMeasure": "Immobilised rather than soluble ligand, since glycosaminoglycan-binding-deficient chemokines migrate cells in vitro and recruit none in vivo, and monomeric variants that signal normally in vitro are likewise inactive.", "interpretationLimit": "A limited set of chemokines around 2003, with the authors saying certain chemokines rather than all, and a standing objection that deficient mutants can still act by diffusion. The finding identifies the wrong variable without supplying the right one - no immobilised concentration, binding capacity or gradient length scale is measured.", "evidence": [ "L05" ] }, { "axis": "Steric and immune accessibility", "whatToMeasure": "Sialoglycan display and the inhibitory lectins that read it, per environment and per lineage - because repertoires and lectin expression vary markedly across cancer types and disease states, and stromal fibroblasts as well as tumour cells generate the ligands.", "interpretationLimit": "A review with no density, occupancy or expression level, and whose central message is that the axis is context-dependent - so any value would be per-environment by the source's own argument. Therapy is said to modify ligand availability and immune composition dynamically, which flags a time dependence without characterising it.", "evidence": [ "L176" ] }, { "axis": "Thickness, and what the available measurement actually is", "whatToMeasure": "The perfused boundary region, recording that it is an inverse proxy - higher means thinner - with values of 2.11 and 1.97 micrometres reported for two groups in vessels of 4 to 25 micrometres, and a decline with age.", "interpretationLimit": "Twenty-two participants, post hoc, in sublingual microvessels of healthy older adults. These are perfused boundary region values and must never be recorded as glycocalyx thickness. Nothing in the record connects the layer to permeability, and no value exists for any tumour.", "evidence": [ "L177" ] } ], "records": { "L05": { "id": "L05", "year": 2003, "topic": "Transport", "title": "Glycosaminoglycan binding and oligomerization are essential for the in vivo activity of certain chemokines", "url": "https://doi.org/10.1073/pnas.0334864100", "studyType": "Chemokine variants engineered to lose glycosaminoglycan binding or to remain monomeric, compared in standard in vitro chemotaxis against in vivo recruitment, around 2003", "diseaseContext": "Healthy reference", "useInModel": "Says that for this signal class a soluble concentration is the wrong quantity, which makes it a representation finding rather than a measurement. Variants unable to bind glycosaminoglycans still drove migration in standard chemotaxis assays and recruited no cells in vivo; monomeric variants that signalled normally in vitro were likewise inactive. So the directing signal is chemokine immobilised on the glycan layer, and the concentration in fluid is a different quantity from the one cells follow. This atlas records concentrations. For chemokines that is not a missing number but a mis-specified variable - the gradient is a property of the matrix, and a well-mixed field cannot carry it however accurately it is calibrated. It also means oligomerisation state is part of the signal rather than a detail of the molecule.", "limit": "Around 2003, a limited set of chemokines, and the authors say certain chemokines rather than all - so the scope of the claim is explicitly partial. Some argue the case is not closed, since glycosaminoglycan-deficient mutants can still act by diffusion under some conditions. Nothing here measures an immobilised chemokine concentration, a binding capacity of the layer, or a gradient length scale, so the variable is identified as wrong without the right one being supplied.", "provenance": "Re-extracted from the record's own screened content with its scope and the standing objection kept. Both variant classes and their in vitro and in vivo discordance as reported; the consequence for how this atlas represents chemokine signals is its own", "quantitativeExtraction": "extracted" }, "L176": { "id": "L176", "year": 2026, "topic": "Steric accessibility", "title": "Tissue-specific factors that govern the sialoglycan-Siglec axis in cancer", "url": "https://doi.org/10.1042/BSR20250119", "studyType": "Review of sialylation changes in cancer and their engagement of sialic acid-binding lectins, drawing on single-cell evidence, Bioscience Reports 46(1):BSR20250119", "diseaseContext": "Shared cancer", "useInModel": "An inhibitory checkpoint whose ligand is a sugar, which puts it outside everything the atlas's address class can reach. Aberrant sialylation is a persistent glycosylation change in cancer, displayed on malignant and stromal cells, and many sialoglycans engage sialic acid-binding immunoglobulin-like lectins on immune cells that transmit inhibitory signals - glyco-immune checkpoints. Tumour hypersialylation suppresses myeloid and lymphoid antitumour activity, promotes immune evasion and contributes to metastatic behaviour. Four features matter for this atlas. The ligand is not a gene product, so it cannot be addressed by an antibody the way every member of the address class is addressed, and reaching it means acting on an enzyme rather than binding a target. It is environment-specific by construction: sialoglycan repertoires and lectin expression vary markedly across cancer types and disease states, with tissue-of-origin programmes setting basal sialyltransferase expression - which the atlas has repeatedly inferred for markers and here is asserted directly. Stromal cells generate it, with single-cell evidence that cancer-associated fibroblasts acquire hypersialylation and actively produce inhibitory ligands. And it is reprogrammed by oncogenic regulators including MYC, SOX2 and androgen receptor signalling, which couples it to the prostate row's central variable.", "limit": "A review, so the mechanisms are synthesised rather than measured here and no sialylation density, ligand occupancy or lectin expression level is given. Its central message is that the axis is context-dependent, which means any value the atlas might later take would be per-environment and per-lineage rather than general. The claim that therapy dynamically modifies both ligand availability and immune composition is stated as an emerging consideration rather than quantified, so the time dependence is flagged and not characterised. Nothing here is a clinical outcome.", "provenance": "Abstract read in full; the glyco-immune checkpoint framing, the suppression of myeloid and lymphoid activity, the stated variation across cancer types and disease states, the tissue-of-origin constraint on sialyltransferase expression, the single-cell fibroblast finding, the named oncogenic regulators and the therapy-dependence as reported", "quantitativeExtraction": "extracted" }, "L177": { "id": "L177", "year": 2025, "topic": "Thickness", "title": "Sex differences in endothelial glycocalyx thickness and the response to glycocalyx-targeted therapy among older adults", "url": "https://doi.org/10.14814/phy2.70428", "studyType": "Post hoc analysis of 22 participants from a 12-week supplementation trial, with glycocalyx thickness estimated as the perfused boundary region by sidestream dark field videomicroscopy, Physiological Reports 13:e70428", "diseaseContext": "Healthy reference", "useInModel": "Held for what it reveals about the measurement rather than for its result, because the inventory asks for thickness first and the available clinical quantity is not a thickness. Glycocalyx thickness is estimated as the perfused boundary region, where a higher value means a thinner glycocalyx - an inverse proxy derived from how far red cells stray from the vessel wall. Reported values were 2.11 plus or minus 0.14 micrometres in postmenopausal females against 1.97 plus or minus 0.13 in older males for vessels 4 to 25 micrometres, with body mass index retaining an association in multivariate analysis where sex did not. So if the atlas stores a glycocalyx thickness it will be storing a number measured indirectly and reported in the opposite direction to the state of interest, which must travel with the value. The layer also thins with age, so this geometry has a demographic dependence that none of the atlas's other barrier geometries carry.", "limit": "Twenty-two participants, post hoc, in a supplement trial rather than a study designed for this question, and in sublingual microvessels rather than any tissue the atlas models. The quantity is an inverse proxy and not a measured thickness, so these figures are perfused boundary region values and should never be recorded as glycocalyx thickness. Healthy older adults, no tumour, and nothing connects the layer to permeability in this record. The supplementation result is a secondary finding in a small post hoc comparison and carries no weight here.", "provenance": "Abstract read in full; the perfused boundary region method and its inverse relationship to thickness, both group values with standard deviations and the vessel calibre range, the multivariate attenuation of sex against body mass index, and the stated decline with age as reported", "quantitativeExtraction": "extracted" }, "L18": { "id": "L18", "year": 2007, "topic": "Molecular structure", "title": "Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development", "url": "https://doi.org/10.1101/gad.398207", "studyType": "Reduced N-sulfation of heparan sulfate in mouse vascular development, with PDGF-BB binding measured in vitro and pericyte coverage and migration assessed in vivo", "diseaseContext": "Healthy reference", "useInModel": "Tests what the glycan layer has to be like for a ligand to stay put, and the answer is a pattern rather than a sequence. Reducing N-sulfation of heparan sulfate cut PDGF-BB binding and produced pericyte detachment and delayed migration in vivo, reproducing the phenotype of a ligand retention-motif mutant. The requirement is for sufficiently long, appropriately spaced N-sulfated domains rather than a precise sugar sequence. That is the second structural property in this category that is a pattern and not an inventory, after junctional arrangement - and it is a statistical description, so a model needs sulfation density and spacing rather than a list of present molecules. It also makes the retention of a growth factor a property of the matrix, which is the same conclusion the chemokine record reaches from the ligand side.", "limit": "Mouse development in healthy tissue, so nothing here describes the layer in a tumour. The heparan sulfate requirement for retention in development is described as inferred from the binding properties of the motif rather than directly demonstrated, and that qualification should travel with it. No sulfation density, domain length, spacing or binding capacity is given as a number, so the pattern is named and not parameterised.", "provenance": "Re-extracted from the record's own screened content with its inference qualification kept. The N-sulfation manipulation, the binding and in vivo phenotypes, the phenocopy of the retention-motif mutant, and the pattern-not-sequence requirement as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I065", "name": "Basement membrane", "category": "Structures", "whereToCheck": "Vessel and epithelial interfaces", "states": [ "Intact", "fragmented", "remodeled" ], "behaviors": [ "Collagen IV", "laminins", "nidogens", "perlecan", "thickness and gaps" ], "slots": { "size": { "status": "references available", "referenceIds": [ "rayat-gbm" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "rayat-gbm" ], "priorResearch": { "path": "simulation/data/profiles/basement-membrane.json", "summary": "The sheet beneath every epithelium and around every vessel, whose breach is the definition of invasive carcinoma. The inventory asks for intact, fragmented and remodelled states, with collagen IV, laminins, nidogens, perlecan, and thickness and gaps. What the row actually supplies is a threshold rather than a thickness, and it is the atlas's first hard geometric limit: migration independent of matrix metalloproteinases declines as a linear function of pore size and arrests at 10 percent of the nuclear cross section - 7 square micrometres for tumour cells, 4 for T cells, 2 for neutrophils - with proteolysis and actomyosin force acting as modulators that extend the range rather than as gates (L178). The composition the inventory lists is related to the mechanics by assembly rather than by presence, and the methods used to measure those mechanics include one that is explicitly non-quantitative (L179).", "stateAxes": [ { "axis": "Gaps, as a threshold with cell-type-specific values", "whatToMeasure": "Pore cross-section against the passing cell's nuclear cross-section, since arrest comes at 10 percent of it - 7 square micrometres for tumour cells, 4 for T cells, 2 for neutrophils - with a linear decline in migration above that limit.", "interpretationLimit": "Engineered collagen lattices and synthetic porous substrates, not basement membrane and not tissue, so these describe interstitial passage better than crossing a dense sheet. Values are at arrest in specific cell types under specific conditions, and nuclear deformability varies with lamin composition and cell state, which the study does not survey.", "evidence": [ "L178" ] }, { "axis": "What proteolysis actually does", "whatToMeasure": "Whether a cell is passing by deformation or by widening the pore, because MMP-independent migration exists and declines with pore size while enzymes extend the range - so proteolysis shifts the threshold rather than permitting or forbidding passage.", "interpretationLimit": "Demonstrated in degradable against non-degradable substrates rather than in tissue, and the atlas holds no measurement of pericellular proteolysis in any environment. The finding is about the structure of the dependency rather than its magnitude.", "evidence": [ "L178" ] }, { "axis": "Mechanics, and the method that produced them", "whatToMeasure": "Stiffness with its measurement method attached, since atomic force microscopy, tensile stiffness assays and non-quantitative approaches such as cell bursting are all in use and differ in what they can support.", "interpretationLimit": "From a review that supplies no values, across tissues whose basement membranes differ substantially. One method in common use is explicitly non-quantitative, so a stiffness figure without its provenance is not interpretable - and the review notes the biological and engineering literatures describing this structure do not share foundations.", "evidence": [ "L179" ] }, { "axis": "Intact, fragmented, remodelled", "whatToMeasure": "The three states the inventory names, none of which any record here measures - the same absence the junction row reported for the same three words.", "interpretationLimit": "Both Structures rows asked to resolve intact, remodelled and disrupted states have produced evidence only from healthy tissue, engineered substrates or untreated models. The state every drawn environment presents is the one the category cannot describe.", "evidence": [ "L179" ] } ], "records": { "L178": { "id": "L178", "year": 2013, "topic": "Thickness and gaps", "title": "Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force", "url": "https://doi.org/10.1083/jcb.201210152", "studyType": "Migration quantified in MMP-degradable collagen lattices and non-degradable substrates of varying porosity, with nuclear deformation measured to the point of physical arrest, Journal of Cell Biology 201(7):1069-1084", "diseaseContext": "Shared cancer; healthy reference", "useInModel": "The atlas's first hard geometric threshold, and it is cell-type-specific. Migration independent of matrix metalloproteinases declined as a linear function of pore size and with deformation of the nucleus, with arrest reached at 10 percent of the nuclear cross section - 7 square micrometres for tumour cells, 4 for T cells, 2 for neutrophils. Residual migration under space restriction depended on MMP-dependent cleavage enlarging pore diameters and on integrin- and actomyosin-dependent force that jointly propelled the nucleus. Three things follow. The project has recorded local mechanisms without length scales repeatedly; here is a threshold with numbers and a linear relationship above it, so a model can interpolate rather than guess. The limiting structure is the nucleus, which means the hardest constraint in the Structures category is set by a component of the Intracellular category. And proteolysis is a modulator rather than a gate: migration happens without it and declines with pore size, while enzymes extend the range by widening pores - so blocking proteases shifts a threshold rather than closing a door.", "limit": "Engineered collagen lattices and synthetic porous substrates, not basement membrane and not tissue - so the thresholds are properties of cells moving through characterised pore geometries rather than measurements of any real interface. Basement membrane is a dense sheet rather than a porous lattice, so these numbers describe interstitial passage better than they describe crossing this family. The values are cross-sectional areas at arrest in specific cell types under specific conditions, and nuclear deformability varies with lamin composition and cell state, which this does not survey. Nothing here measures a pore size in any drawn environment.", "provenance": "Abstract read in full; the experimental systems, the linear dependence on pore size, the arrest criterion at 10 percent of nuclear cross section with all three cell-type values, and the roles of proteolysis and force generation as modulators as reported", "quantitativeExtraction": "extracted" }, "L179": { "id": "L179", "year": 2025, "topic": "Molecular structure", "title": "Basement membrane structure and function: Relating biology to mechanics", "url": "https://doi.org/10.1016/j.matbio.2025.08.004", "studyType": "Review relating basement membrane macromolecular structure to mechanical properties, with a survey of measurement methods and their limitations, Matrix Biology 141:16-31", "diseaseContext": "Shared cancer; healthy reference", "useInModel": "Connects this family's composition to its mechanics, which is the step the inventory's component list implies and does not make, and is unusually candid about how the numbers are obtained. The review's argument is that basement membrane macromolecular structure is what confers mechanical properties adapted to resisting physiological stress, that these membranes are altered in cancer, diabetes and fibrosis, and that the alterations may contribute to pathogenesis and progression. It then surveys the methods - atomic force microscopy, tensile stiffness assays, and non-quantitative assays such as cell bursting - assessing their strengths, limitations and accessibility for in vivo work. For this atlas the methodological survey is the more useful half: any stiffness value it later ingests will carry a method with it, and one of the methods in common use is explicitly non-quantitative. The review is also written to bridge biologists and engineers, which is a candid statement that the two literatures describing this structure do not share foundations.", "limit": "A review, so it supplies no value for thickness, pore size, stiffness or any other property - it explains how such values arise and how they are measured. The disease alterations are described as potentially contributing to pathogenesis, which is a hypothesis rather than a result. Nothing here is specific to any drawn environment, and the mechanical properties discussed are of basement membrane generally across tissues that differ substantially.", "provenance": "Abstract read in full; the structure-to-mechanics argument, the named diseases in which basement membranes are altered with its hedged causal claim, all three classes of measurement method including the explicitly non-quantitative one, and the stated interdisciplinary gap as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I066", "name": "Interstitial fibrillar matrix", "category": "Structures", "whereToCheck": "Stroma", "states": [ "Aligned", "crosslinked", "degraded" ], "behaviors": [ "Collagens I/III", "fibronectin", "pore paths", "stiffness" ], "slots": { "size": { "status": "references available", "referenceIds": [ "grant-collagen-length", "grant-collagen-width" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "grant-collagen-length", "grant-collagen-width" ], "priorResearch": { "path": "simulation/data/profiles/interstitial-fibrillar-matrix.json", "summary": "The fibrillar scaffold of the stroma, which the inventory asks to resolve as aligned, crosslinked and degraded, with collagens I and III, fibronectin, pore paths and stiffness. Three of the row's four findings are about transport and one is about force. There is no convection inside a tumour: without lymphatic drainage, fluid from leaky vessels has nowhere to go, pressure rises until it approaches microvascular pressure, the gradient that would carry a large molecule in disappears, and pressure is uniform across the interior while falling steeply at the margin - so the gradient and the exit are both at the rim (V44). Degradation of this matrix is not a diffusible field: six soluble proteolytic routes could be removed with invasion intact, and deleting one membrane-tethered enzyme abolished it (L28). Which pressure collapses a vessel is contested and resolves toward solid stress (L26). And crosslinking this matrix stiffens it, clusters integrins, raises PI3 kinase activity and drives invasion, with reducing the crosslinking enzyme lowering tumour incidence (L180).", "stateAxes": [ { "axis": "Crosslinked, and the force it transmits", "whatToMeasure": "Crosslinking and the integrin clustering it produces, since forced clustering reproduced the invasive phenotype without altering the matrix - so the operative variable is what the cell reads rather than the bulk property alone.", "interpretationLimit": "Mouse models and engineered matrices in one tissue with a fixed oncogenic background. No stiffness value in pascals is held, and none for human tumour, so the loop is causal and unparameterised - crosslinking raises stiffness by an unknown amount from an unknown baseline.", "evidence": [ "L180" ] }, { "axis": "Degraded, as a surface property rather than a field", "whatToMeasure": "Whether a membrane-tethered collagenase is present at a cell-matrix contact, because six soluble proteolytic routes were removable with invasion intact and deleting the single tethered enzyme abolished it, in fibroblasts and tumour cells alike.", "interpretationLimit": "Cell and explant systems with mouse genetics, and invasion assays rather than a tumour in a drawn environment. It establishes which enzyme is required for collagen traffic and not how much matrix is turned over anywhere; other substrates may be handled by the routes excluded here.", "evidence": [ "L28" ] }, { "axis": "Transport through it, and why convection is absent", "whatToMeasure": "Interstitial pressure relative to microvascular pressure, and position relative to the margin - since pressure is uniform across the interior and falls steeply at the rim, putting both the gradient and the exit there.", "interpretationLimit": "A review that explains why measured pressures matter without measuring them, and whose spatial profile is a general description rather than a per-environment map. It predates the dispute over whether fluid pressure or solid stress collapses vessels and assumes the former.", "evidence": [ "V44", "L26" ] }, { "axis": "Aligned, and pore paths", "whatToMeasure": "Fibre orientation and pore cross-section - the latter being exactly what the basement membrane row's arrest threshold needs, since passage fails at 10 percent of a cell's nuclear cross-section.", "interpretationLimit": "Neither is served by any record here. Alignment is a named state with no evidence, and pore geometry is the quantity two Structures rows now depend on and neither measures - so the atlas holds a threshold and the matrix that threshold applies to, and cannot connect them.", "evidence": [] } ], "records": { "L180": { "id": "L180", "year": 2009, "topic": "Stiffness", "title": "Matrix crosslinking forces tumor progression by enhancing integrin signaling", "url": "https://doi.org/10.1016/j.cell.2009.10.027", "studyType": "Manipulation of collagen crosslinking in both directions in breast models, with integrin signalling inhibition and forced clustering, and lysyl oxidase reduction in an MMTV-Neu background, Cell 139(5):891-906", "diseaseContext": "Breast", "useInModel": "A closed causal loop from a mechanical property to a phenotype, with both arms manipulated - which the atlas had recorded as existing in only one other place. Breast tumorigenesis was accompanied by collagen crosslinking, matrix stiffening and increased focal adhesions. Inducing crosslinking stiffened the matrix, promoted focal adhesions, enhanced PI3 kinase activity and induced invasion of an oncogene-initiated epithelium; inhibiting integrin signalling repressed invasion into a stiffened matrix, and forcing integrin clustering reproduced the whole sequence without changing the matrix. In the other direction, reducing lysyl oxidase-mediated crosslinking prevented fibrosis, decreased focal adhesions and PI3 kinase activity, impeded malignancy and lowered tumour incidence. For this atlas that is a mechanical input with a named transduction route and an intervention point - the crosslinking enzyme - and the forced-clustering arm is what makes it a mechanism rather than a correlation, since it shows the matrix matters through integrin clustering specifically.", "limit": "Mouse models and engineered matrices in one tissue, with the oncogenic background fixed, so this is how stiffness acts in breast rather than a general law. No stiffness value in pascals is extracted here and none for human tumour, so the loop is causal and unparameterised - the atlas can say crosslinking raises stiffness and cannot say by how much or from what baseline. Lowered tumour incidence is the strongest claim in the record and comes from one genetic background.", "provenance": "Abstract read in full; the accompanying changes in tumorigenesis, the induction arm with its signalling consequences, the integrin inhibition and forced-clustering experiments, and the lysyl oxidase reduction arm including the effect on tumour incidence as reported", "quantitativeExtraction": "extracted" }, "L26": { "id": "L26", "year": 2014, "topic": "Transport comparator", "title": "Compression of pancreatic tumor blood vessels by hyaluronan is caused by solid stress and not interstitial fluid pressure", "url": "https://doi.org/10.1016/j.ccr.2014.06.003", "studyType": "Published commentary disputing the mechanism in Q02, Cancer Cell 26(1):14-15", "diseaseContext": "Pancreatic", "useInModel": "Keeps a measurement and rejects its mechanism, which is a distinction the atlas should preserve rather than collapse. The pressures reported in the pancreatic hyaluronan work are not disputed; what is disputed is which quantity closes the vessel. This commentary argues that hyaluronan compresses pancreatic tumour vessels through solid stress - mechanical stress stored in matrix and cells - rather than through interstitial fluid pressure, on the ground that a fluid pressure cannot by itself collapse a vessel it acts on from outside while that fluid is continuous with the vessel's own. The atlas already holds a record in which proliferating tumour cells generate solid stress compressing intratumoural vessels, so the dispute resolves toward a quantity it was already tracking - and it means the interstitial fluid pressure framing inherited from the older review should not be used to explain vessel collapse.", "limit": "A two-page commentary rather than a new experiment, so it establishes that the causal variable is contested and not which one is right. Neither solid stress nor interstitial fluid pressure is measured in any drawn environment in this atlas, so the dispute is recorded without either quantity being available. A second commentary in the same issue addresses what the two pressures mean and how they are measured, which this record does not summarise.", "provenance": "Re-extracted from the record's own screened content. The retained measurement, the disputed mechanism, the physical argument offered against fluid pressure, and the existence of a companion commentary as reported", "quantitativeExtraction": "extracted" }, "L28": { "id": "L28", "year": 2004, "topic": "Matrix and movement", "title": "Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP", "url": "https://doi.org/10.1083/jcb.200408028", "studyType": "Invasion assays in cells from gene-targeted mice, in vitro and in vivo, J Cell Biol 167(4):769-781", "diseaseContext": "Shared cancer", "useInModel": "Says a soluble protease concentration is the wrong object, which makes this the second representation finding of its kind in the atlas. Collagenolytic and invasive activity survived removal of plasminogen, the gelatinase A and TIMP-2 axis, gelatinase B, collagenase-3, collagenase-2 and stromelysin-1 - six soluble proteolytic routes, deleted or suppressed, with invasion intact. Deleting or suppressing the single membrane-tethered enzyme MT1-MMP abolished it, in fibroblasts and in tumour cells, in vitro and in vivo, and the two cell types were indistinguishable in the activity. So matrix degradation is a property of cell surfaces in contact with matrix rather than a diffusible field with a rate constant, and the concentration of protease in the interstitium carries almost no information. The glycan row reached the same conclusion for chemokines, whose directing form is immobilised on the matrix. Two different molecule classes, same error: the atlas records concentrations and the operative form is surface-bound.", "limit": "Cell and explant systems with mouse genetics, and the in vivo component is invasion assays rather than a tumour in a drawn environment. It establishes which enzyme is required for collagen traffic and not how much matrix is turned over anywhere, and other matrix components may be handled differently. Six routes were excluded for collagen specifically, which does not make them irrelevant to other substrates.", "provenance": "Re-extracted from the record's own screened content. All six excluded proteolytic routes, the requirement for the membrane-tethered enzyme in both cell types and both settings, and the pericellular character of the activity as reported. The pairing with the chemokine finding is this atlas's own", "quantitativeExtraction": "extracted" }, "V44": { "id": "V44", "year": 2004, "topic": "Transport", "title": "High interstitial fluid pressure - an obstacle in cancer therapy", "url": "https://doi.org/10.1038/nrc1456", "studyType": "Review, Nat Rev Cancer 4(10):806-813", "diseaseContext": "Shared cancer", "useInModel": "Explains why nothing moves by convection inside a tumour, which is the step between the junction row's entry problem and the matrix's own geometry. Without lymphatic drainage, fluid entering from leaky vessels has nowhere to go, so pressure rises until it approaches microvascular pressure and the gradient that would carry a large molecule into tissue disappears. The spatial description matters as much: pressure is reported as uniform across the tumour interior and falling steeply at the margin, so the gradient and the exit are both at the rim. Taken with the junction row, the atlas can now name the limiting step at each stage of delivery - permeability limits entry and puts tissue-surface concentration one hundred to one thousand times below plasma, and once inside there is no convection, so transport is diffusion alone through a matrix whose pore geometry the atlas does not measure.", "limit": "A review. It explains why the pressures measured in breast and pancreatic tumours matter for delivery and does not measure them, and the spatial profile is a general description rather than a per-environment map. It also predates the dispute recorded elsewhere in this atlas over whether interstitial fluid pressure or solid stress is the quantity that collapses vessels, and its framing assumes the former.", "provenance": "Re-extracted from the record's own screened content. The drainage argument, the approach of interstitial to microvascular pressure, the loss of the convective gradient, and the uniform-interior-steep-margin profile as reported. The assembly of the delivery chain across rows is this atlas's own", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I067", "name": "Hyaluronan and other proteoglycans", "category": "Structures", "whereToCheck": "Tissue-specific interstitium", "states": [ "Abundance", "fragment size", "hydration" ], "behaviors": [ "Pressure", "diffusion", "ligand retention" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "synovial-ha" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "synovial-ha" ], "priorResearch": { "path": "simulation/data/profiles/hyaluronan-and-other-proteoglycans.json", "summary": "The hydrated, space-filling fraction of the interstitium, which the inventory asks to resolve as abundance, fragment size and hydration, with pressure, diffusion and ligand retention. The row's organising finding is that fragment size rather than abundance is the state that matters, and that the enzymes which change it are a double-edged intervention. In gastric cancer, matrix hyaluronan rose during neoadjuvant chemotherapy, a hyaluronidase degraded it to low-molecular-weight form, and that product promoted lymphatic metastasis through CD44, ATF3 and the TGF-beta receptor (L181); in an unrelated tissue the same polymer was protective at high molecular weight and harmful at low, through the same receptor (L182). The atlas already held both halves of this family's delivery story: interstitial pressures of 75 to 130 mmHg in pancreatic tumour against 8 to 13 in normal pancreas, exceeding capillary pressure (Q02), and a phase 3 hyaluronidase trial that raised response from 36 to 47 percent and failed its endpoint (Q03). Proliferation-generated solid stress is the compressing quantity (V43).", "stateAxes": [ { "axis": "Fragment size, which inverts the effect", "whatToMeasure": "The molecular weight distribution rather than the amount, because high-molecular-weight polymer and its low-molecular-weight fragments act oppositely through the same receptor, and the conversion is enzymatic.", "interpretationLimit": "Neither record gives a molecular weight value or a threshold, so high and low are categories rather than measurements. One is gastric cancer in patients and nude mice, the other intervertebral disc degeneration in mice - held for the principle and the shared receptor rather than as calibration for any drawn environment.", "evidence": [ "L181", "L182" ] }, { "axis": "Pressure, and which pressure", "whatToMeasure": "Interstitial fluid pressure against capillary pressure - 75 to 130 mmHg in pancreatic tumour against 8 to 13 in normal pancreas, with capillary pressure typically 15 to 40 - and separately solid stress, which is the quantity that appears to do the compressing.", "interpretationLimit": "Mouse, pancreatic, small groups - four to eight animals per pressure measurement. Solid stress is nowhere measured as a force; it is inferred from vessel geometry. So the atlas holds numbers for the consequence and none for the cause.", "evidence": [ "Q02", "V43", "L26" ] }, { "axis": "Abundance, and its dependence on treatment", "whatToMeasure": "Hyaluronan content over the course of therapy rather than at baseline, since the proportion in matrix increased significantly during neoadjuvant chemotherapy - so the barrier is not a fixed property of the tumour.", "interpretationLimit": "Reported as a significant increase in proportion without a value or a time course, in gastric cancer. No abundance measurement exists for this family in any drawn environment, which makes the treatment-dependence a direction without a magnitude.", "evidence": [ "L181" ] }, { "axis": "Hydration, diffusion and ligand retention", "whatToMeasure": "The three remaining things the inventory asks for, none of which any record here measures - though the glycan row establishes that retention of chemokines and growth factors is a property of this kind of matrix rather than of the fluid.", "interpretationLimit": "Hydration has no record at all. Diffusion through this specific fraction has none either, which matters because the delivery chain's third stage - the geometry a molecule diffuses through - is the atlas's weakest link and this is the fraction that fills it.", "evidence": [] } ], "records": { "L181": { "id": "L181", "year": 2026, "topic": "Fragment size", "title": "Blocking CEMIP2-mediated low-molecular-weight hyaluronic acid-TGF-beta signaling inhibits chemotherapy-associated lymphatic metastasis in gastric cancer", "url": "https://doi.org/10.1016/j.canlet.2026.218462", "studyType": "Patient and nude mouse observation of chemotherapy-associated lymphatic metastasis with hyaluronidase identification, mechanistic dissection and targeted siRNA delivery by engineered exosome mimics, Cancer Letters 649:218462", "diseaseContext": "Gastric / GEJ", "useInModel": "Makes fragment size the variable rather than abundance, and raises a specific problem for the atlas's own calibration target. Chemotherapy-associated lymphatic metastasis occurred during neoadjuvant treatment in both patients and mice; the proportion of hyaluronan in the matrix increased significantly during chemotherapy; CEMIP2 was the most highly expressed hyaluronidase and degraded hyaluronan into low-molecular-weight form, which promoted the metastasis; and the route was low-molecular-weight hyaluronan activating CD44 and ATF3 to upregulate the TGF-beta receptor TGFBR1. Targeted CEMIP2 silencing suppressed it. Two consequences. The barrier is treatment-dependent - hyaluronan rises during chemotherapy, so the delivery problem the atlas has described gets worse as treatment proceeds rather than staying fixed. And the degradation product is harmful, which bears on the phase 3 trial this atlas calls the result it should be calibrated against: a therapeutic hyaluronidase raised objective response from 36 to 47 percent and failed its primary endpoint. A mechanism in which hyaluronidase products drive metastasis through CD44 is a candidate explanation for that gap, and it is a hypothesis rather than a finding - different enzyme, different organ, and nothing tests the link.", "limit": "Gastric cancer in patients and nude mice, with a different hyaluronidase from the therapeutic one and a different organ from the trial it bears on - so the connection to the phase 3 failure is this atlas's inference and is untested. Nude mice lack an adaptive immune system, which matters for a metastasis phenotype. No hyaluronan concentration, fragment size distribution or molecular weight threshold is given, so low-molecular-weight is a category rather than a measurement. The exosome-mimic delivery is a proof of principle in mice.", "provenance": "Abstract read in full; the clinical and mouse observation, the rise in matrix hyaluronan during chemotherapy, the identification of the dominant hyaluronidase and its product, the CD44-ATF3-TGFBR1 route, and the siRNA delivery result as reported. The bearing on the hyaluronidase trial is labelled as this atlas's inference", "quantitativeExtraction": "extracted" }, "L182": { "id": "L182", "year": 2026, "topic": "Fragment size", "title": "HYAL2-generated low-molecular-weight hyaluronic acid promotes intervertebral disc degeneration via the CD44/AKT signaling axis", "url": "https://doi.org/10.1016/j.bbrc.2026.153576", "studyType": "Mouse intervertebral disc degeneration model with hyaluronidase ablation, overexpression and exogenous fragment exposure, plus receptor knockdown and pathway reactivation, Biochemical and Biophysical Research Communications 811:153576", "diseaseContext": "Healthy reference", "useInModel": "A second independent instance of the same principle in a different tissue, which is what makes fragment size a general variable rather than one cancer's quirk. The balance between high- and low-molecular-weight hyaluronan is described as critical; hyaluronidase 2 expression rose in degenerating discs and its genetic ablation attenuated disease; both overexpressing the enzyme and adding exogenous low-molecular-weight hyaluronan induced senescence, inflammatory activation and matrix degradation; CD44 was the essential receptor, its knockdown abolished the effect, and reactivating the suppressed downstream kinase reversed the phenotype. So in two unrelated tissues the same polymer is protective at high molecular weight and harmful at low, the conversion is enzymatic, and the receptor reading the difference is the same one. For this atlas that means abundance is the wrong state to carry for this family - the size distribution is - and that a single receptor is reading a physical property of a polymer rather than a molecular identity.", "limit": "Mouse intervertebral disc degeneration, which is not a drawn environment and is far from cancer - held for the principle and the receptor, not as evidence about any environment the atlas models. No molecular weight values or thresholds are given, so high and low remain categories. The downstream kinase effect is a reversal experiment in culture, and the ablation phenotype is attenuation rather than prevention.", "provenance": "Abstract read in full; the stated criticality of the size balance, the enzyme's increased expression and ablation phenotype, both gain-of-function routes, the receptor requirement by knockdown, and the downstream reversal as reported", "quantitativeExtraction": "extracted" }, "L26": { "id": "L26", "year": 2014, "topic": "Transport comparator", "title": "Compression of pancreatic tumor blood vessels by hyaluronan is caused by solid stress and not interstitial fluid pressure", "url": "https://doi.org/10.1016/j.ccr.2014.06.003", "studyType": "Published commentary disputing the mechanism in Q02, Cancer Cell 26(1):14-15", "diseaseContext": "Pancreatic", "useInModel": "Keeps a measurement and rejects its mechanism, which is a distinction the atlas should preserve rather than collapse. The pressures reported in the pancreatic hyaluronan work are not disputed; what is disputed is which quantity closes the vessel. This commentary argues that hyaluronan compresses pancreatic tumour vessels through solid stress - mechanical stress stored in matrix and cells - rather than through interstitial fluid pressure, on the ground that a fluid pressure cannot by itself collapse a vessel it acts on from outside while that fluid is continuous with the vessel's own. The atlas already holds a record in which proliferating tumour cells generate solid stress compressing intratumoural vessels, so the dispute resolves toward a quantity it was already tracking - and it means the interstitial fluid pressure framing inherited from the older review should not be used to explain vessel collapse.", "limit": "A two-page commentary rather than a new experiment, so it establishes that the causal variable is contested and not which one is right. Neither solid stress nor interstitial fluid pressure is measured in any drawn environment in this atlas, so the dispute is recorded without either quantity being available. A second commentary in the same issue addresses what the two pressures mean and how they are measured, which this record does not summarise.", "provenance": "Re-extracted from the record's own screened content. The retained measurement, the disputed mechanism, the physical argument offered against fluid pressure, and the existence of a companion commentary as reported", "quantitativeExtraction": "extracted" }, "Q02": { "id": "Q02", "year": 2012, "topic": "Transport comparator", "title": "Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma", "url": "https://pubmed.ncbi.nlm.nih.gov/22439937/", "studyType": "Autochthonous KPC/KC mouse pancreatic cancer with in vivo pressure catheter, vessel morphometry and drug-delivery imaging, Cancer Cell 21(3):418-429", "diseaseContext": "Pancreatic", "useInModel": "Gives the pressure that explains why pancreatic vessels are shut, and the size of the delivery gain from opening them. Interstitial fluid pressure measured by catheter was 8-13 mmHg in normal pancreas, mean 10.4 across 8 animals, against 75-130 mmHg in autochthonous PDA, mean 99 in 7 KPC tumours and 87 in 4 KC tumours. That exceeds typical capillary pressure of 15-40 mmHg and overlaps arteriolar pressure of 40-80, which is the mechanical reason the vessels are collapsed rather than absent. Hyaluronan is identified as the determinant: 3 mg/ml of it more than doubled the baseline pressure of carcinoma cells engrafted in collagen alone. A single intravenous dose of the hyaluronidase PEGPH20 brought pressure to 16 mmHg in KC and 22 mmHg in KPC tumours at 24 hours, statistically indistinguishable from normal pancreas, and produced a more than 6.5-fold increase in doxorubicin fluorescence in the tumour. Vessel number did not change - only diameter - so the gain came from reopening existing vessels, not from new ones. With gemcitabine, median survival went from 55.5 days to 91.5 days; the enzyme alone reached 63 days and was not significant.", "limit": "Mouse, pancreatic, small groups: 14 to 16 animals per survival arm and 4 to 8 per pressure measurement. The mechanism is formally disputed - two commentaries in the same journal argue that the vessel compression is caused by solid stress rather than by interstitial fluid pressure, so the measured pressures stand while the causal account does not (L26). And the delivery gain did not translate: the clinical trial of the same enzyme is Q03.", "provenance": "Full text read; pressures, delivery fold-change and survival medians taken from results and figure legends", "quantitativeExtraction": "extracted" }, "V43": { "id": "V43", "year": 2004, "topic": "Transport", "title": "Cancer cells compress intratumour vessels", "url": "https://doi.org/10.1038/427695a", "studyType": "Mouse tumour imaging, Nature 427(6976):695", "diseaseContext": "Shared cancer", "useInModel": "Gives the mechanism for the vessel that is not there, and it is growth rather than failure to form. Proliferating tumour cells generate solid stress that compresses intratumoural vessels, lymphatics included - so the absent drainage that lets interstitial pressure rise toward microvascular pressure is a mechanical consequence of proliferation. That matters for the delivery chain this atlas has assembled: the second stage, where convection disappears, is caused by the first thing a tumour does. It also settles which way to read the recorded dispute over vessel collapse: a commentary argues that hyaluronan compresses pancreatic vessels through solid stress rather than interstitial fluid pressure, and this record supplies solid stress from an independent source, so the atlas should carry solid stress as the compressing quantity and interstitial pressure as its consequence.", "limit": "Mouse tumour models in a brief report. Solid stress is not measured in any drawn environment here, and compression is inferred from vessel geometry rather than from a measured force - so the mechanism is identified and the quantity is absent, which is the same position the atlas is in for the pressures it does hold.", "provenance": "Re-extracted from the record's own screened content. The proliferation-generated solid stress, the inclusion of lymphatics among the compressed vessels, and the inference of compression from geometry as reported. The reading of the vessel-collapse dispute is this atlas's own", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I068", "name": "Cell adhesion machinery", "category": "Structures", "whereToCheck": "Cell-cell and cell-matrix contacts", "states": [ "Expression", "activation", "clustering" ], "behaviors": [ "Integrins", "ICAM/VCAM", "cadherins", "mechanical coupling" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "adhesion-hev-rolling" ], "priorResearch": { "path": "simulation/data/profiles/cell-adhesion-machinery.json", "summary": "The molecules that hold cells to each other and to matrix, which the inventory asks to resolve as expression, activation and clustering, with integrins, ICAM and VCAM, cadherins and mechanical coupling. The row's content turns out to be about entry. Lymphocyte entry into a tumour is concentrated at a specialised venular subtype rather than spread across the vasculature: under 10 percent of lymphocytes rolled along ordinary tumour vessels against nearly 40 percent along tumour-associated high endothelial venules, with extravasation rising to match, and these were major entry sites at baseline and under checkpoint blockade, their presence predicting response (V38). Those venules are a distinct phenotype with an identifying addressin, appearing in tumours alongside tertiary lymphoid structures (V39). And crossing the wall is not one event but an ordered sequence of ICAM-2, then JAM-A, then PECAM-1, each separately blockable (V40).", "stateAxes": [ { "axis": "Where entry happens - portals rather than vasculature", "whatToMeasure": "The density of specialised high endothelial venules and the fraction of rolling and extravasating lymphocytes attributable to them: under 10 percent at ordinary tumour vessels against nearly 40 percent at these venules.", "interpretationLimit": "Intravital imaging in mouse tumours, giving proportions of observed lymphocytes rather than absolute fluxes - a ratio, not a rate, with no cells per vessel per unit time. The association with checkpoint response is correlative, and nothing establishes what makes these venules appear, which is what a model would need in order to change them.", "evidence": [ "V38", "V39" ] }, { "axis": "Crossing, as an ordered sequence", "whatToMeasure": "Which step of the sequence is limiting, since ICAM-2, JAM-A and PECAM-1 act in turn and each is separately blockable - so a single transmigration rate is a collapsed variable.", "interpretationLimit": "Established for neutrophils crossing activated venular endothelium, not for lymphocytes entering a tumour through the specialised venules this row's other records describe, and whether the order holds there is untested. No step duration, transition probability or flux, so the sequence is ordered and unparameterised.", "evidence": [ "V40" ] }, { "axis": "Activation and clustering, not expression", "whatToMeasure": "Integrin activation state and clustering rather than abundance, because the matrix row shows forced clustering reproducing an invasive phenotype with the matrix unchanged - so clustering carries the signal and expression is only a precondition.", "interpretationLimit": "No record in this row measures activation or clustering directly; the inference comes from the matrix row's manipulation. So the two states the inventory asks for beyond expression are argued for rather than measured here, and no clustering density, bond lifetime or force value exists anywhere in the atlas.", "evidence": [ "V40" ] }, { "axis": "Mechanical coupling", "whatToMeasure": "The force transmitted across adhesions, which the inventory names and which the atlas touches only through the matrix row's stiffness loop - crosslinking to clustering to kinase activity to invasion.", "interpretationLimit": "Not served by any record in this row. The atlas holds a causal loop through integrin clustering and no bond force, catch-bond lifetime or traction measurement anywhere, so mechanical coupling is a named behaviour with its mechanism one row over and its magnitude nowhere.", "evidence": [] } ], "records": { "V38": { "id": "V38", "year": 2022, "topic": "Accessibility", "title": "Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy", "url": "https://doi.org/10.1016/j.ccell.2022.01.002", "studyType": "Mouse intravital imaging with human melanoma cohorts", "diseaseContext": "Melanoma / Shared cancer", "useInModel": "Says lymphocyte entry into a tumour happens at portals rather than across the vasculature, and quantifies the concentration. By intravital imaging, under 10 percent of lymphocytes rolled along non-HEV tumour vessels against nearly 40 percent along tumour-associated high endothelial venules, with extravasation rising to match, and these vessels were major sites of entry both at baseline and under checkpoint blockade - and their presence predicted response to combination checkpoint therapy. Three uses. The atlas carries twenty immune rows and has had no entry mechanism for any of them; this is it, and it is localised rather than distributed. It supplies a third candidate explanation for immune exclusion alongside the steric and the signalled ones: a tumour may lack T cells because it lacks the portals, which is distinguishable from both by looking for the venular phenotype. And because portal presence predicts checkpoint response, this is a measurable and clinically validated quantity rather than a mechanistic conjecture.", "limit": "Intravital imaging in mouse tumours, so the rolling and extravasation fractions are mouse measurements in model tumours rather than human values. Rolling and extravasation are proportions of observed lymphocytes rather than absolute fluxes, so the atlas gains a ratio and not a rate - no cells per vessel per unit time. The predictive association with checkpoint response is correlative. It does not establish what makes these venules appear, which is the question a model would need in order to change them.", "provenance": "Re-extracted from the record's own screened content. Both rolling proportions, the matching rise in extravasation, the status of these vessels as major entry sites at baseline and under treatment, and the predictive association as reported. The framing as a third exclusion hypothesis is this atlas's own", "quantitativeExtraction": "extracted" }, "V39": { "id": "V39", "year": 2021, "topic": "Accessibility", "title": "High endothelial venules (HEVs) in immunity, inflammation and cancer", "url": "https://doi.org/10.1007/s10456-021-09792-8", "studyType": "Review, Angiogenesis 24:719-753", "diseaseContext": "Shared cancer", "useInModel": "Gives the portal a phenotype and a marker, which is what makes the entry finding actionable rather than descriptive. High endothelial venules are a distinct venular state identified by peripheral node addressin with the MECA-79 antibody, built for lymphocyte entry, and in tumours they appear alongside tertiary lymphoid structures. That last association matters for this atlas, which already records tertiary lymphoid structures improving immunotherapy response in melanoma and generating antibody-producing plasma cells - so the portal and the local lymphoid organisation arrive together, and a row that counts one should expect the other. It is also the reference for what separates a specialised venule from a merely inflamed one, which is the distinction a model needs if it is to treat entry as portal-limited rather than as a property of inflammation.", "limit": "A review, so it supplies a phenotype and a marker rather than any density, number of portals per tumour, or flux through one. The co-occurrence with tertiary lymphoid structures is an association and does not establish which comes first or whether either requires the other. Across immunity, inflammation and cancer, so not specific to any drawn environment.", "provenance": "Re-extracted from the record's own screened content. The venular phenotype and its identifying addressin and antibody, the purpose-built character for lymphocyte entry, and the co-occurrence with tertiary lymphoid structures in tumours as reported", "quantitativeExtraction": "extracted" }, "V40": { "id": "V40", "year": 2009, "topic": "Accessibility", "title": "Endothelial cell activation leads to neutrophil transmigration as supported by the sequential roles of ICAM-2, JAM-A and PECAM-1", "url": "https://doi.org/10.1182/blood-2008-11-188375", "studyType": "Mouse inflamed cremaster, intravital imaging with blocking", "diseaseContext": "Healthy reference", "useInModel": "Breaks crossing the vessel wall into an ordered sequence, which means a single transmigration rate is a collapsed variable. ICAM-2, then JAM-A, then PECAM-1 act in turn as a leukocyte crosses the venular wall after endothelial activation - distinct steps, each separately blockable. For a simulation that has two consequences. A model with one crossing probability cannot represent an intervention that blocks the second step but not the first, and the atlas holds several agents whose targets sit in this sequence. And because the steps are sequential rather than parallel, expression of all three molecules is not the same as a functioning route - the route can be interrupted anywhere along it while every component is present.", "limit": "One leukocyte type crossing venular endothelium after activation, so the ordering is established for neutrophils in that setting rather than for lymphocytes entering a tumour through the specialised venules this row's other records describe. No step duration, transition probability or flux is given, so the sequence is ordered and unparameterised. Whether the same order holds at tumour-associated high endothelial venules is untested here.", "provenance": "Re-extracted from the record's own screened content. The three molecules, their sequential rather than parallel roles, the dependence on endothelial activation, and the separate blockability of each step as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "adhesion-hev-rolling" ] }, { "id": "I069", "name": "Synapses and neuromuscular junctions", "category": "Structures", "whereToCheck": "Neural modules", "states": [ "Functional", "weakened", "lost", "remodeling" ], "behaviors": [ "Pre/post-synaptic structure", "transmission", "clearance" ], "slots": { "size": { "status": "references available", "referenceIds": [ "held-synaptic-vesicles", "held-synaptic-cleft" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "held-synaptic-vesicles" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "held-synaptic-vesicles", "held-synaptic-cleft" ], "priorResearch": { "path": "simulation/data/profiles/synapses-and-neuromuscular-junctions.json", "summary": "The contacts between neurons, and between motor neurons and muscle, which the inventory asks to resolve as functional, weakened, lost or remodelling. The atlas already held the central-nervous half of this row's biology from three directions - complement and microglia mediating early synapse loss in Alzheimer's models, amyloid-beta dimers from patient brains impairing plasticity, and progranulin deficiency driving circuit-specific microglial pruning via complement - all mechanism and no magnitude. This row adds the magnitude and the junction. Synaptic density is now measurable in a living person: global cortical SV2A binding was 16.4 percent lower in patients than age-matched controls, with regional reductions of 16 to 26 percent (L184). It is also unstable - a night of sleep deprivation raised the same marker by 3 to 6 percent across regions, a fifth to a third of the disease effect (L185). And at the neuromuscular junction, denervation proved region-specific and, in a TDP-43 model, concurrent with motor neuron loss rather than preceding it (L183).", "stateAxes": [ { "axis": "Lost, as a quantity in a living person", "whatToMeasure": "SV2A binding by PET, with the sleep state and circadian time of the scan recorded alongside it - 16.4 percent lower globally in disease with regional reductions of 16 to 26 percent, against a 3 to 6 percent movement from one night of lost sleep.", "interpretationLimit": "A six-patient pilot in a disease outside the drawn environments, with different tracers across species and cross-species agreement in direction rather than magnitude - 30 percent in mouse against 16 in human. The marker is binding availability of a vesicle protein rather than a synapse count, and what a change in it reflects is unresolved.", "evidence": [ "L184", "L185" ] }, { "axis": "Neuromuscular junction state, and where", "whatToMeasure": "Denervation by muscle group rather than as a whole, since it was pronounced in hindlimb, mild in cranial and absent in forelimb and trunk - and alongside terminal Schwann cell presence, which correlated directly with it.", "interpretationLimit": "A severe mouse model with 21-day median survival driven by overexpression of wild-type human protein rather than a patient mutation, so the compressed course may explain the concurrence of denervation with neuron loss. Morphology rather than function - no transmission measured at any junction. The regional pattern partly reflects the model's expression distribution.", "evidence": [ "L183" ] }, { "axis": "Whether loss precedes or follows neuronal death", "whatToMeasure": "The ordering, per genotype, because it is not fixed: dying-back is established for SOD1-dependent models and in this TDP-43 model denervation followed the same time course as motor neuron loss.", "interpretationLimit": "One model per genotype, and the authors note evidence in non-SOD1 genetic forms is limited by a lack of suitable animal models - so the ordering is unsettled rather than established to differ. The atlas should carry it as genotype-dependent and not resolve it.", "evidence": [ "L183" ] }, { "axis": "Clearance - who removes a synapse", "whatToMeasure": "Complement deposition and microglial engagement, which two drawn environments converge on from different genetic starting points - and which the atlas holds as mechanism in both without a rate or a fraction in either.", "interpretationLimit": "Both records are mouse models, and the convergence on complement is across Alzheimer's and progranulin-deficient frontotemporal dementia rather than within one disease. No pruning rate, no fraction of synapses removed, and no human measurement.", "evidence": [] } ], "records": { "L183": { "id": "L183", "year": 2023, "topic": "Pre/post-synaptic structure", "title": "Neuromuscular junction denervation and terminal Schwann cell loss in the hTDP-43 overexpression mouse model of amyotrophic lateral sclerosis", "url": "https://doi.org/10.1111/nan.12925", "studyType": "Time-course immunohistochemistry with NMJ-morph quantification of motor neuron number, denervation status and terminal Schwann cell morphology across muscle groups in Thy1-hTDP-43 mice, Neuropathology and Applied Neurobiology 49(5):e12925", "diseaseContext": "ALS", "useInModel": "Serves the neuromuscular half of this row and corrects a generalisation the atlas would otherwise have made. Denervation was pronounced in hindlimb muscles, mild in cranial muscles and absent in forelimb and trunk - so one disease in one animal affects junctions qualitatively differently by location, and an environment treated as homogeneous averages over regions that differ in kind rather than degree. The temporal point matters more. Dying-back pathology, where denervation precedes motor neuron loss, is established for SOD1-dependent models, and the authors note evidence in other genetic forms is limited; in this TDP-43 model denervation followed the same time course as motor neuron loss rather than preceding it. So the atlas should not carry denervation as an early event in ALS generally - the ordering is model-dependent and genotype-dependent, which is a finer version of the caution already recorded about microglia sitting at opposite ends of the causal chain in Alzheimer's and ALS. Terminal Schwann cells were lost from hindlimb junctions in direct correlation with denervation status, which ties this structure to the peripheral nerve row.", "limit": "A severe model with a median survival of 21 days, driven by neuronal overexpression of wild-type human TDP-43 rather than by a patient mutation, so the compressed time course may itself explain why denervation and neuron loss coincide. Mouse, with pathology assessed by immunohistochemistry and morphological quantification rather than function - no transmission measurement at any junction. The region-specific pattern is a property of this model's expression distribution as much as of the disease. Terminal Schwann cell loss correlates with denervation without the direction being established.", "provenance": "Abstract read in full; the regional denervation pattern across four muscle groups, the restriction to motor nerve terminals, the stated concurrence of denervation with motor neuron loss, the median survival, the terminal Schwann cell correlation, and the authors' note on the limits of dying-back evidence outside SOD1 models as reported", "quantitativeExtraction": "extracted" }, "L184": { "id": "L184", "year": 2026, "topic": "Transmission", "title": "SV2A PET reveals synaptic density loss in experimental autoimmune encephalomyelitis and in a pilot multiple sclerosis study", "url": "https://doi.org/10.1073/pnas.2517709123", "studyType": "Dynamic SV2A PET with a clinically translatable tracer in a mouse model, corroborated by autoradiography, alongside PET with the first clinically implemented SV2A tracer in six patients against six age-matched controls, PNAS 123:e2517709123", "diseaseContext": "Healthy reference; demyelinating disease", "useInModel": "Gives the atlas a structure measured quantitatively in a living person, which nothing else in the Structures category is. In the mouse model, tracer uptake fell globally with nearly a 30 percent decrease in regional distribution volume across all analysed brain regions, corroborated by autoradiography and with reduced levels in cervical and lumbar cord. In patients, global cortical binding was 16.4 percent lower than in age-matched controls, with regional reductions of 16 to 26 percent. This is the third exception the atlas has found to its own structural complaint that every marker is read from fixed tissue taken once - after a target verified by PET in three dimensions in the living patient, and subtype inferred serially from plasma - and it is the first for a structure rather than a cell surface or a transcriptional state. It also makes synapse loss a quantity rather than an observation, which matters because the atlas already holds complement-mediated early synapse loss in Alzheimer's models and circuit-specific microglial pruning in progranulin deficiency without any number attached to either.", "limit": "Six patients against six controls - a pilot, explicitly described as such - in a demyelinating disease that is not one of the drawn environments, so the human numbers establish that the measurement works rather than what the value is in any environment the atlas models. Two different tracers were used across species. SV2A binding is interpreted as a proxy for synaptic density and is in fact availability of a vesicle protein, which the companion sleep finding shows moves with state as well as with structure. The cross-species agreement is between a 30 percent mouse reduction and a 16 percent human one, which is consistency of direction rather than of magnitude.", "provenance": "Abstract read in full; both tracers, the mouse reduction with its significance and the autoradiographic corroboration, the spinal cord findings, the human cohort sizes, the global cortical reduction with its p value and the regional range as reported", "quantitativeExtraction": "extracted" }, "L185": { "id": "L185", "year": 2026, "topic": "Transmission", "title": "Sleep deprivation increases levels of the synaptic density marker SV2A in the human brain", "url": "https://doi.org/10.1371/journal.pbio.3003816", "studyType": "Randomised study of 40 healthy adults scanned twice on consecutive days at matched circadian time, half normal sleep and half after about 28 hours of continuous wakefulness, PLoS Biology 24:e3003816", "diseaseContext": "Healthy reference", "useInModel": "Shows that the atlas's one in vivo structural measurement is unstable on the timescale of a day, and quantifies the instability against the disease signal. Sleep deprivation significantly increased SV2A binding in multiple regions - thalamus by 4.6 percent, hippocampus by 5.6, parietal cortex by 3.2 - with no change in controls, and the increase correlated with slow wave activity during recovery sleep. Set against the companion record's 16.4 percent global cortical reduction in disease, a night of lost sleep moves this marker by between a fifth and a third of the disease effect. So any synaptic density the atlas ingests needs a sleep-state timestamp, and an uncontrolled one is a material confound rather than noise. This is the atlas's fifth instance of a quantity requiring a timestamp it does not record - after circadian stem cell release and endometrial cycle phase - and the first for a structure. It also means SV2A availability is reading state as well as architecture, which is what the proxy caveat in the companion record refers to.", "limit": "Forty healthy young adults, mean age 27.5 years, so neither the age nor the health status of the populations the atlas models. One night of total deprivation is an extreme manipulation rather than the ordinary variation a clinical scan would encounter, and whether habitual sleep quality shifts the marker comparably is untested. Scans were matched for circadian time, which controls one confound and demonstrates that it had to be. The increase is in tracer binding; whether it reflects more synapses, more vesicle protein per synapse, or altered tracer access is not resolved here.", "provenance": "Abstract read in full; the randomised design and matched circadian timing, the duration of wakefulness, all three regional increases with their percentages, the absence of change in controls, and the correlation with recovery slow wave activity as reported. The comparison with the disease effect size is this atlas's own", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I070", "name": "Myelin and axonal tracts", "category": "Structures", "whereToCheck": "CNS and peripheral nerve modules", "states": [ "Intact", "damaged", "degenerating" ], "behaviors": [ "Conduction", "geometry", "support" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "axonopathy-endplate", "axonopathy-ventral-root" ], "priorResearch": { "path": "simulation/data/profiles/myelin-and-axonal-tracts.json", "summary": "Wrapped axons and the tracts they form, which the inventory asks to resolve as intact, damaged or degenerating, with conduction, geometry and support. This is the one Structures row whose inventory asks for physical properties rather than a component list, and the one where the asked-for property has a standard metric: the g-ratio, axon diameter over total fibre diameter, which sets conduction velocity and is relatively consistent across axon diameters in health (L187). The row's more surprising finding is that this structure's most consequential function is not structural. Oligodendroglia support axon survival through mechanisms independent of myelination - the most abundant central lactate transporter is enriched in them, disrupting it causes axon damage and neuron loss, and it is reduced in ALS patients and mouse models (L186). The atlas already held the other half of this structure's ALS story: a staged distal axonopathy with 40 percent of end-plates denervated at 47 days before any cell body loss (L112).", "stateAxes": [ { "axis": "Geometry, with a metric that sets a function", "whatToMeasure": "The g-ratio - axon diameter over total fibre diameter - binned by axon diameter cohort, since it is relatively consistent across diameters in health and size-dependent deviations are the signal.", "interpretationLimit": "Published values carry method risk. There was no standardised tool for computing this from segmented electron microscopy until 2025, and the named failure modes in conventional analyses are insufficient sampling, pseudo-replication and misleading regression slopes. No g-ratio value for any tissue, species or disease is extracted here, and the link to conduction velocity is asserted as background rather than measured.", "evidence": [ "L187" ] }, { "axis": "Support, which is metabolic and separable from myelination", "whatToMeasure": "Lactate transporter availability on the supporting cell rather than myelin content, because support is independent of myelination and disrupting the transporter causes axon damage and neuron loss.", "interpretationLimit": "Disruption in animal and cell culture models; the human finding is reduced transporter levels in patient tissue, an association rather than a demonstrated cause. No transfer rate, lactate concentration or gradient, so this joins the atlas's three other metabolic exchange terms as established and unquantified.", "evidence": [ "L186" ] }, { "axis": "Degenerating, and in what order", "whatToMeasure": "Where along the axon the loss starts, per genotype - because in one model the answer is the distal end with a staged timeline and in another it is concurrent with cell body loss.", "interpretationLimit": "One transgenic model per genotype, with the staged percentages belonging to SOD1-G93A at those ages and explicitly not transferable as human stage boundaries, and the human evidence a single autopsy. Absence of cell body loss at a timepoint is a negative on the measurements made rather than proof nothing had changed.", "evidence": [ "L112" ] }, { "axis": "Conduction", "whatToMeasure": "Conduction velocity itself, which the inventory names first and which no record here measures - only the geometric ratio asserted to set it.", "interpretationLimit": "The atlas holds a metric that is said to determine conduction velocity and no velocity, in any tract, species or disease. This is the same shape as the synapse row, where transmission is unmeasured, so neither of the two Structures rows about signalling structures measures signalling.", "evidence": [] } ], "records": { "L112": { "id": "L112", "year": 2004, "topic": "Non-cell-autonomous toxicity", "title": "Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man", "url": "https://doi.org/10.1016/j.expneurol.2003.10.004", "studyType": "Spatiotemporal quantification at neuromuscular junctions, ventral roots and spinal cord across ages in SOD1-G93A mice, with one human autopsy, Exp Neurol 185(2):232-240", "diseaseContext": "ALS", "useInModel": "A staged timeline with percentages, which this atlas has almost nowhere else, and it runs the opposite way to the obvious model. In SOD1-G93A mice - clinically weak at 80 days and dead at 131 plus or minus 5 - 40% of end-plates were already denervated at 47 days with no evidence of ventral root or cell body loss; at 80 days 60% of ventral root axons were lost with still no loss of motor neurons; and motor neuron loss was only well underway by 100 days. The disease begins at the distal axon and proceeds dying back. Two further details carry weight. Microglial and astrocytic activation around motor neurons was not identified until after distal axon degeneration had begun - so in this environment glia are downstream, which is the opposite temporal position to the complement-at-synapses-before-plaques finding the atlas records for Alzheimer's disease. And the single human autopsy showed denervation and reinnervation changes in muscle alongside normal-appearing motor neurons, which is the same ordering and also evidence that repair was active and losing. A model that starts this disease at the motor neuron has the causality backwards.", "limit": "One transgenic mouse model, and the human evidence is a single sporadic case who died unexpectedly - informative precisely because death was not from end-stage disease, and a single case. The percentages are for this model at these ages and should not be carried as human stage boundaries. Absence of cell body loss at a timepoint is a negative on the measurements made, not proof that nothing had changed in the cell body.", "provenance": "Abstract read in full; all four timepoints with their percentages, the glial timing, and the human autopsy findings as reported", "quantitativeExtraction": "extracted" }, "L186": { "id": "L186", "year": 2012, "topic": "Support", "title": "Oligodendroglia metabolically support axons and contribute to neurodegeneration", "url": "https://doi.org/10.1038/nature11314", "studyType": "Transporter localisation with disruption in animal and cell culture models, plus comparison of patient and mouse model tissue, Nature 487(7408):443-448", "diseaseContext": "ALS; healthy reference", "useInModel": "Says this structure's most consequential function is not structural, which is the opposite of what the row's name implies. Oligodendroglia support axon survival and function through mechanisms independent of myelination; lactate is transported exclusively by monocarboxylate transporters; the most abundant such transporter in the central nervous system is highly enriched in oligodendroglia; and disrupting it produces axon damage and neuron loss in animal and cell culture models. The same transporter is reduced in patients with ALS and in mouse models of it. Two consequences. A model that represents myelin as insulation will miss the mechanism whose disruption actually kills axons - the supporting cell is feeding the axon, and that is separable from wrapping it. And this is the atlas's fourth metabolic exchange term, after oxygen, arginine and lipid: a metabolite handed from one cell to another across a short distance, sharing the mathematics the project already owns, and like the other three it has no flux.", "limit": "Disruption experiments are animal and cell culture; the human evidence is reduced transporter levels in patient tissue, which is an association rather than a demonstration that the reduction causes the disease. No transfer rate, lactate concentration or gradient between oligodendrocyte and axon is given, so the exchange is established and unquantified - the same position as the atlas's other three metabolic exchange terms. Lactate is one metabolite and the mechanisms independent of myelination may include others not addressed here.", "provenance": "Abstract read in full; the independence of support from myelination, the exclusivity of monocarboxylate transport for lactate, the transporter's enrichment in oligodendroglia, the disruption phenotypes in both model types, and its reduction in patients and mouse models as reported", "quantitativeExtraction": "extracted" }, "L187": { "id": "L187", "year": 2025, "topic": "Geometry", "title": "MyeliMetric: A Python-Based Toolbox for Standardized G-Ratio Analysis of Axon-Myelin Integrity", "url": "https://doi.org/10.1080/17590914.2025.2603411", "studyType": "Methodological tool development with validation against synthetic and published rodent demyelination datasets, ASN Neuro 18:2603411", "diseaseContext": "Healthy reference", "useInModel": "Supplies the one place in the Structures category where the geometry the inventory asks for has a standard metric that sets a function - and then says the field has been computing it badly. The g-ratio is the ratio of axon diameter to total fibre diameter including myelin, described as a key metric for myelin integrity and axonal conduction velocity, with deviations from the physiological range signalling pathology, and it is relatively consistent across axon diameters in health. That is a geometry-to-function relationship of the kind the atlas has wanted throughout this category. The caution is the other half: there was no standardised open-source tool for computing it from segmented electron microscopy until this one, and the stated problems in conventional analyses are insufficient sampling, pseudo-replication, and artefacts including misleading regression slopes - which the tool addresses by binning axons into diameter cohorts. A companion commentary in the same journal is titled to the effect that the field has been doing it wrong. So published g-ratio values carry method risk, and any the atlas ingests should carry how they were computed and whether sampling was adequate.", "limit": "A tool paper, so it supplies no g-ratio value for any tissue, species or disease - it establishes how the number should be obtained and what goes wrong otherwise. Validation is against synthetic data and published rodent demyelination datasets, not against a ground truth in human tissue. The physiological range it refers to is not stated here. And the relationship to conduction velocity is asserted as established background rather than measured in this record.", "provenance": "Abstract read in full; the definition of the ratio, its stated relevance to integrity and conduction velocity, the consistency-across-diameters principle, the absence of a prior standard tool, all three named analytical failure modes, the binning approach and the validation sources as reported. The companion commentary's existence is noted from the same search", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "axonopathy-endplate", "axonopathy-ventral-root" ] }, { "id": "I071", "name": "PDGF-B/PDGFR-beta axis", "category": "Molecular", "whereToCheck": "Vessel mural interface", "states": [ "Ligand source", "matrix retention", "receptor activation" ], "behaviors": [ "Pericyte recruitment", "local concentration", "response" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "pdgf-hs-strong-binding-fragments" ], "priorResearch": { "path": "simulation/data/profiles/pdgf-b-pdgfr-beta-axis.json", "summary": "PDGF-B is released by endothelium and recruits pericytes to the vessel wall through PDGFR-beta, and it works by being retained where it is released. A C-terminal motif holds it in matrix, and removing that motif is close to removing the signal: coverage falls by up to about 75% in brain, leaving roughly a quarter of the capillary bed covered, in what is described as the most pericyte-deficient brain vasculature compatible with adult life (L19). The pericytes that remain are displaced rather than absent - in tumour vessels the endothelium-to-pericyte distance rose about sevenfold, and the share of pericytes more than 10 micrometres out went from about 4% to more than 80% (V04). Attacking the matrix instead of the ligand does the same thing: cutting heparan sulfate N-sulfation reduced binding and detached pericytes (L18).", "stateAxes": [ { "axis": "Ligand source", "whatToMeasure": "Which cell released it, recorded alongside the vascular pattern, since endothelial and non-endothelial sources act differently", "interpretationLimit": "Mouse tumour models. Source is established as mattering without a measurement of the relative contribution in any drawn environment.", "evidence": [ "V04" ] }, { "axis": "Matrix retention", "whatToMeasure": "Whether the ligand is held where released - through the retention motif on the ligand side and heparan sulfate sulfation on the matrix side", "interpretationLimit": "Both sides have been removed genetically with converging phenotypes, but the heparan sulfate requirement in vascular development is described as inferred from the motif's binding properties rather than directly demonstrated. No retained fraction is measured in any tissue.", "evidence": [ "V05", "L18" ] }, { "axis": "Receptor activation", "whatToMeasure": "PDGFR-beta signalling in the mural cell, separately from ligand presence nearby", "interpretationLimit": "Named by the inventory and the least served of the three. The atlas records the consequences of the axis working or failing without a receptor-level measurement anywhere.", "evidence": [ "V04", "V05" ] } ], "records": { "L18": { "id": "L18", "year": 2007, "topic": "Molecular structure", "title": "Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development", "url": "https://doi.org/10.1101/gad.398207", "studyType": "Reduced N-sulfation of heparan sulfate in mouse vascular development, with PDGF-BB binding measured in vitro and pericyte coverage and migration assessed in vivo", "diseaseContext": "Healthy reference", "useInModel": "Tests what the glycan layer has to be like for a ligand to stay put, and the answer is a pattern rather than a sequence. Reducing N-sulfation of heparan sulfate cut PDGF-BB binding and produced pericyte detachment and delayed migration in vivo, reproducing the phenotype of a ligand retention-motif mutant. The requirement is for sufficiently long, appropriately spaced N-sulfated domains rather than a precise sugar sequence. That is the second structural property in this category that is a pattern and not an inventory, after junctional arrangement - and it is a statistical description, so a model needs sulfation density and spacing rather than a list of present molecules. It also makes the retention of a growth factor a property of the matrix, which is the same conclusion the chemokine record reaches from the ligand side.", "limit": "Mouse development in healthy tissue, so nothing here describes the layer in a tumour. The heparan sulfate requirement for retention in development is described as inferred from the binding properties of the motif rather than directly demonstrated, and that qualification should travel with it. No sulfation density, domain length, spacing or binding capacity is given as a number, so the pattern is named and not parameterised.", "provenance": "Re-extracted from the record's own screened content with its inference qualification kept. The N-sulfation manipulation, the binding and in vivo phenotypes, the phenocopy of the retention-motif mutant, and the pattern-not-sequence requirement as reported", "quantitativeExtraction": "extracted" }, "V04": { "id": "V04", "year": 2003, "topic": "Pericytes and vasculature", "title": "Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors", "url": "https://pubmed.ncbi.nlm.nih.gov/14561699/", "studyType": "Mouse tumor recruitment experiments", "diseaseContext": "Shared cancer", "useInModel": "Measures what losing matrix retention costs. PDGF-B carries a C-terminal motif that holds it in matrix; in mice lacking it, the distance from endothelium to the outermost pericyte parts rose about sevenfold in tumour vessels, and the share of pericytes sitting more than 10 micrometres from the endothelium went from about 4% in wild-type to more than 80%. Where the ligand comes from matters as well as whether it is held: endothelial and non-endothelial sources affect recruitment and vascular pattern differently.", "limit": "Mouse tumour models. The displacement is a distance rather than a function - a pericyte 10 micrometres out is not shown to have stopped doing anything - and growth-factor presence alone does not specify spatial distribution or mature coverage.", "provenance": "Full text reviewed; displacement distribution and fold change extracted", "quantitativeExtraction": "extracted" }, "V05": { "id": "V05", "year": 2003, "topic": "Pericytes and vasculature", "title": "Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall", "url": "https://pubmed.ncbi.nlm.nih.gov/12897053/", "studyType": "Genetic mouse study", "diseaseContext": "Shared all", "useInModel": "Matrix retention of endothelial PDGF-B influences mural recruitment and organization.", "limit": "Not a human quantitative recruitment constant.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "pdgf-hs-strong-binding-fragments" ] }, { "id": "I072", "name": "VEGF/VEGFR and angiopoietin/TIE axes", "category": "Molecular", "whereToCheck": "Vascular growth/remodeling", "states": [ "Ligand balance", "receptor state" ], "behaviors": [ "Vessel stability", "angiogenesis", "leakage" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "ang-tie2-mrna-ang1", "ang-tie2-mrna-ang2" ], "priorResearch": { "path": "simulation/data/profiles/vegf-vegfr-and-angiopoietin-tie-axes.json", "summary": "These are the axes that build and stabilise vessels, and VEGF turns out to be another signal whose arrangement matters more than its amount. VEGF-A comes in isoforms that differ in matrix binding - VEGF121 free, VEGF165 held through exon 7 sequences, VEGF189 and VEGF206 held harder through an additional exon 6 domain - and mice restricted to the free isoform made fewer capillary branches and widened existing vessels instead, with directed filopodial extension impaired. The defect was not in proliferation or in Nrp1 signalling, so it is spatial (L15). The angiopoietins act on the stability side, Ang1 from perivascular cells as the TIE2 agonist and Ang2 as its counterweight - though that reading is contested.", "stateAxes": [ { "axis": "Ligand balance - VEGF isoform distribution", "whatToMeasure": "Which isoforms are present and what fraction is matrix-held, not total VEGF-A", "interpretationLimit": "The consequence is established in mouse development with engineered single-isoform animals, and the gradient reading is the authors' interpretation of phenotypes rather than a measured gradient. No isoform distribution is measured in any drawn environment.", "evidence": [ "L15" ] }, { "axis": "Ligand balance - angiopoietin", "whatToMeasure": "Ang1 and Ang2 with the TIE2 state, and separately whether integrin beta1 is being engaged, since Ang2 acts through both", "interpretationLimit": "This is the family's most contested state. The prevailing account has Ang2 antagonising Ang1 at TIE2 to destabilise; one tumour study reports Ang2 as protective in tumour endothelium with anti-Ang2 benefit reversed by giving Ang1. Both accounts are recorded because the disagreement is real.", "evidence": [ "L17", "L16", "V09" ] }, { "axis": "Receptor state", "whatToMeasure": "Receptor engagement on the endothelial cell rather than ligand concentration nearby, and which receptor - TIE2 or integrin beta1 for Ang2", "interpretationLimit": "Ang2 destabilises endothelium through integrin beta1 as well as through TIE2, so a model representing only the receptor the axis is named for will not reproduce the ligand's behaviour.", "evidence": [ "L16" ] } ], "records": { "L15": { "id": "L15", "year": 2002, "topic": "Molecular structure", "title": "Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis", "url": "https://doi.org/10.1101/gad.242002", "studyType": "Single-isoform mouse genetics, Genes Dev 16(20):2684-2698", "diseaseContext": "Healthy reference", "useInModel": "Shows that what VEGF does depends on whether it is held or free. Mice making only the freely diffusible isoform formed fewer capillary branches, and endothelial cells were integrated into existing vessels to widen their lumen instead of forming new ones, with directed filopodial extension impaired. Mice making only a heparin-binding isoform went the other way, with excess filopodia and abnormally thin branches. The defect was not explained by isoform differences in proliferation or in signalling through Nrp1, so it is the spatial arrangement rather than the amount or the receptor. The binding difference is structural: VEGF165 holds matrix through exon 7 sequences and VEGF189 and VEGF206 add a second heparin-binding domain from exon 6, while VEGF121 does not bind.", "limit": "Mouse development with engineered single-isoform animals, not tumour. The gradient-steepness reading is the authors' interpretation of the phenotypes rather than a measured gradient, and the mechanism by which matrix affinity controls morphogenesis is described in reviews as still unclear. Mouse isoform numbering runs one amino acid shorter than human.", "provenance": "Abstract and indexed publisher text screened; phenotypes and isoform biochemistry taken as reported", "quantitativeExtraction": "pending" }, "L16": { "id": "L16", "year": 2015, "topic": "Molecular structure", "title": "Endothelial destabilization by angiopoietin-2 via integrin beta1 activation", "url": "https://doi.org/10.1038/ncomms6962", "studyType": "Endothelial cell and mouse work, Nat Commun 6:5962", "diseaseContext": "Healthy reference", "useInModel": "Gives angiopoietin-2 a route that does not run through the receptor the balance is usually written around: Ang2, and not Ang1, activates integrin beta1 and destabilises endothelium that way. So reading this axis as competition for TIE2 misses part of what the ligand does, and a model that represents only the receptor will not reproduce it.", "limit": "Cell and mouse work, healthy, not a drawn environment. It adds a mechanism rather than settling which one dominates in tumour.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "L17": { "id": "L17", "year": 2013, "topic": "Resistance", "title": "Angiopoietin-2 functions as a Tie2 agonist in tumor models, where it limits the effects of VEGF inhibition", "url": "https://doi.org/10.1158/0008-5472.CAN-12-2064", "studyType": "Mouse tumour xenografts with antibody and ligand manipulation, Cancer Res 73(1):108-118", "diseaseContext": "Shared cancer", "useInModel": "Contradicts the textbook reading of this family's central state. Rather than destabilising tumour vessels by antagonising Ang1, Ang2 is reported to play a protective role in tumour endothelium, and the anti-tumour effect of an Ang2-blocking antibody was reversed by giving the TIE2 agonist Ang1 - which implies the benefit of blocking Ang2 depends on TIE2 agonism rather than on removing an antagonist.", "limit": "Mouse xenografts. It is a direct challenge to the prevailing model rather than a replacement for it, and which account holds in any drawn environment is not established here.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "V09": { "id": "V09", "year": 2015, "topic": "Pericytes and vasculature", "title": "Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2", "url": "https://pubmed.ncbi.nlm.nih.gov/25704811/", "studyType": "Mouse stage-dependent perturbation", "diseaseContext": "Breast / Shared cancer", "useInModel": "Early versus established hypoxic tumors respond differently to pericyte targeting; ANG2 participates.", "limit": "Do not pool stage-specific effects or generalize them to all cancers.", "provenance": "Abstract or indexed publisher text screened; quantitative extraction pending", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "ang-tie2-mrna-ang1", "ang-tie2-mrna-ang2" ] }, { "id": "I073", "name": "TGF-beta and matrix-linked signals", "category": "Molecular", "whereToCheck": "Stroma and immune interfaces", "states": [ "Latent versus active", "receptor state" ], "behaviors": [ "Fibrosis", "exclusion", "context-specific signaling" ], "slots": { "size": { "status": "references available", "referenceIds": [ "mechanics-tgfb-llc-helix", "mechanics-tgfb-llc-straitjacket" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "mechanics-tgfb-llc-helix", "mechanics-tgfb-llc-straitjacket" ], "priorResearch": { "path": "simulation/data/profiles/tgf-beta-and-matrix-linked-signals.json", "summary": "TGF-beta is not secreted as a signal; it is deposited as a reservoir. It leaves the cell bound to its latency-associated peptide and anchored into matrix through LTBP-1, and that anchor is required rather than incidental - integrin alphaVbeta6 recognises the peptide but still cannot activate without LTBP-1, and LTBP-3 will not substitute (L12). Releasing it is a mechanical event: pulling on the peptide unfolds it, LTBP-1 lowers the force needed, and stretching the complex alone releases active cytokine. Contractile force transmitted through integrins activates the reservoir, and does so more efficiently the stiffer the matrix is, because a cell pulling on compliant matrix moves the matrix instead of the peptide (L13). So this family's activity is stored in the stroma and gated by its mechanics.", "stateAxes": [ { "axis": "Latent versus active", "whatToMeasure": "The activated fraction at a location, not total TGF-beta, with the matrix stiffness and the contractile cells around it recorded alongside", "interpretationLimit": "This is the axis the family turns on and nothing assembled measures it in any drawn environment. Total TGF-beta reports the reservoir; the activated fraction is what signals, and the two can move in opposite directions.", "evidence": [ "L12", "L13" ] }, { "axis": "Mechanically competent", "whatToMeasure": "Matrix stiffness together with the force-generating cells present, since activation requires something stiff to pull against", "interpretationLimit": "The stiffness dependence is a direction rather than a calibrated curve - more force and stiffer matrix give more activation - and no force threshold or stiffness value is given for any environment. The atlas records collagen fraction as a stated gap for breast, which is the nearest available proxy and is not the same quantity.", "evidence": [ "L13" ] }, { "axis": "Which integrin is activating", "whatToMeasure": "alphaVbeta6 and alphaVbeta8 separately, because they may not share a mechanism", "interpretationLimit": "alphaVbeta6 requires traction and is abolished by actin inhibitors or by truncating the integrin tail. alphaVbeta8 is reported to activate without drastic rearrangement or cytoskeletal force, and an earlier account has it recruiting MT1-MMP to cleave instead. The models conflict, so the mechanical gate may apply to one route and not the other.", "evidence": [ "L14", "L12" ] }, { "axis": "Receptor state on the receiving cell", "whatToMeasure": "Receptor expression and downstream signalling in the cell being acted on, separately from ligand availability", "interpretationLimit": "Named by the inventory and thinly served. The atlas records the consequence - excluded T-cell patterns, blunted checkpoint response - without a receptor-level measurement in any environment.", "evidence": [ "U02" ] } ], "records": { "L12": { "id": "L12", "year": 2004, "topic": "Molecular structure", "title": "Integrin alphaVbeta6-mediated activation of latent TGF-beta requires the latent TGF-beta binding protein-1", "url": "https://doi.org/10.1083/jcb.200312172", "studyType": "Cell and biochemical study, J Cell Biol 165(5):723-734", "diseaseContext": "Healthy reference", "useInModel": "Establishes that this signal is stored rather than secreted. TGF-beta leaves the cell bound to its latency-associated peptide and anchored to matrix through LTBP-1, and that anchor is not incidental: integrin alphaVbeta6 recognises an RGD motif on the peptide, but activation still requires LTBP-1, and LTBP-3 cannot substitute. The domains needed are the one that binds the propeptide and the basic hinge that targets matrix.", "limit": "Cell culture and biochemistry, healthy, and about one integrin. It establishes the requirement rather than a rate, and nothing here measures latent reservoir or activation in any drawn environment.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "L13": { "id": "L13", "year": 2011, "topic": "Molecular structure", "title": "The single-molecule mechanics of the latent TGF-beta1 complex", "url": "https://doi.org/10.1016/j.cub.2011.11.037", "studyType": "Single-molecule force spectroscopy and bead stretching", "diseaseContext": "Healthy reference", "useInModel": "Makes the activation step mechanical rather than chemical. Pulling on the latency-associated peptide unfolds it and releases active TGF-beta, with LTBP-1 acting as a leverage point that lowers the force threshold; stretching LTBP1-TGF-beta complexes on beads released active cytokine, so force alone is sufficient. Cell contractile forces transmitted through integrins activate latent reservoirs from non-compliant matrix, and the activation is more efficient with higher cell force and with a stiffer matrix. A cell pulling on soft matrix activates little, because the matrix yields instead of the peptide.", "limit": "Single molecules and engineered systems, not tissue. No force threshold or stiffness value is given for any drawn environment, and the stiffness dependence is a direction rather than a calibrated curve.", "provenance": "Abstract and indexed publisher text screened; the force requirement taken as the papers state it", "quantitativeExtraction": "pending" }, "L14": { "id": "L14", "year": 2019, "topic": "Molecular structure", "title": "Cryo-EM reveals integrin-mediated TGF-beta activation without release from latent TGF-beta", "url": "https://doi.org/10.1016/j.cell.2019.11.028", "studyType": "Cryo-electron microscopy of the integrin-latent complex", "diseaseContext": "Healthy reference", "useInModel": "Keeps the second activating integrin separate from the first. alphaVbeta8 appears to activate TGF-beta without drastic conformational rearrangement and without cytoskeletal force, and without the cytokine leaving the latent complex at all - which is a different mechanism from the force-dependent alphaVbeta6 route. An earlier account had alphaVbeta8 recruiting MT1-MMP to cleave the complex instead. The two models conflict and the matter is unsettled.", "limit": "Structural work on purified components. Which integrin dominates in any drawn environment is not established here, and if alphaVbeta8 acts without force then the mechanical gate applies to one route and not the other.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "U02": { "id": "U02", "year": 2018, "topic": "Exclusion and signaling", "title": "TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells", "url": "https://www.nature.com/articles/nature25501", "studyType": "Human trial-correlative plus mouse study", "diseaseContext": "Bladder / Shared cancer", "useInModel": "TGF-beta-associated fibroblast programs connect to excluded T-cell patterns.", "limit": "Clinical association plus mouse mechanism does not guarantee combination benefit in humans.", "provenance": "Indexed abstract or publisher excerpt screened; full numerical extraction pending", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "mechanics-tgfb-llc-helix", "mechanics-tgfb-llc-straitjacket" ] }, { "id": "I074", "name": "Inflammatory and regulatory cytokines", "category": "Molecular", "whereToCheck": "Local soluble fields", "states": [ "IL-1", "IL-6", "TNF", "IFNs", "IL-10", "others by context" ], "behaviors": [ "Source", "diffusion", "degradation", "receptor response" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "variation-il6" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "variation-il6" ], "priorResearch": { "path": "simulation/data/profiles/inflammatory-and-regulatory-cytokines.json", "summary": "Cytokines are the local soluble field, and the useful finding is how local. A cytokine spreads from a point source and is removed by receptor-bearing cells around it, giving an exponentially decaying field whose length is set by consumer density rather than by the size of the tissue (L08). For interferon gamma in melanoma that length is about 30 to 40 micrometres - a few cell diameters, and well under the roughly 109 micrometres between vessels at the measured breast density (L09). For IL-2 it runs 80 to 120 micrometres in vivo. So the consequences of one T cell firing reach the cells immediately around it, not the tissue, and neighbouring tumour cells are exposed to different amounts.", "stateAxes": [ { "axis": "Field length rather than concentration", "whatToMeasure": "The spreading length scale, measured as diffusion against consumption, together with consumer density - since the length is set by the consumers rather than by the producer", "interpretationLimit": "Measured for IL-2 in lymph node and for interferon gamma in melanoma, and nowhere else here. The scale is tunable by receptor expression and consumer density, so it is a property of a tissue state and not a constant to be carried between environments.", "evidence": [ "L08", "L09" ] }, { "axis": "Which cell is the source", "whatToMeasure": "The producing cell type, separately from the cytokine, because the two can be different lineages", "interpretationLimit": "In CAR-T cytokine release syndrome the major IL-1 and IL-6 source was monocytes rather than the engineered T cells. Whether that holds for a bispecific engager is contested, and the records disagree.", "evidence": [ "L10", "L11" ] }, { "axis": "Effector versus toxic", "whatToMeasure": "The cytokines separately rather than as one activation readout, since blocking some reduced toxicity without costing antitumour activity", "interpretationLimit": "Blocking TNF reduced engager-driven cytokine release without reducing antitumour activity, and IL-1 blockade abolished both CRS and neurotoxicity where IL-6 blockade did not. So the cytokines are not interchangeable and a single composite readout hides the distinction that matters.", "evidence": [ "L10", "L11" ] }, { "axis": "Receptor response", "whatToMeasure": "Response in the receiving cell against the dose it actually experienced at its position, not against the dose added", "interpretationLimit": "Named by the inventory and the hardest to serve, because the exposure is positional. Nothing assembled here measures a dose-response against local exposure in any drawn environment.", "evidence": [ "L09", "T20" ] } ], "records": { "L08": { "id": "L08", "year": 2017, "topic": "Mathematical model", "title": "A tunable diffusion-consumption mechanism of cytokine propagation enables plasticity in cell-to-cell communication in the immune system", "url": "https://doi.org/10.1016/j.immuni.2017.03.011", "studyType": "Imaging with fitted diffusion-consumption model, Immunity 46(4):609-620", "diseaseContext": "Healthy reference", "useInModel": "Gives the three quantities the inventory asks of this family and shows they set a length rather than a concentration. A cytokine spreads from a point source and is removed by receptor-bearing cells nearby, producing an exponentially decaying field whose length scale is set by how many consumers there are, not by the size of the tissue. For IL-2 the measured interaction scale was 80 to 120 micrometres in vivo, with the broader range running 30 to 150 depending on consumer density. The authors note the niche expands and shrinks as the regulatory T-cell compartment grows during a response.", "limit": "Lymph node and culture, fitted to a model rather than measured directly, and for IL-2 rather than the cytokines that matter most in tumour. Taking one cell diameter as 10 micrometres is the paper's own convention.", "provenance": "Abstract and indexed publisher text screened; length scales taken as the paper states them", "quantitativeExtraction": "pending" }, "L09": { "id": "L09", "year": 2023, "topic": "Spatial atlas", "title": "The spread of interferon-gamma in melanomas is highly spatially confined, driving nongenetic variability in tumor cells", "url": "https://doi.org/10.1073/pnas.2304190120", "studyType": "Mouse B16 culture and human melanoma measurement", "diseaseContext": "Melanoma", "useInModel": "Measures the reach of the effector cytokine that matters most here, and it is short: a spreading length scale of about 30 to 40 micrometres for interferon gamma, in mouse B16 melanoma and in human melanomas, consistent with simple diffusion and consumption. That is a few cell diameters, and shorter than the spacing between vessels, so the consequences of a T cell firing reach the cells immediately around it rather than the tissue. The same confinement makes neighbouring tumour cells experience different amounts, which is a source of non-genetic variability.", "limit": "Melanoma, in culture and in human tissue, not the other twelve environments. The scale is tunable by receptor expression and consumer density, so it is a property of a tissue state rather than a constant.", "provenance": "Abstract and indexed publisher text screened; length scale taken as the paper states it", "quantitativeExtraction": "pending" }, "L10": { "id": "L10", "year": 2018, "topic": "Clinical outcome", "title": "Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells", "url": "https://doi.org/10.1038/s41591-018-0036-4", "studyType": "Humanised mouse model with depletion and blockade, Nat Med 24(6):739-748", "diseaseContext": "Shared cancer", "useInModel": "Separates two toxicities that look like one. Human monocytes were the major source of IL-1 and IL-6 in cytokine release syndrome, and depleting them or blocking the IL-6 receptor prevented it - but IL-6 blockade failed to prevent delayed lethal neurotoxicity with meningeal inflammation, while IL-1 receptor blockade abolished both. So the cell that causes the syndrome is not the cell the therapy acts on, and the two toxicities run through different cytokines.", "limit": "CAR T cells in a humanised mouse model, not a bispecific engager in patients. T-cell-derived signals start the cascade even though monocytes carry it, so the division of labour is not clean.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "L11": { "id": "L11", "year": 2023, "topic": "Resistance", "title": "Dissecting the mechanisms underlying the cytokine release syndrome mediated by T-cell bispecific antibodies", "url": "https://doi.org/10.1158/1078-0432.CCR-23-0850", "studyType": "Preclinical dissection of CD20-TCB cytokine release, Clin Cancer Res 29(21):4449", "diseaseContext": "Shared cancer", "useInModel": "Warns against carrying the CAR-T account into engagers. Tocilizumab did not reduce CD20-TCB-induced cytokine release in vivo or in vitro, so whatever it does for engager CRS it does not do by removing the cytokine. T-cell-derived TNF contributed to myeloid activation, and blocking TNF reduced cytokine release without costing antitumour activity. Engager CRS is also mainly a first-dose event that attenuates on repeat dosing.", "limit": "Preclinical and one construct. It establishes that the CAR-T mechanism does not transfer intact; it does not establish what the engager mechanism is.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "T20": { "id": "T20", "year": 2007, "topic": "Chemistry and metabolism", "title": "Inhibitory effect of tumor cell-derived lactic acid on human T cells", "url": "https://pubmed.ncbi.nlm.nih.gov/17255361/", "studyType": "Human T-cell laboratory study", "diseaseContext": "Shared cancer", "useInModel": "Lactic-acid conditions alter proliferation, cytokines and cytotoxicity.", "limit": "Separate lactate concentration, pH and assay conditions; no universal suppression coefficient.", "provenance": "Indexed abstract or publisher excerpt screened; full numerical extraction pending", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I075", "name": "Chemokines and chemokine receptors", "category": "Molecular", "whereToCheck": "Recruitment and niche gradients", "states": [ "CXCL/CCL axes verified per tissue" ], "behaviors": [ "Migration", "retention", "desensitization", "matrix binding" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "variation-mip1b" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "variation-mip1b" ], "priorResearch": { "path": "simulation/data/profiles/chemokines-and-chemokine-receptors.json", "summary": "Chemokines direct where cells go once they are in tissue, and they do it bound rather than dissolved. Variants unable to bind glycosaminoglycans still drove migration in a transwell assay and recruited nothing in vivo; monomeric variants that signalled normally in vitro were also inactive (L05). The directing signal is chemokine immobilised on matrix, which makes a gradient a property of the matrix a cell is crawling through rather than of the fluid around it. What a cell reads from such a gradient is direction extracted against noise, with receptor desensitisation forming part of the reading rather than the end of it (L06).", "stateAxes": [ { "axis": "Immobilised versus soluble", "whatToMeasure": "The matrix-bound fraction and its spatial arrangement, not a tissue concentration", "interpretationLimit": "This is the axis the family turns on and nothing assembled measures it in any drawn environment. The in vivo requirement is established for certain chemokines rather than all, and some argue GAG-deficient mutants can still act by diffusion, so the generality is contested.", "evidence": [ "L05", "L06" ] }, { "axis": "Axis verified in this tissue", "whatToMeasure": "Which ligand-receptor pair is actually operating in the tissue in question, rather than carried from another", "interpretationLimit": "The inventory asks for axes verified per tissue and the atlas has one, CXCR3 with CXCL9 and CXCL10, from mouse models. The environment blueprints name CCL20-CCR6 for prostate with no record behind it, which is exactly the kind of carry-over this axis exists to prevent.", "evidence": [ "L07" ] }, { "axis": "Desensitised", "whatToMeasure": "Receptor state after exposure, read as part of how a gradient is interpreted rather than as a loss of responsiveness", "interpretationLimit": "Established for dendritic cells reading CCL21 through GRK6, not for T cells on tumour axes. No desensitisation rate appears here for any receptor in any environment.", "evidence": [ "L06" ] } ], "records": { "L05": { "id": "L05", "year": 2003, "topic": "Transport", "title": "Glycosaminoglycan binding and oligomerization are essential for the in vivo activity of certain chemokines", "url": "https://doi.org/10.1073/pnas.0334864100", "studyType": "Chemokine variants engineered to lose glycosaminoglycan binding or to remain monomeric, compared in standard in vitro chemotaxis against in vivo recruitment, around 2003", "diseaseContext": "Healthy reference", "useInModel": "Says that for this signal class a soluble concentration is the wrong quantity, which makes it a representation finding rather than a measurement. Variants unable to bind glycosaminoglycans still drove migration in standard chemotaxis assays and recruited no cells in vivo; monomeric variants that signalled normally in vitro were likewise inactive. So the directing signal is chemokine immobilised on the glycan layer, and the concentration in fluid is a different quantity from the one cells follow. This atlas records concentrations. For chemokines that is not a missing number but a mis-specified variable - the gradient is a property of the matrix, and a well-mixed field cannot carry it however accurately it is calibrated. It also means oligomerisation state is part of the signal rather than a detail of the molecule.", "limit": "Around 2003, a limited set of chemokines, and the authors say certain chemokines rather than all - so the scope of the claim is explicitly partial. Some argue the case is not closed, since glycosaminoglycan-deficient mutants can still act by diffusion under some conditions. Nothing here measures an immobilised chemokine concentration, a binding capacity of the layer, or a gradient length scale, so the variable is identified as wrong without the right one being supplied.", "provenance": "Re-extracted from the record's own screened content with its scope and the standing objection kept. Both variant classes and their in vitro and in vivo discordance as reported; the consequence for how this atlas represents chemokine signals is its own", "quantitativeExtraction": "extracted" }, "L06": { "id": "L06", "year": 2017, "topic": "Experimental platform", "title": "Dendritic cells interpret haptotactic chemokine gradients in a manner governed by signal-to-noise ratio and dependent on GRK6", "url": "https://doi.org/10.1016/j.cub.2017.03.048", "studyType": "Quantitative imaging of migration on defined immobilised gradients", "diseaseContext": "Healthy reference", "useInModel": "Says what a cell actually reads when the gradient is bound rather than dissolved: direction is extracted according to signal-to-noise ratio, and receptor desensitisation through GRK6 is part of the reading rather than a loss of it. In lymphatic tissue CCL21 is held by charged interstitial components in a stable gradient decaying away from the vessel, and the gradients measured in vivo are well suited to guiding cells.", "limit": "Dendritic cells on CCL21, not T cells on the axes that matter in tumour. It establishes how an immobilised gradient is read; it does not say that any such gradient exists in a drawn environment.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "L07": { "id": "L07", "year": 2020, "topic": "Accessibility", "title": "Macrophage-derived CXCL9 and CXCL10 are required for antitumor immune responses following immune checkpoint blockade", "url": "https://doi.org/10.1158/1078-0432.CCR-19-1868", "studyType": "Mouse tumour models with depletion and receptor knockout, Clin Cancer Res 26(2):487-504", "diseaseContext": "Shared cancer", "useInModel": "Names the axis that brings effector T cells in and the cell that supplies it. CXCL9 and CXCL10 rose markedly after dual PD-1 and CTLA-4 blockade, and both CD8 infiltration and therapeutic benefit were CXCR3-dependent. Macrophages were the predominant source of CXCL9, and depleting them abolished both the infiltration and the efficacy - so the recruiting signal for the T cell comes from a myeloid cell rather than from the tumour.", "limit": "Mouse models with human correlation only through biopsy expression. Whether the axis is required for entry or chiefly for function inside the tumour is contested: other work reports CXCR3 and CXCL9 critical for a productive response under anti-PD-1 without being required for infiltration itself.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I076", "name": "Complement components and receptors", "category": "Molecular", "whereToCheck": "Plasma and locally produced pools", "states": [ "Active fragments", "deposited versus soluble" ], "behaviors": [ "C1q/C3 and receptor states", "opsonization", "inflammation" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [], "priorResearch": { "path": "simulation/data/profiles/complement-components-and-receptors.json", "summary": "Complement is the only family in this category whose default state is on. It runs continuously as surveillance, amplifies on whatever surface it meets, and is held off host tissue by regulation rather than by not being made - the canonical review puts the warning in its own abstract, that the system can act against healthy cells if not properly controlled (L34). That inverts the question the inventory asks of every other family. Elsewhere the measurement is whether a signal was produced or where it was retained; here production is continuous and the informative measurement is whether restraint held. It also solves, by chemistry, the problem the rest of this category has: chemokines, TGF-beta, VEGF and PDGF-B all depend on matrix to hold them where they were released, while complement's opsonin carries a metastable thioester and bonds covalently to the surface that activated it. The family therefore emits two physically different things from one cascade - a fixed tag and a diffusing anaphylatoxin - and they cannot be one field in a model.", "stateAxes": [ { "axis": "Active fragments, not components", "whatToMeasure": "The cleavage products and their receptors, separated by physical type - deposited C3b as a surface tag, C3a and C5a as diffusible ligands - rather than total C3 or C1q protein.", "interpretationLimit": "No fragment concentration is measured in any environment in this atlas. The cancer evidence is one syngeneic mouse model and the neurodegeneration evidence is mouse genetics with blockades; both establish that fragments matter without saying how much of any fragment is present anywhere.", "evidence": [ "L33", "A04", "L34" ] }, { "axis": "Deposited against soluble - the inventory's own axis, and the physical one", "whatToMeasure": "Where the covalently fixed opsonin sits, as a density on identified surfaces, against the concentration of the diffusing fragments in the surrounding space. These are two different measurements of two different objects and should never be combined into a complement activity score.", "interpretationLimit": "The mechanism is established and the number it implies is missing: no deposition radius - how far from the convertase that made it a fragment can land - is quantified anywhere the atlas has looked. Beware a false lead here: the large conformational movement of the thioester domain within the protein on activation is an internal distance of order 8 to 10 nanometres and is not a deposition range.", "evidence": [ "L34" ] }, { "axis": "Restraint - the axis the inventory does not name", "whatToMeasure": "Regulator density on host surfaces alongside any activation measurement, since in a system that is always running the signal is the loss of control rather than the onset of activity.", "interpretationLimit": "This axis is inferred from the system's architecture (L34) and from the shape of the two disease mechanisms here, in which the pathology is pruning machinery running where it should not (A04, F05). No regulator is measured in any environment in this atlas, so the axis is named and entirely unserved.", "evidence": [ "L34", "A04", "F05" ] } ], "records": { "A04": { "id": "A04", "year": 2016, "topic": "Synapse removal", "title": "Complement and microglia mediate early synapse loss in Alzheimer mouse models", "url": "https://pubmed.ncbi.nlm.nih.gov/27033548/", "studyType": "Mouse genetics and pharmacological inhibition with microglial engulfment assays, Science 352(6286):712-716", "diseaseContext": "Alzheimer's", "useInModel": "Puts this family before the pathology rather than after it. C1q, the initiating protein of the classical cascade, was increased and associated with synapses before overt plaque deposition - so complement is early, not a late inflammatory consequence. Inhibiting C1q, C3 or the microglial receptor CR3 each reduced both the number of phagocytic microglia and the extent of early synapse loss, which gives three separable intervention points in one cascade. C1q was necessary for soluble amyloid-beta oligomers to damage synapses and hippocampal long-term potentiation, so the toxicity the atlas records for soluble oligomers under I085 runs through this family rather than alongside it. And adult microglia engulfed synaptic material in a CR3-dependent way when exposed to those oligomers. The authors' reading is that the developmental pruning pathway is inappropriately reactivated.", "limit": "Mouse models. Disease stages and mechanisms cannot be assigned wholesale to human Alzheimer's, and the interventions are genetic or pharmacological blockades rather than measurements of how much complement is deposited on how many synapses. No fragment concentration or deposition density is given, here or anywhere else in this atlas.", "provenance": "Abstract read in full; the pre-plaque timing and the three intervention points as reported", "quantitativeExtraction": "extracted" }, "F05": { "id": "F05", "year": 2016, "topic": "Glia and complement", "title": "Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC4860138/", "studyType": "Transcriptome profiling and genetic rescue in aging progranulin-null mice, Cell 165(4):921-935", "diseaseContext": "FTD", "useInModel": "The strongest causal claim this family makes anywhere, and it is a rescue. Progranulin deficiency produced an age-dependent, progressive upregulation of lysosomal and innate immunity genes, increased complement production and enhanced synaptic pruning by microglia. The pruning was not diffuse: it preferentially eliminated inhibitory synapses in the ventral thalamus, and the resulting hyperexcitability in thalamocortical circuits produced obsessive-compulsive-like grooming behaviour - a specific circuit, a specific synapse class, and a behaviour that follows from the circuit. Deleting a single complement gene, C1qa, reduced the pruning and mitigated the neurodegeneration, the behaviour and the premature mortality. The authors state the consequence plainly: complement activation and microglia-mediated pruning are drivers of this neurodegeneration rather than consequences of it.", "limit": "A progranulin-null mouse, so this is GRN-specific and should not be generalised to MAPT or to sporadic frontotemporal dementia. The selectivity for inhibitory synapses in one nucleus is reported as a finding rather than explained, and nothing is quantified as a rate or a deposition density.", "provenance": "Abstract read in full; the circuit, synapse class and C1qa rescue as reported", "quantitativeExtraction": "extracted" }, "L33": { "id": "L33", "year": 2008, "topic": "Exclusion and signaling", "title": "Modulation of the antitumor immune response by complement", "url": "https://doi.org/10.1038/ni.1655", "studyType": "Syngeneic mouse tumour model with receptor blockade, Nat Immunol 9(11):1225-1235", "diseaseContext": "Shared cancer", "useInModel": "The cancer half of this family, and it points the opposite way to the intuition that complement attacks tumours. C5a generated in the tumour microenvironment enhanced tumour growth by suppressing the antitumour CD8 T-cell response. The route was recruitment of myeloid-derived suppressor cells into the tumour and amplification of their T-cell-directed suppressive ability, which operated through their production of reactive oxygen and nitrogen species. Blocking the C5a receptor pharmacologically impaired tumour growth to a degree the authors describe as similar to paclitaxel. So in tumour this family's diffusible arm is an exclusion signal, and it belongs with the other mechanisms the atlas records for keeping T cells away from tumour cells rather than with cytotoxic ones.", "limit": "A syngeneic mouse model, and the comparison to paclitaxel is within that model rather than a clinical equivalence. It concerns the diffusible fragment C5a, not deposited C3b, so it says nothing about opsonisation. Nothing is measured in any drawn environment, and no C5a concentration is given.", "provenance": "Abstract read in full; the mechanism and the paclitaxel comparison as the authors state them", "quantitativeExtraction": "pending" }, "L34": { "id": "L34", "year": 2010, "topic": "Molecular structure", "title": "Complement: a key system for immune surveillance and homeostasis", "url": "https://doi.org/10.1038/ni.1923", "studyType": "Review of complement function, structure and dynamics, Nat Immunol 11(9):785-797", "diseaseContext": "Shared all", "useInModel": "Establishes the thing that makes this family unlike every other one in this category: its default state is on. The system runs continuously as surveillance, amplifies on whatever surface it encounters, and distinguishes healthy host cells from altered ones and from intruders - and the review states in its own abstract that it can take action against healthy cells if not properly controlled. That inverts the measurement question. Everywhere else in this category the informative variable is whether a signal was produced or where it was retained; here production is continuous and the informative variable is whether restraint held. The other structural point to carry is that one cascade yields two physically different products - a fragment that is covalently fixed to the surface where it was generated, and small fragments that diffuse and signal through receptors - so complement cannot be represented as a single field.", "limit": "A review, and a 2010 one. It supplies the system's architecture and its regulatory logic, not numbers for any environment. In particular it does not give a deposition radius for the covalently fixed fragment, which is the quantity this mechanism most obviously implies and which the atlas has not found measured anywhere.", "provenance": "Abstract read; the architecture and the regulation framing are as the review presents them", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I077", "name": "Coagulation and fibrinolysis components", "category": "Molecular", "whereToCheck": "Blood; leakage; clots", "states": [ "Fibrinogen/fibrin", "thrombin", "inhibitors" ], "behaviors": [ "Clotting", "vessel occlusion", "tissue exposure" ], "slots": { "size": { "status": "references available", "referenceIds": [ "armstrong-fibrinogen" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "armstrong-fibrinogen" ], "priorResearch": { "path": "simulation/data/profiles/coagulation-and-fibrinolysis-components.json", "summary": "This is the only family in the atlas whose extracellular matrix is made from blood. Its proteins are plasma-confined and inert until they meet tissue factor, so the inventory's three locations - blood, leakage, clots - are three states of the same molecules rather than three pools. In tumour, the permeability the VEGF family produces lets whole plasma into the interstitium, where tissue factor on tumour and host connective-tissue cells clots fibrinogen in place into a cross-linked, urea-insoluble gel that serves as provisional stroma and is later replaced by granulation tissue and collagen (L21). What separates a tumour from a healing wound is not how much fibrin is there - accumulation was quantitatively similar - but that influx and initial clotting are higher, implying faster turnover, and that the response never resolves: wounds returned toward normal within days and tumours stayed elevated (L21). Systemically the same activation appears as thrombosis that varies about thirtyfold across tumour sites, 98 per 1000 person-years in pancreatic against 13.9 overall and 3.1 in thyroid (L24).", "stateAxes": [ { "axis": "Fibrinogen and fibrin - soluble influx against deposited gel", "whatToMeasure": "Not a concentration but a partition and a rate: how much fibrinogen enters, how much of it is cross-linked and urea-insoluble where it stopped, and how fast that deposit turns over. A steady-state fibrin level cannot separate a tumour from a wound, because those were measured as equal.", "interpretationLimit": "One study separates these quantities, in guinea-pig carcinomas against skin wounds with tracer fibrinogen, and the faster turnover is inferred from higher influx at equal accumulation rather than measured. Nothing in a drawn environment.", "evidence": [ "L21" ] }, { "axis": "Thrombin and tissue factor - where activation happens", "whatToMeasure": "Tissue factor on tumour and host stromal cell surfaces, scored by location against the vessel and the leak rather than by level, since the protein is inert until plasma reaches it.", "interpretationLimit": "Established as the initiating activity in tumour stroma within one laboratory's framework (L21), and demonstrated in reverse by delivering tissue factor on purpose to tumour endothelium (L22, L23). No measurement of endogenous tissue factor in any drawn environment, so the atlas knows this activity matters without knowing its distribution anywhere.", "evidence": [ "L21", "L22" ] }, { "axis": "Inhibitors - and the fact that PAI-1 does not act like one", "whatToMeasure": "PAI-1 and uPA as protein concentrations in tumour tissue extract, against the validated 14 and 3 ng/mg protein cutoffs, reported with the nodal status the validation was done in.", "interpretationLimit": "Validated in lymph-node-negative breast cancer, with the stated use narrow - identifying node-negative, HER2-negative patients who can be spared adjuvant chemotherapy. Carrying the cutoffs to another environment is unsupported. The assay needs a tissue extract rather than a stain, which constrains where the number can be had at all.", "evidence": [ "L20" ] } ], "records": { "L20": { "id": "L20", "year": 2014, "topic": "Clinical outcome", "title": "uPA and PAI-1 as biomarkers in breast cancer: validated for clinical use in level-of-evidence-1 studies", "url": "https://doi.org/10.1186/s13058-014-0428-4", "studyType": "Review of two level-of-evidence-1 validations, Breast Cancer Res 16:428", "diseaseContext": "Breast", "useInModel": "The only place in this family where a quantity has a validated cutoff in a drawn environment. uPA and PAI-1 are measured as protein concentration in breast tumour tissue extract against cutoffs of 3 and 14 ng/mg protein, and both are statistically independent predictors of outcome in lymph-node-negative disease, confirmed in two independent level-of-evidence-1 studies - a randomised prospective trial in which the biomarker evaluation was the trial's primary purpose, and a pooled analysis of individual patient data. High levels also predict benefit from adjuvant chemotherapy. The reason it matters beyond breast cancer is the direction: PAI-1 is uPA's inhibitor, yet at the concentrations found in tumour tissue both promote progression and both point the same way clinically. An inhibitor that behaves like its enzyme means this family cannot be reasoned about from its reaction diagram.", "limit": "Validated in lymph-node-negative breast cancer, and the stated clinical use is narrow - identifying node-negative, HER2-negative patients who can be spared adjuvant chemotherapy. It is not a general statement about this family in other environments. The assay needs a tissue extract rather than a stain, which is a real practical constraint on where the number can be obtained.", "provenance": "Abstract and indexed publisher text screened; cutoffs and evidence level taken as reported", "quantitativeExtraction": "pending" }, "L21": { "id": "L21", "year": 1988, "topic": "Matrix and movement", "title": "Fibrinogen influx and accumulation of cross-linked fibrin in healing wounds and in tumor stroma", "url": "https://pubmed.ncbi.nlm.nih.gov/3279791/", "studyType": "Tracer fibrinogen in guinea-pig wounds and syngeneic carcinomas, Am J Pathol 130(3):455-465", "diseaseContext": "Shared cancer", "useInModel": "Says what distinguishes a tumour from a wound, and it is not the amount. Labelled fibrinogen injected into guinea pigs entered both skin wounds and syngeneic carcinomas and was clotted in place to urea-insoluble cross-linked fibrin, confirmed by gel electrophoresis. Total and urea-insoluble accumulation were quantitatively similar in the two, but influx and initial clotting were higher in tumours - which, at equal accumulation, means fibrin turns over faster there. And the time courses diverge: influx and accumulation fell back toward normal within a few days of wounding and stayed elevated in tumours indefinitely. So the measurable that separates the two states is persistence and turnover, not a steady-state concentration.", "limit": "Guinea pig, 1988, and one laboratory's framework in which leaked plasma clotted by tissue factor forms the provisional stroma. The faster turnover is inferred from the mismatch between higher influx and equal accumulation rather than measured directly. Nothing here is in a drawn environment.", "provenance": "Abstract and indexed text screened; the influx-versus-accumulation inference is the authors' own", "quantitativeExtraction": "pending" }, "L22": { "id": "L22", "year": 2009, "topic": "Vascular transport", "title": "Infarction of tumor vessels by NGR-peptide-directed targeting of tissue factor: experimental results and first-in-man experience", "url": "https://doi.org/10.1182/blood-2008-04-150318", "studyType": "Mouse xenografts in three tumour types plus first-in-man dosing, Blood 113(21):5019-5027", "diseaseContext": "Lung / Melanoma / Shared cancer", "useInModel": "Runs this family forwards on purpose. A fusion of truncated tissue factor to the peptide GNGRAHA, which targets CD13 and integrin alpha-v beta-3 on tumour endothelium, produced partial to complete thrombotic occlusion of tumour vessels on histology in established human adenocarcinoma, melanoma and fibrosarcoma xenografts, and significant growth retardation or regression in all three. Untargeted tissue factor did neither, so the effect is from where the activity was placed rather than from adding coagulant. Contrast-enhanced MRI showed reduced perfusion, and first-in-man dosing was tolerated and reduced tumour perfusion on MRI.", "limit": "Xenografts for the efficacy claims; the human part here is low-dose first-in-man tolerability and an imaging signal, not a response result. It shows that occlusion can be caused and measured, not what the untreated occlusion fraction is in any environment.", "provenance": "Abstract screened; histology and MRI findings taken as reported", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I078", "name": "Target antigens and peptide-HLA complexes", "category": "Molecular", "whereToCheck": "Specific cell surfaces", "states": [ "Isoform", "density", "polarity", "shedding", "internalization" ], "behaviors": [ "Accessible copies", "distribution", "epitope geometry", "HLA restriction" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "surface-p53-kms26", "surface-p53-kle", "surface-p53-tyk-nu" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "surface-p53-kms26", "surface-p53-kle", "surface-p53-tyk-nu" ], "priorResearch": { "path": "simulation/data/profiles/target-antigens-and-peptide-hla-complexes.json", "summary": "This family is whatever a targeting arm binds on a cell surface, and it divides into two kinds that behave differently. A surface protein presents many copies and can be reached by an antibody if its accessible face points at the blood; the atlas records, across the thirteen environments carried in measurements.json, that of 37 targets surveyed only 3 are physically reachable by an antibody. A peptide-HLA complex presents few copies and reaches intracellular proteins that no antibody could otherwise see, which is how a mutation inside a cell becomes a surface target at all (T04), and tebentafusp shows the approach can work clinically (R04). The two kinds share a family because they share a job, not because they share a scale.", "stateAxes": [ { "axis": "Isoform", "whatToMeasure": "Which isoform or splice product carries the epitope, and whether the targeting arm distinguishes them", "interpretationLimit": "Nothing assembled here resolves isoform-level targeting for any antigen in a drawn environment. The STMN2 cryptic splice product is the one example of a splice-generated target, and it is intracellular.", "evidence": [ "T04", "F04" ] }, { "axis": "Density", "whatToMeasure": "Accessible copies per cell, by quantitative flow for a surface protein or by HLA immunoprecipitation with targeted mass spectrometry for a peptide-HLA complex", "interpretationLimit": "This is the central quantity and no threshold for it is published. Killing and cytokine release sit at different antigen intensities, so there is not one threshold but at least two, and neither is given a number. The atlas's one density figure, 11,326 to 165,507 HER2 receptors per cell, comes from a method its own authors call not fully validated and trended inversely with the clinical score.", "evidence": [ "T28", "T30" ] }, { "axis": "Polarity", "whatToMeasure": "Which face of the cell the antigen presents on, and whether that face meets blood", "interpretationLimit": "The atlas already records this per environment and the answer is mostly no: of 37 targets surveyed across the thirteen environments carried in measurements.json, 3 are physically reachable by an antibody. An antibody arrives basolaterally and a T cell infiltrates, so the two arms of an engager do not face the same surface.", "evidence": [ "T05" ] }, { "axis": "Shedding", "whatToMeasure": "Soluble antigen in plasma, since shed antigen binds the construct before it reaches tissue", "interpretationLimit": "Named by the inventory and unserved. No shed antigen concentration is assembled here for any target in any environment, although it would subtract directly from the free construct I010 records as unmeasured.", "evidence": [ "T02" ] }, { "axis": "Internalization", "whatToMeasure": "Whether the complex is internalised after binding, and how fast relative to synapse formation", "interpretationLimit": "Named by the inventory and unserved here for engagers. Internalisation is the mechanism an antibody-drug conjugate depends on and an engager does not, so the two should not share a parameter.", "evidence": [ "T01" ] } ], "records": { "F04": { "id": "F04", "year": 2023, "topic": "RNA processing and rescue", "title": "Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies.", "url": "https://pubmed.ncbi.nlm.nih.gov/36927019/", "studyType": "Mechanistic work in TDP-43-deficient human motor neurons plus antisense oligonucleotide treatment in gene-edited mice, Science 379(6637):1140-1149", "diseaseContext": "ALS / FTD", "useInModel": "The only repair in this category, and it works by going around the broken node rather than fixing it. TDP-43 binding to a GU-rich region sterically blocks recognition of a cryptic 3' splice site in STMN2 pre-mRNA; losing it produces cryptic splicing and polyadenylation of the transcript encoding stathmin-2, a protein required for axonal regeneration. Targeting dCasRx or antisense oligonucleotides to that site suppressed the cryptic splicing and restored both axonal regeneration and stathmin-2-dependent lysosome trafficking in TDP-43-deficient human motor neurons. In mice gene-edited to carry the human cryptic sequences, injecting an oligonucleotide into cerebrospinal fluid corrected the misprocessing and restored stathmin-2 levels - and the paper states the crucial qualifier: independently of TDP-43 binding. The upstream defect was left in place and a specific downstream function was recovered. That is a different therapeutic logic from every other intervention in this category, all of which engaged their target and failed to help.", "limit": "Preclinical throughout. Restored axonal regeneration and lysosome trafficking in cultured human neurons and restored protein levels in a humanised mouse are not clinical functional recovery, and the mouse required gene editing to contain the human cryptic sequences at all. It repairs one transcript of the hundreds affected by TDP-43 loss, so it tests whether that transcript matters rather than treating the proteinopathy.", "provenance": "Abstract read in full; the steric mechanism, both rescue readouts and the TDP-43-independence of the correction as reported", "quantitativeExtraction": "extracted" }, "T01": { "id": "T01", "year": 2022, "topic": "Binding geometry", "title": "Development of T-cell engagers selective for cells co-expressing two antigens", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC9553182/", "studyType": "Preclinical cells and mice", "diseaseContext": "Breast / Shared cancer", "useInModel": "Dual Ly6E/B7-H4 recognition; co-expression, arm placement and healthy-tissue expression belong in selectivity models.", "limit": "Not a human therapeutic-window validation; two antigens do not automatically form a strict AND gate.", "provenance": "Indexed abstract or publisher excerpt screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "T02": { "id": "T02", "year": 2018, "topic": "Transport", "title": "Relative Target Affinities of T-Cell-Dependent Bispecific Antibodies Determine Biodistribution in a Solid Tumor Mouse Model.", "url": "https://pubmed.ncbi.nlm.nih.gov/29339550/", "studyType": "Preclinical mouse biodistribution", "diseaseContext": "Breast / Shared cancer", "useInModel": "Relative HER2/CD3 affinities affect tissue distribution and CD3-rich tissue sinks.", "limit": "Mouse distribution cannot supply patient-specific tumor concentrations.", "provenance": "Indexed abstract or publisher excerpt screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "T04": { "id": "T04", "year": 2021, "topic": "Target identity", "title": "Targeting a neoantigen derived from a common TP53 mutation", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8208645/", "studyType": "Structural, cell and mouse study", "diseaseContext": "Shared cancer", "useInModel": "Mutant p53 R175H peptide-HLA recognition connects intracellular mutations to a surface-accessible target.", "limit": "Requires the appropriate peptide-HLA complex; mutation status alone is insufficient.", "provenance": "Indexed abstract or publisher excerpt screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "T05": { "id": "T05", "year": 2020, "topic": "Accessibility", "title": "A Novel GUCY2C-CD3 T-Cell Engaging Bispecific Construct (PF-07062119) for the Treatment of Gastrointestinal Cancers", "url": "https://doi.org/10.1158/1078-0432.CCR-19-3275", "studyType": "Preclinical package - multiple tumour cell lines in vitro, subcutaneous and orthotopic human colorectal xenografts with adoptive human T-cell transfer, a syngeneic model in human CD3-epsilon transgenic mice, immunohistochemistry and mass cytometry for biodistribution, plus cynomolgus macaque toxicity and pharmacokinetics, Clinical Cancer Research 26(9):2188-2202", "diseaseContext": "Colorectal and other gastrointestinal cancers", "useInModel": "The selectivity argument for an address that is on the wrong side of the normal cell, and the strongest preclinical package in this atlas for any address-class agent. Guanylyl cyclase C is expressed widely across colorectal cancer and other gastrointestinal malignancies, and normally sits on the apical surface facing the lumen - so a systemically delivered bispecific should reach it in tumours, where polarity is lost, and not in intact epithelium. The package supports that: immunohistochemistry and mass cytometry showed selective drug biodistribution to tumours with recruitment of activated T cells, efficacy followed in multiple colorectal xenograft models including KRAS- and BRAF-mutant ones and in an immunocompetent syngeneic model, combination with anti-PD-1 or anti-PD-L1 and with antiangiogenic therapy enhanced it further, and cynomolgus macaque toxicology indicated a monitorable and manageable profile. This record should be read together with the phase 1 result, where the dose-limiting toxicities were grade 3 colitis and diarrhoea and the overall response rate was 2.5 percent. Held here as the best-documented transfer failure in the atlas: a specificity mechanism that was demonstrated by biodistribution and survived primate toxicology, and did not hold in humans.", "limit": "Xenografts with adoptively transferred human T cells are not a human immune compartment, and the syngeneic model uses a transgenic human CD3-epsilon. Selective biodistribution is shown by staining and mass cytometry rather than quantified as a tumour-to-normal ratio. The macaque toxicity conclusion is qualitative. Most importantly, nothing in this record anticipates the human colitis and diarrhoea that followed, so it demonstrates the limits of this evidence type rather than being wrong on its own terms.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. The expression claim, all model systems, the biodistribution and T-cell recruitment findings, the mutant subsets, both combination results and the macaque toxicology conclusion as reported. The transfer-failure framing is this atlas's own, drawn from pairing this record with T06", "quantitativeExtraction": "extracted" }, "T28": { "id": "T28", "year": 2025, "topic": "Binding geometry", "title": "T cell engagers: expanding horizons in oncology and beyond", "url": "https://doi.org/10.1038/s41416-025-03125-y", "studyType": "Review of T-cell engager design and pharmacology", "diseaseContext": "Shared cancer", "useInModel": "Two design facts this atlas needs. First, killing and cytokine release do not share a threshold: T-cell killing can occur at relatively low CD3 and TCR engagement while robust cytokine secretion requires higher antigen intensity, so efficacy and toxicity sit on separate curves against the same variable. Second, a 2+1 format that engages two antigen molecules on one cell binds high-density cells strongly and low-density cells weakly - which is avidity doing the discrimination rather than affinity.", "limit": "A review. It states the dual threshold qualitatively and gives no antigen density at which either sits, for any target or tissue.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "T30": { "id": "T30", "year": 2023, "topic": "Accessibility", "title": "Systematic discovery of neoepitope-HLA pairs for neoantigens shared among patients and tumor types", "url": "https://doi.org/10.1038/s41587-023-01945-y", "studyType": "HLA immunoprecipitation with targeted mass spectrometry", "diseaseContext": "Shared cancer", "useInModel": "Shows that the quantity this family most needs is measurable: absolute copies per cell of a peptide-HLA complex, obtained by immunoprecipitating HLA and running targeted mass spectrometry, demonstrated for KRAS epitopes on HLA-A*11:01. It also shows presentation is not proportional to expression - epitopes from a polyantigen cassette were presented at higher absolute copies per cell than from cells expressing the full-length mutant protein.", "limit": "Cell lines and engineered constructs, not patient tissue from a drawn environment. It establishes the method and that presentation and expression come apart; it does not give a copy number for any target in any environment here.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I079", "name": "TCR/CD3 and costimulation", "category": "Molecular", "whereToCheck": "T cells and contacts", "states": [ "Receptor density", "clustering", "activation" ], "behaviors": [ "Signaling", "CD28", "CD2/CD58", "context-specific requirements" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "abundance-tcr-wildtype-cd4" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "abundance-tcr-wildtype-cd4" ], "priorResearch": { "path": "simulation/data/profiles/tcr-cd3-and-costimulation.json", "summary": "The TCR-CD3 complex is what an engager's second arm grips, and what it does normally is read peptide-HLA and decide whether to signal. The reading is partly geometric. A TCR bound to peptide-HLA holds the two membranes about 13 nm apart, and the inhibitory phosphatase CD45 has an ectodomain of about 25 nm in its R0 isoform and about 40 nm in RABC, so it is squeezed out of the contact by size rather than by signal - about 50% exclusion for the larger isoform against about 20% for the smaller (T31). CD45 is already partly excluded from the tips of microvilli before any antigen is met. A T cell carries on the order of 30,000 to 40,000 receptor molecules, though responses persist far below that (T34).", "stateAxes": [ { "axis": "Receptor density", "whatToMeasure": "CD3 copies per T cell rather than TCR, since that is what the engager binds, measured on T cells from the tissue in question", "interpretationLimit": "The published counts are of TCR, around 30,000 to 40,000 per cell, not of CD3, and come from healthy mouse systems. Responses persist at 500 to 1,000 molecules per cell at high dose, so a threshold on this side is no better defined than on the antigen side.", "evidence": [ "T34" ] }, { "axis": "Clustering", "whatToMeasure": "Whether a close contact forms, with the intermembrane distance the construct imposes, rather than whether binding occurred", "interpretationLimit": "Geometry decides this and the dimensions are known: about 13 nm for a TCR-peptide-HLA contact against a CD45 ectodomain of 25 to 40 nm. The reconstituted system gives the mechanism and the exclusion fractions, not a rate in a cell contact, and whether CD45 movement initiates or sustains signalling is contested.", "evidence": [ "T31", "T09", "T03" ] }, { "axis": "Activation", "whatToMeasure": "Function under repeated engagement rather than at first contact, since the failure mode is serial rather than acute", "interpretationLimit": "Killing and cytokine release separate as antigen intensity rises, so a single activation readout reports on only one of the two outcomes that matter.", "evidence": [ "T28", "T18" ] }, { "axis": "Costimulated versus signal-1-only", "whatToMeasure": "CD2-CD58 engagement alongside CD3, and CD58 on the target cell, since the costimulus depends on the tumour supplying its half", "interpretationLimit": "CD2-CD58 is a low-affinity fast-off interaction, Kd about 9 to 22 micromolar, so it reports on contact being held rather than on binding strength. CD58 is not measured on tumour cells in any drawn environment here.", "evidence": [ "T32", "T18", "T33" ] } ], "records": { "T03": { "id": "T03", "year": 2010, "topic": "Binding geometry", "title": "Epitope distance to the target cell membrane and antigen size determine the potency of T cell-mediated lysis by BiTE antibodies specific for a large melanoma surface antigen.", "url": "https://doi.org/10.1007/s00262-010-0844-y", "studyType": "Panel of bispecific T-cell engagers built from many monoclonal antibodies against one large melanoma surface antigen, tested against CHO cells expressing full-length antigen, deletion mutants and antigen fusion proteins, Cancer Immunology, Immunotherapy 59(8):1197-1209", "diseaseContext": "Melanoma", "useInModel": "Gives the address class a geometric parameter and shows that the parameter everyone measures does not predict potency. Engagers against melanoma chondroitin sulfate proteoglycan with similar binding affinities differed greatly in their potency of redirected lysis. Those binding the membrane-proximal domain were more potent than those binding distal domains, and the effect was corroborated with a second engager against a different antigen using fusion proteins between the two. Separately, cells expressing small surface antigens were lysed better than cells expressing larger ones. So epitope height above the membrane and antigen size both set potency independently of affinity. For a project whose stated subject includes molecular structure this is the most directly structural determinant of efficacy it holds: whether a cytolytic synapse can close depends on how far the bound epitope sits from the membrane and how much antigen is in the way. The atlas's address class has so far accumulated reach, specificity and density; this adds geometry, and it must be carried separately from affinity rather than folded into it.", "limit": "Engineered CHO cells expressing constructs, not tumours, and lysis in vitro rather than any clinical outcome. No universal optimal epitope distance follows - the result is that distance and size matter and that closer and smaller were better in this system. Two antigens, one engager format, and no measurement in nanometres of the distances compared. Nothing here relates the effect to the peptide-HLA address in this same family, where the target sits at the membrane by construction.", "provenance": "Re-extracted from the full abstract, replacing a one-line screening note. The antigen's identity and functions, the construction of the engager panel, the dissociation of affinity from potency, the membrane-proximal advantage, its corroboration with a second antigen, and the antigen size effect as reported", "quantitativeExtraction": "extracted" }, "T09": { "id": "T09", "year": 2017, "topic": "Synapse", "title": "Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC5357723/", "studyType": "Preclinical myeloma study", "diseaseContext": "Shared cancer", "useInModel": "FcRH5 epitope placement affects CD45 exclusion and synapse formation.", "limit": "Myeloma is supporting evidence outside the provisional ten; transfer requires validation.", "provenance": "Indexed abstract or publisher excerpt screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "T18": { "id": "T18", "year": 2022, "topic": "Resistance", "title": "Cancer cell-intrinsic resistance to BiTE therapy is mediated by loss of CD58 costimulation and modulation of the extrinsic apoptotic pathway", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8928392/", "studyType": "Functional CRISPR study", "diseaseContext": "Shared cancer", "useInModel": "Connects CD58 costimulation and extrinsic apoptosis machinery to BiTE resistance.", "limit": "Target binding and signaling cannot be used as interchangeable readouts of death.", "provenance": "Indexed abstract or publisher excerpt screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "T28": { "id": "T28", "year": 2025, "topic": "Binding geometry", "title": "T cell engagers: expanding horizons in oncology and beyond", "url": "https://doi.org/10.1038/s41416-025-03125-y", "studyType": "Review of T-cell engager design and pharmacology", "diseaseContext": "Shared cancer", "useInModel": "Two design facts this atlas needs. First, killing and cytokine release do not share a threshold: T-cell killing can occur at relatively low CD3 and TCR engagement while robust cytokine secretion requires higher antigen intensity, so efficacy and toxicity sit on separate curves against the same variable. Second, a 2+1 format that engages two antigen molecules on one cell binds high-density cells strongly and low-density cells weakly - which is avidity doing the discrimination rather than affinity.", "limit": "A review. It states the dual threshold qualitatively and gives no antigen density at which either sits, for any target or tissue.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "T31": { "id": "T31", "year": 2017, "topic": "Binding geometry", "title": "In vitro reconstitution of T cell receptor-mediated segregation of the CD45 phosphatase", "url": "https://doi.org/10.1073/pnas.1710358114", "studyType": "Reconstituted membrane system with defined components", "diseaseContext": "Healthy reference", "useInModel": "Puts dimensions on the synapse the rest of this work argues about. The gap a TCR-peptide-HLA pair holds is about 13 nm; the CD45 ectodomain is about 25 nm for the R0 isoform and about 40 nm for RABC, so CD45 is excluded sterically rather than by signalling. Exclusion scales with size - the larger RABC was excluded about 50% against about 20% for R0 - which is why epitope height on the target antigen decides whether a synapse closes.", "limit": "A reconstituted system with purified components, not a cell contact. It gives the geometry and the mechanism, not a rate, and the timing is contested: CD45 relocalisation may sustain signalling rather than start it, since the earliest biochemical events appear faster than the movement.", "provenance": "Abstract and indexed publisher text screened; dimensions and exclusion fractions taken as the paper states them", "quantitativeExtraction": "pending" }, "T32": { "id": "T32", "year": 2021, "topic": "Binding geometry", "title": "CD58 immunobiology at a glance", "url": "https://doi.org/10.3389/fimmu.2021.705260", "studyType": "Review, Front Immunol 12:705260", "diseaseContext": "Shared cancer", "useInModel": "Characterises the costimulus an engager does not supply. CD2 on the T cell binds CD58 on the target with low affinity and a fast off-rate, Kd about 9 to 22 micromolar, and the pair works by holding a close contact of about the same 13 nm dimension that excludes CD45. CD2 is described as the primary costimulatory pathway for CD8 T cells lacking CD28, which is the population an engager is usually trying to recruit.", "limit": "A review. The affinity is for the isolated interaction and the costimulatory claims are largely preclinical; nothing here measures CD58 on tumour cells in any drawn environment.", "provenance": "Abstract and indexed publisher text screened; affinity range taken as the review states it", "quantitativeExtraction": "pending" }, "T33": { "id": "T33", "year": 2025, "topic": "Experimental platform", "title": "EVOLVE platform, a trispecific T cell engager with integrated CD2 costimulation, for the treatment of solid and hematologic tumors", "url": "https://doi.org/10.1073/pnas.2510829122", "studyType": "Preclinical trispecific construct across several targets", "diseaseContext": "Shared cancer", "useInModel": "Tests whether supplying the missing costimulus helps. A CD58 domain fused into a CD3 engager maintained T-cell viability and effector function better than other pathways under chronic stimulation, and killed better than CD3-affinity-matched bispecifics against HER2, CD20, B7-H4 and ULBP2. The integration matters: in related work a separate CD2-targeted bispecific reduced the engager's cytotoxicity rather than helping, so costimulation delivered in the same molecule is not equivalent to costimulation delivered alongside.", "limit": "Preclinical, across cell lines and models rather than any drawn environment. Whether a fused format or a separate agonist is better is unresolved in the literature, and CD2 engagement alone can activate T cells independently of the TCR depending on epitope, which is a safety question this record does not settle.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "T34": { "id": "T34", "year": 2001, "topic": "Healthy reference", "title": "How much TCR does a T cell need?", "url": "https://doi.org/10.1016/S1074-7613(01)00170-4", "studyType": "Quantitative flow cytometry with calibrated beads in transgenic mice", "diseaseContext": "Healthy reference", "useInModel": "Gives the density on the T-cell side of the synapse, which the atlas had only for the tumour side. Wild-type CD4 T cells carried roughly 40,000 receptor molecules, with the commonly cited figure around 30,000. More useful for an engager model: responses persisted far below that, with 500 to 1,000 molecules per CD8 T cell still responding, though substantially only at high immunogen dose.", "limit": "Mouse transgenic systems and conventional antigen, not an engager. The count is of TCR rather than of CD3, and no equivalent number is published here for T cells inside any drawn environment, where the relevant density may differ.", "provenance": "Abstract and indexed publisher text screened; counts taken as reported", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I080", "name": "Checkpoint receptor/ligand pairs", "category": "Molecular", "whereToCheck": "Immune and neighboring cells", "states": [ "Induced versus baseline", "spatial contacts" ], "behaviors": [ "PD-1/PD-L1 and other verified axes", "suppression" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "surface-pdl1-raji-high", "surface-pdl1-raji-low" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "surface-pdl1-raji-high", "surface-pdl1-raji-low" ], "priorResearch": { "path": "simulation/data/profiles/checkpoint-receptor-ligand-pairs.json", "summary": "Checkpoint pairs are brakes that act at contact. PD-1 on the T cell meets PD-L1 on a tumour or myeloid cell, is phosphorylated by Lck, recruits the phosphatase SHP2, and that phosphatase strongly prefers CD28 as its substrate over the T-cell receptor - CD3-zeta is barely touched and ZAP70 only at higher PD-1 levels (T35). So the brake works mainly by removing costimulation rather than by silencing antigen recognition. Because the interaction needs contact, where the cells are matters as much as how much is expressed, and proximity of PD-1 to PD-L1 cells is taken as the evidence that the axis is actually engaged (T36).", "stateAxes": [ { "axis": "Induced versus baseline", "whatToMeasure": "PD-L1 alongside an interferon-response readout on the same section, since the level alone cannot say which route produced it", "interpretationLimit": "No study assembled here separates the two spatially. Proximity readouts report where PD-1 and PD-L1 cells sit, not what drove the expression, and distinguishing them would need interferon-response markers scored on the same tissue.", "evidence": [ "T36" ] }, { "axis": "Spatial contact", "whatToMeasure": "Distance between PD-1 positive and PD-L1 positive cells, with the scoring method stated, because the axis only acts at contact", "interpretationLimit": "Thresholds are not comparable between studies - some apply a fixed cut-off, others fit a distance distribution - and no distance is established as the one at which the axis operates. Proximity on a section is inferred engagement, not observed engagement.", "evidence": [ "T36", "T37" ] }, { "axis": "Which substrate is being suppressed", "whatToMeasure": "CD28 and CD226 phosphorylation rather than TCR-proximal signalling, since those are what PD-1-recruited SHP2 prefers", "interpretationLimit": "From reconstitution and mouse work. The TCR is not entirely spared and the degree is debated, and PD-1 blockade still works in T-cell-specific SHP2 knockouts, so SHP2-independent routes exist.", "evidence": [ "T35" ] } ], "records": { "T35": { "id": "T35", "year": 2017, "topic": "Binding geometry", "title": "T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition", "url": "https://doi.org/10.1126/science.aaf1292", "studyType": "Biochemical reconstitution with intact-cell confirmation, Science 355:1428-1433", "diseaseContext": "Healthy reference", "useInModel": "Names what PD-1 actually switches off, and it is not the T-cell receptor. PD-1 is phosphorylated by Lck on PD-L1 ligation, recruits SHP2, and that phosphatase strongly prefers CD28 over the TCR as a substrate, in reconstitution and in intact cells. Follow-up work found CD3-zeta barely dephosphorylated and ZAP70 affected only at higher PD-1, with CD226 also targeted. A companion study found CD28 costimulation is required for CD8 T-cell proliferation after PD-1 blockade.", "limit": "Reconstituted systems and mouse models, not a drawn environment. The TCR is not entirely spared and the degree is debated, and PD-1 blockade still works in T-cell-specific SHP2 knockouts, so SHP2-independent routes exist and this is not the whole mechanism.", "provenance": "Abstract and indexed publisher text screened; substrate preference taken as the paper states it", "quantitativeExtraction": "pending" }, "T36": { "id": "T36", "year": 2014, "topic": "Clinical outcome", "title": "PD-1 blockade induces responses by inhibiting adaptive immune resistance", "url": "https://doi.org/10.1038/nature13954", "studyType": "Human melanoma biopsies before and during anti-PD-1, Nature 515(7528):568-571", "diseaseContext": "Melanoma", "useInModel": "Establishes the checkpoint as a response to immune attack rather than a fixed property of a tumour. Responders had more CD8, PD-1 and PD-L1 expressing cells at the invasive margin and inside the tumour, with PD-1 and PD-L1 cells in close proximity - the proximity itself taken as evidence of a physical interaction, since the axis only works at contact. The authors conclude PD-L1 marks adaptive resistance to an existing T-cell response rather than being a static biomarker.", "limit": "Melanoma on anti-PD-1, so it describes the setting it was measured in. Proximity is inferred from sections rather than observed as engagement, and thresholds differ between studies - some score a fixed cut-off, others fit a distance distribution - so proximity figures are not comparable across papers.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "T37": { "id": "T37", "year": 2019, "topic": "Spatial atlas", "title": "Spatial proximity between T and PD-L1 expressing cells as a prognostic biomarker for oropharyngeal squamous cell carcinoma", "url": "https://doi.org/10.1038/s41416-019-0634-z", "studyType": "Multiplex immunofluorescence, 72 patients, Br J Cancer 122(4):539-544", "diseaseContext": "Shared cancer", "useInModel": "Shows the spatial reading is prognostic where the expression level alone is not: frequent proximity of CD8 or PD-1 positive cells to PD-L1 positive cells predicted overall survival in HPV-negative disease. It also illustrates the measurement problem - this study fits a distance distribution rather than applying a fixed cut-off, which is why proximity results do not transfer between papers.", "limit": "Seventy-two patients in a cancer outside the drawn environments, and prognostic rather than predictive of checkpoint response. No distance threshold here is established as the one at which the axis operates.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I081", "name": "Cytolytic and apoptosis machinery", "category": "Molecular", "whereToCheck": "Effector-target interface and target interior", "states": [ "Granule readiness", "death sensitivity" ], "behaviors": [ "Perforin", "granzymes", "Fas/FasL", "caspases", "resistance" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "functional-ctl-killing" ], "priorResearch": { "path": "simulation/data/profiles/cytolytic-and-apoptosis-machinery.json", "summary": "This is where the engager thread ends: everything I078, I079 and I080 arrange exists to produce the event this family carries out. Four things the records establish all run against the intuitive version of that event. The rate is slow - one cytotoxic T cell killed 2 to 16 cells per day measured in living tissue, against multiple targets in 9 hours in vitro (L30, T08). The stoichiometry is not one-to-one: the probability a target died rose once more than two T cells had contacted it (L30). The hit has a latency, because perforin delivers granzyme through the target's own membrane-repair machinery into endosomes that release gradually and rupture after about 15 minutes (L32). And the killing does not stay on the antigen - Fas-FasL is necessary for antigen-specific killing and also kills antigen-negative neighbours, which improves clearance of heterogeneous tumours in vivo (T19). Through all of it the effector keeps moving: motile kinapses rather than static synapses in vivo (L30), and in vitro highly motile T cells forming no clusters (T08) - two systems eleven years apart agreeing on the one point a model is most likely to get wrong.", "stateAxes": [ { "axis": "Granule readiness, and the rate actually achieved", "whatToMeasure": "Not granzyme and perforin content but kills per effector per unit time, with the spread across individual effectors reported rather than averaged - 2 to 16 per day in tissue, against multiple targets in 9 hours in vitro. The authors of the in vitro work attribute the rate to movement and target scanning rather than to the lysis step, so what to measure is search, not cytotoxic capacity.", "interpretationLimit": "The only in vivo rate here is for virus-specific T cells against virus-infected mouse tissue, not for an engager-redirected T cell against tumour, and the in vitro rate is from a B-lineage cell-line system. The two differ by about an order of magnitude and neither is measured in a drawn environment, so the pair bounds the plausible rather than supplying a value.", "evidence": [ "L30", "T08" ] }, { "axis": "Death sensitivity, as mitochondrial priming", "whatToMeasure": "How close the target's mitochondria sit to the apoptotic threshold, measured functionally by BH3 profiling, and measured for normal cells in the same environment as well as for the tumour - because the gap between them is what selectivity is made of.", "interpretationLimit": "Validated against cytotoxic chemotherapy response, not against T-cell or engager-mediated killing, and whether priming predicts susceptibility to granzyme-initiated death is untested. Ovarian cancer is the only drawn environment among the four malignancies profiled, and the result is a correlation across patients rather than a threshold measured in tissue.", "evidence": [ "L31", "T18" ] }, { "axis": "Where the killing lands - on the engaged cell or on its neighbours", "whatToMeasure": "The antigen status of the cells that die, not just of the cells that are targeted, and the spatial arrangement of antigen-negative cells rather than their fraction.", "interpretationLimit": "This axis contains an unresolved contradiction in the atlas's own records. T08 reports that bystanding target-negative cells were not detectably affected; T29 reports antigen-negative cells efficiently lysed when close to antigen-positive ones; T19 shows Fas-dependent bystander killing in vivo and makes it necessary for on-target killing too. The weight is with bystander killing happening, but no record expresses the required proximity as a distance, so it cannot be given a radius.", "evidence": [ "T19", "T29", "T08" ] } ], "records": { "L30": { "id": "L30", "year": 2016, "topic": "Effector behavior", "title": "In vivo killing capacity of cytotoxic T cells is limited and involves dynamic interactions and T cell cooperativity", "url": "https://doi.org/10.1016/j.immuni.2016.01.010", "studyType": "Two-photon imaging of virus-infected mouse tissue with mathematical modelling, Immunity 44(2):233-245", "diseaseContext": "Healthy reference", "useInModel": "The record that disciplines every killing rate in this atlas. In vitro assays suggest T cells kill rapidly and efficiently; measured in living tissue by two-photon microscopy and by fitting a model to the imaging, one cytotoxic T cell killed on average 2 to 16 virus-infected cells per day. Three further findings change how killing should be represented. T cells remained migratory and formed motile kinapses rather than static synapses, so a model that immobilises an effector on contact has the wrong dynamics. The probability that an infected cell died rose once more than two T cells had contacted it, which is cooperativity - killing is not a one-to-one transaction and the per-contact probability is not constant. And individual T cells varied strongly in functional capacity by calcium reporting, so an average effector is a poor stand-in for a population. Where targets downmodulated MHC class I, the T cells failed to kill at all.", "limit": "Mouse, virus-infected tissue, herpesviruses and poxviruses - not tumour and not any drawn environment. The 2-to-16 range is per day and per cell across systems rather than a value to carry, and the upper and lower ends come from different infections. An engager-redirected T cell is not the same effector as a virus-specific CTL, so the rate bounds the plausible rather than supplying it.", "provenance": "Abstract read in full; rate, cooperativity threshold and kinapse observation as reported", "quantitativeExtraction": "pending" }, "L31": { "id": "L31", "year": 2011, "topic": "Target identity", "title": "Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy", "url": "https://doi.org/10.1126/science.1206727", "studyType": "BH3 profiling of patient tumour cells against clinical response in four malignancies, Science 334(6059):1129-1133", "diseaseContext": "Ovarian (HGSC) / Leukemia", "useInModel": "Turns the inventory's second state, death sensitivity, into something with an assay and a clinical correlate. BH3 profiling measures how close a cell's mitochondria sit to the apoptotic threshold by exposing them to peptides from the BH3 domains of death-signalling proteins - a property the authors call mitochondrial priming. Measured before treatment in cells from patients with multiple myeloma, acute myelogenous and lymphoblastic leukaemia and ovarian cancer, highly primed cancers showed superior clinical response to chemotherapy while chemoresistant cancers were poorly primed. The part that matters most for a model of a microenvironment is the comparator: normal tissues were also poorly primed. So the selectivity of a cytotoxic agent is partly a property of how close the target already was to dying, not of what the drug recognises - which means death sensitivity has to be a per-cell-type parameter rather than a global threshold.", "limit": "Cytotoxic chemotherapy, not T-cell or engager-mediated killing, and the link between mitochondrial priming and susceptibility to granzyme-initiated death is not tested here. Ovarian cancer is the only drawn environment among the four, and the result is a correlation with response across patients rather than a measured threshold in tissue.", "provenance": "Abstract read in full; the normal-tissue comparator is the authors' own stated finding", "quantitativeExtraction": "pending" }, "T08": { "id": "T08", "year": 2005, "topic": "Effector behavior", "title": "Serial killing of tumor cells by cytotoxic T cells redirected with a CD19-/CD3-bispecific single-chain antibody construct", "url": "https://pubmed.ncbi.nlm.nih.gov/15688411/", "studyType": "Video-assisted microscopy of redirected human T cells against B-lineage targets, Int J Cancer 115(1):98-104", "diseaseContext": "Leukemia / Lymphoma", "useInModel": "The in vitro ceiling on how much one T cell can do, with the numbers that set it. At femtomolar concentrations the construct switched T cells from a scanning mode to a killing mode; individual T cells eliminated multiple targets within a 9-hour window, and complete target elimination was reached within 24 hours at effector-to-target ratios as low as 1:5. Killing began within minutes of adding the construct, and the authors attribute the overall rate to T-cell movement and scanning rather than to the lysis step - so the limiting process is search, not killing. Two structural observations matter as much as the rate: T cells stayed highly motile throughout and the construct induced no clusters of T cells and targets, and repeated lysis transferred CD19 from target to T cell, leaving CD19/CD3 double-positive T cells behind. That last detail means a surface-marker readout of target antigen can be contaminated by the act of killing.", "limit": "In vitro, B-lineage targets, and a cell-line system. The rate is about an order of magnitude faster than the only in vivo measurement the atlas holds (L30), which is for virus-infected targets rather than tumour. The paper also reports that bystanding target-negative cells were not detectably affected - which two later records contradict (T29, T19), so that specific claim should not be carried forward.", "provenance": "Abstract read in full; timings, ratio and the motility and antigen-transfer observations as reported", "quantitativeExtraction": "extracted" }, "T18": { "id": "T18", "year": 2022, "topic": "Resistance", "title": "Cancer cell-intrinsic resistance to BiTE therapy is mediated by loss of CD58 costimulation and modulation of the extrinsic apoptotic pathway", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8928392/", "studyType": "Functional CRISPR study", "diseaseContext": "Shared cancer", "useInModel": "Connects CD58 costimulation and extrinsic apoptosis machinery to BiTE resistance.", "limit": "Target binding and signaling cannot be used as interchangeable readouts of death.", "provenance": "Indexed abstract or publisher excerpt screened; full numerical extraction pending", "quantitativeExtraction": "pending" }, "T19": { "id": "T19", "year": 2021, "topic": "Bystander effects", "title": "A critical role for fas-mediated off-target tumor killing in T cell immunotherapy", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC7933082/", "studyType": "CRISPR/Cas9 screen with in vivo antigen-heterogeneous tumour models, reproduced in CAR-T and bispecific systems, plus a clinical correlate from NCT02348216, Cancer Discov 11(3):599-613", "diseaseContext": "Shared cancer", "useInModel": "Says killing does not stay where the antigen is, and that this is load-bearing rather than incidental. A CRISPR screen found Fas-FasL to be necessary for antigen-specific T-cell killing - so the pathway is not an alternative route but part of the main one. The same pathway then mediated off-target killing of antigen-negative tumour cells, and that localised bystander cytotoxicity improved clearance of antigen-heterogeneous tumours in vivo, which the authors report as not previously shown. It reproduced in CAR-T and bispecific antibody models and was augmented by inhibiting regulators of Fas signalling. The clinical anchor is the strongest part: tumoral FAS expression alone predicted survival among CAR-T-treated patients in a large trial. The consequence for a model is that antigen heterogeneity is less protective than an antigen-gated killing rule implies, and that the geography of antigen-negative cells matters more than their fraction.", "limit": "Mouse models for the in vivo bystander effect, with the human evidence being a survival correlation with tumoral FAS expression rather than a measured bystander effect in patients. The effect is described as localised, and no distance is given, so it cannot be turned into a radius. Do not assume unlimited antigen-negative clearance: Fas sensitivity is itself a tumour-cell property that can be lost.", "provenance": "Abstract read in full; the screen result, in vivo claim and clinical correlate as reported", "quantitativeExtraction": "extracted" }, "T29": { "id": "T29", "year": 2017, "topic": "Resistance", "title": "Bispecific T cell engager (BiTE) antibody constructs can mediate bystander tumor cell killing", "url": "https://doi.org/10.1371/journal.pone.0183390", "studyType": "In vitro co-culture with mixed antigen-positive and negative cells", "diseaseContext": "Shared cancer", "useInModel": "Antigen-negative cells are not automatically spared. EGFR-negative cells were efficiently lysed by engager-activated T cells when they sat close to EGFR-positive ones. So a density threshold applies to the cell that recruits the T cell, not to every cell that dies, and heterogeneous antigen does not translate directly into heterogeneous killing.", "limit": "In vitro co-culture. The proximity required is not expressed as a distance, and nothing here establishes whether bystander killing happens at the densities found in any drawn environment.", "provenance": "Abstract and indexed publisher text screened; full numerical extraction pending", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "functional-ctl-killing" ] }, { "id": "I082", "name": "Matrix-remodeling enzymes and inhibitors", "category": "Molecular", "whereToCheck": "Extracellular space and surfaces", "states": [ "Active versus inactive" ], "behaviors": [ "Proteases", "cleavage", "matrix turnover", "drug degradation" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "controls-mt1-control", "controls-mt1-silenced", "controls-mt1-rescue" ], "priorResearch": { "path": "simulation/data/profiles/matrix-remodeling-enzymes-and-inhibitors.json", "summary": "These enzymes cut the matrix that everything else in the atlas has to move through, and the single most important thing about them is that they work at a membrane rather than in solution. Collagenolytic and invasive activity survived the removal of six soluble proteolytic routes - plasminogen, the gelatinase A / TIMP-2 axis, gelatinase B, collagenase-3, collagenase-2 and stromelysin-1 - and was abolished by deleting the one membrane-tethered enzyme, MT1-MMP (L28). Whether proteolysis is needed at all depends on the matrix: amoeboid movement without cutting is only plausible in collagen that lacks the covalent cross-links real tissue has (L29). The inventory asks for active against inactive, which is right and incomplete - the axis that carries the information is tethered against soluble, and it is why thirty years of targeting these enzymes by abundance failed in the clinic (L27).", "stateAxes": [ { "axis": "Tethered against soluble - the axis the inventory's active/inactive does not capture", "whatToMeasure": "Whether the proteolytic activity is on a membrane in contact with matrix or free in the interstitium. For collagen the relevant measurement is MT1-MMP at cell surfaces, not protease concentration in extracellular fluid.", "interpretationLimit": "Established in cells from gene-targeted mice in three-dimensional culture and in invasion assays, not in a tumour in any drawn environment. It establishes which enzyme is required for collagen traffic, not how much matrix is turned over anywhere, and other matrix components may be handled differently.", "evidence": [ "L28", "L29" ] }, { "axis": "Active against inactive, as the inventory asks", "whatToMeasure": "Activated enzyme rather than total, reported with its inhibitor, since these are secreted as pro-enzymes and met by TIMPs in excess.", "interpretationLimit": "The atlas holds no activity measurement for this family anywhere - no activated fraction, no enzyme-to-inhibitor ratio, in any environment. What it holds instead is the consequence of having measured abundance and acted on it (L27), and a demonstration that the soluble half of the system is dispensable for the main job (L28). So this axis is named, agreed to matter, and unserved.", "evidence": [ "L27", "L28" ] }, { "axis": "The matrix being cut - cross-link state and hyaluronan content", "whatToMeasure": "Collagen cross-link density, because it decides whether proteolysis is required at all, and hyaluronan concentration, because it is what sets the pressure. 3 mg/ml of hyaluronan more than doubled the baseline pressure of carcinoma cells in collagen alone.", "interpretationLimit": "Cross-linking is treated as present or absent rather than quantified (L29), and no cross-link density is measured in any drawn environment. The hyaluronan figure is from a reconstituted matrix implanted in mice (Q02), not from tissue.", "evidence": [ "L29", "Q02" ] } ], "records": { "L27": { "id": "L27", "year": 2002, "topic": "Negative clinical comparator", "title": "Matrix metalloproteinase inhibitors and cancer: trials and tribulations", "url": "https://doi.org/10.1126/science.1067100", "studyType": "Review of the clinical programme and its failure, Science 295(5564):2387-2392", "diseaseContext": "Shared cancer", "useInModel": "The reference case for this family going wrong, and it went wrong in the way this atlas keeps finding. Matrix metalloproteinases were targeted for thirty years on the strength of being massively upregulated in malignant tissue and able to degrade every matrix component. Preclinical efficacy was described as compelling, inhibitors were developed quickly, and the human trials were disappointing. The review attributes this to new information about cellular source, substrate and mode of action at different stages - that is, to the arrangement of the activity rather than its level. Upregulated abundance was the premise, and abundance turned out not to be the variable. The same sentence could be written about the chemokine, TGF-beta, VEGF and PDGF-B families in this category.", "limit": "A 2002 review, so later selective inhibitors and later trial designs are outside it. It explains a class failure; it does not establish that matrix proteolysis is unimportant, and the dominant enzyme identified since is one the first-generation trials were not designed around (L28).", "provenance": "Abstract screened; the attribution of failure is the review's own", "quantitativeExtraction": "pending" }, "L28": { "id": "L28", "year": 2004, "topic": "Matrix and movement", "title": "Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP", "url": "https://doi.org/10.1083/jcb.200408028", "studyType": "Invasion assays in cells from gene-targeted mice, in vitro and in vivo, J Cell Biol 167(4):769-781", "diseaseContext": "Shared cancer", "useInModel": "Says a soluble protease concentration is the wrong object, which makes this the second representation finding of its kind in the atlas. Collagenolytic and invasive activity survived removal of plasminogen, the gelatinase A and TIMP-2 axis, gelatinase B, collagenase-3, collagenase-2 and stromelysin-1 - six soluble proteolytic routes, deleted or suppressed, with invasion intact. Deleting or suppressing the single membrane-tethered enzyme MT1-MMP abolished it, in fibroblasts and in tumour cells, in vitro and in vivo, and the two cell types were indistinguishable in the activity. So matrix degradation is a property of cell surfaces in contact with matrix rather than a diffusible field with a rate constant, and the concentration of protease in the interstitium carries almost no information. The glycan row reached the same conclusion for chemokines, whose directing form is immobilised on the matrix. Two different molecule classes, same error: the atlas records concentrations and the operative form is surface-bound.", "limit": "Cell and explant systems with mouse genetics, and the in vivo component is invasion assays rather than a tumour in a drawn environment. It establishes which enzyme is required for collagen traffic and not how much matrix is turned over anywhere, and other matrix components may be handled differently. Six routes were excluded for collagen specifically, which does not make them irrelevant to other substrates.", "provenance": "Re-extracted from the record's own screened content. All six excluded proteolytic routes, the requirement for the membrane-tethered enzyme in both cell types and both settings, and the pericellular character of the activity as reported. The pairing with the chemokine finding is this atlas's own", "quantitativeExtraction": "extracted" }, "L29": { "id": "L29", "year": 2009, "topic": "Matrix and movement", "title": "Protease-dependent versus -independent cancer cell invasion programs: three-dimensional amoeboid movement revisited", "url": "https://doi.org/10.1083/jcb.200807195", "studyType": "Invasion in cross-linked against non-cross-linked collagen networks, J Cell Biol 185(1):11-19", "diseaseContext": "Shared cancer", "useInModel": "Closes the obvious objection to L28 and hands the atlas a matrix specification. Protease-independent amoeboid migration, in which a cell squeezes through a collagen-lined pore without cutting anything, is reported as only plausible when the collagen network lacks the covalent cross-links that characterise normal tissue. Cancer cells had an absolute requirement for MT1-MMP for invasion through cross-linked networks. So whether proteolysis is required at all depends on a property of the matrix that most in vitro models get wrong - which means a simulation's matrix has to declare its cross-linking state before any statement about protease-dependent movement in it means anything.", "limit": "Three-dimensional culture systems, not tissue. Cross-linking is treated as present or absent rather than quantified, and no cross-link density is measured in any drawn environment in this atlas.", "provenance": "Abstract screened; the cross-linking condition is the authors' stated boundary on amoeboid movement", "quantitativeExtraction": "pending" }, "Q02": { "id": "Q02", "year": 2012, "topic": "Transport comparator", "title": "Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma", "url": "https://pubmed.ncbi.nlm.nih.gov/22439937/", "studyType": "Autochthonous KPC/KC mouse pancreatic cancer with in vivo pressure catheter, vessel morphometry and drug-delivery imaging, Cancer Cell 21(3):418-429", "diseaseContext": "Pancreatic", "useInModel": "Gives the pressure that explains why pancreatic vessels are shut, and the size of the delivery gain from opening them. Interstitial fluid pressure measured by catheter was 8-13 mmHg in normal pancreas, mean 10.4 across 8 animals, against 75-130 mmHg in autochthonous PDA, mean 99 in 7 KPC tumours and 87 in 4 KC tumours. That exceeds typical capillary pressure of 15-40 mmHg and overlaps arteriolar pressure of 40-80, which is the mechanical reason the vessels are collapsed rather than absent. Hyaluronan is identified as the determinant: 3 mg/ml of it more than doubled the baseline pressure of carcinoma cells engrafted in collagen alone. A single intravenous dose of the hyaluronidase PEGPH20 brought pressure to 16 mmHg in KC and 22 mmHg in KPC tumours at 24 hours, statistically indistinguishable from normal pancreas, and produced a more than 6.5-fold increase in doxorubicin fluorescence in the tumour. Vessel number did not change - only diameter - so the gain came from reopening existing vessels, not from new ones. With gemcitabine, median survival went from 55.5 days to 91.5 days; the enzyme alone reached 63 days and was not significant.", "limit": "Mouse, pancreatic, small groups: 14 to 16 animals per survival arm and 4 to 8 per pressure measurement. The mechanism is formally disputed - two commentaries in the same journal argue that the vessel compression is caused by solid stress rather than by interstitial fluid pressure, so the measured pressures stand while the causal account does not (L26). And the delivery gain did not translate: the clinical trial of the same enzyme is Q03.", "provenance": "Full text read; pressures, delivery fold-change and survival medians taken from results and figure legends", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "controls-mt1-control", "controls-mt1-silenced", "controls-mt1-rescue" ] }, { "id": "I083", "name": "DAMPs and extracellular nucleic acids", "category": "Molecular", "whereToCheck": "Injury/necrosis-associated sites", "states": [ "Released", "degraded", "vesicle-bound" ], "behaviors": [ "Sensing", "inflammation", "clearance" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "auwera-plasma-dna" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "auwera-plasma-dna" ], "priorResearch": { "path": "simulation/data/profiles/damps-and-extracellular-nucleic-acids.json", "summary": "The inventory asks for three states - released, degraded, vesicle-bound - and all three turn out to be load-bearing, which is unusual. Released is not a single thing: HMGB1 carries three mutually exclusive signals selected by redox state, a chemoattractant when reduced, a proinflammatory cytokine when disulfide-bonded, inert when further oxidised, and in injured tissue it is reduced first and disulfide-bonded later - so the signal changes identity over time with no change in concentration (L35). Degraded is not a path to zero: CD39 and CD73 convert extracellular nucleotides into pericellular adenosine, which suppresses the effector cells the nucleotide was alarming, so degradation inverts the sign rather than clearing the signal (L39). And vesicle-bound is a transport mechanism rather than a store - cGAMP, an intracellular second messenger, is packaged into extracellular vesicles and viral particles and delivered to cells that never sensed anything (L37). The family's largest surprise is upstream of all three: the sensing pathway runs inside the tumour cell itself, where chromosome segregation errors spill DNA from ruptured micronuclei into the cytosol and drive invasion and metastasis through cGAS-STING and non-canonical NF-kappa-B (L36).", "stateAxes": [ { "axis": "Released - but in which redox form", "whatToMeasure": "The fraction of each redox form rather than total protein, with the local oxidising conditions recorded alongside, because the form decides whether the same molecule recruits cells, activates them, or does nothing.", "interpretationLimit": "Established as decisive in sterile muscle injury with engineered mutants; no environment in this atlas has a measured value on this axis. The redox state is also fragile to sample handling, so a measurement has to defend its preanalytics before it means anything.", "evidence": [ "L35" ] }, { "axis": "Degraded - which is conversion, not removal", "whatToMeasure": "The nucleotide and its product together, plus the surface density of the converting ectoenzymes, since the question is not how much danger signal remains but how much suppressive signal it became and where.", "interpretationLimit": "Established in regulatory T cell biology and transplantation rather than tumour, with no nucleotide or adenosine concentration measured in any environment. The product is described as pericellular, consistent with the rest of this category, but no distance is given.", "evidence": [ "L39" ] }, { "axis": "Vesicle-bound - a transport state with its own distribution", "whatToMeasure": "Cargo per vesicle and vesicle flux, treated as a delivery route rather than as a reservoir, since the recipient cell is activated without having sensed anything itself.", "interpretationLimit": "Demonstrated in viral systems and cell culture. No cargo quantity, vesicle flux or transfer distance exists anywhere the atlas has looked, and this axis cannot be resolved independently of I084.", "evidence": [ "L37" ] }, { "axis": "Extracellular nucleic acid - length, not amount", "whatToMeasure": "Fragment length distribution, because that is what separates tumour-derived from host material: 134 to 144 base pairs against the 167 base-pair nucleosome footprint, with the mutant allele sitting at 132 to 145 against 165 for wild type in the same patient.", "interpretationLimit": "Measured in plasma, which is downstream of every environment rather than inside any of them, and nothing here speaks to extracellular nucleic acid at the injury site the inventory names. Residence times quoted for fragments of this size span about 16 minutes to 2.5 hours across secondary sources with no consensus and should not be carried as a value.", "evidence": [ "L38" ] } ], "records": { "L35": { "id": "L35", "year": 2012, "topic": "Molecular structure", "title": "Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release", "url": "https://doi.org/10.1084/jem.20120189", "studyType": "Cysteine-mutant and inhibitor work with ex vivo detection of redox forms in injured muscle, J Exp Med 209(9):1519-1528", "diseaseContext": "Shared all", "useInModel": "One molecule, three mutually exclusive signals, chosen by redox state rather than by concentration. Reduced cysteines make HMGB1 a chemoattractant; a disulfide bond makes the same protein a proinflammatory cytokine; further oxidation of those cysteines to sulfonates by reactive oxygen species abrogates both activities. The two functions were separated experimentally: a non-oxidisable mutant with serines replacing all cysteines did not drive cytokine production but recruited leukocytes more effectively than wild type, while the inhibitor BoxA blocked recruitment without blocking activation. The part that matters most for a model is the time course - the different forms were detected within injured muscle ex vivo, completely reduced at first and disulfide-bonded later. So the signal changes identity over time while the concentration need not change at all, and the switch is thrown by the local oxidising environment rather than by the cell that released it.", "limit": "Sterile muscle injury and engineered mutants, not tumour and not any drawn environment. No redox-form fractions are quantified anywhere, so the axis is established as decisive without any environment having a measured value on it. The redox state is also an assay hazard: sample handling can oxidise the protein being measured.", "provenance": "Abstract read in full; the three states, the separation experiments and the ex vivo time course as reported", "quantitativeExtraction": "pending" }, "L37": { "id": "L37", "year": 2015, "topic": "Transport", "title": "Transmission of innate immune signaling by packaging of cGAMP in viral particles", "url": "https://doi.org/10.1126/science.aab3628", "studyType": "Virology and extracellular vesicle work with transfer to dendritic cells, Science 349(6253):1232-1236", "diseaseContext": "Shared all", "useInModel": "Serves the inventory's third state directly, and breaks a boundary this atlas's categories assume. cGAMP, the second messenger that cGAS makes in response to cytosolic DNA, was found packaged into viral particles and into extracellular vesicles, and those particles delivered it efficiently to target cells - transfer to dendritic cells activated innate immunity and antiviral defences. Cell-free cytomegalovirus and Modified Vaccinia Ankara contained it. A second messenger is supposed to be an intracellular quantity; this one leaves the cell as cargo and activates the pathway in a cell that never sensed anything. So vesicle-bound is not a storage state but a transport mechanism with its own distribution, and this family cannot be separated from I084.", "limit": "Viral systems and cell culture, not tumour and not any drawn environment. The efficiency of delivery is reported qualitatively; no cGAMP quantity per vesicle, no vesicle flux and no transfer distance is given anywhere the atlas has looked.", "provenance": "Abstract read in full; the packaging, the delivery and the viral findings as reported", "quantitativeExtraction": "pending" }, "L38": { "id": "L38", "year": 2016, "topic": "Molecular structure", "title": "Fragment Length of Circulating Tumor DNA", "url": "https://doi.org/10.1371/journal.pgen.1006162", "studyType": "Xenograft rat models plus human melanoma and lung cancer plasma sequencing, PLoS Genet 12(7):e1006162", "diseaseContext": "Melanoma / Lung / Shared cancer", "useInModel": "The one place in this family with a hard physical number that separates tumour-derived material from host material. Human tumour DNA in rat plasma - from glioblastoma stem-like cells in brain and hepatocellular carcinoma in flank - had a shorter principal fragment length than the background rat cell-free DNA, 134 to 144 base pairs against 167. The same shift appeared in humans with melanoma and lung cancer against healthy controls, and within a single melanoma patient the BRAF V600E mutant allele occurred more commonly at 132 to 145 base pairs while the wild-type allele sat at 165. Size-selecting shorter fragments substantially increased the EGFR T790M mutant allele frequency in human lung cancer. The 167 base-pair background is the nucleosome footprint - about 147 wrapped plus linker - so what the shift says is that tumour-derived nucleic acid is packaged or trimmed differently from host, and that difference is measurable.", "limit": "Plasma, which is downstream of every environment rather than inside any of them, and the within-patient comparisons are from small numbers. It is a property of circulating material and says nothing about extracellular nucleic acid at the injury site the inventory asks about. Reported half-lives for fragments of this size span roughly 16 minutes to 2.5 hours across secondary sources with no consensus, so residence time should not be carried as a value.", "provenance": "Abstract read in full; fragment lengths and the size-selection result as reported. Half-life range is from secondary sources and flagged as such", "quantitativeExtraction": "pending" }, "L39": { "id": "L39", "year": 2007, "topic": "Chemistry and metabolism", "title": "Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression", "url": "https://doi.org/10.1084/jem.20062512", "studyType": "Ectoenzyme expression and function in regulatory T cells with Cd39-null mice, J Exp Med 204(6):1257-1265", "diseaseContext": "Shared all", "useInModel": "The record that says the inventory's second state is not a path to zero. Extracellular nucleotides are the archetypal danger signal, and CD39 with CD73 convert them into pericellular adenosine - so degrading the DAMP does not clear it, it turns it into something with the opposite effect. The coordinated expression of these two ectoenzymes on regulatory T cells together with the adenosine A2A receptor on activated effector T cells forms an immunosuppressive loop, and regulatory T cells from Cd39-null mice showed impaired suppression in vitro and failed to block allograft rejection in vivo. The word to retire from this family is clearance: the pathway is a sign inversion at a cell surface, and where the converting cells sit decides where the danger signal becomes a suppressive one.", "limit": "Regulatory T cell biology and transplantation rather than tumour, and no nucleotide or adenosine concentration is measured in any environment here. The adenosine is described as pericellular, which matches the pattern this category keeps finding, but no distance is given.", "provenance": "Abstract read in full; the ectoenzyme pair, the receptor loop and the Cd39-null result as reported", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I084", "name": "Extracellular vesicles", "category": "Molecular", "whereToCheck": "Blood and interstitium", "states": [ "Source", "cargo", "size", "uptake" ], "behaviors": [ "Distribution", "signaling", "target sequestration" ], "slots": { "size": { "status": "references available", "referenceIds": [ "grenier-ev" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "grenier-ev" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "grenier-ev" ], "priorResearch": { "path": "simulation/data/profiles/extracellular-vesicles.json", "summary": "The useful summary of this family is that a vesicle is a surface, not a packet. The internal-cargo story fails on arithmetic: counting vesicles and microRNA molecules in the same samples across six sources gave 0.00825 plus or minus 0.02 microRNA molecules per vesicle, so over 100 vesicles would have to be examined to find one copy of even an abundant species, and the authors conclude that most individual vesicles cannot function as microRNA carriers (L42). What does work, works on the outside. Lymphoma vesicles carrying CD20 bound therapeutic antibody, consumed complement and shielded the tumour cells behind them (L44); vesicular PD-L1 suppressed T cells in the draining lymph node and its removal inhibited growth even in antibody-resistant models (L45). The time available is short - melanoma-derived vesicles cleared from blood with a half-life of about 2 minutes, liver first then lungs (L43) - so this is local, fast and surface-mediated rather than a long-range courier service. One cargo does cross: cGAMP, which travels in vesicles and activates a pathway in cells that sensed nothing (L37), and which is a small molecule rather than a nucleic acid. And the inventory's size state is partly unmeasurable as specified, since the field's own guideline treats size labels as operational, method-dependent conventions and warns that non-vesicular particles abound in most preparations (L41).", "stateAxes": [ { "axis": "Cargo - with a stoichiometry, not a bulk level", "whatToMeasure": "Copies of the species of interest per vesicle, obtained by counting both the vesicles and the molecules in the same sample, rather than a concentration in a vesicle preparation. The reference value is 0.00825 plus or minus 0.02 microRNA molecules per vesicle across six sources.", "interpretationLimit": "Measured for microRNA specifically, in standard preparations that the later guideline says contain non-vesicular particles, and in six cell and fluid sources rather than tissue. It does not bound protein or small-molecule cargo, and a rare high-content subpopulation would be invisible to a population average - which is why the authors proposed revised models rather than discarding the hypothesis.", "evidence": [ "L42", "L41" ] }, { "axis": "Surface - which is what actually does the work", "whatToMeasure": "Density of the parent cell's functional surface proteins per vesicle, specifically the antigen a drug targets and any inhibitory ligands, since both demonstrated functions in this family are surface interactions.", "interpretationLimit": "Established qualitatively in two systems - antigen binding therapeutic antibody and ligand engaging its receptor - with no copy number per vesicle given in either, and neither system in a drawn environment. Without that density the sink term this axis implies cannot be parameterised.", "evidence": [ "L44", "L45" ] }, { "axis": "Size - an operational label, not a physical state", "whatToMeasure": "Diameter together with the method that measured it, plus density or biochemical composition and the conditions and cell of origin, as the guideline directs - and never a subtype name standing in for any of these.", "interpretationLimit": "The under-200 and over-200 nanometre conventions are reporting categories whose measured value depends on the characterisation method, and biogenesis cannot be inferred from them. This axis as the inventory words it is not a measurable property but a classification decision.", "evidence": [ "L41" ] }, { "axis": "Distribution and uptake - with a residence time", "whatToMeasure": "Clearance from the compartment of interest, and the organ or tissue the material arrives in. The only value held is a circulating half-life of about 2 minutes with little serum signal at 4 hours, liver first then lungs.", "interpretationLimit": "An intravenous bolus of exogenously prepared cell-line vesicles in mice, labelled with a surface fusion protein that could itself affect clearance. It is a circulating half-life, and the inventory asks about blood and interstitium - no interstitial residence time exists anywhere the atlas has looked.", "evidence": [ "L43" ] } ], "records": { "L41": { "id": "L41", "year": 2024, "topic": "Atlas resource", "title": "Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches", "url": "https://doi.org/10.1002/jev2.12404", "studyType": "International Society for Extracellular Vesicles consensus guideline, J Extracell Vesicles 13(2):e12404", "diseaseContext": "Shared all", "useInModel": "The field policing its own vocabulary, which matters because one of the inventory's four states for this family is partly unmeasurable as specified. The guideline warns against misusing the term exosome, because a biogenesis route cannot be read off a preparation, and it treats size labels as operational rather than definitional: small vesicles are often described as under 200 nanometres in diameter and large ones as over, with the explicit qualification that the measured diameter depends on the characterisation method used. It also flags that non-vesicular extracellular particles abound in most preparations - so a measured effect attributed to vesicles may not come from vesicles at all. The practical rule the atlas should adopt is the guideline's own: describe these objects by the conditions and cell that produced them, by density or biochemical composition, and by the method that measured them, rather than by a subtype name.", "limit": "A guideline, not a measurement. It constrains how claims in this family may be stated and supplies no quantity for any environment. Its size figures are reporting conventions rather than physical findings, and should never be used as a transport parameter.", "provenance": "Abstract and the society's own summary of the nomenclature section screened; the size conventions and the non-vesicular particle caution as stated", "quantitativeExtraction": "pending" }, "L42": { "id": "L42", "year": 2014, "topic": "Molecular structure", "title": "Quantitative and stoichiometric analysis of the microRNA content of exosomes", "url": "https://doi.org/10.1073/pnas.1408301111", "studyType": "Paired counting of vesicles and microRNA molecules across six sources including ovarian cancer cells, PNAS 111(41):14888-14893", "diseaseContext": "Ovarian (HGSC) / Shared all", "useInModel": "The number that decides how this family may be represented at all. Counting both the vesicles and the microRNA molecules in the same replicate samples, from plasma, seminal fluid, dendritic cells, mast cells and ovarian cancer cells, gave on average 0.00825 plus or minus 0.02 microRNA molecules per exosome - far less than one copy per vesicle even for the most abundant microRNAs in the preparation. If the cargo were distributed evenly, over 100 vesicles would have to be examined to find a single copy of a given abundant species. The authors' conclusion is that most individual vesicles in standard preparations do not carry biologically significant numbers of microRNAs and are individually unlikely to function as vehicles for microRNA-based communication. They also found that exosome fractions held only a small minority of the microRNA content of plasma. So a vesicle cannot be modelled as a packet of signal, and the extracellular microRNA that exists is mostly somewhere else.", "limit": "Standard exosome preparations, which the later guideline (L41) notes contain non-vesicular particles, and six sources rather than any tissue. It is a stoichiometry for microRNA specifically and does not bound protein or metabolite cargo. Rare high-content vesicles within a heterogeneous population would be invisible to a population average, which is the authors' own stated reason for proposing revised models rather than rejecting the hypothesis outright.", "provenance": "Abstract read in full; the per-vesicle figure, its spread and the plasma-fraction finding as reported", "quantitativeExtraction": "extracted" }, "L43": { "id": "L43", "year": 2013, "topic": "Transport", "title": "Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection", "url": "https://doi.org/10.1016/j.jbiotec.2013.03.013", "studyType": "Luciferase-labelled melanoma-derived vesicles with pharmacokinetic and imaging analysis in mice, J Biotechnol 165(2):77-84", "diseaseContext": "Melanoma", "useInModel": "Gives this family a residence time, and it is short. Melanoma-derived vesicles labelled with a luciferase-lactadherin fusion and injected intravenously disappeared from the blood with a half-life of approximately 2 minutes, with little signal remaining in serum at 4 hours. Sequential imaging put the signal first in liver and then in lungs. Read against the antibody transport numbers the atlas already holds, this is a different regime entirely - a vesicle has minutes in circulation where an antibody has days - which means systemic vesicle traffic cannot be a mechanism for sustained long-range signalling, and whatever these objects do they most likely do close to where they were released.", "limit": "Mouse, intravenous bolus of exogenously prepared vesicles from a cell line, which is not the same as vesicles released continuously inside a tumour. The label is a surface fusion protein and could itself affect clearance. The half-life is for the circulating compartment and says nothing about residence time in interstitium, which is where the inventory asks this family to be checked.", "provenance": "Abstract read in full; half-life, 4-hour serum finding and organ sequence as reported", "quantitativeExtraction": "extracted" }, "L44": { "id": "L44", "year": 2011, "topic": "Resistance", "title": "Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3", "url": "https://doi.org/10.1073/pnas.1102855108", "studyType": "B-cell lymphoma vesicle biology with ABCA3 blockade and silencing, PNAS 108(37):15336-15341", "diseaseContext": "Lymphoma / Shared cancer", "useInModel": "Serves the inventory's hardest behaviour - target sequestration - and serves it mechanically. Lymphoma cells released vesicles carrying CD20 that bound therapeutic anti-CD20 antibody, consumed complement, and shielded the tumour cells from antibody attack. Blocking or silencing the transporter ABCA3 reduced the amount of vesicle released and increased the susceptibility of the target cells to antibody-mediated lysis, which makes vesicle output a manipulable variable rather than a fixed property. Two consequences for this atlas. First, a vesicle bearing the target antigen is a sink term on the drug, and in a model it belongs with clearance rather than with signalling. Second, the complement consumption partly fills a gap stated under I076: that family's deposited arm in tumour was recorded as entirely absent, and here is tumour-derived material consuming complement. ABCA3 also links resistance to antibodies and resistance to chemotherapy through one pathway.", "limit": "B-cell lymphoma cell systems with a naked antibody acting through complement and antibody-mediated lysis, which is not how a T-cell engager works - an engager that is soaked up by antigen-positive vesicles loses drug without the complement step. Lymphoma is a drawn environment which became a drawn environment on 2026-10-14; no sequestered fraction is quantified, and nothing here gives the vesicle antigen density needed to turn this into a sink rate.", "provenance": "Abstract read in full; antigen carriage, antibody binding, complement consumption and the ABCA3 results as reported", "quantitativeExtraction": "pending" }, "L45": { "id": "L45", "year": 2019, "topic": "Exclusion and signaling", "title": "Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory", "url": "https://doi.org/10.1016/j.cell.2019.02.016", "studyType": "Mouse models with vesicle-secretion-deficient tumour cells and reconstitution, Cell 177(2):414-427", "diseaseContext": "Prostate / Shared cancer", "useInModel": "Says the vesicle acts somewhere other than where it was made, and that an antibody does not cover it. Removing vesicular PD-L1 inhibited tumour growth even in models resistant to anti-PD-L1 antibody, and the suppression it normally exerts was located in the draining lymph node rather than in the tumour - a different organ from the one the ligand's cellular form acts in. Systemically introduced vesicular PD-L1 rescued growth of tumours unable to secrete their own, which is a transfer experiment establishing sufficiency. Exposure to secretion-deficient tumour cells suppressed growth of wild-type cells injected at a distant site, simultaneously or months later. And antibody blockade worked additively rather than redundantly with removal of the vesicular pool. For a model that means the vesicular and cell-surface pools of the same ligand are separate compartments acting at different sites, and a drug that engages one does not neutralise the other.", "limit": "Mouse models with secretion genetically disabled, which removes all vesicle cargo rather than PD-L1 alone, so attributing the whole effect to this one ligand is a reading rather than a demonstration. No vesicular PD-L1 concentration or copy number is given, nothing is measured in a drawn environment, and the draining lymph node is not a compartment this project's simulations currently represent at all.", "provenance": "Abstract read in full; the lymph-node localisation, rescue experiment and additivity as reported", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I085", "name": "Amyloid-beta species", "category": "Molecular", "whereToCheck": "AD extracellular and vascular compartments", "states": [ "Monomer", "oligomer", "fibril", "deposited forms" ], "behaviors": [ "Production", "clearance", "binding", "vascular and synaptic effects" ], "slots": { "size": { "status": "references available", "referenceIds": [ "afm-pitch", "afm-step" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "afm-abeta" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "afm-dwell", "afm-growth" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "afm-pitch", "afm-step", "afm-dwell", "afm-growth", "afm-abeta" ], "priorResearch": { "path": "simulation/data/profiles/amyloid-beta-species.json", "summary": "The inventory asks for monomer, oligomer, fibril and deposited forms, and the records make that distinction the whole question. Soluble dimers extracted from Alzheimer's cortex inhibited long-term potentiation, enhanced long-term depression, reduced spine density and disrupted memory in normal rats, while insoluble plaque cores from the same cortex did nothing to long-term potentiation until they were solubilised - so the deposited form is largely inert and acts as a reservoir holding the toxic one (A07). Why the material accumulates is settled in the other direction from intuition: measured in human CNS in vivo, clearance of both Abeta40 and Abeta42 is impaired in Alzheimer's disease while production is unchanged (L46). So this family is a drainage failure rather than a synthesis problem, which places it downstream of the vascular and perivascular families in this atlas. And the inventory's own instruction to check the vascular compartment turns out to name the safety-limiting site: the dose-limiting toxicity of removing amyloid is an imaging abnormality in that compartment, at 12.6% and 24.0% in the two phase 3 trials (A09, A10).", "stateAxes": [ { "axis": "Monomer against oligomer against fibril against deposit", "whatToMeasure": "Concentration of the soluble dimer and small oligomer fraction, separately from plaque load, because the two behave oppositely: dimers are synaptotoxic at assay exposures and plaque cores were inactive until solubilised. Dimers are reported as the smallest synaptotoxic species, which sets the lower bound on what has to be resolved.", "interpretationLimit": "Established by applying human-derived material to normal rodent tissue, which shows what each state can do rather than what it is doing in a patient. No concentration of any soluble species in human tissue exists in this atlas, so the axis that matters most is the one with no measured values on it.", "evidence": [ "A07" ] }, { "axis": "Deposited structure - and which object the parameters came from", "whatToMeasure": "The filament fold, not just the burden: two S-shaped protofilament folds give two types, type I predominating in sporadic disease and type II in familial disease and other conditions.", "interpretationLimit": "Two warnings attach. Brain filaments differ structurally from filaments assembled in vitro, so aggregation kinetics measured on synthetic peptide describe a different object. And App knock-in mice deposit type II - the familial fold - so the standard animal model does not reproduce the structure of the sporadic disease this atlas's environment represents. Filament structure also does not give soluble species concentrations or dynamics.", "evidence": [ "L47", "A06", "A08" ] }, { "axis": "Clearance, which is the axis that moved", "whatToMeasure": "Clearance rate of Abeta40 and Abeta42 from the CNS compartment, against production rate, in the same individuals - since in late-onset disease the first is impaired and the second is not.", "interpretationLimit": "A whole-compartment rate that does not say which route failed: perivascular drainage, proteolysis, or transport across the barrier are not separated. It applies to sporadic late-onset disease and not to autosomal dominant forms, where production is altered by definition. The hourly rates are not extracted into this atlas.", "evidence": [ "L46" ] } ], "records": { "A06": { "id": "A06", "year": 2017, "topic": "Molecular structure", "title": "Cryo-EM structures of tau filaments from Alzheimer's disease", "url": "https://pubmed.ncbi.nlm.nih.gov/28678775/", "studyType": "Cryo-electron microscopy at 3.4-3.5 angstrom resolution of filaments from one Alzheimer's brain, Nature 547(7662):185-190", "diseaseContext": "Alzheimer's", "useInModel": "Fixes what the ordered part of this family actually is, and it is a small part. The cores of both paired helical and straight filaments are made of two identical protofilaments comprising residues 306 to 378, which adopt a combined cross-beta and beta-helix structure that the authors describe as defining the seed for tau aggregation. The two filament types are ultrastructural polymorphs: same protofilament, different inter-protofilament packing. Two consequences the atlas should carry. The ordered core spans about 73 residues of a protein whose longest isoform runs to 441, so most of the molecule is outside the structure that defines the species - which bears directly on where a binder can usefully sit. And the result established that patient-derived amyloid filaments can be solved at atomic resolution at all, which is what made the structural classification of these diseases possible.", "limit": "One individual, and static structures. A fibril fold does not give the concentration or the dynamics of the soluble species, and this record says nothing about which tau state is toxic. The seed claim is an interpretation of the structure rather than a measured seeding rate.", "provenance": "Abstract read in full; core residues, resolution, polymorph relationship and the seed interpretation as reported", "quantitativeExtraction": "extracted" }, "A07": { "id": "A07", "year": 2008, "topic": "Soluble aggregate effects", "title": "Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory", "url": "https://www.nature.com/articles/nm1782", "studyType": "Soluble oligomers extracted from human Alzheimer's cortex, assayed in rodent hippocampus and behaviour, Nat Med 14(8):837-842", "diseaseContext": "Alzheimer's", "useInModel": "Answers the inventory's species question with an experiment rather than an argument. Soluble oligomers taken directly from Alzheimer's cortex inhibited long-term potentiation, enhanced long-term depression and reduced dendritic spine density in normal rodent hippocampus, and disrupted memory of a learned behaviour in normal rats - and the effects were specifically attributable to dimers, which the authors call the smallest synaptotoxic species. The decisive control is the other direction: insoluble plaque cores from the same cortex did not impair long-term potentiation unless they were first solubilised to release dimers, so plaque cores are largely inactive and act as a reservoir that sequesters the toxic species. Two mechanistic details carry across the atlas. The pathways split - metabotropic glutamate receptors were required for the long-term depression effect and NMDA receptors for the spine loss, so one species produces two lesions through two receptors. And epitope mattered: antibodies to the N-terminus prevented the deficits while antibodies to the midregion or C-terminus were less effective, which is the same lesson the engager families record about where on a target a binder sits.", "limit": "Human-derived material applied to normal rodent tissue and normal rats, at assay exposures rather than in a diseased brain, so it establishes what the species can do and not what it is doing in any patient. No concentration of dimer in human tissue is given here or anywhere in this atlas. The plaque-core result is a strong negative for the deposited form but sits in tension with the clinical effect of an antibody directed at insoluble plaque (A10).", "provenance": "Abstract read in full; the dimer attribution, the plaque-core control, the receptor split and the epitope result as reported", "quantitativeExtraction": "extracted" }, "A08": { "id": "A08", "year": 2018, "topic": "Molecular structure", "title": "Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC6208733/", "studyType": "Cryo-EM and immuno-gold negative-stain EM across 17 Alzheimer's cases and 2 atypical cases, Acta Neuropathol 136(5):699-708", "diseaseContext": "Alzheimer's", "useInModel": "Answers whether the fold varies between patients, and the answer is no. Filaments from the frontal cortex of 17 Alzheimer's cases - 15 sporadic and 2 inherited - plus 2 cases of posterior cortical atrophy were examined, with high-resolution structures from three. Paired helical filaments outnumbered straight filaments in every case, both were built from two C-shaped protofilaments with the combined cross-beta and beta-helix fold, and the authors conclude there is no significant variation in tau filament structure between individuals with Alzheimer's disease. Immuno-EM located repeats 3 and 4 in the filament cores of all cases and found the N-terminal regions of repeats 1 and 2 absent from them. So within one disease the conformation is a constant, which is what allows the fold to serve as a disease identity across diseases (L48) - and it tells an antibody designer that the ordered core excludes the regions most antibodies have been raised against.", "limit": "Frontal cortex, with other regions assessed only by immuno-EM rather than at high resolution, and 17 cases is enough to exclude gross variation rather than subtle polymorphism. Structural convergence between individuals does not mean the soluble species, the phosphorylation state or the regional distribution converge, and none of those is measured here.", "provenance": "Abstract read in full; case numbers, filament proportions, the repeat localisation and the invariance conclusion as reported", "quantitativeExtraction": "extracted" }, "L46": { "id": "L46", "year": 2010, "topic": "Transport", "title": "Decreased clearance of CNS beta-amyloid in Alzheimer's disease", "url": "https://doi.org/10.1126/science.1197623", "studyType": "In vivo stable-isotope metabolic labelling of Abeta40 and Abeta42 in human CNS, Science 330(6012):1774", "diseaseContext": "Alzheimer's", "useInModel": "Decides which of the inventory's first two behaviours is the variable, in humans, in vivo. Metabolic labelling measured both production and clearance rates of Abeta40 and Abeta42 in the central nervous system of people with Alzheimer's disease and cognitively normal controls. Clearance of both species was impaired in Alzheimer's; on average there was no difference in production rate for either. The conclusion is that common late-onset Alzheimer's disease is characterised by an overall impairment in clearance. For a model this is a strong structural constraint: amyloid accumulation should not be represented as an increased source term. It is a drainage failure, which places this family downstream of the vascular and perivascular families in this atlas rather than downstream of a synthesis rate.", "limit": "A short report, and the specific hourly rates are not extracted here - only the direction and the absence of a production difference, both of which are the paper's stated findings. It is late-onset sporadic disease and says nothing about autosomal dominant forms, where production is altered by definition. Clearance as measured here is a whole-compartment rate and does not identify which route - perivascular drainage, proteolysis, transport across the barrier - is the one that failed.", "provenance": "Abstract read in full; the impaired-clearance and unchanged-production findings as reported, rates not extracted", "quantitativeExtraction": "pending" }, "L47": { "id": "L47", "year": 2022, "topic": "Molecular structure", "title": "Cryo-EM structures of amyloid-beta 42 filaments from human brains", "url": "https://doi.org/10.1126/science.abm7285", "studyType": "Cryo-electron microscopy of filaments extracted from human brain and from knock-in mice, Science 375(6577):167-172", "diseaseContext": "Alzheimer's", "useInModel": "Gives the deposited form a structure, and then delivers two warnings about where aggregation parameters come from. Two structurally related S-shaped protofilament folds give rise to two filament types: type I was found mostly in sporadic Alzheimer's disease and type II in familial Alzheimer's disease and other conditions. The first warning is that the filaments from brain differ structurally from filaments assembled in vitro - so aggregation kinetics measured on synthetic peptide describe a different object from the one in tissue. The second is worse for model-building: in App knock-in mice the deposits were made of type II filaments, the familial type, so the standard animal model does not reproduce the structure found in the sporadic disease the atlas's Alzheimer's environment represents.", "limit": "Structural, and static. Filament folds do not give the concentration or dynamics of the soluble species that A07 identifies as the synaptotoxic one, and the authors position the work as groundwork for assembly inhibitors and imaging agents rather than as a mechanism of toxicity. Type assignments are by predominance across cases, not absolute.", "provenance": "Abstract read in full; the two folds, their disease distribution, the in vitro divergence and the mouse finding as reported", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I086", "name": "Tau species", "category": "Molecular", "whereToCheck": "AD and FTLD-tau modules", "states": [ "Isoform", "phosphorylation", "soluble/filament state" ], "behaviors": [ "Misfolding", "localization", "propagation candidates", "toxicity" ], "slots": { "size": { "status": "references available", "referenceIds": [ "geometry-tau-phf-wide", "geometry-tau-phf-narrow", "geometry-tau-phf-crossover", "geometry-tau-sf-width", "geometry-tau-sf-crossover" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "geometry-tau-phf-wide", "geometry-tau-phf-narrow", "geometry-tau-phf-crossover", "geometry-tau-sf-width", "geometry-tau-sf-crossover" ], "priorResearch": { "path": "simulation/data/profiles/tau-species.json", "summary": "For this family the species is a conformation, and the information that moves is a shape rather than an amount. Filament folds differ between tauopathies and define a hierarchical classification that complements clinical diagnosis and has already corrected one - a case diagnosed as progressive supranuclear palsy carried filaments intermediate between two folds and turned out to be a new entity (L48). Within Alzheimer's disease the fold is instead a constant: across 17 cases, 15 sporadic and 2 inherited, there was no significant variation in filament structure (A08). The shape is also transmissible and carries the lesion pattern with it - human brain extracts injected into mice recapitulated the hallmark lesions of the disease each extract came from, in the same host, and the aggregates could then be propagated from mouse to mouse (L49). The ordered part of the molecule is small: residues 306 to 378 of a protein running to 441, comprising repeats 3 and 4 with the N-terminal halves of repeats 1 and 2 outside the core (A06, A08). And the inventory's first state, isoform, turns out to sit causally upstream of the third - MAPT intron 10 mutations that shift the four-repeat balance produce a specific fold (L48).", "stateAxes": [ { "axis": "Filament fold - the state that is the species", "whatToMeasure": "The conformation itself, by cryo-EM on patient-derived material, since the fold distinguishes diseases that look alike and is invariant within Alzheimer's disease. The ordered core to report is residues 306 to 378, with the inter-protofilament packing distinguishing paired helical from straight filaments as ultrastructural polymorphs.", "interpretationLimit": "Structural, static, and post-mortem. A fold is an end-state deposit: it does not identify which conformation is toxic, how fast any forms, or what the soluble precursor population looks like. No marker, stain or fluid assay reports a fold, so this axis is measurable only by a method that cannot be applied to a living patient.", "evidence": [ "L48", "A06", "A08" ] }, { "axis": "Isoform - and it is upstream, not parallel", "whatToMeasure": "The four-repeat to three-repeat balance, reported alongside the fold rather than on its own, since inherited mutations that shift this balance produce a specific filament fold shared with a sporadic disease.", "interpretationLimit": "The link from four-repeat overproduction to that fold is the authors' suggestion from a structural coincidence between inherited and sporadic cases, not a demonstrated mechanism. No isoform ratio is quantified in any environment in this atlas.", "evidence": [ "L48" ] }, { "axis": "Phosphorylation - the one state with a human measurement", "whatToMeasure": "Phospho-threonine-217, in plasma, which reaches an area under the curve of 0.96 against other neurodegenerative diseases and 0.89 against neuropathological diagnosis, and separates mutation carriers about 20 years before estimated onset of cognitive impairment.", "interpretationLimit": "Cross-sectional cohorts, so the lead time is an age-stratified separation in a genetic kindred rather than a trajectory. It is a correlate, not the species: it reports neither fold nor soluble toxic form. Platforms are not interchangeable, and the autosomal-dominant result cannot be carried to sporadic disease.", "evidence": [ "L50" ] }, { "axis": "Soluble against filament", "whatToMeasure": "The soluble species, which is the state this family has least evidence on - the structures describe deposits and the plasma assay describes a phospho-epitope, leaving the soluble intermediate unmeasured.", "interpretationLimit": "Named by the inventory and essentially unserved. The atlas has atomic structures of the filament, a validated blood correlate, and nothing quantifying soluble tau species in human tissue - which is the same gap recorded for amyloid-beta under I085, where the soluble form is the one shown to be toxic.", "evidence": [ "A06", "L50" ] } ], "records": { "A06": { "id": "A06", "year": 2017, "topic": "Molecular structure", "title": "Cryo-EM structures of tau filaments from Alzheimer's disease", "url": "https://pubmed.ncbi.nlm.nih.gov/28678775/", "studyType": "Cryo-electron microscopy at 3.4-3.5 angstrom resolution of filaments from one Alzheimer's brain, Nature 547(7662):185-190", "diseaseContext": "Alzheimer's", "useInModel": "Fixes what the ordered part of this family actually is, and it is a small part. The cores of both paired helical and straight filaments are made of two identical protofilaments comprising residues 306 to 378, which adopt a combined cross-beta and beta-helix structure that the authors describe as defining the seed for tau aggregation. The two filament types are ultrastructural polymorphs: same protofilament, different inter-protofilament packing. Two consequences the atlas should carry. The ordered core spans about 73 residues of a protein whose longest isoform runs to 441, so most of the molecule is outside the structure that defines the species - which bears directly on where a binder can usefully sit. And the result established that patient-derived amyloid filaments can be solved at atomic resolution at all, which is what made the structural classification of these diseases possible.", "limit": "One individual, and static structures. A fibril fold does not give the concentration or the dynamics of the soluble species, and this record says nothing about which tau state is toxic. The seed claim is an interpretation of the structure rather than a measured seeding rate.", "provenance": "Abstract read in full; core residues, resolution, polymorph relationship and the seed interpretation as reported", "quantitativeExtraction": "extracted" }, "A08": { "id": "A08", "year": 2018, "topic": "Molecular structure", "title": "Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC6208733/", "studyType": "Cryo-EM and immuno-gold negative-stain EM across 17 Alzheimer's cases and 2 atypical cases, Acta Neuropathol 136(5):699-708", "diseaseContext": "Alzheimer's", "useInModel": "Answers whether the fold varies between patients, and the answer is no. Filaments from the frontal cortex of 17 Alzheimer's cases - 15 sporadic and 2 inherited - plus 2 cases of posterior cortical atrophy were examined, with high-resolution structures from three. Paired helical filaments outnumbered straight filaments in every case, both were built from two C-shaped protofilaments with the combined cross-beta and beta-helix fold, and the authors conclude there is no significant variation in tau filament structure between individuals with Alzheimer's disease. Immuno-EM located repeats 3 and 4 in the filament cores of all cases and found the N-terminal regions of repeats 1 and 2 absent from them. So within one disease the conformation is a constant, which is what allows the fold to serve as a disease identity across diseases (L48) - and it tells an antibody designer that the ordered core excludes the regions most antibodies have been raised against.", "limit": "Frontal cortex, with other regions assessed only by immuno-EM rather than at high resolution, and 17 cases is enough to exclude gross variation rather than subtle polymorphism. Structural convergence between individuals does not mean the soluble species, the phosphorylation state or the regional distribution converge, and none of those is measured here.", "provenance": "Abstract read in full; case numbers, filament proportions, the repeat localisation and the invariance conclusion as reported", "quantitativeExtraction": "extracted" }, "L48": { "id": "L48", "year": 2021, "topic": "Molecular structure", "title": "Structure-based classification of tauopathies", "url": "https://doi.org/10.1038/s41586-021-03911-7", "studyType": "Cryo-EM of patient-derived filaments across multiple tauopathies, Nature 598(7880):359-363", "diseaseContext": "Alzheimer's / FTD", "useInModel": "Makes the conformation the identity of the disease. Filament folds differ between Alzheimer's disease, Pick's disease, chronic traumatic encephalopathy and corticobasal degeneration; progressive supranuclear palsy defines a new three-layered fold which globular glial tauopathy shares; argyrophilic grain disease instead resembles the four-layered corticobasal fold, and so does ageing-related tau astrogliopathy; and familial British and familial Danish dementia filaments are the same as those of Alzheimer's disease and primary age-related tauopathy. The authors propose a hierarchical classification on filament fold that complements clinical diagnosis and neuropathology - and they demonstrate it correcting one: a case diagnosed as progressive supranuclear palsy had filaments intermediate between globular glial tauopathy and PSP, identifying a new entity. The mechanistic hinge for this atlas is that inherited mutations at positions +3 and +16 in intron 10 of MAPT, which shift the balance of four-repeat tau, produce the argyrophilic grain fold - so isoform ratio is causally upstream of conformation rather than a parallel axis.", "limit": "Structural and cross-sectional, from patient-derived material rather than any live process. The classification is a taxonomy of end-state deposits and does not identify which conformation is toxic, how fast any of them form, or what the soluble precursor population looks like. The intron 10 inference about four-repeat overproduction is the authors' suggestion from a structural coincidence, not a demonstrated mechanism.", "provenance": "Abstract read in full; the fold assignments, the proposed classification, the reclassified case and the intron 10 inference as reported", "quantitativeExtraction": "pending" }, "L50": { "id": "L50", "year": 2020, "topic": "Clinical outcome", "title": "Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders", "url": "https://doi.org/10.1001/jama.2020.12134", "studyType": "Three cross-sectional cohorts totalling over 1,400 participants including a neuropathology cohort and a PSEN1 kindred, JAMA 324(8):772-781", "diseaseContext": "Alzheimer's", "useInModel": "The best human measurement of any family in this atlas, in any category. Plasma tau phosphorylated at threonine 217 separated neuropathologically defined Alzheimer's from non-Alzheimer's with an area under the curve of 0.89, against 0.50 to 0.72 for plasma P-tau181 and neurofilament light. In a clinical cohort it separated Alzheimer's dementia from other neurodegenerative diseases at 0.96, against 0.50 to 0.81 for P-tau181, neurofilament light and MRI - and was not significantly different from CSF P-tau217, CSF P-tau181 or tau PET, which ran 0.90 to 0.99. In a Colombian PSEN1 E280A kindred, carriers were separable from non-carriers from about age 25, roughly 20 years before the estimated onset of mild cognitive impairment. The finding that matters most for this atlas is a correlation: plasma P-tau217 tracked tau tangles in participants who had amyloid plaques, at a Spearman rho of 0.64, and not in those who did not, at 0.15 with p = 0.33. That is the amyloid-tau coupling quantified in human tissue, and it is the same coupling the donanemab trial exploited by stratifying on tau.", "limit": "Cross-sectional cohorts, so the 20-year lead time is an age-stratified separation in a genetic kindred rather than a measured trajectory in an individual. A blood phosphorylation state is not the filament fold and not the soluble toxic species; it is an accessible correlate. The autosomal-dominant cohort cannot be carried to sporadic disease, and assay platforms for this analyte are not interchangeable.", "provenance": "Abstract read in full; all areas under the curve, the kindred lead time and both correlation coefficients as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I087", "name": "TDP-43 and RNA-processing targets", "category": "Molecular", "whereToCheck": "Relevant ALS/FTD cells", "states": [ "Nuclear loss", "cytoplasmic aggregation" ], "behaviors": [ "UNC13A/STMN2 processing", "localization", "downstream function" ], "slots": { "size": { "status": "references available", "referenceIds": [ "geometry-tdp-width", "geometry-tdp-rise" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "geometry-tdp-width", "geometry-tdp-rise" ], "priorResearch": { "path": "simulation/data/profiles/tdp-43-and-rna-processing-targets.json", "summary": "The inventory names this family's two states as nuclear loss and cytoplasmic aggregation and its behaviours as UNC13A and STMN2 processing - which is unusually specific, and correct. TDP-43's job in the nucleus is to repress cryptic exon inclusion, and losing it lets cryptic exons into hundreds of transcripts (L52). Two of those are the ones the inventory names, and each carries a different kind of finding. UNC13A is where the genetics meet the pathology: the strongest genome-wide risk variants for these diseases sit in the intron harbouring its cryptic exon, overlapping TDP-43's own binding sites, and they increase cryptic inclusion only once TDP-43 has failed - so risk genotype and pathological state multiply rather than add (F02, F03). STMN2 is where the atlas holds a repair: TDP-43 sterically blocks a cryptic 3' splice site, and an oligonucleotide aimed at that site restored axonal regeneration and lysosome trafficking in TDP-43-deficient human neurons, and restored the protein in humanised mice independently of TDP-43 binding (F04). The two states are coupled by positive feedback: nuclear TDP-43 suppresses its own cytoplasmic transcript, so losing it from the nucleus raises cytoplasmic TARDBP mRNA, measurably so in affected ALS motor neurons (L54).", "stateAxes": [ { "axis": "Nuclear loss - measured by what it stops repressing", "whatToMeasure": "Cryptic exon inclusion in the transcripts the inventory names, as a fraction of transcript, rather than TDP-43 abundance - since the function lost is repression and the inclusion event is its direct readout. Cryptic exons in depleted neurons were predictive of those in patient brain, so the in vitro readout has been validated against tissue.", "interpretationLimit": "Established in depletion models and confirmed cross-sectionally in patient tissue, so the direction is secure and no rate of inclusion per unit of nuclear loss exists. Hundreds of transcripts are affected and the contribution of any one to the phenotype is not isolated. It does not apply to ALS or FTD subtypes without TDP-43 mislocalisation.", "evidence": [ "F02", "F03", "L52" ] }, { "axis": "Cytoplasmic aggregation - with a fold, and an unusual one", "whatToMeasure": "The filament structure, which spans residues 282 to 360 of the low-complexity domain as a single protofilament in a double-spiral fold, identical across two cortical regions and two individuals - and which lacks the beta-sheet stacking that defines cross-beta amyloid.", "interpretationLimit": "Two individuals with one diagnosis, so invariance is across regions and a pair rather than across the disease, and nothing covers the other TDP-43 proteinopathies or the TDP-43 pathology common in Alzheimer's and Parkinson's. The fold has no similarity to TDP-43 filaments assembled in vitro, which is the third aggregating family in a row where in vitro material is the wrong object.", "evidence": [ "L53" ] }, { "axis": "The coupling between the two states", "whatToMeasure": "Cytoplasmic TARDBP mRNA alongside nuclear protein, since the two are linked by autoregulation: nuclear TDP-43 routes its own transcript to decay, and losing it raises the cytoplasmic message.", "interpretationLimit": "Established qualitatively, with no loop gain, rate constant or threshold measured. Increased cytoplasmic transcript is not the same as protein aggregating there, and that step is not demonstrated. It is nonetheless a structural requirement for any model of this family, because the two states cannot be independent variables.", "evidence": [ "L54" ] } ], "records": { "F02": { "id": "F02", "year": 2022, "topic": "RNA processing", "title": "TDP-43 represses cryptic exon inclusion in the FTD–ALS gene UNC13A", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8891019/", "studyType": "Human brain, neuronal cell lines and iPSC-derived motor neurons with risk-variant testing, Nature 603(7899):124-130", "diseaseContext": "ALS / FTD", "useInModel": "Connects the strongest genetic risk factor for these diseases to the loss of this family's nuclear function, and does it through a splicing event. A major job of TDP-43 is repressing cryptic exon inclusion. Losing it from the nucleus - in human brain, in neuronal lines and in iPSC-derived motor neurons - caused a cryptic exon to be included in UNC13A mRNA and reduced UNC13A protein. The variants most strongly associated with risk in genome-wide association studies sit in the intron that harbours that cryptic exon, and they increase its splicing specifically in the face of TDP-43 dysfunction. The structure of that statement is what matters for a model: the risk genotype does almost nothing on its own and acts only once the protein has failed, so genotype and pathological state multiply rather than add.", "limit": "TDP-43-pathology context, so it does not apply to molecular subtypes of ALS or FTD without TDP-43 mislocalisation. Human tissue work is cross-sectional and the cell models are depletion rather than disease, so no rate of cryptic inclusion per unit of nuclear loss is established. UNC13A protein reduction is measured in models, not quantified in patients.", "provenance": "Abstract read in full; the cryptic exon, the protein reduction and the variant interaction as reported", "quantitativeExtraction": "extracted" }, "F03": { "id": "F03", "year": 2022, "topic": "RNA processing", "title": "TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8891020/", "studyType": "Independent companion study in cultured cells and in patient brain and spinal cord, Nature 603(7899):131-137", "diseaseContext": "ALS / FTD", "useInModel": "The same finding reached independently and published alongside, which is why the atlas holds both. TDP-43 depletion induced robust inclusion of a cryptic exon in UNC13A, producing nonsense-mediated decay and loss of the protein. Two common intronic polymorphisms strongly associated with risk overlap TDP-43 binding sites, and they potentiated cryptic exon inclusion both in cultured cells and in brain and spinal cord from patients. The mechanism named here is more specific than in the companion paper - the variants sit on the binding sites themselves, so the risk allele weakens the very interaction that represses the exon. Two groups, two systems, one answer: this is the most independently corroborated mechanism in the neurodegenerative half of this atlas.", "limit": "Depletion models for the causal work with patient tissue used as confirmation, so the direction is secure and the magnitude in a patient is not. Association plus experimental potentiation does not give a patient-level rate, and UNC13A is one of hundreds of transcripts affected, so its contribution to the phenotype is not isolated.", "provenance": "Abstract read in full; the decay mechanism, the binding-site overlap and the patient-tissue confirmation as reported", "quantitativeExtraction": "extracted" }, "L52": { "id": "L52", "year": 2024, "topic": "RNA processing", "title": "Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD", "url": "https://doi.org/10.1126/scitranslmed.adg7162", "studyType": "Paired transcriptomics and proteomics in TDP-43-depleted human iPSC neurons with patient CSF proteomics, Sci Transl Med 16:eadg7162", "diseaseContext": "ALS / FTD", "useInModel": "Turns a subtraction into an addition, and supplies the measurement this family lacked. Loss of TDP-43 function includes cryptic exons in hundreds of transcripts, and the usual account is loss of function through transcript degradation. Here the mis-spliced transcripts were also translated: 65 peptides mapping to 12 cryptic exons were identified in TDP-43-depleted human iPSC-derived neurons, the cryptic exons found in those neurons were predictive of those expressed in post-mortem brain from patients with TDP-43 proteinopathy, and the inclusion of cryptic sequences altered the proteins' interactions with other proteins. So TDP-43 loss creates novel proteins with altered interactomes alongside depleting normal ones - a gain of function layered on a loss of function, which means this family cannot be modelled as a node simply being removed. The translational part is the more immediately useful: 18 de novo peptides across 13 genes were present in cerebrospinal fluid from patients across the ALS and FTD spectrum, which the authors offer as a strategy to assay TDP-43 function in patient CSF.", "limit": "Depletion in iPSC-derived neurons for the discovery work, with patient CSF used for presence rather than for quantitative comparison - no concentration, no diagnostic accuracy and no relation to disease stage is established here. That the cryptic peptides alter protein interactions is shown; that any of them is pathogenic is not. The assay is a proposal, and should not be compared to the validated phospho-tau measurement recorded under I086.", "provenance": "Abstract read in full; peptide and exon counts, the predictive relationship to brain tissue and the CSF finding as reported", "quantitativeExtraction": "extracted" }, "L53": { "id": "L53", "year": 2022, "topic": "Molecular structure", "title": "Structure of pathological TDP-43 filaments from ALS with FTLD", "url": "https://doi.org/10.1038/s41586-021-04199-3", "studyType": "Cryo-EM of filaments from frontal and motor cortex of two individuals with ALS and FTLD, Nature 601(7891):139-143", "diseaseContext": "ALS / FTD", "useInModel": "Gives the aggregated state a structure, and the structure is unlike the other two aggregating families in this atlas. An identical amyloid-like filament comprising a single protofilament was found in frontal and motor cortex and in both individuals. The ordered core spans residues 282 to 360 within the low-complexity domain and adopts a previously undescribed double-spiral fold. The chemistry is the distinctive part: an abundance of glycine and neutral polar residues produces numerous turns and restricts beta-strand length, so the structure lacks the beta-sheet stacking that defines cross-beta amyloid - it is amyloid-like without being cross-beta, unlike the tau and amyloid-beta folds the atlas holds. Two consequences. The fold shows no similarity to TDP-43 filaments formed in vitro, which is the third family in a row where in vitro aggregates are the wrong object. And an uneven distribution of residues creates structurally and chemically distinct surfaces facing external densities, which the authors read as possible ligand-binding sites - the first structural handle for a disease with no disease-modifying therapy and no early diagnosis.", "limit": "Two individuals with the same diagnosis, so the invariance is across regions and a pair rather than across a disease, and nothing here speaks to the other TDP-43 proteinopathies or to the TDP-43 pathology common in Alzheimer's and Parkinson's. A static fold gives no concentration or dynamics for the soluble species, and the ligand-site interpretation is read from surface chemistry rather than demonstrated by binding.", "provenance": "Abstract read in full; core residues, the fold description, the absence of cross-beta stacking and the in vitro divergence as reported", "quantitativeExtraction": "extracted" }, "L54": { "id": "L54", "year": 2016, "topic": "RNA processing", "title": "Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43", "url": "https://doi.org/10.1093/nar/gkw499", "studyType": "Mechanistic work on TARDBP mRNA processing with examination of ALS spinal motor neurons, Nucleic Acids Res 44(12):5820-5836", "diseaseContext": "ALS", "useInModel": "Supplies the feedback term, and it is positive. TDP-43 regulates its own transcript: it inhibits selection of the most proximal polyadenylation signal and induces splicing of multiple alternative introns within TARDBP's last exon, which routes the message to nonsense-mediated decay and holds down the cytoplasmic pool. When TDP-43 is depleted the transcript switches to the most proximal signal and cytoplasmic TARDBP mRNA rises. The authors then show this in disease: in ALS spinal motor neurons, and especially in neurons with mislocalised TDP-43, cytoplasmic TARDBP mRNA is increased - so losing the protein from the nucleus breaks the brake on making more of it in the cytoplasm, which they describe as a vicious cycle that may accelerate progression. For a simulation this is a structural requirement rather than a parameter: nuclear loss and cytoplasmic accumulation are coupled by positive feedback, which is a sufficient account of progressive self-sustaining pathology without invoking the prion-like templating that I086 relies on.", "limit": "Mechanism established in cell systems with human tissue used to confirm the direction in affected neurons; no loop gain, no rate constant and no threshold is measured, so the feedback is established qualitatively. mRNA in the cytoplasm is not the same as protein aggregating there, and the step from increased transcript to inclusion formation is not demonstrated here.", "provenance": "Abstract read in full; the autoregulatory mechanism, the depletion result and the ALS motor neuron finding as reported", "quantitativeExtraction": "pending" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I088", "name": "SOD1; C9orf72 products; progranulin", "category": "Molecular", "whereToCheck": "Genetically/pathologically matched ALS/FTD modules", "states": [ "Variant", "repeat products", "haploinsufficiency" ], "behaviors": [ "Subtype-specific toxicity or loss of function" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "abundance-progranulin-noncarriers", "abundance-progranulin-heterozygotes" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "abundance-progranulin-noncarriers", "abundance-progranulin-heterozygotes" ], "priorResearch": { "path": "simulation/data/profiles/sod1-c9orf72-products-progranulin.json", "summary": "The inventory put three genes in one row and gave them one behaviour - subtype-specific toxicity or loss of function - and that single phrase is the whole content of the family. The three members point in opposite therapeutic directions. SOD1 is a toxic gain of function and the intervention lowers it (L55). Progranulin is a pure loss and the intervention raises it, successfully, to approximately healthy levels (L57). C9orf72 is both at once: the expanded repeat is transcribed and translated without a start codon into dipeptide repeat proteins while the normal gene product is also reduced, and the measured consequence is bidirectional failure of nucleocytoplasmic transport at the pore (F07, F08). Two of the three have been treated in people with the mechanism confirmed, and neither moved its clinical endpoint - which makes this row the sharpest statement of the problem this whole category has been circling. And gene dose behaves unexpectedly: the same GRN frameshift gives an adult dementia when heterozygous and a childhood lysosomal storage disease when homozygous, so dose changes the disease rather than its severity (L56).", "stateAxes": [ { "axis": "Variant - and which direction it breaks", "whatToMeasure": "The genotype, and then the sign of the defect, because the three members of this row need opposite interventions: lower the toxic protein, raise the deficient one, and for the repeat address both a gain and a loss.", "interpretationLimit": "Each member is served by evidence that does not transfer to the others. Reducing SOD1 says nothing about progranulin replacement, and neither says anything about the repeat. The atlas should not carry a single parameter for this row.", "evidence": [ "L55", "L57", "F08" ] }, { "axis": "Repeat products - a length, an RNA structure and a non-canonical protein", "whatToMeasure": "Repeat length as a dose variable, since degeneration was both dosage-dependent and repeat-length-dependent across 8, 28 and 58 repeats; plus the repeat-associated non-AUG translation products and the G-quadruplex structure that antisense oligonucleotides and small molecules were able to target.", "interpretationLimit": "Fly models with 8 to 58 repeats against patient expansions of hundreds to thousands, so the gradient is real and the scale is not. Nuclear RNA retention was confirmed in mammalian cells and aged patient-derived neurons; no transport flux, pore density or retention fraction is measured in human tissue.", "evidence": [ "F08", "F07" ] }, { "axis": "Haploinsufficiency - which is not a severity dial", "whatToMeasure": "Progranulin concentration, in the knowledge that one copy and no copies give different diseases - adult frontotemporal lobar degeneration with TDP-43 inclusions against childhood neuronal ceroid lipofuscinosis - so the dose-response is not monotonic in any single phenotype.", "interpretationLimit": "The homozygous phenotype rests on one family with two siblings plus a re-examination of progranulin-deficient mice, and concerns one frameshift allele. The measurable pools are plasma and cerebrospinal fluid while the protein's relevant location is lysosomal, so a normalised fluid concentration is not a normalised cell.", "evidence": [ "L56", "L57" ] } ], "records": { "F07": { "id": "F07", "year": 2015, "topic": "Nuclear transport", "title": "The C9orf72 repeat expansion disrupts nucleocytoplasmic transport", "url": "https://pubmed.ncbi.nlm.nih.gov/26308891/", "studyType": "Candidate genetic screen in Drosophila expressing 30 repeats, with patient iPSC-derived neurons and patient brain tissue, Nature 525(7567):56-61", "diseaseContext": "ALS / FTD", "useInModel": "Identifies the pathway and shows it can be pushed in either direction. A candidate-based genetic screen in flies expressing 30 GGGGCC repeats found RanGAP - a key regulator of nucleocytoplasmic transport - to be a potent suppressor of neurodegeneration, and enhancing nuclear import or suppressing nuclear export each suppressed degeneration independently. RanGAP physically interacts with the repeat RNA and is mislocalised in repeat-expressing flies, in neurons derived from patient induced pluripotent stem cells, and in patient brain tissue - a three-system chain from model to human. Nuclear import was impaired in both the fly and the patient-derived neurons, and the deficits were rescued by small molecules and by antisense oligonucleotides targeting the repeat's G-quadruplexes. The structural detail worth keeping is that the druggable feature is a nucleic acid secondary structure rather than a protein, which is a different kind of target from anything else in this category.", "limit": "Thirty repeats in a fly against hundreds to thousands in patients, so repeat length, expression level and species all affect the model, as the atlas already noted. Mislocalisation in patient tissue is cross-sectional. Rescue of a fly phenotype and of import in cultured neurons is not a treatment, and no transport rate is quantified in human tissue.", "provenance": "Abstract read in full; the screen result, the bidirectional suppression, the three-system mislocalisation and the G-quadruplex rescue as reported", "quantitativeExtraction": "extracted" }, "F08": { "id": "F08", "year": 2015, "topic": "Nuclear transport", "title": "GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport", "url": "https://pubmed.ncbi.nlm.nih.gov/26308899/", "studyType": "Transgenic Drosophila lines carrying 8, 28 or 58 repeats with a large-scale unbiased genetic screen, plus mammalian cells and patient iPSC-derived neurons, Nature 525(7567):129-133", "diseaseContext": "ALS / FTD", "useInModel": "The independent companion study, published back to back with F07, and it supplies the dose relationship and the unbiased confirmation. Transgenic flies expressing transcripts with 8, 28 or 58 repeats, built without a translation start site but carrying a reporter open reading frame, showed degeneration that was both dosage-dependent and repeat-length-dependent, along with repeat-associated non-AUG translation of dipeptide repeat proteins as seen in patients. An unbiased large-scale screen then returned 18 genetic modifiers, all encoding components of the nuclear pore complex or the machinery that exports nuclear RNA and imports nuclear proteins. Nuclear envelope architecture was morphologically abnormal in vitro and in vivo, and a substantial RNA export defect retained RNA in the nuclei of fly cells, mammalian cells and aged patient-derived neurons. So the defect is bidirectional transport failure at the pore, and repeat length is a dose variable with a demonstrated gradient rather than a threshold.", "limit": "Flies for the screen and the dose series, with mammalian and patient-derived cells confirming the export defect. Repeat lengths are far below patient ranges. Eighteen modifiers converging on one complex is strong evidence of pathway and weak evidence of magnitude - no transport flux, pore density or retention fraction is measured in human tissue.", "provenance": "Abstract read in full; repeat lengths, the dose and length dependence, the modifier count and the export defect as reported", "quantitativeExtraction": "extracted" }, "L55": { "id": "L55", "year": 2022, "topic": "Clinical negative result", "title": "Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS", "url": "https://doi.org/10.1056/NEJMoa2204705", "studyType": "VALOR phase 3, 108 participants randomised 2:1 over 24 weeks with an open-label extension to 52 weeks, N Engl J Med 387(12):1099-1110", "diseaseContext": "ALS", "useInModel": "The most informative negative result in this atlas, because two different kinds of biomarker moved and the clinical endpoint did not. Intrathecal tofersen reduces synthesis of SOD1. In 108 participants with SOD1-mutant ALS it produced greater reductions than placebo both in total SOD1 protein in cerebrospinal fluid - the target itself - and in plasma neurofilament light chain, which is a marker of neuroaxonal damage rather than of engagement. In the primary analysis among participants predicted to progress faster, the functional rating scale changed by -6.98 with tofersen against -8.14 with placebo: a difference of 1.2 points with a confidence interval from -3.2 to 5.5 and a p-value of 0.97. No secondary clinical endpoint differed. Then the extension: at 52 weeks the change was -6.0 in those who started at entry and -9.5 in those who switched from placebo at week 28, a difference of 3.5 points with an interval of 0.4 to 6.7, with other endpoints also favouring early start. That comparison is not adjusted for multiplicity, and it is the most specific alternative explanation this atlas holds for the pattern of mechanistically successful drugs failing: the variable may be when treatment starts rather than whether the mechanism is right.", "limit": "A rare genetic subtype, with the primary analysis in a predicted-faster-progression subgroup of 60 participants. The early-against-delayed comparison is from an open-label extension and is not multiplicity-adjusted, so it generates a hypothesis rather than establishing benefit. Lumbar puncture adverse events were common and neurologic serious adverse events occurred in 7% of recipients. Reducing a toxic gain-of-function protein does not generalise to the loss-of-function members of this same inventory row.", "provenance": "Abstract read in full; both biomarker directions, the primary and extension effect sizes with intervals, and the adverse event rates as reported", "quantitativeExtraction": "extracted" }, "L56": { "id": "L56", "year": 2012, "topic": "Target identity", "title": "Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage", "url": "https://doi.org/10.1016/j.ajhg.2012.04.021", "studyType": "Linkage analysis and exome sequencing in a family with two affected siblings, with re-examination of progranulin-deficient mice, Am J Hum Genet 90(6):1102-1107", "diseaseContext": "FTD", "useInModel": "Shows that gene dose here changes which disease you get rather than how severe it is. Two siblings with neuronal ceroid lipofuscinosis turned out to be homozygous for a frameshift mutation in GRN - the same gene whose heterozygous mutations are a major cause of frontotemporal lobar degeneration with TDP-43 inclusions, described as the second most common early-onset dementia. The age at onset and the neuropathology of the two conditions are markedly different: a childhood lysosomal storage disease against an adult dementia. Re-examination of progranulin-deficient mice then revealed the rectilinear profiles typical of neuronal ceroid lipofuscinosis, which had been there and unremarked. For a model this forbids treating the inventory's haploinsufficiency state as a severity dial - one copy and no copies are different diseases, so the dose-response is not monotonic in any single phenotype.", "limit": "One family with two siblings, so the homozygous phenotype rests on a small human observation supported by a mouse re-examination. It concerns one frameshift allele and does not establish that every GRN null behaves this way, and it gives no progranulin concentration for either state.", "provenance": "Abstract read in full; the homozygous phenotype, the contrast with heterozygous disease and the mouse re-examination as reported", "quantitativeExtraction": "pending" }, "L57": { "id": "L57", "year": 2024, "topic": "Clinical PK and response", "title": "Phase 1 study of latozinemab in progranulin-associated frontotemporal dementia", "url": "https://doi.org/10.1002/trc2.12452", "studyType": "First-in-human multiple-dose phase 1 in eight symptomatic GRN-mutation carriers, Alzheimers Dement TRCI 10:e12452", "diseaseContext": "FTD", "useInModel": "The engagement evidence that makes F09's failure interpretable. Heterozygous GRN mutations reduce progranulin in plasma and cerebrospinal fluid and cause frontotemporal dementia with penetrance above 90%. Latozinemab, an antibody that lowers sortilin and thereby stops progranulin being shuttled to the lysosome for degradation, was given in multiple intravenous doses to eight symptomatic patients and raised plasma and CSF progranulin to levels approximating those seen in healthy volunteers. Related work in cynomolgus monkeys raised plasma and CSF progranulin two- to threefold, and a cross-reactive antibody restored plasma progranulin and rescued a behavioural deficit in a mouse model. So the pathogenic quantity was not merely engaged - it was corrected to normal. Read with F09, this is the sharpest negative in the whole category: the deficiency was repaired and the clinical co-primary endpoint did not move.", "limit": "Eight patients, open-label, with pharmacodynamics as the endpoint - this establishes that progranulin can be normalised, not that normalising it helps. Plasma and CSF progranulin are accessible surrogates for a protein whose relevant pool is lysosomal and intracellular, so 'restored to normal' is restored in the compartments that can be sampled. The phase 3 result is a sponsor disclosure rather than a peer-reviewed analysis (F09).", "provenance": "Abstract read in full; the normalisation claim, the primate fold-change and the mouse rescue as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I089", "name": "Nucleus, chromatin and genome", "category": "Intracellular", "whereToCheck": "Every nucleated cell", "states": [ "Cell type", "mutation", "epigenetic state" ], "behaviors": [ "Transcription", "repair", "nuclear transport", "cell-cycle state" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "surface-lamin-a549-ratio" ], "priorResearch": { "path": "simulation/data/profiles/nucleus-chromatin-and-genome.json", "summary": "The first Intracellular row, present in every nucleated cell, and the one the atlas already needed before writing it - a Structures row recorded that whether a cell crosses a basement membrane is decided by nuclear deformability, a constraint set by an organelle its category could not contain. That link now closes and extends. Confined migration deforms the nucleus enough to rupture its envelope, mixing nucleo-cytoplasmic content, herniating chromatin and damaging DNA, with incidence rising with confinement and with lamin depletion (L213). The lamins give the constraint a parameter that is a ratio: A to B stoichiometry sets an activation barrier, separates viscous from elastic stiffness, sorts subpopulations during three-dimensional migration, and produces a biphasic net effect with intermediate ratios enhancing tumour growth (L214). On the genome side, pathogenic repair mutations turn out not to determine repair deficiency in 1,131 prostate carcinomas (L215), and chromatin accessibility is mapped across 410 tumours and 23 cancer types (L216).", "stateAxes": [ { "axis": "Mutation, which is not the functional state", "whatToMeasure": "Both the genotype and the functional deficiency, because they diverge. In 1,131 prostate carcinomas, 19.1 percent carried pathogenic repair-gene variants; among 680 scored tumours, deficiency at a score of 42 or above was present in 19.2 percent of mutated and 5.2 percent of wild-type cases at p below 0.0001; deficiency was highest with biallelic BRCA2 or PALB2 and with BRIP1, occasional with ATM, NBN, FANCM, BRCA1 and CDK12, and absent in CHEK2 cases; and the functional score tracked aggressive features more closely than the mutations did.", "interpretationLimit": "One tumour type, one cohort, and a derived index with a conventional cut-off of 42 - so both frequencies inherit that threshold and would move with it. The mutated subgroup among scored tumours is 120 cases, and the CHEK2 negative rests on a subgroup whose size is not extracted. Pathogenic variant classification is an interpretation. No treatment response is measured, so the clinical implication is inferred from the biomarker rather than from outcomes.", "evidence": [ "L215" ] }, { "axis": "Cell type, as nuclear mechanics with an optimum", "whatToMeasure": "The A to B lamin ratio rather than any single lamin level. Lamin-A was rate-limiting for three-dimensional migration across glioma lines, adenocarcinoma lines and primary mesenchymal stem cells; the A to B stoichiometry set an activation barrier, with high ratios giving extruded nuclear shapes after passage; the A and B assemblies confer viscous and elastic stiffness respectively; subpopulations with different ratios sorted during migration, consistent in xenografts, with intermediate ratios enhancing tumour growth; and net migration was biphasic in lamin-A, since wild-type levels protected against stress-induced death while deep knockdown broadly impaired stress resistance.", "interpretationLimit": "Cell lines in engineered micropores, with xenografts for consistency rather than measurement. The optimum's location is not given: rate-limiting, biphasic and intermediate appear without the lamin levels or ratios at which the peak sits, so the atlas holds a curve without its peak - the same deficiency as its two schedule-dependent records. No moduli for the viscous and elastic contributions, and no pore size paired with a lamin level, so geometry-driven sorting has no mapping from geometry to composition.", "evidence": [ "L214" ] }, { "axis": "Repair, as a requirement for migration", "whatToMeasure": "Envelope integrity and repair capacity together with migration, because they are coupled. Nuclear deformation in confining spaces caused localised loss of envelope integrity, uncontrolled nucleo-cytoplasmic exchange, chromatin herniation across the envelope and DNA damage; rupture incidence rose with confinement and with lamin depletion; and cells restored integrity using ESCRT III, with the authors concluding that efficient envelope and DNA damage repair are required for survival.", "interpretationLimit": "No rupture frequency per passage, no migration-attributable mutation rate, and no pore size at which rupture starts - so a mechanism linking a Structures variable to this family's state has no transfer function. Damage is detected as damage, so the mutagenic consequence is inferred rather than sequenced. Lines in engineered geometries, with in vivo support rather than in vivo quantification, and experimental lamin depletion rather than physiological variation.", "evidence": [ "L213", "L178" ] }, { "axis": "Epigenetic state", "whatToMeasure": "Chromatin accessibility, which is mapped at scale: 562,709 accessible elements across 410 primary tumours in 23 cancer types, yielding putative distal enhancers that distinguish molecular subtypes, driving transcription factors from protein-DNA footprints, inherited risk loci appearing as active regulatory elements in the tumours, regulatory interactions underlying immune evasion, and noncoding mutations driving enhancer activation with possible survival effects.", "interpretationLimit": "Bulk accessibility from tissue pieces, so every element is averaged across tumour, stromal and immune cells - the exact mixing this atlas's family structure exists to avoid, which makes the resource powerful for the environment and weak for the family. The enhancer, interaction and survival claims carry the authors' own hedges. No functional validation here. None of the three neurodegenerative environments is covered, so a third of the drawn set has no epigenetic evidence at all.", "evidence": [ "L216" ] }, { "axis": "Nuclear transport, and cell-cycle state", "whatToMeasure": "Transport is served, in one environment group and causally: the C9orf72 repeat expansion disrupts nucleocytoplasmic transport, a transport regulator is a potent suppressor of neurodegeneration, and an independent companion study supplies a repeat-length dose relationship. Cell-cycle state, the fourth named behaviour, is not served at all.", "interpretationLimit": "The transport evidence lives in the molecular rows that hold those gene products and is cited rather than duplicated; it is fly and patient tissue for one genotype in two environments, so it is not a general account of this family's transport. For cell-cycle state the atlas holds nothing in this row - no index, no fraction, no duration - in any of the twenty drawn environments, which for a family present in every nucleated cell is the row's largest hole.", "evidence": [ "F07", "F08" ] } ], "records": { "F07": { "id": "F07", "year": 2015, "topic": "Nuclear transport", "title": "The C9orf72 repeat expansion disrupts nucleocytoplasmic transport", "url": "https://pubmed.ncbi.nlm.nih.gov/26308891/", "studyType": "Candidate genetic screen in Drosophila expressing 30 repeats, with patient iPSC-derived neurons and patient brain tissue, Nature 525(7567):56-61", "diseaseContext": "ALS / FTD", "useInModel": "Identifies the pathway and shows it can be pushed in either direction. A candidate-based genetic screen in flies expressing 30 GGGGCC repeats found RanGAP - a key regulator of nucleocytoplasmic transport - to be a potent suppressor of neurodegeneration, and enhancing nuclear import or suppressing nuclear export each suppressed degeneration independently. RanGAP physically interacts with the repeat RNA and is mislocalised in repeat-expressing flies, in neurons derived from patient induced pluripotent stem cells, and in patient brain tissue - a three-system chain from model to human. Nuclear import was impaired in both the fly and the patient-derived neurons, and the deficits were rescued by small molecules and by antisense oligonucleotides targeting the repeat's G-quadruplexes. The structural detail worth keeping is that the druggable feature is a nucleic acid secondary structure rather than a protein, which is a different kind of target from anything else in this category.", "limit": "Thirty repeats in a fly against hundreds to thousands in patients, so repeat length, expression level and species all affect the model, as the atlas already noted. Mislocalisation in patient tissue is cross-sectional. Rescue of a fly phenotype and of import in cultured neurons is not a treatment, and no transport rate is quantified in human tissue.", "provenance": "Abstract read in full; the screen result, the bidirectional suppression, the three-system mislocalisation and the G-quadruplex rescue as reported", "quantitativeExtraction": "extracted" }, "F08": { "id": "F08", "year": 2015, "topic": "Nuclear transport", "title": "GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport", "url": "https://pubmed.ncbi.nlm.nih.gov/26308899/", "studyType": "Transgenic Drosophila lines carrying 8, 28 or 58 repeats with a large-scale unbiased genetic screen, plus mammalian cells and patient iPSC-derived neurons, Nature 525(7567):129-133", "diseaseContext": "ALS / FTD", "useInModel": "The independent companion study, published back to back with F07, and it supplies the dose relationship and the unbiased confirmation. Transgenic flies expressing transcripts with 8, 28 or 58 repeats, built without a translation start site but carrying a reporter open reading frame, showed degeneration that was both dosage-dependent and repeat-length-dependent, along with repeat-associated non-AUG translation of dipeptide repeat proteins as seen in patients. An unbiased large-scale screen then returned 18 genetic modifiers, all encoding components of the nuclear pore complex or the machinery that exports nuclear RNA and imports nuclear proteins. Nuclear envelope architecture was morphologically abnormal in vitro and in vivo, and a substantial RNA export defect retained RNA in the nuclei of fly cells, mammalian cells and aged patient-derived neurons. So the defect is bidirectional transport failure at the pore, and repeat length is a dose variable with a demonstrated gradient rather than a threshold.", "limit": "Flies for the screen and the dose series, with mammalian and patient-derived cells confirming the export defect. Repeat lengths are far below patient ranges. Eighteen modifiers converging on one complex is strong evidence of pathway and weak evidence of magnitude - no transport flux, pore density or retention fraction is measured in human tissue.", "provenance": "Abstract read in full; repeat lengths, the dose and length dependence, the modifier count and the export defect as reported", "quantitativeExtraction": "extracted" }, "L178": { "id": "L178", "year": 2013, "topic": "Thickness and gaps", "title": "Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force", "url": "https://doi.org/10.1083/jcb.201210152", "studyType": "Migration quantified in MMP-degradable collagen lattices and non-degradable substrates of varying porosity, with nuclear deformation measured to the point of physical arrest, Journal of Cell Biology 201(7):1069-1084", "diseaseContext": "Shared cancer; healthy reference", "useInModel": "The atlas's first hard geometric threshold, and it is cell-type-specific. Migration independent of matrix metalloproteinases declined as a linear function of pore size and with deformation of the nucleus, with arrest reached at 10 percent of the nuclear cross section - 7 square micrometres for tumour cells, 4 for T cells, 2 for neutrophils. Residual migration under space restriction depended on MMP-dependent cleavage enlarging pore diameters and on integrin- and actomyosin-dependent force that jointly propelled the nucleus. Three things follow. The project has recorded local mechanisms without length scales repeatedly; here is a threshold with numbers and a linear relationship above it, so a model can interpolate rather than guess. The limiting structure is the nucleus, which means the hardest constraint in the Structures category is set by a component of the Intracellular category. And proteolysis is a modulator rather than a gate: migration happens without it and declines with pore size, while enzymes extend the range by widening pores - so blocking proteases shifts a threshold rather than closing a door.", "limit": "Engineered collagen lattices and synthetic porous substrates, not basement membrane and not tissue - so the thresholds are properties of cells moving through characterised pore geometries rather than measurements of any real interface. Basement membrane is a dense sheet rather than a porous lattice, so these numbers describe interstitial passage better than they describe crossing this family. The values are cross-sectional areas at arrest in specific cell types under specific conditions, and nuclear deformability varies with lamin composition and cell state, which this does not survey. Nothing here measures a pore size in any drawn environment.", "provenance": "Abstract read in full; the experimental systems, the linear dependence on pore size, the arrest criterion at 10 percent of nuclear cross section with all three cell-type values, and the roles of proteolysis and force generation as modulators as reported", "quantitativeExtraction": "extracted" }, "L213": { "id": "L213", "year": 2016, "topic": "Repair", "title": "Nuclear envelope rupture and repair during cancer cell migration", "url": "https://doi.org/10.1126/science.aad7297", "studyType": "Mammalian tumour cell migration through confining microenvironments in vitro and in vivo, with lamin depletion and ESCRT III perturbation, Science 352(6283):353-358", "diseaseContext": "Shared cancer", "useInModel": "Completes a causal link across two of the atlas's categories: the geometry of the environment damages the genome of the cell passing through it. Nuclear deformation during migration through tight interstitial spaces caused localised loss of nuclear envelope integrity, which produced uncontrolled exchange of nucleo-cytoplasmic content, herniation of chromatin across the envelope, and DNA damage. The incidence of rupture rose with the degree of confinement and with depletion of nuclear lamins, and cells restored integrity using ESCRT III machinery. Set against the atlas's existing threshold - migration arrests at 10 percent of the nuclear cross-section (L178) - this says the cells that do not arrest still pay, in envelope integrity and in mutations. Three consequences. Pore geometry is not only a gate on migration but an input to genome instability, so a Structures variable feeds an Intracellular state. The compartment boundary a simulation would treat as fixed is transiently abolished, so nuclear and cytoplasmic pools are not reliably separate in a migrating cell. And repair capacity becomes a determinant of whether migration is survivable, which makes this a requirement rather than a response.", "limit": "Tumour cell lines in engineered confining geometries, with in vivo work supporting the phenomenon rather than quantifying it - so there is no rupture frequency per passage, no mutation rate attributable to migration, and no pore size at which rupture begins. Incidence increased with confinement is a direction without a dose. DNA damage is detected as damage rather than as sequence change, so the mutagenic consequence is inferred. Lamin depletion is experimental, and whether physiological lamin variation produces the same effect is the companion record's question rather than this one's.", "provenance": "Abstract read in full; all four consequences of deformation listed, both factors increasing rupture incidence, the repair machinery named, and the authors' conclusion about repair being required for survival as reported", "quantitativeExtraction": "extracted" }, "L214": { "id": "L214", "year": 2014, "topic": "Cell type", "title": "Nuclear lamin stiffness is a barrier to 3D migration, but softness can limit survival", "url": "https://doi.org/10.1083/jcb.201308029", "studyType": "Migration of human glioma and adenocarcinoma lines and primary mesenchymal stem cells through constraining micropores, with lamin-A knockdown across a range and in vivo xenografts, Journal of Cell Biology 204(5):669-682", "diseaseContext": "Shared cancer; glioblastoma and adenocarcinoma lines, with primary mesenchymal stem cells as reference", "useInModel": "Gives the nucleus a controlling parameter that is a ratio, and shows the response to it is biphasic - so there is an optimum rather than a direction. Lamin-A proved rate-limiting for three-dimensional migration across diverse human cells, from glioma and adenocarcinoma lines to primary mesenchymal stem cells. The stoichiometry of A- to B-type lamins set an activation barrier, with a high A to B ratio producing extruded nuclear shapes after passage, because the juxtaposed A and B polymer assemblies confer viscous and elastic stiffness respectively - two mechanical contributions separated by composition. Subpopulations with different A to B levels sorted during three-dimensional migration, and xenografts in vivo were consistent with that sorting, with intermediate A to B enhancing tumour growth. But net migration was biphasic in lamin-A: wild-type levels protected against stress-induced death while deep knockdown caused broad defects in stress resistance. For the atlas this is a third non-monotonicity and the first in a level rather than in time - the others are schedule-dependent. It also supplies a mechanism for subpopulation selection by geometry: the matrix sorts cells by a nuclear property, so a migrating population's composition is a function of the pores it came through.", "limit": "Cell lines and engineered micropores for the mechanism, with xenografts for consistency rather than for measurement. Rate-limiting, biphasic and intermediate are reported without the lamin-A levels at which the optimum sits, so the atlas holds the shape of the curve and not its peak - the same deficiency as its two time-based non-monotonicities. Viscous and elastic contributions are attributed to A and B assemblies without moduli extracted here. Human cells, mouse hosts. No pore size is paired with a lamin level, so the sorting is demonstrated without a geometry-to-composition mapping.", "provenance": "Abstract read in full; the cell types tested, lamin-A as rate-limiting, the A to B activation barrier with extruded shapes, the assignment of viscous and elastic stiffness, the sorting result and its xenograft consistency with intermediate ratios enhancing growth, and the biphasic survival relationship as reported", "quantitativeExtraction": "extracted" }, "L215": { "id": "L215", "year": 2025, "topic": "Mutation", "title": "Complex Relationships Between Homologous Recombination Deficiency (HRD) Score and Mutational Status of Homologous Recombination Repair (HRR) Genes in Prostate Carcinomas", "url": "https://doi.org/10.3390/ijms262411851", "studyType": "Next-generation sequencing of 34 homologous recombination repair genes in 1,131 prostate carcinomas with HRD scores in 680 of them, International Journal of Molecular Sciences 26(24):11851", "diseaseContext": "Prostate", "useInModel": "The marker problem reaching the genome itself, in a drawn environment, at a scale that makes it hard to argue with. A pathogenic mutation is the most definitive kind of marker this atlas handles, and here it fails to determine the functional state it is used to infer. Pathogenic or likely pathogenic variants in repair genes were found in 216 of 1,131 cases, 19.1 percent. Among tumours with scores, deficiency at the conventional cut-off of 42 or above was present in 23 of 120 mutated tumours, 19.2 percent, against 29 of 560 wild-type tumours, 5.2 percent, at p below 0.0001. So the mutation raises the odds roughly fourfold and about four in five mutated tumours are not deficient, while one in twenty wild-type tumours is. The gene matters: the highest scores were in biallelic BRCA2 or PALB2 inactivation and in BRIP1 mutation, deficiency appeared occasionally with ATM, NBN, FANCM, BRCA1 and CDK12, and never with CHEK2. The functional score was also more strongly associated with aggressive features than the mutations were. Most CDK12-mutated tumours instead showed a tandem duplication copy number phenotype. The authors' own conclusion is that patient selection for this drug class requires significant revision of existing genetic profiling. For this atlas the lesson is general: genotype and functional state are separate variables for this family and a model that infers one from the other will be wrong four times in five.", "limit": "One tumour type and one cohort, with the mutation and score subsets unequal - 1,131 sequenced and 680 scored, and 120 mutated among the scored. The deficiency score is itself a derived index with a conventional cut-off of 42, so the 19.2 against 5.2 percent comparison inherits that threshold's arbitrariness and a different cut-off would move both numbers. Never in CHEK2 cases is a negative in a subgroup whose size is not extracted here. Pathogenic classification of variants is an interpretation. No treatment outcome is measured, so the clinical claim is an inference from the biomarker's behaviour rather than from response data.", "provenance": "Abstract read in full; both cohort sizes, the 19.1 percent mutation frequency with its numerator, the cut-off of 42, both deficiency frequencies with numerators and the p value, the gene-by-gene pattern including the CHEK2 negative, the comparison to aggressive features, the CDK12 phenotype, and the authors' stated conclusion as reported", "quantitativeExtraction": "extracted" }, "L216": { "id": "L216", "year": 2018, "topic": "Epigenetic state", "title": "The chromatin accessibility landscape of primary human cancers", "url": "https://doi.org/10.1126/science.aav1898", "studyType": "Genome-wide ATAC-seq of 410 tumour samples across 23 cancer types from The Cancer Genome Atlas, integrated with existing multi-omic data from the same programme, Science 362(6413):eaav1898", "diseaseContext": "Shared cancer across 23 types, covering most of the atlas's drawn cancer environments", "useInModel": "The epigenetic state axis at a scale no other record in this atlas approaches, and the only resource here that covers most of the drawn cancer environments in one dataset. 562,709 transposase-accessible DNA elements were identified across 410 primary tumours in 23 cancer types, substantially extending the known compendium of cis-regulatory elements. Integration identified putative distal enhancers distinguishing molecular subtypes, named driving transcription factors through protein-DNA footprints, and nominated long-range gene-regulatory interactions. Three findings matter directly here: inherited cancer risk loci appear as active regulatory elements in the tumours themselves, gene-regulatory interactions underlying immune evasion were identified, and noncoding mutations driving enhancer activation were pinpointed with possible effects on survival. For the atlas that last pair is the useful part - it connects this family's epigenetic state to the Immune category's central problem and to outcome, from primary human tissue rather than from lines. It also means accessibility, not expression, is where several of the atlas's regulatory claims would have to be checked.", "limit": "Bulk chromatin accessibility from primary tumour samples, so every element is averaged over whatever cells were in the piece of tissue - tumour, stroma and immune cells together - which is exactly the mixing the atlas's family-by-family structure exists to avoid. Putative, nominates and may affect are the paper's own words for the enhancer, interaction and survival claims. No functional validation of any element is part of this record. Twenty-three cancer types and none of the three neurodegenerative environments, so this resource is silent on a third of the atlas's drawn set, and sample numbers per type are small relative to the element count.", "provenance": "Abstract read in full; sample and cancer-type counts, the element count, the four categories of integrative finding, and the three specific results about risk loci, immune evasion and noncoding enhancer mutations as reported with the authors' own hedging preserved", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "surface-lamin-a549-ratio" ] }, { "id": "I090", "name": "Mitochondria and energy machinery", "category": "Intracellular", "whereToCheck": "Cells by state", "states": [ "Respiration", "stress", "dysfunction" ], "behaviors": [ "ATP supply", "redox", "apoptosis", "metabolic flux" ], "slots": { "size": { "status": "references available", "referenceIds": [ "iborra-mitochondria" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "iborra-mitochondria" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "iborra-mitochondria" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "iborra-mitochondria" ], "priorResearch": { "path": "simulation/data/profiles/mitochondria-and-energy-machinery.json", "summary": "The row that corrects the atlas one row after it was written. Closing the Neural category, the choroid plexus row concluded that the project's missing fluxes are a limit of access - rates exist where a compartment can be sampled twice, and interstitial fluid cannot be. That was too narrow. Human metabolic fluxes have been measured in solid tumours by labelling the input instead of sampling twice: intraoperative 13C-glucose infusion in nine lung cancer patients (L217), and 13C-lactate infusion showing that lactate's contribution to the tricarboxylic acid cycle predominates over glucose in living human lung tumours (L218). A third route is non-invasive and repeatable - hyperpolarised [1-13C]pyruvate imaging in 31 prostate cancer patients (L219). And the row raises a structural problem the atlas has no machinery for: mitochondria reported to transfer between families, replacing the recipient's own (L220).", "stateAxes": [ { "axis": "Metabolic flux, measurable in humans after all", "whatToMeasure": "Which carbon source actually enters the cycle, by labelling the input. In nine lung cancer patients infused with 13C-glucose during surgery, enhanced glycolysis and glucose oxidation were common, every tumour oxidised multiple nutrients including lactate, regions within single tumours differed metabolically, and non-glucose nutrients contributed in well-perfused areas. Infusing patients with 13C-lactate labelled cycle metabolites extensively, and a direct comparison in vivo indicated lactate predominates over glucose - most apparent in tumours with high fluorodeoxyglucose uptake and aggressive behaviour, with MCT1 deletion in mice showing the uptake is tumour-cell-autonomous.", "interpretationLimit": "Labelling patterns at a single intraoperative timepoint, so the atlas gains an ordering of carbon sources and not a rate in units - predominates is a comparison of contributions. One tumour type for both studies, nine patients in one of them, and anaesthesia, fasting state and surgical manipulation inside the measurement. Cell-autonomy rests on a mouse deletion. Regional heterogeneity has no length scale.", "evidence": [ "L217", "L218" ] }, { "axis": "Respiration, as a conversion imaged in a living patient", "whatToMeasure": "The lactate to pyruvate ratio after a hyperpolarised pyruvate bolus, which resolves pyruvate and its lactate, alanine and bicarbonate products within seconds at over ten-thousand-fold signal enhancement. In 31 patients with biopsy-proven prostate cancer the median delivery time was 66 seconds, uptake appeared about 20 seconds after injection, no dose-limiting toxicities occurred, and 0.43 millilitres per kilogram of a 230 millimolar agent gave the best signal-to-noise ratio.", "interpretationLimit": "A first-in-man safety and feasibility study, so the grade and treatment-response relationships it quotes are preclinical rather than results from these patients. The ratio depends on delivery, transport and enzyme activity together and is measured over seconds after a large exogenous load, so it is not a steady-state flux and reports the response to a bolus rather than resting operation. One tumour type, and the method needs on-site hyperpolarisation equipment.", "evidence": [ "L219" ] }, { "axis": "Dysfunction, possibly by replacement rather than by damage", "whatToMeasure": "Whether the organelles in a cell are its own. Tumour cells are reported to donate functional or dysfunctional mitochondria to neighbouring T cells through tunneling nanotubes and extracellular vesicles, with a mitophagy imbalance driving homoplasmic replacement of the recipient's mitochondria, T cell senescence and impaired memory formation - and transfer in the opposite direction is reported to reinforce oxidative metabolism and survival in tumour cells.", "interpretationLimit": "Review-level, with the field stating that direct evidence for a causal role in therapeutic resistance remains limited and varies across modalities. No transfer rate, no proportion of recipient cells, no operating distance and no patient tissue demonstration is held. Functional consequences are said to depend strongly on donor-recipient context, so the sign is not fixed. Carried for the structural problem rather than as evidence.", "evidence": [ "L220" ] }, { "axis": "Stress, redox, ATP supply and apoptosis", "whatToMeasure": "Four quantities the inventory names - two as states and two as behaviours - none of which any record in this row measures in any drawn environment.", "interpretationLimit": "Not served at all. No redox ratio, no ATP concentration or supply rate, no apoptotic fraction attributable to this component, and no mitochondrial stress response anywhere in the twenty environments. The atlas's nearest ATP evidence belongs to a Chemistry row not yet written, and its nearest apoptosis mechanism is the Bax-dependent astrocyte killing of motor neurons, where the pathway is named and this component is not measured.", "evidence": [] } ], "records": { "L217": { "id": "L217", "year": 2016, "topic": "Metabolic flux", "title": "Metabolic Heterogeneity in Human Lung Tumors", "url": "https://doi.org/10.1016/j.cell.2015.12.034", "studyType": "Intraoperative 13C-glucose infusions in nine patients with non-small cell lung cancer, with paired isotope analysis of tumour against benign lung and of multiple regions per tumour, Cell 164(4):681-694", "diseaseContext": "Lung (NSCLC)", "useInModel": "A metabolic flux measured in living human tumours, which the atlas had concluded one row earlier it could not have - and obtained by a method that conclusion did not consider. Nine patients were infused with 13C-glucose during surgery, letting tumour metabolism be compared with benign lung in the same person. Enhanced glycolysis and glucose oxidation were common, and every tumour showed evidence of oxidising multiple nutrients, lactate among them. Metabolically heterogeneous regions were found within single tumours as well as between tumours, and non-glucose nutrients appeared to contribute in the well-perfused areas - the opposite of what a perfusion-limited picture predicts. The authors' conclusion is that tumour metabolism in vivo is heterogeneous and strongly influenced by the microenvironment, which is this project's premise stated as a result. Three uses. The atlas gains a human in vivo flux. It gains a spatial scale for heterogeneity below the environment and below the family. And it gains a warning that perfusion does not determine which fuel is used, so a model coupling consumption to blood flow has the relationship backwards in the best-supplied regions.", "limit": "Nine patients, one tumour type, and a single intraoperative timepoint - so these are labelling patterns at one moment rather than rates per unit time, and no flux in units is extracted here. Infusion during surgery puts anaesthesia, fasting state and surgical manipulation inside the measurement. Evidence for oxidation of multiple nutrients and potential contributions are the authors' own hedges, and the individual nutrient contributions are not quantified in this extraction. Regional heterogeneity is established without a length scale. Benign lung is the comparator, not another organ.", "provenance": "Abstract read in full; the patient count and intraoperative design, the common findings, the evidence for multiple nutrients including lactate, the within- and between-tumour heterogeneity, the association with well-perfused areas, and the authors' conclusion as reported with their hedging preserved", "quantitativeExtraction": "extracted" }, "L218": { "id": "L218", "year": 2017, "topic": "Metabolic flux", "title": "Lactate Metabolism in Human Lung Tumors", "url": "https://doi.org/10.1016/j.cell.2017.09.019", "studyType": "13C-lactate infusions in patients with non-small cell lung cancer with isotope analysis of tricarboxylic acid cycle metabolites, direct in vivo comparison against glucose, and MCT1 deletion from tumour cells in mice, Cell 171(2):358-371.e9", "diseaseContext": "Lung (NSCLC)", "useInModel": "Overturns the picture this atlas would otherwise have inherited from culture, with human in vivo isotope labelling. Cancer cells consume glucose and secrete lactate in culture, and whether lactate contributes to energy metabolism in living tumours was unknown. Infusing patients with 13C-lactate produced extensive labelling of tricarboxylic acid cycle metabolites, and directly comparing lactate and glucose in vivo indicated that lactate's contribution to the cycle predominates. Evidence of lactate use was most apparent in tumours with high fluorodeoxyglucose uptake and aggressive behaviour - so the tumours that look most glycolytic on imaging are the ones most clearly burning lactate, close to the reverse of the usual inference from that scan. Deleting MCT1 from tumour cells in mice eliminated lactate-dependent labelling, establishing the uptake as tumour-cell-autonomous rather than a stromal artefact. Two consequences. The atlas's lactate exchange entries, carried as hand-offs without a flux, describe a major fuel with human in vivo evidence and a named transporter. And a model assigning glucose as the carbon source and lactate as waste is wrong about the dominant term in human lung tumours.", "limit": "One tumour type, and the patient numbers for the lactate infusions are not extracted here. Predominates is a comparison of labelling contributions rather than an absolute flux, so the atlas gains an ordering and not a rate. The MCT1 deletion is mouse, so cell-autonomy is established in a model rather than in patients. Most apparent in tumours with high fluorodeoxyglucose uptake and aggressive behaviour is an association without a coefficient here. Infusion in a clinical setting carries the same fasting and anaesthetic confounds as the companion study.", "provenance": "Abstract read in full; the stated prior uncertainty, the extensive labelling from 13C-lactate infusion in patients, the direct in vivo comparison concluding lactate predominates, the association with high FDG uptake and aggressive behaviour, and the MCT1 deletion result as reported", "quantitativeExtraction": "extracted" }, "L219": { "id": "L219", "year": 2013, "topic": "Respiration", "title": "Metabolic imaging of patients with prostate cancer using hyperpolarized [1-13C]pyruvate", "url": "https://doi.org/10.1126/scitranslmed.3006070", "studyType": "First-in-man safety and feasibility study of hyperpolarized [1-13C]pyruvate magnetic resonance imaging in 31 patients with biopsy-proven prostate cancer, with dose escalation, Science Translational Medicine 5(198):198ra108", "diseaseContext": "Prostate", "useInModel": "A metabolic conversion measured non-invasively in living patients, which makes it the only candidate in this atlas for a flux that could be followed in one person over time. Hyperpolarisation gives more than a ten-thousand-fold signal enhancement over conventional magnetic resonance, letting injected pyruvate and its products lactate, alanine and bicarbonate be distinguished within seconds. Thirty-one patients with biopsy-proven prostate cancer were injected; median delivery time was 66 seconds, uptake appeared about 20 seconds after injection, no dose-limiting toxicities occurred, and the highest dose - 0.43 millilitres per kilogram of a 230 millimolar agent - gave the best signal-to-noise ratio. The quantity reported is the lactate to pyruvate ratio, which in preclinical models rose with tumour grade and fell after successful treatment. Two uses. This is the atlas's fifth in vivo measurement exception and the first that is a conversion rather than a level, a density or a shape. And it is the one measurement here that could in principle be repeated in the same patient on either side of an intervention, which is what calibrating a dynamic model would require.", "limit": "A first-in-man safety and feasibility study, so its endpoints are tolerability and signal quality rather than any biological result - the grade and treatment-response relationships quoted are preclinical, not from these 31 patients. The lactate to pyruvate ratio is a ratio of hyperpolarised signals over seconds that depends on delivery, transport and enzyme activity together, so it is not a steady-state flux and its relationship to metabolic rate needs stating wherever it is used. The measurement lasts seconds after a bolus, so it reports the response to a large exogenous pyruvate load rather than resting operation. One tumour type, and the agent requires on-site hyperpolarisation equipment.", "provenance": "Abstract read in full; the signal enhancement factor, the products resolved, patient count, median delivery time, uptake latency, absence of dose-limiting toxicity, the best-performing dose and concentration, and the preclinical provenance of the grade and response relationships as reported", "quantitativeExtraction": "extracted" }, "L220": { "id": "L220", "year": 2026, "topic": "Dysfunction", "title": "Mitochondrial transfer-driven immune evasion in the tumor microenvironment", "url": "https://doi.org/10.1093/intimm/dxag027", "studyType": "Review of intercellular mitochondrial transfer as a mechanism of tumour immune evasion, covering tunneling nanotube and extracellular vesicle routes, International Immunology 38(11):603-609", "diseaseContext": "Shared cancer", "useInModel": "Proposes something this atlas has no machinery for: a component that moves between families. The claim is that tumour cells act as pathogenic mitochondrial donors, transferring functional or dysfunctional mitochondria to neighbouring T cells through tunneling nanotubes and extracellular vesicles, with a mitophagy imbalance leading to homoplasmic replacement of the recipient's own mitochondria - driving T cell senescence, impairing memory formation and weakening immunosurveillance. The framing matters for the project's structure. Every edge in this atlas is a signal, a contact, a force or a metabolite; this would be an organelle with its own genome relocating from one family to another and replacing its counterpart. A simulation organised as families with states cannot express that without a notion of components that are themselves transferable, and the companion literature reports the traffic running both ways, with tumour cells also acquiring mitochondria from stromal and immune neighbours. Recorded for the structural problem it poses, with its evidential weakness stated.", "limit": "A review, and the field's own assessment is that direct evidence establishing this as a causal determinant of therapeutic resistance remains limited and varies significantly across modalities - the companion reviews use may and potentially throughout. So the atlas holds a proposed mechanism and no measurement: no transfer rate, no proportion of recipient cells affected, no distance over which it operates, and no demonstration in patient tissue extracted here. Functional consequences are stated to depend strongly on donor-recipient context, so the sign of the effect is not fixed. Carried as a structural challenge rather than as evidence for a mechanism.", "provenance": "Abstract read in full; the two transfer routes named, the mitophagy imbalance and homoplasmic replacement described, the stated consequences for T cells, and the field's own limitation about direct causal evidence as stated in the companion review", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I091", "name": "ER and Golgi", "category": "Intracellular", "whereToCheck": "Secretory and other cells", "states": [ "Protein load", "stress", "trafficking" ], "behaviors": [ "Folding", "glycosylation", "secretion", "receptor processing" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "functional-hybridoma-density", "functional-hybridoma-bound-count" ], "priorResearch": { "path": "simulation/data/profiles/er-and-golgi.json", "summary": "The folding and secretory compartment, and the row that finally gives the atlas a per-cell output rate. Individual cells' antibody secretion has been measured at around 14,000 molecules per minute, with a membrane-bound density near 100 per square micrometre (L222) - in hybridomas, so an engineered cell's figure, but the first time any family in this atlas has a number for what it emits. The row also separates identity from output: without XBP-1, antibody-secreting cells are still generated efficiently, at normal frequencies, with typical plasma cell surface markers, while secretion falls and the characteristic morphology never forms (L223). The same gene in a different family does something else entirely - constitutively activated in tumour-associated dendritic cells it blunts anti-tumour immunity, and silencing it there extends survival (L221). And the framing record states the premise this project runs on, applied to an organelle: this component's stress is imposed by what the environment demands of the cell (L224).", "stateAxes": [ { "axis": "Secretion, with a rate at last", "whatToMeasure": "Molecules per cell per minute, and separately the surface density of the membrane-bound form. Individual hybridoma cells secreted antibody in the range of 14,000 molecules per minute, with the membrane-bound fraction at about 100 per square micrometre; membrane-bound, secreted and dual-expressing cells were distinguished in under 30 minutes, and sorting gave an 800-fold enrichment of antigen-specific cells in a single round.", "interpretationLimit": "Hybridomas are immortalised fusions selected for high output, so this is an engineered cell's rate and must not be read as a human plasma cell's. In the range of is the authors' phrasing, making it an order of magnitude rather than a calibrated value, with no distribution width extracted. Secretion into a sealed droplet over a short window is not secretion into tissue, where uptake, degradation and convection act. The rate is a by-product of a screening methods paper.", "evidence": [ "L222" ] }, { "axis": "Protein load, which identity does not predict", "whatToMeasure": "Output as its own variable rather than as an attribute of cell type. Without XBP-1, antibody-secreting cells were generated efficiently, were at normal frequencies in resting and immunised mice, and carried surface markers typical for plasma cells - while secretion was reduced though not abolished and the characteristic morphology failed to develop. The regulatory programme for differentiation proceeded relatively normally without high-rate secretion.", "interpretationLimit": "Mouse with B cell-specific deletion, and the reduction is not quantified here - so the atlas has a direction for the same quantity it holds a per-cell rate for elsewhere, measured in a different system. Relatively normally is the authors' characterisation and the morphology is scored qualitatively. One branch of the response only. The paper also notes that earlier claims of an indispensable role were revised by later conditional deletion work, which is a caution about how firmly this kind of result sits.", "evidence": [ "L223" ] }, { "axis": "Stress, imposed from outside the cell", "whatToMeasure": "What the environment is demanding, since the response is described as managing stress imposed by secretory demands associated with environmental forces. The one worked case is ovarian: lipid peroxidation byproducts fuel constitutive XBP1 activation in tumour-associated dendritic cells, producing a triglyceride programme, abnormal lipid accumulation, and loss of their capacity to support anti-tumour T cells - reversible by deletion or by targeted silencing, with extended survival.", "interpretationLimit": "Mouse models, and the whole chain is qualitative: no lipid concentration, no peroxidation rate, no XBP1 activity level and no survival magnitude. The framing that the environment imposes the load comes from a review and is not quantified anywhere in this atlas - no record measures a secretory demand. So the axis has a named cause, a named consequence, an effective intervention, and not one number between them.", "evidence": [ "L221", "L224" ] }, { "axis": "Trafficking, folding, glycosylation and receptor processing", "whatToMeasure": "Four of the things the inventory names, none of which any record in this row measures. Glycosylation is the sharpest absence rather than the vaguest: the atlas's glycan row established that what decides function is sulfation pattern - domain length and spacing rather than sequence - and sialylation density, neither of which is a gene product. This is the compartment where that decoration is applied, so the properties the atlas cannot represent are manufactured here, by enzymes nothing measures.", "interpretationLimit": "No folding rate, no trafficking transit time, no glycosylation activity and no receptor maturation measurement in any of the twenty environments. For glycosylation the gap is structural rather than incidental: a panel can reach the biosynthetic enzymes and never their product's pattern, which is the deciding variable. Receptor processing matters for the atlas's address class, where internalisation rate is already one of six parameters with no value - and this is the compartment that would set it.", "evidence": [] } ], "records": { "L221": { "id": "L221", "year": 2015, "topic": "Stress", "title": "ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis", "url": "https://doi.org/10.1016/j.cell.2015.05.025", "studyType": "Ovarian cancer models with dendritic-cell-specific XBP1 deletion and selective nanoparticle-mediated XBP1 silencing in tumour-associated dendritic cells, with lipid and T cell support assays and survival endpoints, Cell 161(7):1527-1538", "diseaseContext": "Ovarian (HGSC)", "useInModel": "A complete causal chain from a metabolite the atlas already holds without a flux, through this component, to a failure in another family - and an intervention that reversed it. Constitutive activation of XBP1 in tumour-associated dendritic cells drove ovarian cancer progression by blunting anti-tumour immunity. The activation was fuelled by lipid peroxidation byproducts, and it induced a triglyceride biosynthetic programme leading to abnormal lipid accumulation, which in turn inhibited the dendritic cells' capacity to support anti-tumour T cells. Deleting XBP1 specifically in dendritic cells, or silencing it in the tumour-associated cells with targeted nanoparticles, restored their immunostimulatory activity in situ and extended survival by evoking protective type 1 responses. Three uses. The atlas carries adipocyte-derived lipid as an exchange term with no flux; here lipid oxidation products are the input to a stress programme with a measured consequence, which is the first time a lipid term in this atlas does any work. It is a cross-family intervention point with the lever inside an organelle rather than on a surface receptor. And the effective intervention was delivered to the dendritic cells rather than to the tumour, without touching the lipid that caused it.", "limit": "Mouse ovarian cancer models throughout, so the human relevance of the constitutive activation is not established here. Extended survival is reported without a magnitude extracted, and no lipid concentration, peroxidation rate or XBP1 activity level is given - so the chain is complete in its ordering and empty in its quantities. Nanoparticle silencing is a delivery system whose targeting efficiency is not extracted. The triglyceride programme and the inhibition of T cell support are linked by correlation plus the genetic test rather than by a measured lipid threshold.", "provenance": "Abstract read in full; the lipid peroxidation input, the triglyceride programme and lipid accumulation, the inhibition of T cell support, both genetic and nanoparticle interventions with restored activity and extended survival, and the type 1 response as reported", "quantitativeExtraction": "extracted" }, "L222": { "id": "L222", "year": 2022, "topic": "Secretion", "title": "High-throughput single-cell antibody secretion quantification and enrichment using droplet microfluidics-based FRET assay", "url": "https://doi.org/10.1016/j.isci.2022.104515", "studyType": "Droplet microfluidic Forster resonance energy transfer assay measuring secretion by individual hybridoma cells, with droplet-based single-cell sorting, iScience 25(6):104515", "diseaseContext": "Healthy reference; hybridoma cell lines", "useInModel": "The atlas's first per-cell output rate in units, for a family whose entire purpose is output. Antibody secretion by individual hybridoma cells was recorded in the range of 14,000 antibodies per minute, and the density of the membrane-bound fraction was about 100 antibodies per square micrometre. Cells expressing membrane-bound, secreted, or both forms were distinguished in under 30 minutes, and combining the assay with droplet sorting gave an 800-fold enrichment of antigen-specific cells in one round. Two uses. Every secretory edge in this atlas names a molecule and a direction without a quantity; this gives the shape of the number a secretion term should carry - molecules per cell per minute - and a second quantity beside it, surface density per square micrometre, which is what a contact-dependent interaction would need instead. And the method is single-cell, so it measures the distribution rather than a population average, which matters because the atlas's recurring finding is that populations are not uniform.", "limit": "Hybridoma cell lines, which are immortalised fusions selected for high output - so 14,000 per minute is an engineered cell's rate and must not be read as a human plasma cell's. In the range of is the paper's own phrasing, so this is an order of magnitude rather than a calibrated value, and no distribution width is extracted. Secretion into a sealed droplet over a short window is not secretion into tissue, where uptake, degradation and convection act. The assay's subject is screening and enrichment, so the rate is a by-product of a methods paper rather than its result. No human cell of any kind is measured.", "provenance": "Abstract read in full; the secretion rate as stated with its own hedging, the membrane-bound density, the discrimination time, and the enrichment factor as reported", "quantitativeExtraction": "extracted" }, "L223": { "id": "L223", "year": 2012, "topic": "Protein load", "title": "High rate of antibody secretion is not integral to plasma cell differentiation as revealed by XBP-1 deficiency", "url": "https://doi.org/10.4049/jimmunol.1201042", "studyType": "In vitro and in vivo generation of antibody-secreting cells in XBP-1 deficiency, with frequencies in resting and immunised mice, surface marker phenotyping and morphology, Journal of Immunology 189(7):3328-3338", "diseaseContext": "Healthy reference", "useInModel": "Separates a cell's identity from its output, in the family where the two would seem least separable - and it does so with the same gene that the ovarian dendritic cell record manipulates. XBP-1 is an essential branch of the unfolded protein response, induced when a cell must handle large amounts of protein, as antibody-secreting cells do. Without it, antibody-secreting cells were still generated efficiently, were present at normal frequencies in both resting and immunised mice, and displayed surface markers typical for plasma cells. What changed was the output and the shape: antibody secretion was reduced but not abolished, and the cells failed to develop the characteristic morphology. The authors' conclusion is that the gene regulatory programme controlling plasma cell differentiation can proceed relatively normally without high rates of immunoglobulin secretion. Two uses. The atlas's marker problem gets a clean instance in a secretory family: the panel reported a normal plasma cell while the function the panel is taken to indicate was impaired, and the morphology - which is not in any panel - was the thing that tracked the defect. And it means secretory capacity has to be a state variable in its own right, not something inferred from a cell's identity.", "limit": "Mouse, with B cell-specific deletion, and the reduction in secretion is not quantified in this extraction - so the atlas holds a direction and no magnitude for a quantity it elsewhere has a per-cell rate for. Relatively normally is the authors' own characterisation. Morphology is scored qualitatively. The record speaks to one branch of the response, so it does not establish that the whole unfolded protein response is dispensable, and the paper notes the field's earlier claims of an indispensable role were revised by later conditional deletion work - which is itself a caution about how this kind of result settles.", "provenance": "Abstract read in full; the stated role of XBP-1 in the response, the efficient generation and normal frequencies in both states, the typical surface markers, the reduced but not ablated secretion, the morphological failure, and the authors' conclusion as reported", "quantitativeExtraction": "extracted" }, "L224": { "id": "L224", "year": 2016, "topic": "Folding", "title": "The unfolded protein response in immunity and inflammation", "url": "https://doi.org/10.1038/nri.2016.62", "studyType": "Review of the unfolded protein response in immune cell development, differentiation, function and survival, and in chronic inflammatory disease and antitumour responses, Nature Reviews Immunology 16(8):469-484", "diseaseContext": "Shared cancer; chronic inflammatory disease", "useInModel": "Supplies the framing that makes this row a microenvironment component rather than a housekeeping detail. The response is described as a highly conserved pathway that lets a cell manage endoplasmic reticulum stress imposed by the secretory demands associated with environmental forces - which is this project's thesis applied to an organelle: the state of this component is set by what the environment demands of the cell, not by the cell's type. The review covers the response's role in the development, differentiation, function and survival of immune cells, and in chronic inflammatory disease and antitumour responses. For the atlas it justifies carrying this component as an environment-coupled state across the Immune category rather than only in secretory families, and it is the reason the two mechanistic records here both concern immune cells.", "limit": "A review, so it carries no measurement, no cohort and no effect size - it establishes that the coupling is recognised rather than how strong it is. Imposed by secretory demands associated with environmental forces is a framing rather than a quantified relationship, and no record in this atlas measures a secretory demand or the stress it produces. Immunity and inflammation specifically, so the parenchymal and stromal families are outside its scope.", "provenance": "Abstract read in full; the pathway's described function and the explicit attribution to environmental forces, the four immune-cell processes covered, and the disease contexts named as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "functional-hybridoma-density", "functional-hybridoma-bound-count" ] }, { "id": "I092", "name": "Endosomes and lysosomes", "category": "Intracellular", "whereToCheck": "Uptake/clearance compartments", "states": [ "Acidity", "cargo", "maturation" ], "behaviors": [ "Internalization", "recycling", "degradation", "drug escape" ], "slots": { "size": { "status": "references available", "referenceIds": [ "lysosome-untreated" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "lysosome-untreated" ], "priorResearch": { "path": "simulation/data/profiles/endosomes-and-lysosomes.json", "summary": "Where the atlas's delivery chain continues after the cell surface, and the first place in the project where two consecutive stages both have numbers. Of the cargo a cell internalises, about 70 percent is returned by exocytosis as the carriers egress from late endosomes and lysosomes (L226), and of what remains, 1 to 2 percent escapes into the cytosol - only during a limited window while the carrier occupies a transient compartment with both early and late endosomal characteristics (L225). The two papers were published back to back. The compartment is also the atlas's test case for a believed resistance mechanism: weak-base kinase inhibitors accumulate in lysosomes extensively and that does not reduce target-site concentration, because their uncharged forms diffuse freely and the system sits at equilibrium (L227) - while where an active transporter drives the sequestration instead, blocking it does raise intracellular drug (L228).", "stateAxes": [ { "axis": "Drug escape, as a window rather than a rate", "whatToMeasure": "Whether the carrier is in the competent compartment, and for how long. Escape into the cytosol ran at 1 to 2 percent efficiency and occurred only during a limited window of time while the carrier resided in a specific compartment sharing early and late endosomal characteristics. Entry preceding it used clathrin-mediated endocytosis and macropinocytosis, by constitutive and inducible pathways, in a cell-type-specific manner.", "interpretationLimit": "One carrier class and one cargo, so the figure belongs to lipid nanoparticles delivering siRNA and not to conjugates or small molecules. The window has no duration and the competent compartment is defined by marker overlap rather than by pH or size - so both quantities a model would need are missing, and the ones held make a single escape rate constant the wrong form rather than the wrong value. Cultured cells and mouse liver, an estimate with a range, and no distribution across cells.", "evidence": [ "L225" ] }, { "axis": "Recycling, which removes most of the cargo", "whatToMeasure": "The exocytosed fraction, because it dominates. About 70 percent of internalised siRNA underwent exocytosis as carriers egressed from late endosomes and lysosomes. Niemann-Pick type C1 regulates the major recycling pathways, and cells lacking it retained carriers in late endosomes and lysosomes and silenced the target gene more strongly.", "interpretationLimit": "A fraction of internalised material over the experiment rather than an efflux rate constant, reported as approximately 70 percent with no distribution or cell-type breakdown. Cultured cells, one carrier and one cargo. The increased silencing in NPC1-deficient cells has no magnitude here, and NPC1 deficiency is a disease genotype with other consequences for lipid handling that are not separated from the delivery effect.", "evidence": [ "L226" ] }, { "axis": "Cargo, and whether this compartment causes resistance", "whatToMeasure": "How the drug got in, because that decides the answer. For weak bases whose uncharged form diffuses freely, sequestration can only lower target-site concentration if it also lowers the extracellular concentration - and for imatinib, nilotinib and dasatinib it did not, leaving Bcr-Abl signalling unaffected even when sunitinib pre-treatment raised lysosomal accumulation further. Where an active transporter drives the sequestration, blocking it with lansoprazole substantially increased intracellular accumulation of substrate drugs and reversed resistance in cells and in mice.", "interpretationLimit": "The two records reach opposite conclusions about whether this compartment causes resistance, and the atlas holds both. The likely resolution is that they concern different entry mechanisms - free diffusion against active transport - and no record here tests both in one system, so the resolution is inference. Both are in vitro or mouse, and the negative study's own argument depends on extracellular concentration being set by a medium volume, which in tissue it is not. No concentrations or effect sizes are extracted from either.", "evidence": [ "L227", "L228" ] }, { "axis": "Acidity, maturation, internalisation and degradation", "whatToMeasure": "The first state the inventory names is acidity, and no record in this row measures a pH. Maturation appears only as the observation that the escape-competent compartment is intermediate between early and late. Internalisation appears as routes and their cell-type specificity, with no rate. Degradation appears not at all.", "interpretationLimit": "No lysosomal or endosomal pH for any family in any of the twenty environments, despite acidity being the state the inventory puts first and despite the whole weak-base argument in this row turning on protonation. No maturation timing, no internalisation rate - which is also one of the six address-class parameters the atlas holds with no value - and no protease activity or degradation half-life for any cargo.", "evidence": [] } ], "records": { "L225": { "id": "L225", "year": 2013, "topic": "Drug escape", "title": "Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape", "url": "https://doi.org/10.1038/nbt.2612", "studyType": "Quantitative fluorescence imaging and electron microscopy of lipid nanoparticles carrying traceable siRNA in several cell types in vitro and in mouse liver, with colloidal-gold-conjugated siRNA detected directly, Nature Biotechnology 31(7):638-646", "diseaseContext": "Healthy reference; mouse liver and cultured cell types", "useInModel": "Puts a number on the behaviour the inventory calls drug escape, and the number is small. By detecting colloidal gold conjugated to the siRNA directly, escape from endosomes into the cytosol was estimated at 1 to 2 percent efficiency - and it happened only during a limited window of time, while the carrier sat in a specific compartment sharing early and late endosomal characteristics. Entry itself was by both constitutive and inducible pathways in a cell-type-specific manner, using clathrin-mediated endocytosis as well as macropinocytosis. Three uses. The atlas's delivery chain stops at the cell surface, and this is the first stage inside the cell with a measured efficiency. The form of the result matters more than its value: escape is a window in a transient compartment, not a rate constant acting on a pool, so a model with a single escape rate is wrong in shape and not only in its number. And entry route is cell-type-specific, which means an uptake term cannot be a property of the carrier alone.", "limit": "One carrier class and one cargo - lipid nanoparticles with siRNA - so 1 to 2 percent belongs to that pairing and should not be transferred to antibody-drug conjugates or small molecules. Cultured cells plus mouse liver, with no human tissue. The figure is the authors' estimate from gold particle counting, with a range rather than a value and no distribution across cells. The limited window is described without a duration, and the compartment is defined by marker overlap rather than by a measured pH or size - so the two quantities a simulation would need, how long the window lasts and what defines the competent compartment, are both absent.", "provenance": "Abstract read in full; both entry pathways and their cell-type specificity, the two endocytic routes named, the 1 to 2 percent escape estimate with its detection method, and the limited time window in a compartment with mixed early and late characteristics as reported", "quantitativeExtraction": "extracted" }, "L226": { "id": "L226", "year": 2013, "topic": "Recycling", "title": "Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling", "url": "https://doi.org/10.1038/nbt.2614", "studyType": "Automated high-throughput confocal microscopy with cellular trafficking probes, defined pathway perturbations and systems-biology interaction analysis, plus NPC1-deficient cells, Nature Biotechnology 31(7):653-658", "diseaseContext": "Healthy reference", "useInModel": "The companion paper, published back to back with the escape measurement, and it supplies the loss that happens before escape is even attempted. About 70 percent of internalised siRNA undergoes exocytosis, through egress of the carriers from late endosomes and lysosomes - so most of what the cell takes up is returned. Niemann-Pick type C1 is identified as an important regulator of the major recycling pathways, and NPC1-deficient cells showed enhanced retention of carriers inside late endosomes and lysosomes together with increased silencing of the target gene. Entry through macropinocytosis required multiple signalling effectors including proton pumps, mTOR and cathepsins. Two uses. Set beside the escape figure this gives the atlas two consecutive intracellular stages with numbers - roughly 70 percent out, then 1 to 2 percent of the remainder reaching the cytosol - which is more quantitative detail than the atlas's four-stage extracellular chain has for all but its first stage. And NPC1 is a named, genetically validated lever: suppressing recycling increased the functional effect, which makes the recycling pathway a target rather than a constraint.", "limit": "Cultured cells, one carrier class and one cargo, so the 70 percent is specific to lipid nanoparticles delivering siRNA. The figure is given as approximately 70 percent with no distribution or cell-type breakdown extracted, and no rate - it is a fraction of internalised material over the experiment rather than an efflux constant. Increased gene silencing in NPC1-deficient cells is reported without a magnitude here. NPC1 deficiency is a disease genotype used as a tool, so it carries other consequences for lipid handling that are not separated from the delivery effect.", "provenance": "Abstract read in full; the signalling effectors required for macropinocytotic entry, the approximately 70 percent exocytosis figure with its stated route, NPC1's identification as a recycling regulator, and the retention and silencing changes in NPC1-deficient cells as reported", "quantitativeExtraction": "extracted" }, "L227": { "id": "L227", "year": 2019, "topic": "Cargo", "title": "The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance", "url": "https://doi.org/10.3390/biom9110675", "studyType": "Direct test of whether lysosomal sequestration of imatinib, nilotinib and dasatinib reduces target-site concentration, with sunitinib pre-treatment to raise lysosomal accumulation and Bcr-Abl signalling as the readout, Biomolecules 9(11):675", "diseaseContext": "Leukemia; shared cancer", "useInModel": "A widely believed resistance mechanism tested directly and found insufficient, with a physical reason that generalises beyond this drug class. The paper's framing is that lysosomal sequestration of weak-base anticancer drugs is a putative resistance mechanism that has never been directly proven. Their analysis gives the condition under which it could work: sequestration can meaningfully reduce the concentration at target sites only if it simultaneously lowers the extracellular concentration, because the uncharged forms of weak bases diffuse freely across membranes and the system sits at equilibrium. Testing it, the three inhibitors accumulated extensively in the lysosomes of cancer cells and that sequestration was not sufficient to reduce the extracellular concentration substantially; lysosomal accumulation also failed to affect Bcr-Abl signalling. Pre-treatment with sunitinib significantly increased lysosomal accumulation without apparent lysosomal biogenesis, and even then extracellular concentrations were unchanged and sensitivity was unaffected. For this atlas the transferable part is the principle: an intracellular sink does not reduce target engagement unless it drains the source. That applies to every compartment the project might model as a sink, and the atlas has several.", "limit": "In vitro throughout, and the authors limit their conclusion to in vitro - so this does not exclude a contribution in tissue, where extracellular concentration is set by perfusion and clearance rather than by a fixed medium volume, which is exactly the condition their argument turns on. Three inhibitors in one target class, with Bcr-Abl signalling as the functional readout. The equilibrium argument holds for weak bases whose uncharged form crosses membranes freely and does not cover drugs moved into lysosomes by active transport, which the atlas's other record on this question addresses and disagrees about. No concentrations are extracted here.", "provenance": "Abstract read in full; the stated lack of prior direct proof, the equilibrium condition the authors derive, the extensive accumulation with its failure to lower extracellular concentration or affect signalling, the sunitinib pre-treatment result, and the authors' own restriction of the conclusion to in vitro as reported", "quantitativeExtraction": "extracted" }, "L228": { "id": "L228", "year": 2024, "topic": "Cargo", "title": "Lansoprazole reverses multidrug resistance in cancer through impeding ABC transporter-mediated chemotherapeutic drug sequestration", "url": "https://doi.org/10.1016/j.drup.2024.101100", "studyType": "Reversal and combination studies in multidrug-resistant cells with lysosomal staining, substrate accumulation and efflux assays, ATPase activity, molecular docking, and multidrug-resistant nude mouse models, Drug Resistance Updates 76:101100", "diseaseContext": "Shared cancer", "useInModel": "The other side of the atlas's disagreement about lysosomes as a drug sink, and it concerns a different mechanism rather than the same one. Lansoprazole attenuated ABCB1- and ABCG2-mediated resistance and was synergistic with substrate drugs in resistant cells, and in mouse models it increased sensitivity to substrate anticancer drugs without obvious toxicity. The mechanism given is specific: it impeded ABCB1-mediated lysosomal sequestration, producing a substantial increase in intracellular accumulation of substrate drugs - and the effect was not due to downregulation or altered subcellular localisation of the transporters, but to competitive binding at their substrate-binding region with promotion of their ATPase activity. So where sequestration is driven by an active transporter rather than by weak-base partitioning, blocking it does change intracellular accumulation. For the atlas this means lysosomal sequestration is not one mechanism with one answer: the question is whether the drug arrives by free diffusion or by pumping, and the two give opposite conclusions about whether the lysosome causes resistance.", "limit": "Cells and mouse xenograft models, with no human data. Substantial increase, synergistic and attenuated are reported without magnitudes extracted here, so the atlas gains a direction and no effect size. A repurposed proton pump inhibitor acting on two transporters, so the result is about this compound's polypharmacology as much as about the lysosome. Its conclusion that sequestration matters sits against the atlas's companion record finding it insufficient for weak-base inhibitors - the mechanisms differ, which is the likely resolution, and no record here tests both in one system.", "provenance": "Abstract read in full; the reversal and synergy findings in vitro and in vivo, the attribution to impeded ABCB1-mediated lysosomal sequestration with increased intracellular accumulation, the exclusion of downregulation and relocalisation, and the ATPase and competitive binding mechanism as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I093", "name": "Proteasome and autophagy machinery", "category": "Intracellular", "whereToCheck": "Cells by state", "states": [ "Flux", "overload", "impairment" ], "behaviors": [ "Protein turnover", "antigen processing", "aggregate handling" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [], "priorResearch": { "path": "simulation/data/profiles/proteasome-and-autophagy-machinery.json", "summary": "The degradation machinery, and the row that turns out to set a surface parameter the atlas has been treating as a property of the cell's genome. In pancreatic cancer, MHC-I loss mutations are rare while MHC-I downregulation is frequent, and the explanation is selective autophagy-dependent lysosomal degradation through the cargo receptor NBR1 - inhibiting autophagy restores surface MHC-I, improves presentation, enhances T cell responses and shrinks tumours, with the effect abolished by depleting CD8 T cells or by reducing surface MHC-I again (L229). It is also the first Intracellular row to serve the neurodegenerative environments. More than 95 percent of ALS cases show TDP-43 in cytoplasmic aggregates, and because the protein is essential the approach is to modify its clearance: RAD23A and USP13 knockdown each reduce insoluble TDP-43 and USP13 knockdown reduces motor neuron death (L230). Engineered autophagy receptors against Tau or TDP-43, delivered in extracellular vesicles, reduce pathology across four model systems (L231).", "stateAxes": [ { "axis": "Antigen processing, which sets a surface density", "whatToMeasure": "Where the antigen is, not whether its gene is intact. MHC-I is selectively routed to lysosomal degradation by an autophagy-dependent mechanism involving NBR1, sitting predominantly in autophagosomes and lysosomes with reduced surface expression; autophagy inhibition restored surface levels, improved presentation, enhanced anti-tumour T cell responses and reduced tumour growth, and both depleting CD8 T cells and reducing surface MHC-I reversed the benefit.", "interpretationLimit": "Mouse syngeneic models and PDAC lines, with the human claim resting on reported downregulation frequency rather than on an intervention. No molecules per cell at any point, so the address-class density parameter gains a determinant and still no value. Chloroquine inhibits lysosomal function broadly, so the pharmacological arm is less selective than the genetic one, and whether the NBR1 route operates in any other environment is untested.", "evidence": [ "L229" ] }, { "axis": "Aggregate handling, by modifying clearance rather than the cargo", "whatToMeasure": "The degradation machinery around the aggregating protein, because the protein itself is not a safe target - it is essential, which is the authors' stated reason for screening modifiers instead. RAD23A knockdown reduced insoluble TDP-43 in an inducible human cell line and in primary rat cortical neurons; loss of its worm orthologue improved locomotion and increased TDP-43's degradation rate; and USP13 knockdown reduced sarkosyl-insoluble mutant protein in both systems, reduced death in primary rat motor neurons and improved locomotion in worms.", "interpretationLimit": "An immortalised cell line, primary rat neurons and a nematode, with no human tissue or patient data, and mutant overexpression models of aggregation that the atlas's own records show behave differently from sporadic disease. Reductions are unquantified here and no degradation rate is given, though rate is what the worm experiment measured. Knockdowns are dependencies rather than interventions, and whether either modifier compromises wild-type TDP-43 function - the reason direct depletion was rejected - is not established.", "evidence": [ "L230", "L231" ] }, { "axis": "Flux, overload and impairment", "whatToMeasure": "The rate at which protein is actually cleared, which is the inventory's first state and which no record in this atlas measures for any family in any environment.", "interpretationLimit": "Not served. No autophagic flux, no proteasome capacity, no protein half-life and no measure of overload anywhere - so the three states this row is asked to resolve have no values, while the two behaviours it can serve both have mechanisms. The gap is sharper than usual because flux is routinely measured in cell biology: this is an ingestion failure rather than an absence in the literature, and the atlas should say so.", "evidence": [] }, { "axis": "Protein turnover as a target, with a size constraint", "whatToMeasure": "Whether the machinery addressed can handle the thing being degraded. The engineered receptor work names three challenges - crossing the blood-brain barrier and the plasma membrane, specifically recognising the pathological form of a protein, and engaging mechanisms able to eliminate large entities - and recruits autophagy rather than the proteasome precisely because the targets are large heterogeneous inclusions.", "interpretationLimit": "The size constraint is stated as a design rationale rather than measured: no aggregate dimension, no proteasome size cut-off and no comparison of the two routes on the same cargo appears here. Mouse and iPSC models with no patient data, and no delivery efficiency or brain concentration for either vehicle - so the first of the three challenges is named and quantified no better than the atlas already quantifies it.", "evidence": [ "L231" ] } ], "records": { "L229": { "id": "L229", "year": 2020, "topic": "Antigen processing", "title": "Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I", "url": "https://doi.org/10.1038/s41586-020-2229-5", "studyType": "Pancreatic ductal adenocarcinoma cells and syngeneic mouse models with genetic and pharmacological autophagy inhibition, NBR1 cargo receptor identification, CD8 depletion and MHC-I reduction as reversal tests, and combination with dual checkpoint blockade, Nature 581(7806):100-105", "diseaseContext": "Pancreatic (PDAC)", "useInModel": "Shows that a surface antigen's density is set by an intracellular degradation pathway, which connects this row to the atlas's address class and to its antigen row. The framing is a genotype-phenotype gap the atlas has now seen several times: in pancreatic cancer, mutations causing loss of MHC-I are rarely found despite frequent downregulation of its expression - so the lost antigen is not a lost gene. The mechanism is selective rather than bulk: MHC-I molecules are targeted for lysosomal degradation by an autophagy-dependent route involving the cargo receptor NBR1, with the protein found predominantly in autophagosomes and lysosomes instead of at the surface. Inhibiting autophagy restored surface MHC-I, improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic hosts - and those anti-tumour effects were reversed by depleting CD8 T cells or by reducing surface MHC-I, which establishes the mechanism through both of its required intermediates rather than by correlation. Inhibition genetically or with chloroquine synergised with combined anti-PD1 and anti-CTLA4. Three uses. Antigen density, one of the six address-class parameters the atlas holds no value for, turns out to have an intracellular determinant that can be raised pharmacologically. The reversal tests in both directions make this one of the better-controlled causal claims in the atlas. And it is a cross-category link: a Chemistry-adjacent surface molecule governed by an Intracellular machine.", "limit": "Mouse syngeneic models and PDAC cell lines, so the human relevance rests on the reported frequency of MHC-I downregulation rather than on a human intervention. No molecules per cell: restored surface levels, improved presentation and reduced growth are directions without magnitudes extracted here, so the parameter this record informs still has no value. Chloroquine inhibits lysosomal function broadly rather than autophagy specifically, so the pharmacological arm is less selective than the genetic one. Synergy with dual checkpoint blockade is preclinical. Whether the NBR1 route operates in other environments is untested here.", "provenance": "Abstract read in full; the stated rarity of MHC-I loss mutations against frequent downregulation, the NBR1-dependent selective targeting, the subcellular localisation, all four consequences of autophagy inhibition, both reversal tests, and the synergy with dual checkpoint blockade as reported", "quantitativeExtraction": "extracted" }, "L230": { "id": "L230", "year": 2026, "topic": "Aggregate handling", "title": "Ubiquitin Proteasome System Components, RAD23A and USP13, Modulate TDP-43 Solubility and Neuronal Toxicity", "url": "https://doi.org/10.1523/jneurosci.0906-25.2025", "studyType": "Inducible mutant TDP-43 HEK293 line with discovery proteomics, knockdown validation in primary rat cortical and motor neurons expressing TDP-43 A315T, and locomotor assays in Caenorhabditis elegans models, Journal of Neuroscience 46(3):e0906252025", "diseaseContext": "ALS", "useInModel": "The first Intracellular row evidence the atlas has for ALS, and it adopts the strategy the project keeps finding: do not target the molecule showing the phenotype, target something else that controls it. The authors state the reason explicitly - more than 95 percent of ALS cases at autopsy show TDP-43 redistributed from the nucleus into cytoplasmic aggregates, and because the protein is essential to basic cellular mechanisms, depleting it directly is unlikely to be a promising therapy, so they look for modifiers of its mislocalisation and aggregation instead. Loss of rad-23 improved locomotor deficits in worm models and increased the degradation rate of TDP-43; knocking down its human counterpart RAD23A reduced insoluble TDP-43 in the cell line and in primary rat cortical neurons. Proteomics of the remodelled proteome then identified the deubiquitinase USP13 as a new potent modifier, whose knockdown reduced sarkosyl-insoluble mutant TDP-43 in both systems, reduced cell death in primary rat motor neurons, and improved locomotor deficits in worms. For the atlas this gives the aggregate-handling behaviour two named, independently validated handles in the degradation machinery, and it places them in a family rather than leaving protein clearance as an unlocated process.", "limit": "Three model systems and no human tissue or patient data: an immortalised human cell line, primary rat neurons and a nematode. Mutant overexpression models of aggregation, which the atlas's own records show behave differently from sporadic disease. Reduced insoluble levels and reduced cell death are reported without magnitudes extracted here, and no degradation rate is given despite rate being what the worm result measured. Knockdown rather than a drug, so these are dependencies and not interventions. Whether either modifier affects wild-type TDP-43 function - the reason direct depletion was rejected - is not established here.", "provenance": "Abstract read in full; the stated autopsy frequency and the explicit reasoning against direct depletion, the prior rad-23 result including the degradation rate increase, the RAD23A knockdown results in both systems, and all three USP13 outcomes as reported", "quantitativeExtraction": "extracted" }, "L231": { "id": "L231", "year": 2026, "topic": "Aggregate handling", "title": "Engineered autophagy receptors administered with extracellular vesicles eliminate pathological Tau and TDP-43", "url": "https://doi.org/10.1038/s41551-026-01774-9", "studyType": "LC3A fused to cytoplasm-stable antibodies against Tau or TDP-43, delivered by small extracellular vesicles or adeno-associated virus, tested in Tau P301S adult primary mouse neurons, TDP-43 G298S iPSC-derived motor neurons, intravenously in Tau P301S mice and in TDP-43 delta-NLS mice, Nature Biomedical Engineering", "diseaseContext": "ALS / FTD", "useInModel": "States the atlas's own delivery problem from the outside, and adds a stage the atlas does not have. The authors name three challenges for eliminating pathological protein species in patients: crossing the blood-brain barrier and the plasma membrane, specifically recognising the pathological form of a protein, and engaging mechanisms able to eliminate large entities. The first is the atlas's delivery chain; the third is new to it - the target can be too big for the normal degradative machinery, which is why the design recruits autophagy rather than the proteasome. Their construct fuses LC3A, central to recruiting substrates into autophagosomes, to cytoplasm-stable antibodies, delivered by small extracellular vesicles; it reduced pathology in adult primary mouse neurons, in patient-mutation iPSC-derived motor neurons, and after intravenous injection in mice, with viral delivery enhancing clearance in a second ALS model. Two uses for this project. It is a worked example of an engineered component that enters a family, binds a specific state of a molecule, and routes it to a degradation machine - which is a composite of several of the atlas's rows and would need all of them to simulate. And the second challenge, recognising the pathological form rather than the protein, is the specificity problem the atlas's address class states as a parameter with no value.", "limit": "Mouse neurons, mouse models and iPSC-derived human neurons - no patient data, and the two delivery routes used are extracellular vesicles and adeno-associated virus rather than anything in clinical use for these diseases. Reduced pathology and enhanced clearance are directions without magnitudes extracted here, and no delivery efficiency, brain concentration or duration of effect is given - so the three challenges are named and the first is not quantified any better than the atlas already quantifies it. Overexpression and mutation models throughout. Whether degrading these species changes function rather than pathology is not addressed in this record.", "provenance": "Abstract read in full; the three stated challenges, the construct's composition and both delivery vehicles, and all four model systems with their outcomes as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I094", "name": "Cytoskeleton and motors", "category": "Intracellular", "whereToCheck": "Cell body; processes; axons", "states": [ "Contractile", "motile", "damaged" ], "behaviors": [ "Actin/myosin", "microtubules", "force", "intracellular transport" ], "slots": { "size": { "status": "references available", "referenceIds": [ "minflux-kinesin" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "minflux-kinesin" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "minflux-kinesin" ], "priorResearch": { "path": "simulation/data/profiles/cytoskeleton-and-motors.json", "summary": "The row that closes two absences the atlas had already written down. The motor neuron row recorded that no axonal transport measurement existed anywhere in this atlas; the delivery chain recorded that solid stress is held as pressures for the consequence and nothing for the cause. Both are now served, and neither arrives as a number. Axonal transport comes as a double dissociation: retrograde transport of signalling endosomes was perturbed before symptom onset in TDP-43 mutant mice that had not lost motor neurons, and largely unaffected in FUS mutant mice that had lost 20 percent of theirs (L232), with presymptomatic deficits also present in SOD1 mice (L233). Cell-generated force comes as a structure: a passive stress rise from compression of the cell body and nucleus, then an active rise with contractility, intracellular pressure and blebbing that partially relieves it, with ROCK and myosin II inhibition reducing generation (L234) - and a caution that such forces can be misinterpreted if the substrate's dissipation is ignored (L235).", "stateAxes": [ { "axis": "Intracellular transport, dissociated from degeneration in both directions", "whatToMeasure": "Cargo movement in vivo, timed against pathology, and separately per genotype. Retrograde transport of neurotrophin-containing signalling endosomes was perturbed in TDP-43 M337V mice between 1.5 and 3 months and before motor symptom onset, in animals with neuromuscular pathology and no overt motor neuron loss; it was largely unaffected in Fus delta-14 heterozygotes despite 20 percent motor neuron loss; and it was clearly deficient presymptomatically in SOD1-G93A mice, worsening at an early symptomatic stage.", "interpretationLimit": "All mouse, one cargo, one direction - so this is not axonal transport in general but retrograde signalling endosome movement. Perturbed, largely unaffected and clear deficits carry no velocities, flux or pause frequencies, so the atlas gains a presence and a timing and not a rate. The 1.5 to 3 month window is a mouse interval that does not map onto human disease, and the dissociation compares two models with different constructs rather than resting on one manipulation. No human measurement exists.", "evidence": [ "L232", "L233" ] }, { "axis": "Contractile, as a force with a passive and an active part", "whatToMeasure": "Both phases separately, because they have different causes and only one is a target. Confinement produced a rapid passive stress rise from compression of the cell body and nucleus against the substrate, followed by an active stress increase associated with enhanced contractility, intracellular pressure buildup and bleb formation - with bleb expansion partially relieving pressure and reducing the stress imposed on the surroundings. ROCK and myosin II inhibition each reduced stress generation, with distinct effects on blebbing.", "interpretationLimit": "A methods paper in engineered confinement: no stress in pascals, no confinement height at which either phase begins, and no timing for the transition between them. Cells compressed against a substrate rather than threading an interstitial matrix, and the geometry the atlas actually needs is a pore network whose dimensions it holds for no drawn environment. Both inhibitor effects are directions without magnitudes, and there is no in vivo work or disease context.", "evidence": [ "L234" ] }, { "axis": "Force, and whether a measured one can be trusted", "whatToMeasure": "The substrate as well as the cell. Elastic formulations of traction force microscopy neglect viscous dissipation and can misinterpret forces on viscoelastic substrates; whether a cell engages a substrate elastically or viscoelastically depends on timescale matching between its loading rate and the substrate's relaxation times; and for the substrates analysed, viscoelastic traction magnitudes scale with total dissipation rather than with individual relaxation times.", "interpretationLimit": "A framework and criteria rather than forces - no magnitude for any cell type or disease. Two-dimensional, on engineered hydrogels of finite thickness with Generalized Maxwell substrates; whether the scaling with total dissipation holds in tissue, which is neither two-dimensional nor a Maxwell material, is not established. The validity criteria for elastic treatment are derived inside the same framework and inherit its assumptions.", "evidence": [ "L235" ] }, { "axis": "Motile, damaged, and the microtubule half of the row", "whatToMeasure": "Three of the things the inventory names and none of them is served. Motility appears in this atlas only as the consequence of a geometric constraint - arrest at 10 percent of the nuclear cross-section, with migration declining linearly above it - which is a property of the pore and the nucleus rather than of this family. Microtubules appear only as the track the dissociated transport runs on, with nothing measuring them. The damaged state has no record at all.", "interpretationLimit": "The geometric arrest threshold is held in the basement membrane row and is cited here because it is the atlas's only quantitative statement about whether a cell moves - and it says nothing about actin, myosin or microtubules. So the row's named behaviours divide into two that now have mechanisms and two that have neither mechanism nor value.", "evidence": [ "L178" ] } ], "records": { "L178": { "id": "L178", "year": 2013, "topic": "Thickness and gaps", "title": "Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force", "url": "https://doi.org/10.1083/jcb.201210152", "studyType": "Migration quantified in MMP-degradable collagen lattices and non-degradable substrates of varying porosity, with nuclear deformation measured to the point of physical arrest, Journal of Cell Biology 201(7):1069-1084", "diseaseContext": "Shared cancer; healthy reference", "useInModel": "The atlas's first hard geometric threshold, and it is cell-type-specific. Migration independent of matrix metalloproteinases declined as a linear function of pore size and with deformation of the nucleus, with arrest reached at 10 percent of the nuclear cross section - 7 square micrometres for tumour cells, 4 for T cells, 2 for neutrophils. Residual migration under space restriction depended on MMP-dependent cleavage enlarging pore diameters and on integrin- and actomyosin-dependent force that jointly propelled the nucleus. Three things follow. The project has recorded local mechanisms without length scales repeatedly; here is a threshold with numbers and a linear relationship above it, so a model can interpolate rather than guess. The limiting structure is the nucleus, which means the hardest constraint in the Structures category is set by a component of the Intracellular category. And proteolysis is a modulator rather than a gate: migration happens without it and declines with pore size, while enzymes extend the range by widening pores - so blocking proteases shifts a threshold rather than closing a door.", "limit": "Engineered collagen lattices and synthetic porous substrates, not basement membrane and not tissue - so the thresholds are properties of cells moving through characterised pore geometries rather than measurements of any real interface. Basement membrane is a dense sheet rather than a porous lattice, so these numbers describe interstitial passage better than they describe crossing this family. The values are cross-sectional areas at arrest in specific cell types under specific conditions, and nuclear deformability varies with lamin composition and cell state, which this does not survey. Nothing here measures a pore size in any drawn environment.", "provenance": "Abstract read in full; the experimental systems, the linear dependence on pore size, the arrest criterion at 10 percent of nuclear cross section with all three cell-type values, and the roles of proteolysis and force generation as modulators as reported", "quantitativeExtraction": "extracted" }, "L232": { "id": "L232", "year": 2020, "topic": "Intracellular transport", "title": "Mice Carrying ALS Mutant TDP-43, but Not Mutant FUS, Display In Vivo Defects in Axonal Transport of Signaling Endosomes", "url": "https://doi.org/10.1016/j.celrep.2020.02.078", "studyType": "In vivo imaging of retrogradely transported neurotrophin-containing signalling endosomes in nerve axons of two ALS mouse models carrying mutations in different RNA processing genes, with timed comparison against pathology and symptom onset, Cell Reports 30(11):3655-3662.e2", "diseaseContext": "ALS", "useInModel": "Fills the gap the motor neuron row named as its largest - no axonal transport measurement anywhere in the atlas - and it arrives as a double dissociation rather than a single number. TDP-43 M337V mice, which show neuromuscular pathology without overt motor neuron loss, had transport perturbations manifesting between 1.5 and 3 months, before motor symptom onset. Fus delta-14 heterozygous mice, despite 20 percent motor neuron loss, had largely unaffected transport. So transport failure occurs without cell loss in one genotype and cell loss occurs without transport failure in the other, which means impaired retrograde transport is neither necessary nor sufficient for motor neuron death. The authors' conclusion is that these deficits are not shared by all ALS-linked genes and that there are mechanistic distinctions between diseases caused by mutations in different RNA processing genes. Two uses. The atlas gains the behaviour it was missing, in vivo and timed relative to onset. And it gains a third axis on which the ALS environment splits by genotype, alongside the staged distal timeline and the concurrent-loss model it already holds - with this one separating a mechanism from an outcome rather than reordering them.", "limit": "Two mouse models, no human measurement, and one cargo - neurotrophin-containing signalling endosomes moving retrogradely - so this is not axonal transport in general but one cargo in one direction. Perturbations and largely unaffected are reported without velocities, flux or pause frequencies extracted here, so the atlas gains a presence and a timing rather than a rate. The 1.5 to 3 month window is a mouse developmental interval and does not map onto human disease. Mutant overexpression models of two genes, and the dissociation rests on comparing two models with different constructs rather than on one manipulation.", "provenance": "Abstract read in full; the cargo and direction measured, the TDP-43 model's pathology without motor neuron loss and its 1.5 to 3 month window preceding onset, the Fus model's 20 percent motor neuron loss with largely unaffected transport, and the authors' conclusion about mechanistic distinctions as reported", "quantitativeExtraction": "extracted" }, "L233": { "id": "L233", "year": 2010, "topic": "Intracellular transport", "title": "Deficits in axonal transport precede ALS symptoms in vivo", "url": "https://doi.org/10.1073/pnas.1006869107", "studyType": "In vivo assay characterising axonal transport in single axons of the intact sciatic nerve in presymptomatic and early symptomatic SOD1-G93A mice, Proceedings of the National Academy of Sciences 107(47):20523-20528", "diseaseContext": "ALS", "useInModel": "The third genotype in this row's comparison, and the one that makes the ordering consistent. Using an assay that resolves transport in single axons within the intact sciatic nerve, clear deficits were present in presymptomatic mutant SOD1 mice and worsened at an early symptomatic stage - so impaired retrograde transport may be one of the earliest axonal pathologies in this model. Read with the companion record, the atlas now holds transport deficits appearing before symptoms in two genotypes, SOD1 and TDP-43, and absent in a third, FUS, which lost 20 percent of its motor neurons anyway. For this project that is the useful shape: a mechanism that is early where it occurs and dispensable where it does not. It also matters for the atlas's staged ALS timeline, which has distal end-plate denervation at 47 days preceding any cell body loss in this same SOD1 model - transport failure sits at or before that stage, which makes the distal-to-proximal ordering mechanistically plausible rather than merely observed.", "limit": "One mouse model, no human data, and retrograde transport in sciatic nerve axons - a peripheral readout for a disease the atlas also tracks in cortex and spinal cord. Clear deficits and worsens are reported without velocities or flux extracted here, so again a presence and a timing rather than a rate. Presymptomatic is defined relative to this model's own course. The authors frame the pathogenic importance as a possibility, and the companion record then shows it is not general across ALS genotypes.", "provenance": "Abstract read in full; the single-axon intact-nerve assay, the presence of deficits presymptomatically with worsening at early symptomatic stage, and the authors' hedged claim about earliest axonal pathology as reported", "quantitativeExtraction": "extracted" }, "L234": { "id": "L234", "year": 2026, "topic": "Force", "title": "CFM: confinement force microscopy - a dynamic, precise and stable microconfiner for traction force microscopy in spatial confinement", "url": "https://doi.org/10.1038/s41592-026-03216-5", "studyType": "Microconfiner platform for live-cell imaging with programmable control of confinement level, timing and frequency while measuring traction forces on the microenvironment, with ROCK and myosin II inhibition, Nature Methods 23(11):2066-2076", "diseaseContext": "Healthy reference; shared cancer as the stated motivation", "useInModel": "Supplies the cause-side of a force the atlas has only ever held as a consequence. The delivery chain records interstitial pressures of 75 to 130 millimetres of mercury in tumours and names the compressing quantity as solid stress generated by proliferating cells, with the explicit note that the atlas holds pressures for the consequence and nothing for the cause. This measures the cause, and finds it has two phases. Under confinement a cell shows first a rapid passive stress rise, from compression of the cell body and nucleus against the substrate, and then an active stress increase associated with enhanced contractility, intracellular pressure buildup and bleb formation. Bleb expansion partially relieves that pressure and reduces the stress the cell imposes on its surroundings. ROCK and myosin II inhibition each reduce stress generation, with distinct effects on blebbing. Three uses. The passive phase is mechanically the same event the nucleus row records as damaging the genome, so one compression produces a force outward and DNA damage inward - the same confinement appearing in two of the atlas's rows with different readouts. Blebbing is a negative-feedback term on cell-generated stress, which the atlas's solid stress account does not have. And the two inhibitors make the active phase a target rather than a property.", "limit": "A methods paper in engineered confinement, so the result is a structure and not a magnitude: no stress in pascals, no confinement height at which each phase begins, and no timing for the passive-to-active transition are extracted here. Cells on a substrate under a programmable confiner, which is not an interstitial matrix - the geometry the atlas actually needs is a pore network, whose dimensions it holds for no drawn environment. Reduce stress generation is a direction for both inhibitors without magnitudes. No disease context and no in vivo work.", "provenance": "Abstract read in full; the platform's programmable control, both phases with their stated causes, the pressure-relieving role of blebbing, and the effects of ROCK and myosin II inhibition including their distinct consequences for blebbing as reported", "quantitativeExtraction": "extracted" }, "L235": { "id": "L235", "year": 2026, "topic": "Force", "title": "Traction Force Microscopy for Viscoelastic Substrates: A Semi-Analytical Method", "url": "https://doi.org/10.1002/advs.202522252", "studyType": "Semi-analytical two-dimensional viscoelastic traction force microscopy generalising the elastic Boussinesq framework to Generalized Maxwell substrates, applied to beating cardiomyocytes, epithelial cells and dermal fibroblasts on polyacrylamide and alginate hydrogels, Advanced Science 13:e22252", "diseaseContext": "Healthy reference", "useInModel": "A measurement-provenance caution about the quantity the companion record produces, and it is the strongest of its kind in the atlas because it says published values can be wrong rather than merely incomparable. Elastic formulations of traction force microscopy neglect viscous dissipation and can misinterpret cellular forces on viscoelastic substrates - and living tissue is viscoelastic. The generalisation finds two things that decide the answer: whether the cell engages the substrate elastically or viscoelastically depends on timescale matching between the loading rate and the substrate's relaxation times, and for the substrates analysed, viscoelastic traction magnitudes scale with the substrate's total dissipation rather than with individual relaxation times. So a traction force is not a property of the cell alone: it depends on how fast the cell pulls relative to how fast the material relaxes. For this atlas the instruction is concrete - any cell-generated force it ingests must carry the substrate model used to compute it, and a value obtained with an elastic formulation on a dissipative material should be treated as suspect rather than as a lower bound.", "limit": "A methods paper, so it supplies a framework and criteria rather than forces for any cell type in any disease - no magnitude is extracted here. Two-dimensional, on engineered hydrogels of finite thickness, with Generalized Maxwell substrates of one or two components; whether the scaling with total dissipation holds for tissue, which is neither two-dimensional nor a Maxwell material, is not established. The three cell types are a demonstration set. The criteria for when elastic treatment remains valid are derived within this framework, so they inherit its assumptions.", "provenance": "Abstract read in full; the stated misinterpretation risk on viscoelastic substrates, the dependence of regime on timescale matching, the scaling of magnitude with total dissipation rather than individual relaxation times, and the three cell types and two hydrogel systems as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I095", "name": "Signaling cascades and ion channels", "category": "Intracellular", "whereToCheck": "Membrane and cytoplasm", "states": [ "Activation", "feedback", "desensitization" ], "behaviors": [ "Calcium", "kinase/phosphatase activity", "membrane potential" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [], "priorResearch": { "path": "simulation/data/profiles/signaling-cascades-and-ion-channels.json", "summary": "The last Intracellular row, and the one that tests a claim the rest of the atlas has been building. The project has assembled three instances of exposure being non-monotonic - an engager payload losing effect with continued dosing, platelets helping transiently and harming when sustained, and nuclear lamin levels with a biphasic optimum - and has been recording that schedule is a controlling variable rather than a refinement. This row holds the clinical test. Preclinically, melanoma resistance selected by continuous vemurafenib left resistant tumours drug dependent, so cessation caused regression and discontinuous dosing forestalled lethal resistance (L236). In 79 randomised patients, intermittent dabrafenib plus trametinib was inferior on every efficacy measure (L237). In 137 patients with colorectal cancer on a different drug class, intermittent dosing gave longer progression-free survival on treatment (L238). The feedback and desensitization the inventory asks for are therefore real and their direction is not predictable from this atlas.", "stateAxes": [ { "axis": "Feedback, where resistance has a cost", "whatToMeasure": "Whether the resistant state remains dependent on the inhibited pathway, and whether it is dependent on the drug. In two independent primary human melanoma xenograft models with resistance selected by continuous vemurafenib, one showed continued dependency on BRAF to MEK to ERK signalling through elevated mutant oncoprotein expression; resistant tumours were drug dependent for continued proliferation, so cessation caused regression of established resistant tumours; and discontinuous dosing forestalled lethal drug-resistant disease.", "interpretationLimit": "Preclinical, in two xenograft models, with the pathway-dependency mechanism found in one of the two - so it is not general even within the study. Regression and forestalls carry no magnitudes or intervals here. The discontinuous schedule is a mouse regimen with no stated correspondence to a human interval, which is exactly what the clinical trial had to choose without guidance.", "evidence": [ "L236" ] }, { "axis": "Desensitization, and whether the schedule inference holds in patients", "whatToMeasure": "The clinical endpoint under each schedule, because the preclinical mechanism does not settle it. In 79 randomised melanoma patients, intermittent dosing gave progression-free survival of 8.5 against 10.7 months with a hazard ratio of 1.39, overall survival 18.1 months against not reached with a hazard ratio of 1.69, and response 57 against 77 percent, with quality of life favouring continuous dosing - and with fewer treatment-related adverse events but more grade 3 or worse ones. In 137 colorectal cancer patients on panitumumab plus chemotherapy, intermittent dosing gave progression-free survival on treatment of 17.5 against 11.2 months with no overall survival separation.", "interpretationLimit": "The melanoma trial is phase 2 with 79 patients: no comparison reaches conventional significance and all the intervals cross one, so what it establishes is a consistent direction rather than a difference. The colorectal trial is non-comparative by design, so its two arms were measured against a threshold rather than against each other, and progression-free survival on treatment counts time differently for an intermittent arm by construction - its overall survival figures show no separation. One schedule was tested in each. So the atlas holds two trials that disagree and neither is a clean comparison.", "evidence": [ "L237", "L238" ] }, { "axis": "Membrane potential, served from other rows", "whatToMeasure": "Channel-level excitability, for which the atlas's best evidence sits in the families that showed the phenotype rather than in this row. Nav1.1 is decreased in parvalbumin interneurons in model mice and in patient brain, and restoring it reduced hypersynchrony, memory deficits and premature mortality; cortical hyperexcitability in ALS carries a 4.89 microvolt survival threshold.", "interpretationLimit": "Both records are cited from the neuronal rows rather than generated here, and both are single-channel or single-measure findings in one environment group - so this row's channel axis is a pointer rather than an account. No resting membrane potential for any family in any drawn environment, and nothing at all in the cancer environments, where bioelectric state is an active research question.", "evidence": [ "L190", "L189" ] }, { "axis": "Calcium, and kinase or phosphatase activity", "whatToMeasure": "Two of the three behaviours the inventory names, neither of which any record in this atlas measures. Calcium has no concentration, no transient amplitude and no frequency for any family in any environment. Kinase activity - as distinct from kinase abundance or mutation - has no measurement either, in an atlas whose central controversy in this row is about a kinase cascade's reactivation.", "interpretationLimit": "Not served at all, and the calcium gap is the more surprising of the two: calcium imaging is among the most routine measurements in cell biology and the atlas holds none. The kinase activity gap is sharper in consequence - the schedule argument in this row is entirely about pathway reactivation during drug-free intervals, and no record here measures that reactivation in a patient.", "evidence": [] } ], "records": { "L189": { "id": "L189", "year": 2026, "topic": "Electrophysiology", "title": "Sensory Cortical Hyperexcitability in Amyotrophic Lateral Sclerosis Involves a Broad Hand Representation Within the Primary Somatosensory Cortex", "url": "https://doi.org/10.1002/mus.70371", "studyType": "Retrospective study of 99 patients with sporadic ALS and 42 healthy controls, with sensory nerve action potentials and somatosensory evoked potentials from median and ulnar stimulation, followed to death or tracheostomy with Kaplan-Meier and Cox analyses, Muscle & Nerve 74(6):1246-1255", "diseaseContext": "ALS", "useInModel": "Locates a functional abnormality in the cortex with the periphery as its own control, and attaches a survival threshold to it. Sensory nerve action potential amplitudes did not differ between patients and controls, while cortical evoked potential amplitudes were larger for both median and ulnar stimulation - so the abnormality is cortical and not a peripheral artefact, which the unchanged peripheral recordings establish directly. Patients with ulnar cortical amplitudes at or above 4.89 microvolts had significantly shorter survival, and increased amplitude was an independent predictor of shorter survival for both nerves on multivariate analysis. For this atlas that matters in two ways. It is a functional measurement with a threshold and an outcome, which almost nothing here has. And it sits against the atlas's own record that ALS is a distal axonopathy proceeding dying-back from the neuromuscular junction: distal degeneration does not mean the cortex is spared, since the cortex is measurably hyperexcitable while peripheral sensory conduction is normal. The disease is doing different things at the two ends.", "limit": "Retrospective, single-centre by implication, and sporadic ALS only - so the threshold is derived in this cohort rather than validated in another. Sensory rather than motor cortex, which makes it an unexpected place to find a prognostic signal and means it is not a measurement of the motor neurons the disease kills. Evoked potential amplitude is a population response rather than a property of any cell, so it cannot be assigned to the excitatory neurons this row is about without assumption. The survival association is from one cohort followed to death or tracheostomy.", "provenance": "Abstract read in full; cohort and control numbers, the unchanged peripheral amplitudes, the enlarged cortical amplitudes for both nerves, the correlation between nerves, the amplitude threshold with its log-rank p value, and the multivariate independence as reported", "quantitativeExtraction": "extracted" }, "L190": { "id": "L190", "year": 2012, "topic": "Circuit inhibition", "title": "Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model", "url": "https://doi.org/10.1016/j.cell.2012.02.046", "studyType": "Electroencephalographic and oscillatory analysis in human amyloid precursor protein transgenic mice, with channel subunit measurement in mouse and human brain and transgenic restoration, Cell 149(3):708-721", "diseaseContext": "Alzheimer's", "useInModel": "Answers the question the excitatory row left open, and answers it from the other side of the circuit. That row recorded subclinical epileptiform discharge in a pooled 18.3 percent of Alzheimer patients and had no mechanism for it. Here the chain is complete: amyloid precursor protein transgenic mice showed spontaneous epileptiform discharges indicating network hypersynchrony, occurring primarily during reduced gamma oscillatory activity; gamma is generated by parvalbumin interneurons; those mice and Alzheimer patients both had decreased levels of Nav1.1, the interneuron-specific and parvalbumin-predominant sodium channel subunit; and restoring Nav1.1 in the mice increased inhibitory synaptic activity and gamma oscillations while reducing hypersynchrony, memory deficits and premature mortality. So the excitatory overactivity the atlas measured is an inhibitory failure, the molecular step is confirmed in human brain, and the rescue reaches an endpoint - mortality - that almost no mechanistic study in this atlas reaches.", "limit": "The causal chain is established in one transgenic model that simulates aspects of the disease rather than reproducing it, and the rescue is transgenic restoration rather than a therapeutic intervention. The human contribution is a decreased channel level in patient brain - an association at one timepoint, not a demonstration that the decrease causes the human discharge the excitatory row records. Premature mortality in a transgenic mouse line is not a clinical endpoint. The authors themselves say possibly in Alzheimer's disease for the human extension.", "provenance": "Abstract read in full; the epileptiform discharges and their association with reduced gamma, the attribution of gamma to parvalbumin cells, the decreased channel subunit in both mice and patients, and every element of the restoration phenotype including premature mortality as reported, with the authors' own hedge on human relevance kept", "quantitativeExtraction": "extracted" }, "L236": { "id": "L236", "year": 2013, "topic": "Feedback", "title": "Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance", "url": "https://doi.org/10.1038/nature11814", "studyType": "Two independently derived primary human melanoma xenograft models with resistance selected by continuous vemurafenib administration, drug withdrawal in established resistant tumours, and a discontinuous dosing comparison, Nature 494(7436):251-255", "diseaseContext": "Melanoma (cutaneous)", "useInModel": "The mechanism behind the atlas's schedule finding, stated as a strategy. Resistance was selected by continuous administration in two independent primary human xenograft models; in one, resistant tumours remained dependent on BRAF to MEK to ERK signalling through elevated expression of the mutant oncoprotein itself. The striking result is that the resistant melanomas became drug dependent for continued proliferation, so stopping the drug caused regression of established drug-resistant tumours - and a discontinuous dosing strategy, exploiting the fitness disadvantage resistant cells show without the drug, forestalled the onset of lethal drug-resistant disease. For this project that is the clearest mechanistic case for schedule being a controlling variable rather than a refinement: resistance is not a one-way ratchet but a state with a cost, and the cost is only paid during drug-free intervals. It also means the resistant population's fitness is a function of the treatment, which no static resistance parameter can express.", "limit": "Two xenograft models, so this is preclinical and the atlas now holds the randomised clinical test of the same strategy in the same disease, which came out the other way. Continued dependency through elevated oncoprotein expression was found in one of the two models, so the mechanism is not general even within this study. Regression and forestalls are reported without magnitudes or intervals extracted here. The discontinuous schedule used is a mouse regimen with no stated correspondence to any human dosing interval, which is the gap the clinical trial then had to guess at.", "provenance": "Abstract read in full; the two models and the selection by continuous dosing, the continued pathway dependency through elevated oncoprotein expression in one model, the regression on drug cessation, and the discontinuous dosing result as reported", "quantitativeExtraction": "extracted" }, "L237": { "id": "L237", "year": 2024, "topic": "Desensitization", "title": "A randomised phase 2 study of intermittent versus continuous dosing of dabrafenib plus trametinib in patients with BRAF V600 mutant melanoma (INTERIM)", "url": "https://doi.org/10.1016/j.ejca.2023.113455", "studyType": "Randomised phase 2 trial in 79 patients with BRAF V600 mutant advanced melanoma, intermittent dabrafenib days 1-21 with trametinib days 1-14 every 28 days against continuous dosing, with progression-free survival and quality of life as a composite primary endpoint and circulating tumour DNA by droplet digital PCR, European Journal of Cancer 196:113455", "diseaseContext": "Melanoma (cutaneous)", "useInModel": "The clinical test of the strategy the preclinical record proposed, in the same disease, and it failed on every efficacy measure. Among 79 patients - 39 intermittent, 40 continuous, median age 67, 65 percent stage IV M1c, 29 percent with brain metastases - intermittent dosing was inferior throughout at 19 months median follow-up: median progression-free survival 8.5 against 10.7 months with a hazard ratio of 1.39 and a confidence interval from 0.79 to 2.45 at p equal to 0.255; median overall survival 18.1 months against not reached, hazard ratio 1.69 from 0.87 to 3.28 at p equal to 0.121; and response rate 57 against 77 percent. The toxicity result is not a simple trade either: intermittent patients had fewer treatment-related adverse events, 76 against 88 percent, and more grade 3 or worse events, 53 against 42 percent, with quality of life favouring continuous dosing. This record is the most important corrective in the atlas. The project has been assembling a finding that exposure is non-monotonic in time and that schedule is the controlling variable, with instances in an engager payload, in platelet signalling and in nuclear lamin levels. This is the one case where the inference from that finding to an intermittent regimen was tested in randomised patients, and the regimen was worse. The non-monotonicity may still be real; the extrapolation to a dosing schedule is what failed.", "limit": "Phase 2 with 79 patients, so every efficacy comparison is underpowered and none of the differences reaches conventional significance - the hazard ratios favour continuous dosing and their confidence intervals cross one. Inferior in all efficacy measures is the authors' summary of a consistent direction rather than a demonstrated difference, and the atlas should carry it that way. One intermittent schedule was tested, chosen without a stated mapping from the preclinical regimen, so a different interval might behave differently. Median follow-up of 19 months with overall survival not reached in the control arm.", "provenance": "Abstract read in full; the randomisation and schedule, cohort characteristics, all three efficacy comparisons with hazard ratios, intervals and p values, both adverse event comparisons, the quality of life direction, and the baseline circulating tumour DNA association as reported", "quantitativeExtraction": "extracted" }, "L238": { "id": "L238", "year": 2025, "topic": "Desensitization", "title": "Intermittent or Continuous Panitumumab Plus Fluorouracil, Leucovorin, and Irinotecan for First-Line Treatment of RAS and BRAF Wild-Type Metastatic Colorectal Cancer (IMPROVE)", "url": "https://doi.org/10.1200/jco.24.00979", "studyType": "Open-label multicentre randomised phase 2 non-comparative trial in 137 patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer, continuous against intermittent panitumumab plus FOLFIRI after induction, with progression-free survival on treatment at 12 months as the primary endpoint, Journal of Clinical Oncology 43(7):829-839", "diseaseContext": "Colorectal", "useInModel": "The same question in a different disease and a different drug class, and the answer goes the other way - which is why the atlas must hold all three of these records rather than choose. Sixty-nine patients received continuous therapy and 68 intermittent therapy with treatment-free intervals after induction. At 43.2 months median follow-up, median progression-free survival on treatment was 11.2 months continuous against 17.5 months intermittent, with 12-month rates of 45.7 and 58.5 percent; overall response rates were 68.1 and 61.2 percent, and median overall survival 36.3 and 35.1 months. So the intermittent arm had longer progression-free survival on treatment with a slightly lower response rate and no overall survival difference. Read with the melanoma trial this gives the project its real conclusion about schedule: the sign of a schedule effect is a property of the system, not of schedules. Intermittent dosing was worse in BRAF-mutant melanoma on targeted kinase inhibition and better on this endpoint in wild-type colorectal cancer on an antibody-chemotherapy backbone, and no principle in this atlas predicts which.", "limit": "A non-comparative randomised phase 2 design, which is the central caveat: the two arms were each tested against a pre-specified threshold rather than against each other, so the 11.2 against 17.5 month difference is not a controlled comparison and no hazard ratio or p value is reported for it. Progression-free survival on treatment is a composite endpoint that counts time differently for an intermittent arm by construction, which flatters it - the overall survival figures, 36.3 against 35.1 months, show no separation. One disease, one regimen, and an induction phase before randomisation.", "provenance": "Abstract read in full; the design and its non-comparative nature, both arm sizes and cycle counts, the follow-up duration, both progression-free survival on treatment medians and 12-month rates, response rates and overall survival medians as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I096", "name": "Oxygen and carbon dioxide", "category": "Chemistry", "whereToCheck": "Blood and tissue fields", "states": [ "Spatial gradient", "hypoxia" ], "behaviors": [ "Partial pressures", "consumption", "perfusion dependence" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "recovered-oxygen-hypoxic", "recovered-oxygen-well-oxygenated" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "recovered-oxygen-hypoxic", "recovered-oxygen-well-oxygenated" ], "priorResearch": { "path": "simulation/data/profiles/oxygen-and-carbon-dioxide.json", "summary": "The first Chemistry row, and the one the atlas's own simulation work has been waiting on. Oxygen has been carried as a metabolic exchange term with no flux while the breast parameter set has been calibrating against a median tissue tension labelled as a disputed range. In 18 breast cancer patients the distribution turns out to be bimodal rather than uncertain - 11 hypoxic at an average median of 3.2 millimetres of mercury against 7 well oxygenated at 48.3 - and it rises to 19.2 under neoadjuvant treatment (L239). The row also holds the closest thing to a calibrated model in this atlas: a dose weighted by the oxygen enhancement ratio, from a three-parameter depletion and recovery model, collapses five independent experiments across dose, dose rate, repainting and temporal splitting onto comparable response curves (L240). Alongside: the tracer that maps hypoxia whole-tumour must be normalised to its own delivery phase to mean anything (L241), the clinic lacks a quantitative non-invasive map and says so (L242), and the oxygen effect's dependence on radiation quality runs through chromatin architecture (L243).", "stateAxes": [ { "axis": "Partial pressures, bimodal rather than disputed", "whatToMeasure": "The distribution, not the median. In 18 stage IIB-III breast cancer patients, 11 were hypoxic by the conventional threshold of a median below 10 millimetres of mercury and averaged 3.2, while 7 had well-oxygenated tumours with a median of 48.3. After neoadjuvant chemotherapy with hyperthermia, 8 of the hypoxic patients improved significantly to 19.2 while 3 remained hypoxic at an average of 4.5.", "interpretationLimit": "Eighteen patients, preliminary by the authors' own description, with two treatments combined so the reoxygenation cannot be attributed to either. Polarographic probes sample tracks rather than mapping volume, which is the sparse-sampling problem the imaging literature raises against them. The bimodality is an observation in one cohort with no mixture model fitted, and whether the two groups differ in anything else is not established.", "evidence": [ "L239" ] }, { "axis": "Consumption, as depletion and recovery rates", "whatToMeasure": "The kinetics rather than the level, because that is what predicts outcomes across schedules. A dose weighted by the oxygen enhancement ratio, computed from a three-parameter model with an oxygen depletion rate, an oxygen recovery rate and a baseline level, brought five independent experiments - varying dose, dose rate, repainting and splitting into one to six deliveries two minutes apart - onto comparable response curves, with the weighted dose for 50 percent toxicity agreeing to standard deviations of 0.45 to 1.6 gray.", "interpretationLimit": "Mouse skin toxicity, so a normal-tissue endpoint rather than efficacy. The three parameters are fitted to these data rather than measured independently, so the collapse shows internal consistency rather than external validity, and no value for any of them is extracted here. One delivery geometry, and toxicity scored visually.", "evidence": [ "L240" ] }, { "axis": "Spatial gradient, and the proxy that reports it", "whatToMeasure": "A retention signal divided by its own delivery phase. Across 300 simulated vessel configurations, the tracer's sub-regional signal four hours after injection correlated with median oxygen tension at an R-squared of 0.37 in hypoxic sub-regions, while its ratio to the time-averaged signal over the first 15 minutes correlated at 0.99 - the early phase carrying delivery and the late one retention, so the ratio removes perfusion and leaves oxygen.", "interpretationLimit": "A simulation on xenograft-derived vessel maps, so these are relationships between computed quantities under a diffusion-retention model rather than between a scanner and a probe. Two-dimensional configurations, one tracer, one tumour type's vascular geometry, and an R-squared of 0.99 that any real measurement will reduce through noise and partial volume effects.", "evidence": [ "L241" ] }, { "axis": "Hypoxia, wanted clinically and unmappable", "whatToMeasure": "Spatial variation, which is what would be acted on - the most hypoxic regions requiring higher radiation dose and the most oxygenated lower. The review states that oxygen mapping is critically needed for intensity modulated radiotherapy and that assessment of tumour oxygenation is nonetheless not part of day-to-day practice, because no method exists for quantitative non-invasive mapping.", "interpretationLimit": "A review with no measurement or effect size, reporting the prognostic claim as strongly suggested rather than established and surveying correlations without pooling them. Written in 2017, so whether any method has since entered routine use is not addressed. This is a different kind of gap from most in the atlas: the clinic lacks the measurement too, rather than having it and the project not ingesting it.", "evidence": [ "L242" ] }, { "axis": "Carbon dioxide, and where the oxygen effect acts", "whatToMeasure": "Carbon dioxide is half this row's title and has no record at all - no tension, no gradient, no production rate anywhere in the atlas. What the row does hold on the oxygen side is where the effect lands: the oxygen enhancement ratio's variation with radiation quality tracks the incidence of clustered double-strand breaks within single topologically associating domains and within frequently interacting ones, which kill cells far more readily than dispersed damage.", "interpretationLimit": "The chromatin link is entirely computational, validated against published ratios, with oxygen entering as a strand-break probability rather than as a tension - so it does not connect to any value this row holds in millimetres of mercury, and the genome architecture used is generic rather than measured in any cell type the atlas carries. For carbon dioxide there is nothing to qualify.", "evidence": [ "L243" ] } ], "records": { "L239": { "id": "L239", "year": 2003, "topic": "Partial pressures", "title": "Ultrasound guided pO2 measurement of breast cancer reoxygenation after neoadjuvant chemotherapy and hyperthermia treatment", "url": "https://doi.org/10.1080/0265673031000121517", "studyType": "Ultrasound-guided Eppendorf polarographic oxygen probe measurement in 18 patients with stage IIB-III breast cancer, before and after neoadjuvant chemotherapy combined with hyperthermia, with colour Doppler used to avoid large vessels, International Journal of Hyperthermia 19(5):498-506", "diseaseContext": "Breast", "useInModel": "Bears directly on a disputed range the atlas has already flagged, and suggests the dispute is not a disagreement. The breast parameter set carries median tissue oxygen tension as a validation target of 23 to 28 millimetres of mercury from one source against 44 from another, labelled as a disputed range. In these 18 patients of the same stage and type the distribution was bimodal rather than uncertain: 11 of 18 were hypoxic by the conventional threshold of a median below 10 millimetres of mercury, averaging 3.2, while 7 had well-oxygenated tumours with a median of 48.3 - a fifteen- fold separation between two groups in one cohort. A population median between those two figures is the mean of a mixture, which is what the disputed range may be. The second finding is that the number moves under treatment: 8 of the hypoxic patients improved significantly, to 19.2 millimetres of mercury, while 3 stayed hypoxic at an average of 4.5. So this is a human in vivo parameter, in a drawn environment, with a before and after value - and the atlas should stop treating a single median as the quantity to reproduce.", "limit": "Eighteen patients, described by its own authors as preliminary, and the treatment is chemotherapy combined with hyperthermia rather than chemotherapy alone - so the reoxygenation cannot be attributed to either. Polarographic probe measurement samples tracks through the tumour rather than mapping it, which is the sparse-sampling problem the imaging literature raises, and the ultrasound guidance addresses electrode placement rather than coverage. The bimodality is an observation in one cohort and no mixture model is fitted. Whether the two groups differ in anything other than oxygenation is not established here.", "provenance": "Abstract read in full; the cohort size and stage, the hypoxia threshold used, both subgroup counts with their average and median values, the post-treatment value with its p value, and the three non-responding patients as reported", "quantitativeExtraction": "extracted" }, "L240": { "id": "L240", "year": 2024, "topic": "Consumption", "title": "Oxygen Enhancement Ratio-Weighted Dose Quantitatively Describes Acute Skin Toxicity Variations in Mice After Pencil Beam Scanning Proton FLASH Irradiation", "url": "https://doi.org/10.1016/j.ijrobp.2024.02.050", "studyType": "Five independent experiments irradiating the hind leg of 621 mice across 47 groups, mapping acute skin toxicity against dose, dose rate, repainting, and splitting of delivery into 1 to 6 fractions separated by 2 minutes, with a three-parameter oxygen kinetics model fitted to the data, International Journal of Radiation Oncology Biology Physics 120(1):276-286", "diseaseContext": "Healthy reference; normal tissue toxicity", "useInModel": "The closest thing to a calibrated model in this atlas, and it works by making oxygen the variable that everything else collapses onto. Five independent experiments varied dose, dose rate, repainting and the splitting of a treatment into one to six deliveries two minutes apart - exactly the kind of schedule variation the project has found elsewhere to be non-monotonic and unpredictable. A dose weighted by the oxygen enhancement ratio, computed from a simple oxygen kinetics model with three fitted parameters - an oxygen depletion rate, an oxygen recovery rate, and the oxygen level without irradiation - brought all five onto comparable response curves: the weighted dose giving 50 percent toxicity incidence agreed across experiments with standard deviations of 0.45 to 1.6 gray across five toxicity levels. Two uses. It is an existence proof that a schedule-dependent outcome can be predicted from a mechanistic variable with few parameters, which is what this project is trying to do and has not yet seen done. And it says the mechanistic variable here is oxygen depletion and recovery, so a model that carries oxygen as a static field cannot reproduce any of it.", "limit": "Mouse skin toxicity rather than tumour response, so this calibrates a normal-tissue endpoint and the atlas should not read it as efficacy. The three parameters are fitted to these data rather than measured independently, so the collapse demonstrates internal consistency across experiments rather than external validity - and no value for any of the three is extracted here. Proton pencil beam scanning at the entrance plateau, which is a specific delivery geometry. Acute toxicity scored visually at five levels.", "provenance": "Abstract read in full; the five experiments, mouse and group counts, the four delivery variables mapped, the three fitted parameters named, and the agreement of the 50 percent weighted dose with its standard deviation range as reported", "quantitativeExtraction": "extracted" }, "L241": { "id": "L241", "year": 2013, "topic": "Spatial gradient", "title": "Correlation between tumor oxygenation and 18F-fluoromisonidazole PET data simulated based on microvessel images", "url": "https://doi.org/10.3109/0284186x.2013.812796", "studyType": "Simulation of tissue oxygenation and tracer diffusion-retention dynamics on vessel maps derived from histology of head-and-neck squamous cell carcinoma xenografts, evaluating 300 distinct 2 by 2 millimetre vessel configurations against two PET parameters, Acta Oncologica 52(7):1308-1313", "diseaseContext": "Shared cancer; head and neck squamous cell carcinoma xenograft histology", "useInModel": "Tells the atlas how to read the one hypoxia measurement that covers a whole tumour, and the answer is that the obvious parameter is the wrong one. Oxygen probes sample tracks through a tumour and risk missing hypoxic regions; the tracer gives full coverage. Across 300 vessel configurations, the sub-regional signal four hours after injection correlated poorly with median oxygen tension in hypoxic sub-regions, at an R-squared of 0.37 - while the ratio of that signal to the time-averaged signal in the first 15 minutes correlated almost perfectly, at 0.99. The early signal reflects delivery and the late one retention, so dividing by the early phase removes the perfusion term and leaves the oxygen term. Two uses. Any tracer-based hypoxia value the atlas ingests must say whether it was normalised this way, because the un-normalised version is nearly uninformative where it matters most. And the finding generalises past this tracer: a retention measurement divided by its own delivery phase is a pattern the project should look for wherever it has an uptake proxy.", "limit": "A simulation study on vessel maps from xenograft histology, not a measurement in patients - so the R-squared values describe how two computed quantities relate under a model of diffusion and retention, not how a scanner relates to a probe. Two dimensional 2 by 2 millimetre configurations. One tracer and one tumour type's vascular geometry. The correlation of 0.99 is between simulated quantities and will be lower in any real measurement with noise and partial volume effects.", "provenance": "Abstract read in full; the stated sparse-sampling limitation of probes, the simulation design and 300 configurations, both PET parameters defined, and both R-squared values as reported", "quantitativeExtraction": "extracted" }, "L242": { "id": "L242", "year": 2017, "topic": "Hypoxia", "title": "Assessing Tumor Oxygenation for Predicting Outcome in Radiation Oncology: A Review of Studies Correlating Tumor Hypoxic Status and Outcome in the Preclinical and Clinical Settings", "url": "https://doi.org/10.3389/fonc.2017.00010", "studyType": "Review of non-invasive methods for assessing tumour oxygenation - nitroimidazole tracer positron emission tomography, magnetic resonance methods using endogenous contrast, and electron paramagnetic resonance oximetry - against outcome in preclinical and clinical settings, Frontiers in Oncology 7:10", "diseaseContext": "Shared cancer", "useInModel": "States the gap in the exact terms this project cares about. Hypoxia is recognised as limiting radiotherapy efficacy because it enhances radioresistance; assessing it is strongly suggested to help predict outcome; strategies exist to alleviate it and radiosensitise tumours; and oxygen mapping is described as critically needed for intensity modulated radiotherapy, where the most hypoxic regions require higher doses and the most oxygenated regions lower ones. And then: the assessment of tumour oxygenation is not yet part of day-to-day clinical practice, because there is no method for quantitative and non-invasive mapping of it. That is a parameter whose importance is established, whose spatial variation is the thing that would be acted on, and which cannot be measured routinely - a different situation from the atlas's other unmeasured parameters, several of which are computed routinely in the clinic and simply not ingested here. For this one the clinic has the same gap the project does.", "limit": "A review, so it carries no measurement and no effect size - it establishes the consensus and the gap rather than closing either. The claim that oxygenation predicts outcome is reported as strongly suggested rather than established, and the review's own purpose is to survey correlations rather than to pool them, so no combined estimate is available here. Written in 2017; whether any of the three method classes has since entered routine use is not addressed by this record.", "provenance": "Abstract read in full; the stated mechanism of radioresistance, the described need for oxygen mapping in dose-painted radiotherapy with its direction, and the explicit statement that assessment is not in routine practice for want of a quantitative non-invasive method as reported", "quantitativeExtraction": "extracted" }, "L243": { "id": "L243", "year": 2025, "topic": "Hypoxia", "title": "Impact of Oxygen on DNA Damage Distribution in 3D Genome and its Correlation to Oxygen Enhancement Ratio after High-LET Irradiation", "url": "https://doi.org/10.1667/rade-25-00093.1", "studyType": "Track-structure Monte Carlo simulation with oxygen represented as a probability of inducing DNA strand breaks, computing double-strand break distribution within three-dimensional genome organisation and the resulting oxygen enhancement ratio across linear energy transfer, Radiation Research 205(6):572-581", "diseaseContext": "Healthy reference; shared cancer as the application", "useInModel": "Connects this row to the nucleus row through a mechanism, which is the kind of cross-category coupling the atlas is short of. The oxygen enhancement ratio's variation with radiation quality has lacked a mechanistic account; this model represents oxygen's reaction as a probability of inducing strand breaks and then asks where the resulting double-strand breaks fall within the genome's three-dimensional organisation. The incidence of clustered breaks within a single topologically associating domain, and within frequently interacting domains, tracked the measured ratio across linear energy transfer - with high-energy-transfer radiation producing dense ionisation and an overabundance of lesions that readily form those clustered patterns, which have substantially higher probabilities of killing the cell than other damage patterns. So the path from a Chemistry variable to cell death runs through chromatin architecture, an Intracellular property the atlas holds in its own row. For a project organised by component that is a concrete instance of two rows needing to share a structure rather than a number.", "limit": "Entirely computational: a Monte Carlo simulation using parameters from the authors' earlier work, with agreement against published experimental ratios as its validation. No measurement of domain organisation under hypoxia, and no patient or tissue data. Oxygen enters as a probability of strand-break induction rather than as a tension, so the model does not connect to any oxygen value the atlas holds in millimetres of mercury. The domain architecture used is a generic genome organisation rather than one measured in any cell type the atlas carries.", "provenance": "Abstract read in full; the stated absence of a mechanistic account, the representation of oxygen as a strand-break probability, both clustered damage cases and their correspondence with the ratio across linear energy transfer, and the proposed mechanism for high-energy-transfer radiation as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I097", "name": "Glucose, amino acids and lipids", "category": "Chemistry", "whereToCheck": "Blood; interstitium; cells", "states": [ "Available", "transported", "depleted" ], "behaviors": [ "Uptake", "competition", "metabolic flux" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "nutrient-glucose-tif", "nutrient-glutamine-tif", "nutrient-arginine-tif", "nutrient-tryptophan-tif", "nutrient-alanine-tif", "nutrient-cystine-tif" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "nutrient-glucose-tif", "nutrient-glutamine-tif", "nutrient-arginine-tif", "nutrient-tryptophan-tif", "nutrient-alanine-tif", "nutrient-cystine-tif" ], "priorResearch": { "path": "simulation/data/profiles/glucose-amino-acids-and-lipids.json", "summary": "The nutrient row, and it corrects an assumption the project has been carrying about its own limits. The atlas has recorded that its metabolite hand-offs have no fluxes and that the interstitium cannot be sampled repeatedly; it had not noticed that those hand-offs have no concentrations either, and that the interstitium can be sampled once. Absolute concentrations exist for more than 118 metabolites in tumour interstitial fluid, differing from plasma and varying with tumour type, anatomical location and diet (L244). The row's other half is competition, and it is where the atlas's chemistry and immune categories stop being separable: tumour glucose consumption restricts T cell mTOR, glycolysis and interferon-gamma, and clinical checkpoint antibodies restore microenvironmental glucose (T21); tumour methionine uptake through SLC43A2 strips CD8 T cells of a specific histone mark and of STAT5, reversible by inhibiting the transporter or by feeding the nutrient, in patients (L246).", "stateAxes": [ { "axis": "Available, in the fluid that actually perfuses the tissue", "whatToMeasure": "Interstitial fluid rather than plasma, because they differ. Absolute concentrations of more than 118 metabolites were measured in both; the nutrients available to tumours differ from those in circulation; levels differed between autochthonous and transplant models of the same disease; and tumour type, anatomical location and animal diet each affected local availability.", "interpretationLimit": "Murine and terminal - interstitial fluid comes from excised tumours, so this is a destructive single-timepoint measurement giving concentrations and not rates. Two tumour types, and the demonstration that transplant and autochthonous models differ is itself a caution about transferring any of it to human disease, which is untested. Diet effects make the values conditional on husbandry. No individual metabolite concentration has been ingested into this atlas, so what it currently holds is the existence of the dataset and its three determinants.", "evidence": [ "L244" ] }, { "axis": "Competition, with checkpoint blockade as a metabolic intervention", "whatToMeasure": "The nutrient concentration in the shared fluid, and both consumers' capacity for it. Tumour glucose consumption restricted T cell mTOR activity, glycolytic capacity and interferon-gamma production; enhancing glycolysis in an antigenic regressor tumour was sufficient to override T cell protection; clinical antibodies against CTLA-4, PD-1 and PD-L1 restored glucose in the microenvironment and permitted T cell glycolysis and interferon-gamma; and blocking PD-L1 directly on tumour cells dampened their glycolysis by inhibiting mTOR and lowering glycolysis enzyme expression.", "interpretationLimit": "One mouse sarcoma model, with the checkpoint antibodies used there rather than in patients - so the metabolic contribution to clinical checkpoint blockade is an inference from a mouse system. Restored glucose carries no concentration, so the variable the whole argument turns on is unquantified. Sufficiency was shown in one engineered regressor tumour, and the cell-intrinsic PD-L1 effect is a second mechanism whose relative contribution is not separated from the immune one.", "evidence": [ "T21" ] }, { "axis": "Depleted, and what depletion does to a nucleus", "whatToMeasure": "The downstream mark rather than the nutrient, when the nutrient cannot be measured. Tumour cells outcompeted CD8 T cells for methionine by expressing high levels of SLC43A2; the T cells lost intracellular methionine and S-adenosylmethionine, then dimethylation at lysine 79 of histone H3, then STAT5 expression, then function. Inhibiting the tumour transporter restored the mark and boosted spontaneous and checkpoint-induced immunity, and methionine supplementation improved the mark and STAT5 in tumour-bearing mice and in colon cancer patients.", "interpretationLimit": "Mouse and co-culture for the mechanism, with human data entering as supplementation and as a correlation between tumour transporter expression and T cell signatures. No methionine concentration in any compartment, which is the quantity being competed for - so the atlas holds a complete causal chain whose driving variable is unmeasured. Magnitudes are not extracted, and whether supplementation also helps the tumour is not addressed.", "evidence": [ "L246" ] }, { "axis": "Transported, uptake rates, and lipids", "whatToMeasure": "Three things the inventory names that this row cannot serve. No uptake rate for any nutrient by any family in any environment; no transport capacity measurement despite transporters being the mechanism in both competition records; and for lipids the atlas holds an adipocyte source with no flux and a peroxidation product acting as a stress signal, with no concentration, no uptake and no oxidation rate.", "interpretationLimit": "The gap is specific rather than general. The atlas now has, or can have, interstitial concentrations for more than a hundred metabolites, and it has human orderings of which carbon sources are used in one environment. What stands between those and a flux is an uptake rate per cell type, which nothing here supplies - so the row brings the project materially closer to its exchange terms having numbers and does not close them.", "evidence": [ "L217", "L218" ] } ], "records": { "L217": { "id": "L217", "year": 2016, "topic": "Metabolic flux", "title": "Metabolic Heterogeneity in Human Lung Tumors", "url": "https://doi.org/10.1016/j.cell.2015.12.034", "studyType": "Intraoperative 13C-glucose infusions in nine patients with non-small cell lung cancer, with paired isotope analysis of tumour against benign lung and of multiple regions per tumour, Cell 164(4):681-694", "diseaseContext": "Lung (NSCLC)", "useInModel": "A metabolic flux measured in living human tumours, which the atlas had concluded one row earlier it could not have - and obtained by a method that conclusion did not consider. Nine patients were infused with 13C-glucose during surgery, letting tumour metabolism be compared with benign lung in the same person. Enhanced glycolysis and glucose oxidation were common, and every tumour showed evidence of oxidising multiple nutrients, lactate among them. Metabolically heterogeneous regions were found within single tumours as well as between tumours, and non-glucose nutrients appeared to contribute in the well-perfused areas - the opposite of what a perfusion-limited picture predicts. The authors' conclusion is that tumour metabolism in vivo is heterogeneous and strongly influenced by the microenvironment, which is this project's premise stated as a result. Three uses. The atlas gains a human in vivo flux. It gains a spatial scale for heterogeneity below the environment and below the family. And it gains a warning that perfusion does not determine which fuel is used, so a model coupling consumption to blood flow has the relationship backwards in the best-supplied regions.", "limit": "Nine patients, one tumour type, and a single intraoperative timepoint - so these are labelling patterns at one moment rather than rates per unit time, and no flux in units is extracted here. Infusion during surgery puts anaesthesia, fasting state and surgical manipulation inside the measurement. Evidence for oxidation of multiple nutrients and potential contributions are the authors' own hedges, and the individual nutrient contributions are not quantified in this extraction. Regional heterogeneity is established without a length scale. Benign lung is the comparator, not another organ.", "provenance": "Abstract read in full; the patient count and intraoperative design, the common findings, the evidence for multiple nutrients including lactate, the within- and between-tumour heterogeneity, the association with well-perfused areas, and the authors' conclusion as reported with their hedging preserved", "quantitativeExtraction": "extracted" }, "L218": { "id": "L218", "year": 2017, "topic": "Metabolic flux", "title": "Lactate Metabolism in Human Lung Tumors", "url": "https://doi.org/10.1016/j.cell.2017.09.019", "studyType": "13C-lactate infusions in patients with non-small cell lung cancer with isotope analysis of tricarboxylic acid cycle metabolites, direct in vivo comparison against glucose, and MCT1 deletion from tumour cells in mice, Cell 171(2):358-371.e9", "diseaseContext": "Lung (NSCLC)", "useInModel": "Overturns the picture this atlas would otherwise have inherited from culture, with human in vivo isotope labelling. Cancer cells consume glucose and secrete lactate in culture, and whether lactate contributes to energy metabolism in living tumours was unknown. Infusing patients with 13C-lactate produced extensive labelling of tricarboxylic acid cycle metabolites, and directly comparing lactate and glucose in vivo indicated that lactate's contribution to the cycle predominates. Evidence of lactate use was most apparent in tumours with high fluorodeoxyglucose uptake and aggressive behaviour - so the tumours that look most glycolytic on imaging are the ones most clearly burning lactate, close to the reverse of the usual inference from that scan. Deleting MCT1 from tumour cells in mice eliminated lactate-dependent labelling, establishing the uptake as tumour-cell-autonomous rather than a stromal artefact. Two consequences. The atlas's lactate exchange entries, carried as hand-offs without a flux, describe a major fuel with human in vivo evidence and a named transporter. And a model assigning glucose as the carbon source and lactate as waste is wrong about the dominant term in human lung tumours.", "limit": "One tumour type, and the patient numbers for the lactate infusions are not extracted here. Predominates is a comparison of labelling contributions rather than an absolute flux, so the atlas gains an ordering and not a rate. The MCT1 deletion is mouse, so cell-autonomy is established in a model rather than in patients. Most apparent in tumours with high fluorodeoxyglucose uptake and aggressive behaviour is an association without a coefficient here. Infusion in a clinical setting carries the same fasting and anaesthetic confounds as the companion study.", "provenance": "Abstract read in full; the stated prior uncertainty, the extensive labelling from 13C-lactate infusion in patients, the direct in vivo comparison concluding lactate predominates, the association with high FDG uptake and aggressive behaviour, and the MCT1 deletion result as reported", "quantitativeExtraction": "extracted" }, "L244": { "id": "L244", "year": 2019, "topic": "Available", "title": "Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability", "url": "https://doi.org/10.7554/eLife.44235", "studyType": "Quantitative metabolomics measuring absolute concentrations of more than 118 metabolites in plasma and in tumour interstitial fluid, compared between autochthonous and transplant models of murine pancreatic and lung adenocarcinoma and across diets, eLife 8:e44235", "diseaseContext": "Pancreatic (PDAC); Lung (NSCLC)", "useInModel": "The single largest ingestion opportunity the atlas has found, and it corrects an assumption the project has been carrying. Absolute concentrations were measured for more than 118 metabolites in tumour interstitial fluid - the extracellular fluid that perfuses tumours, and the compartment in which every metabolite hand-off this atlas records takes place. Three findings. The nutrients available to tumours differ from those present in circulation, so plasma is not a proxy for the interstitium and the atlas should not treat a serum value as a local one. Interstitial nutrient levels differed between autochthonous and transplant models of the same disease, which is a warning about every transplant-model number the atlas holds. And tumour type, anatomical location and animal diet each affected local availability - so a nutrient concentration is not a property of a disease but of a disease in a place under a feeding regimen. The atlas has repeatedly recorded that its metabolite exchange terms have no flux; what it had not noticed is that they have no concentration either, and this supplies concentrations for more than a hundred of them in two drawn environments.", "limit": "Murine, and terminal: interstitial fluid is obtained from excised tumours, so this is a destructive single-timepoint measurement and gives concentrations rather than rates - it does not supply the fluxes the atlas lacks, only the other half of what a flux calculation needs. Two tumour types. The comparison showing that transplant and autochthonous models differ is itself the reason to be careful transferring these values to human disease, which is untested here. Diet effects mean the numbers are conditional on husbandry. No individual metabolite concentration is extracted into this atlas by this record, so what is held is the existence, the method and the three determinants.", "provenance": "Abstract read in full; the count of more than 118 metabolites and both compartments measured, the difference between interstitial fluid and plasma, the autochthonous against transplant comparison, and all three stated determinants of local availability as reported", "quantitativeExtraction": "extracted" }, "L246": { "id": "L246", "year": 2020, "topic": "Competition", "title": "Cancer SLC43A2 alters T cell methionine metabolism and histone methylation", "url": "https://doi.org/10.1038/s41586-020-2682-1", "studyType": "Tumour and CD8 T cell co-culture and tumour-bearing mice with genetic and biochemical inhibition of the tumour methionine transporter, methionine supplementation in mice and in patients with colon cancer, and correlation of tumour transporter expression with T cell histone methylation and functional signatures, Nature 585(7824):277-282", "diseaseContext": "Colorectal; shared cancer", "useInModel": "A complete chain from a nutrient concentration to a histone mark to a transcription factor to immune failure, with a rescue in patients - and the most precise cross-category coupling in the atlas. Tumour cells consume methionine avidly and outcompete CD8 T cells for it by expressing high levels of the transporter SLC43A2. The T cells' intracellular methionine and S-adenosylmethionine fall, dimethylation at lysine 79 of histone H3 is lost, STAT5 expression drops and immunity is impaired. Inhibiting the tumour transporter genetically or biochemically restored the histone mark in T cells and boosted both spontaneous and checkpoint-induced tumour immunity; methionine supplementation improved the mark and STAT5 in T cells with increased immunity in tumour-bearing mice and in patients with colon cancer; and clinically, tumour transporter expression correlated negatively with T cell histone methylation and functional gene signatures. Two uses. The atlas now holds two mechanisms by which a Chemistry variable sets an Intracellular state in the nucleus row - oxygen through where clustered DNA breaks fall, and methionine through a specific histone mark - which makes that coupling a pattern rather than an instance. And the intervention points are unusually plentiful: the tumour's transporter, the nutrient itself, and the checkpoint axis, with the nutrient one already given to patients.", "limit": "Mouse models and co-culture for the mechanism, with human data entering as supplementation in colon cancer patients and as a correlation between tumour transporter expression and T cell signatures - so the chain is established in mice and corroborated rather than demonstrated in people. No methionine concentration is reported in any compartment, which is the quantity the competition is over, and the atlas therefore holds the mechanism without its driving variable. Improved and boosted carry no magnitudes here. Whether supplementation helps tumours as well as T cells is not addressed in this extraction.", "provenance": "Abstract read in full; the transporter-mediated competition, the fall in methionine and S-adenosylmethionine, the specific histone mark and the STAT5 consequence, both inhibition approaches with their immune outcomes, the supplementation results in mice and patients, and the clinical correlation as reported", "quantitativeExtraction": "extracted" }, "T21": { "id": "T21", "year": 2015, "topic": "Competition", "title": "Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression", "url": "https://doi.org/10.1016/j.cell.2015.08.016", "studyType": "Mouse sarcoma model with manipulation of tumour glycolysis in an antigenic regressor tumour, and treatment with clinical checkpoint blockade antibodies against CTLA-4, PD-1 and PD-L1, with T cell mTOR activity, glycolytic capacity and interferon-gamma production as readouts, Cell 162(6):1229-1241", "diseaseContext": "Shared cancer", "useInModel": "Reframes the atlas's most important drug class as partly a metabolic intervention. Glucose consumption by tumours metabolically restricted T cells, dampening their mTOR activity, glycolytic capacity and interferon-gamma production and permitting tumour progression - and enhancing glycolysis in an antigenic regressor tumour was sufficient to override the protective ability of T cells, which is a sufficiency test rather than a correlation. The part that matters most for this project: checkpoint blockade antibodies against CTLA-4, PD-1 and PD-L1, the ones used clinically, restored glucose in the tumour microenvironment and thereby permitted T cell glycolysis and interferon-gamma production. And blocking PD-L1 directly on tumour cells dampened their glycolysis by inhibiting mTOR and decreasing glycolysis enzyme expression, so the ligand has a cell-intrinsic metabolic role as well as an immune one. Two consequences. A nutrient concentration is a mediator of checkpoint blockade, which means the atlas's immune rows and its chemistry rows are not separable for these drugs. And an intervention aimed at a receptor changed a field quantity, which is a coupling direction the project had not recorded - every other case it holds runs from a field to a cell.", "limit": "One mouse sarcoma model for the mechanism, with the checkpoint antibodies used in that model rather than in patients - so the metabolic contribution to clinical checkpoint blockade is an inference from a mouse system. Restored glucose is reported without concentrations, so the atlas gains a direction and no value for the quantity the whole argument turns on. Sufficient to override is established for one engineered regressor tumour. The cell-intrinsic PD-L1 effect is a second mechanism in the same paper and its relative contribution is not separated from the immune one.", "provenance": "Abstract read in full, replacing a one-line screening note. abstract read in full; the restriction of T cell metabolism by tumour glucose consumption with all three readouts, the sufficiency result in the regressor tumour, the restoration of microenvironmental glucose by all three antibody classes, and the cell-intrinsic PD-L1 glycolytic effect as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I098", "name": "Lactate, protons and bicarbonate", "category": "Chemistry", "whereToCheck": "Extracellular and intracellular pools", "states": [ "Concentration and buffering" ], "behaviors": [ "Separate lactate level from pH and acidity" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "geometry-ph-control-intratumor", "geometry-ph-control-distant" ], "priorResearch": { "path": "simulation/data/profiles/lactate-protons-and-bicarbonate.json", "summary": "The row the inventory gave an instruction rather than a behaviour list: separate lactate level from pH and acidity. The instruction is right and the evidence makes it larger. Measured between adjacent vessels at 10 micrometre resolution, interstitial pH and oxygen profiles are locally discordant while their means correlate strongly - so averaging manufactures a coupling that does not hold where cells sit - and neither variable tracks nearest-vessel blood flow, with well-perfused vessels turning out hypoxic (L247). Lactic acid is not only an acid or a fuel but a signal, inducing vascular endothelial growth factor and M2-like macrophage polarisation through HIF1-alpha, and inducing the arginase 1 that depletes arginine (L248) - so lactate must be separated from oxygen sensing too, and two of the atlas's five exchange terms turn out to be one pathway. And pH is treatable: oral bicarbonate raised extracellular but not intracellular tumour pH and reduced metastasis, in some models (L249).", "stateAxes": [ { "axis": "Concentration and buffering, where the local and mean relationships differ", "whatToMeasure": "Both pH and oxygen, at the scale a cell experiences, because their relationship changes with scale. At 10 micrometre resolution between adjacent vessels the shapes of both profiles were heterogeneous, local pH profiles were discordant with the corresponding oxygen profiles, and yet the mean profiles correlated strongly. Neither perivascular pH nor oxygen correlated with nearest-vessel blood flow, and some well-perfused vessels were hypoxic with large hypoxic interstitial areas around them.", "interpretationLimit": "One human tumour xenograft in a window chamber, which is a surface preparation rather than an organ interior, and one tumour line. No absolute pH or oxygen values are extracted here, so what the atlas holds is a pattern of relationships; discordant and strong correlation are the authors' characterisations without coefficients. The flow measurement is of the nearest vessel only, so its lack of correlation does not exclude dependence on the wider network. Methods of 1997.", "evidence": [ "L247" ] }, { "axis": "Separate lactate from pH - and from oxygen", "whatToMeasure": "Which of the three the effect belongs to, which no record here fully resolves. Lactic acid produced as a by-product of aerobic or anaerobic glycolysis induces vascular endothelial growth factor and M2-like polarisation of tumour-associated macrophages through HIF1-alpha, and induces macrophage arginase 1 with a role in tumour growth.", "interpretationLimit": "The record studies lactic acid as a species and does not separate the anion from the proton - which is precisely the separation this row is instructed to make, so the atlas's best lactate signalling evidence does not itself comply with the instruction. No concentration, threshold or dose-response, so a signal with no level at which it acts. Mouse and in vitro, no human data. And because the mediator is the oxygen sensor, the instruction needs extending: a HIF readout cannot distinguish hypoxia from lactate, which makes the hypoxia marker panels in the neighbouring row ambiguous wherever lactate is present.", "evidence": [ "L248" ] }, { "axis": "Buffering as an intervention, with the step located", "whatToMeasure": "Extracellular pH specifically, and which step of the cascade responds. Oral sodium bicarbonate selectively raised extracellular but not intracellular tumour pH by 31-phosphorus spectroscopy and increased acid export from growing tumours; spontaneous metastases and lymph node involvement fell while circulating tumour cell levels did not change, and hepatic metastases after intrasplenic injection fell - so the effect is on extravasation and colonisation rather than intravasation. In tail-vein models it inhibited prostate cancer metastases and not melanoma.", "interpretationLimit": "Mouse models, no pH values and no doses extracted, so a direction without a magnitude for the variable being manipulated. The authors state the mechanism is not known with certainty. The melanoma negative is unexplained and makes the effect model-dependent, which is the kind of result the atlas should carry rather than average away.", "evidence": [ "L249" ] }, { "axis": "Lactate as substrate and as signal, in one environment", "whatToMeasure": "How the molecule divides between its two roles, which nothing measures. In human lung tumours labelled lactate infusion showed its contribution to the tricarboxylic acid cycle predominating over glucose, so lactate is a major fuel; in the same kind of environment lactic acid is a signal acting through HIF1-alpha on macrophages.", "interpretationLimit": "The two roles come from different studies in different species - human isotope infusion for the fuel role, mouse and in vitro for the signalling role - and nothing apportions the molecule between them or says whether they compete for it. No lactate concentration exists in this atlas for any environment, which means neither role has a level attached and the question of apportionment cannot even be posed quantitatively.", "evidence": [ "L218", "L248" ] } ], "records": { "L218": { "id": "L218", "year": 2017, "topic": "Metabolic flux", "title": "Lactate Metabolism in Human Lung Tumors", "url": "https://doi.org/10.1016/j.cell.2017.09.019", "studyType": "13C-lactate infusions in patients with non-small cell lung cancer with isotope analysis of tricarboxylic acid cycle metabolites, direct in vivo comparison against glucose, and MCT1 deletion from tumour cells in mice, Cell 171(2):358-371.e9", "diseaseContext": "Lung (NSCLC)", "useInModel": "Overturns the picture this atlas would otherwise have inherited from culture, with human in vivo isotope labelling. Cancer cells consume glucose and secrete lactate in culture, and whether lactate contributes to energy metabolism in living tumours was unknown. Infusing patients with 13C-lactate produced extensive labelling of tricarboxylic acid cycle metabolites, and directly comparing lactate and glucose in vivo indicated that lactate's contribution to the cycle predominates. Evidence of lactate use was most apparent in tumours with high fluorodeoxyglucose uptake and aggressive behaviour - so the tumours that look most glycolytic on imaging are the ones most clearly burning lactate, close to the reverse of the usual inference from that scan. Deleting MCT1 from tumour cells in mice eliminated lactate-dependent labelling, establishing the uptake as tumour-cell-autonomous rather than a stromal artefact. Two consequences. The atlas's lactate exchange entries, carried as hand-offs without a flux, describe a major fuel with human in vivo evidence and a named transporter. And a model assigning glucose as the carbon source and lactate as waste is wrong about the dominant term in human lung tumours.", "limit": "One tumour type, and the patient numbers for the lactate infusions are not extracted here. Predominates is a comparison of labelling contributions rather than an absolute flux, so the atlas gains an ordering and not a rate. The MCT1 deletion is mouse, so cell-autonomy is established in a model rather than in patients. Most apparent in tumours with high fluorodeoxyglucose uptake and aggressive behaviour is an association without a coefficient here. Infusion in a clinical setting carries the same fasting and anaesthetic confounds as the companion study.", "provenance": "Abstract read in full; the stated prior uncertainty, the extensive labelling from 13C-lactate infusion in patients, the direct in vivo comparison concluding lactate predominates, the association with high FDG uptake and aggressive behaviour, and the MCT1 deletion result as reported", "quantitativeExtraction": "extracted" }, "L247": { "id": "L247", "year": 1997, "topic": "Concentration and buffering", "title": "Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation", "url": "https://doi.org/10.1038/nm0297-177", "studyType": "Combined high-resolution measurement at 10 micrometres or better of interstitial pH and oxygen tension profiles between adjacent vessels in a human tumour xenograft, by fluorescence ratio imaging and phosphorescence quenching microscopy, with nearest-vessel blood flow measured alongside, Nature Medicine 3(2):177-182", "diseaseContext": "Shared cancer; human tumour xenograft", "useInModel": "Settles the instruction this row was given and does something rarer besides: it shows averaging creating a relationship that does not hold locally. Measuring both variables between adjacent vessels at 10 micrometre resolution, the authors found heterogeneity in the shapes of both profiles; a discordant relation between local pH profiles and the corresponding oxygen profiles, yet a strong correlation between the mean profiles; no correlation between perivascular pH or oxygen and the blood flow of the nearest vessel; and well-perfused tumour vessels that were nonetheless hypoxic, with large hypoxic areas in the interstitium around them. Three uses, and the first is the inverse of this atlas's usual complaint. The project's standing worry is that bulk measurements hide heterogeneity; here the bulk relationship between two variables is real while the point-by-point one is not, so a model calibrated on mean pH against mean oxygen would reproduce a coupling that does not exist at the scale cells experience. Second, perfusion does not determine either variable - which compounds the finding in the mitochondria row that perfusion does not determine which fuel is used, and goes further, since here it does not determine oxygen either. Third, it is measured at 10 micrometres, which is finer than the atlas's own breast model can resolve.", "limit": "One human tumour xenograft in a window-chamber preparation, which is a surface geometry rather than an organ interior, and a single tumour line - so the generalisation across tumour types is untested here. No absolute values for pH or oxygen tension are extracted into this atlas by this record; what is held is the pattern of relationships. Discordant and strong correlation are the authors' characterisations with no coefficients extracted. The blood flow measurement is of the nearest vessel, so a lack of correlation with it does not exclude dependence on the wider vascular network. Published in 1997 with methods of that period.", "provenance": "Abstract read in full; the resolution and both imaging methods, and all four numbered findings as the authors list them - profile heterogeneity, local discordance with mean correlation, absence of correlation with nearest-vessel flow, and hypoxic well-perfused vessels with surrounding hypoxic interstitium - as reported", "quantitativeExtraction": "extracted" }, "L248": { "id": "L248", "year": 2014, "topic": "Separate lactate level from pH and acidity", "title": "Functional polarization of tumour-associated macrophages by tumour-derived lactic acid", "url": "https://doi.org/10.1038/nature13490", "studyType": "Tumour and macrophage systems identifying lactic acid as the signal, with HIF1-alpha as the mediator and arginase 1 induction tested for its contribution to tumour growth, Nature 513(7519):559-563", "diseaseContext": "Shared cancer", "useInModel": "Makes the inventory's instruction larger than it looks and connects two of the atlas's flux-less exchange terms into one pathway. Lactic acid produced by tumour cells as a by-product of aerobic or anaerobic glycolysis has a signalling function: it induces vascular endothelial growth factor expression and M2-like polarisation of tumour-associated macrophages, and the effect is mediated by HIF1-alpha. The lactate-induced expression of arginase 1 by those macrophages then has an important role in tumour growth. Two structural consequences. The atlas already holds arginine consumption by arginase-expressing myeloid cells suppressing T cells as one of its five metabolite exchange terms, and lactate as another - this record puts them in series, lactate inducing the enzyme that depletes arginine, so at least two of those five terms are one pathway rather than independent entries. And the mediator is HIF1-alpha, the oxygen sensor: lactate acts through the machinery the atlas's oxygen row is about. So this row's instruction to separate lactate from pH understates the problem, because lactate must also be separated from oxygen - a high HIF1-alpha readout can mean hypoxia or it can mean lactate, and the marker panels in both rows cannot tell them apart.", "limit": "The by-product framing is important and underexploited here: the record does not separate the effect of the lactate anion from the effect of the accompanying proton, which is exactly the separation this row is asked to make - lactic acid is studied as a species. No lactate concentration, threshold or dose-response is extracted, so the atlas gains a signal with no level at which it acts. Mouse and in vitro systems throughout, with no human data. Important role in tumour growth is a direction without a magnitude. Whether the arginase induction is sufficient or merely contributory is not resolved in this extraction.", "provenance": "Abstract read in full; lactic acid named as the signalling by-product of both aerobic and anaerobic glycolysis, both induced phenotypes, HIF1-alpha as the mediator, and the role of lactate-induced arginase 1 in tumour growth as reported", "quantitativeExtraction": "extracted" }, "L249": { "id": "L249", "year": 2009, "topic": "Concentration and buffering", "title": "Bicarbonate increases tumor pH and inhibits spontaneous metastases", "url": "https://doi.org/10.1158/0008-5472.CAN-07-5575", "studyType": "Oral sodium bicarbonate in mouse models of metastatic breast cancer, with tumour pH by 31-phosphorus magnetic resonance spectroscopy, acid export by window-chamber fluorescence microscopy, and metastasis assessed after spontaneous, intrasplenic and tail-vein routes across three tumour models, Cancer Research 69(6):2260-2268", "diseaseContext": "Breast; prostate and melanoma as the alternative models", "useInModel": "A therapy that acts on a Chemistry variable, with the step it acts on localised by design and an honest negative attached. Oral sodium bicarbonate selectively raised tumour pH and reduced spontaneous metastases in mouse models of metastatic breast cancer. The selectivity is specific and measured: extracellular pH rose while intracellular pH did not, by 31-phosphorus magnetic resonance spectroscopy. The step was then located by changing the injection route - lymph node involvement fell while circulating tumour cell levels did not change, which argues against intravasation, and hepatic metastases after intrasplenic injection fell, which argues for inhibition of extravasation and colonisation. In tail-vein models the results were mixed, inhibiting prostate cancer metastases and not melanoma. Two uses. The atlas gains an intervention on a field quantity rather than on a cell, with a stated mechanism of action in the metastatic cascade and a model in which it failed. And the intracellular-versus-extracellular selectivity is exactly the distinction this row is instructed to make: the therapy changed one and not the other, and only the one it changed mattered for the outcome.", "limit": "Mouse models throughout, with oral bicarbonate at doses not extracted here, and no pH values given - so the atlas holds a direction of change and no magnitude for the variable being manipulated. The causal story offered for tumour acidity in the paper's own framing is increased glucose metabolism and poor perfusion, which the companion record in this row complicates by finding no correlation between perivascular pH and nearest-vessel blood flow. Mixed tail-vein results mean the effect is model-dependent and the melanoma negative is not explained. The mechanism is stated by the authors as not known with certainty.", "provenance": "Abstract read in full; the selective rise in extracellular but not intracellular pH with its measurement method, the reduction in spontaneous metastases and lymph node involvement, the unchanged circulating tumour cell levels, the intrasplenic result, and both tail-vein outcomes including the melanoma negative as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "geometry-ph-control-intratumor", "geometry-ph-control-distant" ] }, { "id": "I099", "name": "Sodium, potassium, calcium and chloride", "category": "Chemistry", "whereToCheck": "Compartment-specific ionic pools", "states": [ "Gradients", "free versus bound" ], "behaviors": [ "Transport", "osmolarity", "signaling", "excitability" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "afm-salt" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "afm-salt" ], "priorResearch": { "path": "simulation/data/profiles/sodium-potassium-calcium-and-chloride.json", "summary": "The ions, which the project would have treated as housekeeping, and the row that supplies the atlas's first absolute concentration of a named chemical species in living human tissue. In 28 glioma patients at 7 tesla, median total sodium rose from 37.84 millimolar in normal-appearing white matter through 54.69 in oedema and 61.72 in enhancing tumour to 81.88 in necrosis (L251) - a spatial profile, measured non-invasively, in a drawn environment. Potassium carries a mechanism to match: necrosis releases it into the fluid of mouse and human tumours, suppressing T cell effector function through impaired receptor-driven Akt and mTOR signalling in a PP2A-dependent way - explicitly independent of membrane potential, and requiring a rise in intracellular rather than extracellular potassium - with Kv1.3 overexpression reversing it and improving survival (L250). In breast cancer the same imaging falls in treatment responders, with a warning that protocol variation prevents pooling values (L252).", "stateAxes": [ { "axis": "Gradients, with absolute values and a spatial profile", "whatToMeasure": "Concentration by compartment rather than a tissue average. In 28 glioma patients at 7 tesla, median total sodium was 37.84 plus or minus 5.87 millimolar in normal-appearing white matter, 54.69 plus or minus 10.64 in non-enhancing T2 hyperintensity taken as oedema, 61.72 plus or minus 12.95 in contrast-enhancing tumour and 81.88 plus or minus 17.53 in necrosis, with the differences statistically significant.", "interpretationLimit": "One cohort of 28 at one centre and one field strength, and the companion review shows that protocol, phantom, field strength and contrast practice vary enough between studies to prevent pooling - so these values should not be combined with others. Compartments are segmented on conventional imaging and co-registered, so partial volume effects at boundaries are likely. Measured before chemoradiation only.", "evidence": [ "L251", "L252" ] }, { "axis": "Signaling, with the obvious mechanism excluded", "whatToMeasure": "Intracellular potassium, not the membrane potential and not the extracellular level alone. Necrosis-released extracellular potassium impairs receptor-driven Akt and mTOR phosphorylation and effector programmes in T cells; the suppression depends on PP2A activity; it is independent of changes in plasma membrane potential; and it requires an increase in intracellular potassium. Overexpressing Kv1.3 to augment efflux lowered intracellular potassium and improved effector function in vitro and in vivo with enhanced tumour clearance and survival.", "interpretationLimit": "Human tumours supply only the observation that potassium is elevated; every mechanistic step and the rescue are mouse or in vitro. No concentration is reported, so there is no threshold at which suppression begins and no way to ask whether the levels in any drawn environment reach it. The rescue is a genetic manipulation of transferred T cells rather than a drug. The necrotic source is identified and not quantified.", "evidence": [ "L250" ] }, { "axis": "Free versus bound, which the measurement cannot resolve", "whatToMeasure": "The inventory's own distinction, and the row's two halves sit on opposite sides of it without meeting. The potassium mechanism turns on the difference between compartments: the cause is extracellular and the operative variable is intracellular, and the effect is explicitly not mediated by the membrane potential that separates them. The sodium measurement is a total concentration and cannot distinguish the two at all.", "interpretationLimit": "So the atlas holds a mechanism that requires the distinction and a measurement that cannot make it. A rise in total sodium could be more sodium per cell, more extracellular volume, or both - and oedema having the second highest value in the glioma profile suggests volume contributes substantially, which would mean part of the gradient is a water signal rather than an ion one. Nothing in this atlas resolves intracellular from extracellular for any ion in any environment.", "evidence": [ "L250", "L251" ] }, { "axis": "Transport, osmolarity, excitability and calcium", "whatToMeasure": "Four things the inventory names, of which one is answered negatively and three are absent. Excitability is addressed and excluded: the potassium suppression is independent of membrane potential, so the behaviour the inventory names is not the route in the one mechanism the row holds. Transport appears only as the rescue - augmenting efflux through an overexpressed channel. Osmolarity is unmeasured despite a total sodium gradient that may be partly a volume effect. Calcium has no record anywhere in the atlas.", "interpretationLimit": "The excitability exclusion is specific to this mechanism and should not be read as a general finding - the atlas's own best channel results, held in the neuronal rows, are about excitability and matter there. Calcium's absence is the sharper gap: it is among the most routinely measured quantities in cell biology, the signalling row already recorded its absence, and two Chemistry rows have now passed without it.", "evidence": [ "L250" ] } ], "records": { "L250": { "id": "L250", "year": 2016, "topic": "Signaling", "title": "Ionic immune suppression within the tumour microenvironment limits T cell effector function", "url": "https://doi.org/10.1038/nature19364", "studyType": "Measurement of extracellular potassium in the fluid of mouse and human tumours with T cell receptor signalling and effector assays, dependence tested on PP2A, on membrane potential and on intracellular potassium, and Kv1.3 overexpression in tumour-specific T cells tested in vitro and in melanoma-bearing mice, Nature 537(7621):539-543", "diseaseContext": "Melanoma (cutaneous); shared cancer, with human tumour fluid measured", "useInModel": "An ionic mechanism with a human measurement, a named phosphatase, a genetic rescue that improved survival, and an explicit exclusion of the obvious route. Necrosis releases intracellular potassium into the extracellular fluid of mouse and human tumours, profoundly suppressing T cell effector function: elevated extracellular potassium impairs receptor-driven Akt and mTOR phosphorylation and the effector programmes downstream, and the suppression depends on the activity of the serine-threonine phosphatase PP2A. The exclusion is the part this row most needs. The effect is independent of changes in plasma membrane potential and instead requires an increase in intracellular potassium - so excitability, the behaviour the inventory names, is explicitly not the mechanism, and the operative compartment is inside the cell while the cause is outside it. Augmenting efflux by overexpressing the potassium channel Kv1.3 lowered intracellular potassium, improved effector function in vitro and in vivo, and enhanced tumour clearance and survival. The authors call it an ionic checkpoint, which is the right framing for this atlas: a suppressive mechanism with no ligand and no receptor, carried by an ion the project has been treating as housekeeping.", "limit": "Human tumours contribute the measurement that potassium is elevated; every mechanistic step and the rescue are mouse or in vitro. No potassium concentration is extracted into this atlas by this record - elevation and profound suppression are reported without values, so the atlas gains a mechanism and not a level, and therefore no threshold at which suppression begins. Kv1.3 overexpression is a genetic manipulation of transferred T cells rather than a drug. The necrotic source is identified without being quantified, and necrosis is a family this atlas has not yet written.", "provenance": "Abstract read in full; the necrotic release into mouse and human tumour fluid, the impairment of receptor-driven Akt-mTOR signalling, the PP2A dependence, the explicit independence from membrane potential with the requirement for raised intracellular potassium, and the Kv1.3 rescue with its survival benefit as reported", "quantitativeExtraction": "extracted" }, "L251": { "id": "L251", "year": 2020, "topic": "Gradients", "title": "Ultra-high-field sodium MRI as biomarker for tumor extent, grade and IDH mutation status in glioma patients", "url": "https://doi.org/10.1016/j.nicl.2020.102427", "studyType": "Prospective clinical trial of sodium-23 MRI at 7 tesla in 28 glioma patients before chemoradiation, co-registered with 3 tesla segmentation of contrast-enhancing tumour, non-enhancing T2 hyperintensity, necrosis and normal-appearing white matter, with comparison by IDH and MGMT status, NeuroImage: Clinical 28:102427", "diseaseContext": "Glioblastoma", "useInModel": "The atlas's first absolute ion concentration in living human tissue, spatially resolved by compartment, in a drawn environment - and it rises monotonically towards necrosis. Median total sodium concentrations across 28 patients were 37.84 plus or minus 5.87 millimolar in normal-appearing white matter, 54.69 plus or minus 10.64 in non-enhancing T2 hyperintensity taken as oedema, 61.72 plus or minus 12.95 in contrast-enhancing tumour and 81.88 plus or minus 17.53 in necrosis, differing statistically. Three uses. This is a concentration in millimolar, measured non-invasively and therefore repeatable in the same patient, which makes it a sixth kind of in vivo measurement for the atlas and the first that is a specific chemical species. It gives a spatial profile rather than a single tissue value, which is what the project's field models actually need and what its oxygen and pH evidence has not supplied. And the highest value is in necrosis, which converges with the potassium record's finding that necrosis releases intracellular ions - two completely different methods pointing at the same unwritten family as an ion source.", "limit": "Twenty-eight patients at a single 7 tesla centre, so the values belong to this cohort and this field strength. Total sodium concentration does not separate intracellular from extracellular sodium, which is the distinction the inventory asks this row to make - a rise could be more sodium per cell, more extracellular volume, or both, and oedema having the second highest value suggests volume contributes. Compartments are segmented on conventional imaging and co-registered, so partial volume effects at boundaries are likely. Before chemoradiation only, so no treatment response here. The genotype comparisons are secondary and not extracted.", "provenance": "Abstract read in full; the trial design, patient number and field strengths, all four compartment concentrations with their standard deviations as printed, the stated statistical difference, and the genotype comparisons as reported", "quantitativeExtraction": "extracted" }, "L252": { "id": "L252", "year": 2025, "topic": "Transport", "title": "23Na-MRI for Breast Cancer Diagnosis and Treatment Monitoring: A Scoping Review", "url": "https://doi.org/10.3390/bioengineering12020158", "studyType": "Scoping review of seven primary studies reporting quantitative sodium-23 MRI in breast cancer across multiple databases, Bioengineering 12(2):158", "diseaseContext": "Breast", "useInModel": "Extends the ion measurement to a second drawn environment and attaches a provenance caution of the kind the atlas collects. Across seven primary studies, sodium-23 MRI distinguished malignant from benign breast lesions on elevated total sodium concentration, and showed potential for early prediction of treatment response, with significant reductions in total sodium concentration in responders. Two uses. Treatment response appearing as a fall in an ion concentration makes this the second Chemistry variable in the breast environment shown to move under treatment, after tissue oxygen tension - and it moves early, which is what a response biomarker needs. The caution is the other half: the studies varied widely in protocol, use of phantoms, field strength and contrast agent application, which the review says limits inter-study comparability and calls for standardisation. So the atlas should not pool sodium values across sources, and should carry field strength and phantom calibration with any it ingests - which the glioma values in this row satisfy, being from one centre at one field strength.", "limit": "A scoping review of seven studies, so no pooled estimate, no effect size and no concentration is extracted here - what is held is the direction of the findings and the comparability problem. Differentiating malignant from benign is a diagnostic claim rather than a microenvironment measurement. Potential for early prediction is the review's own hedge. The variation it identifies means the seven studies' values cannot be combined, so the environment gains a direction without a number.", "provenance": "Abstract read in full; the number of included studies, the discrimination of malignant from benign lesions by elevated total sodium, the reduction in responders, and all four sources of protocol variation named with the stated limit on comparability as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I100", "name": "ATP, ADP and adenosine", "category": "Chemistry", "whereToCheck": "Intracellular versus extracellular", "states": [ "Release", "enzymatic conversion" ], "behaviors": [ "Energy and purinergic signaling", "CD39/CD73 where verified" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "atp-probe-threshold", "atp-apyrase-response" ], "priorResearch": { "path": "simulation/data/profiles/atp-adp-and-adenosine.json", "summary": "The row the inventory qualified with an instruction - CD39 and CD73 where verified - and the verification turns out to be the most complete and most discouraging in the atlas. Extracellular ATP in the tumour interstitium is in the hundreds of micromolar range while being basically undetectable in healthy tissue, imaged in vivo: a presence against an absence rather than a gradient, and the largest tumour-to-normal contrast the project holds (L253). From that substrate, CD39 and CD73 generate adenosine, which acts at A2A receptors to suppress immunity - and blocking CD73 in 192 patients produced sustained decreases in soluble and cell-surface CD73 with reduced enzymatic activity in tumour cells, alongside objective response rates of 0 percent in escalation and 2.4, 4.8 and 9.5 percent across three drawn environments (L254). Selecting patients whose tumours expressed the target did not rescue it: 27 percent disease control at 16 weeks and 2.7 months of progression-free survival (L255).", "stateAxes": [ { "axis": "Release, with a concentration and an absolute contrast", "whatToMeasure": "Extracellular ATP where it acts rather than in a collected supernatant. Imaged in vivo with a plasma-membrane-targeted luciferase, tumour interstitial ATP is in the hundreds of micromolar range while being basically undetectable in tumour-free tissue - and the authors note that the conventional approaches, chromatography or soluble luciferin-luciferase on supernatants, are laborious and inaccurate.", "interpretationLimit": "Experimentally induced mouse tumours with a transfected probe, so no human measurement and no drawn environment. Hundreds of micromolar is a range with no per-tumour values extracted. A membrane-targeted probe reports the surface of the cells expressing it, which is the right location and still a local view rather than a tissue average, and undetectable in healthy tissue is partly a statement about probe sensitivity. From 2008, with no human equivalent in the atlas.", "evidence": [ "L253" ] }, { "axis": "Enzymatic conversion, verified and non-translating", "whatToMeasure": "Enzyme activity and the product concentration together, because the trials measured the first and not the second. In 192 patients, anti-CD73 produced sustained decreases in free soluble CD73 and in CD73 on peripheral T cells and tumour cells, with reduced CD73 enzymatic activity in tumour cells; objective response was zero percent in escalation and 2.4, 4.8 and 9.5 percent in colorectal, pancreatic and EGFR-mutant lung cohorts of 42 each. In 25 patients selected for CD73-positive relapsed ovarian cancer, disease control at 16 weeks was 27 percent with 2.7 months median progression-free survival.", "interpretationLimit": "Phase I response rates from single-arm cohorts, where low response is normal and does not condemn a target; the phase II is 25 patients, single-arm, and uninterpretable without a comparator. The combination arms confound attribution between two antibodies. Most importantly, neither trial reports an adenosine concentration - so the atlas holds enzyme engagement without the concentration change it was meant to cause, and cannot tell a non-load-bearing axis from a redundant pathway.", "evidence": [ "L254", "L255" ] }, { "axis": "Energy and purinergic signalling", "whatToMeasure": "The receptors through which both ends of this chain act, which nothing in the atlas measures. The suppressive arm runs through A2A receptors on immune cells and the stimulatory arm through purinergic receptors responding to high extracellular ATP - and the atlas holds a concentration for ATP, activity for the converting enzyme, and nothing for any receptor in either direction. For the energy side, the mitochondria row recorded that no ATP concentration, supply rate or demand estimate exists for any family; this row supplies an extracellular concentration, which is a different quantity entirely.", "interpretationLimit": "The distinction between intracellular ATP as energy currency and extracellular ATP as a signal is the one this row must keep, and only the second is served. A hundreds-of-micromolar extracellular concentration says nothing about the intracellular supply the mitochondria row wanted, and the atlas should not let one stand in for the other.", "evidence": [ "L253" ] } ], "records": { "L253": { "id": "L253", "year": 2008, "topic": "Release", "title": "Increased level of extracellular ATP at tumor sites: in vivo imaging with plasma membrane luciferase", "url": "https://doi.org/10.1371/journal.pone.0002599", "studyType": "Chimeric plasma-membrane-targeted luciferase probe allowing in vivo real-time imaging of extracellular ATP, applied to several experimentally induced tumours and to tumour-free tissues, PLoS ONE 3(7):e2599", "diseaseContext": "Shared cancer", "useInModel": "An absolute concentration with the largest tumour-to-normal contrast the atlas holds. Extracellular ATP in the tumour interstitium is in the hundreds of micromolar range while being basically undetectable in healthy tissues - so this is not a gradient but a presence against an absence, which is a stronger starting point for a field variable than anything else in the Chemistry category. The method matters too: the authors state that measuring extracellular ATP is generally done on cell supernatants by chromatography or soluble luciferin-luciferase and is laborious and inaccurate, and their membrane-targeted probe measures it where it acts rather than in a collected fluid. Two further uses. The paper's framing supplies the chain this row is about: most extracellularly generated adenosine comes from the catabolism of extracellular ATP, and cancerous tissue contains elevated adenosine and its breakdown products - so the atlas now has a concentration for the substrate of that chain and none for its product. And a presence against an absence in healthy tissue is consistent with release from dying cells, which makes this a third record pointing at the atlas's unwritten necrotic row.", "limit": "Experimentally induced mouse tumours with a transfected probe, so no human measurement and no drawn environment specifically - and hundreds of micromolar is a range rather than a value, with no per-tumour figures extracted here. A plasma-membrane-targeted luciferase reports ATP at the surface of the cells expressing it, which is the right place and is still a probe-bearing population's local view rather than a tissue average. Undetectable in healthy tissue is a statement about the probe's sensitivity as much as about the concentration. Published in 2008, and the atlas holds no subsequent human equivalent.", "provenance": "Abstract read in full; the probe's design and purpose, the stated inadequacy of the conventional assays, the hundreds of micromolar range in tumour interstitium against undetectable in tumour-free tissue, and the authors' framing of adenosine's origin in extracellular ATP catabolism as reported", "quantitativeExtraction": "extracted" }, "L254": { "id": "L254", "year": 2023, "topic": "CD39/CD73 where verified", "title": "First-in-human study of oleclumab, a potent, selective anti-CD73 monoclonal antibody, alone or in combination with durvalumab in patients with advanced solid tumours", "url": "https://doi.org/10.1007/s00262-023-03430-6", "studyType": "Phase I dose-escalation and expansion in 192 patients - 66 in escalation, and 126 in expansion comprising 42 each with colorectal cancer, pancreatic ductal adenocarcinoma and EGFR-mutant non-small-cell lung cancer - receiving anti-CD73 antibody alone or with anti-PD-L1, with soluble and cell-surface CD73 and tumour CD73 enzymatic activity as pharmacodynamic endpoints, Cancer Immunology, Immunotherapy 72(8):2443-2458", "diseaseContext": "Colorectal; Pancreatic (PDAC); Lung (NSCLC)", "useInModel": "The inventory asked this row for CD39 and CD73 where verified. The verification is as complete as this atlas ever gets, and the benefit did not follow - which makes this one of the most informative negatives in the project. Across 192 patients, free soluble CD73 and CD73 expression on peripheral T cells and on tumour cells all showed sustained decreases, accompanied by reduced CD73 enzymatic activity in tumour cells. So the target was hit, on the tumour, and its catalytic function was measurably suppressed. Objective response during dose escalation was zero percent. In the expansion cohorts response rates were 2.4 percent in colorectal cancer with one complete response, 4.8 percent in pancreatic cancer with one complete and one partial response, and 9.5 percent in EGFR-mutant lung cancer with four partial responses. No dose-limiting toxicities occurred and the common treatment-related events were fatigue, diarrhoea and rash. For this project the lesson is structural rather than pharmacological: an axis can be real, its enzyme can be druggable, engagement can be demonstrated biochemically in the tumour, and the clinical effect can still be near zero. That is the same shape as the atlas's antisense trial, where two biomarkers moved and the functional endpoint did not - and it is a direct warning to a project whose output is intended to predict interventions from mechanisms.", "limit": "A phase I study, so response rate is not its endpoint and these numbers come from single-arm cohorts of 42 without a comparator - low response in phase I is normal and does not by itself condemn a target. The combination arm confounds attribution between the two antibodies. CD73 enzymatic activity is reduced without a stated magnitude or a resulting adenosine measurement, so the atlas holds engagement of the enzyme and not the concentration change it was meant to produce - which is the quantity that would say whether the axis was actually suppressed. Three tumour types, all heavily pretreated. No patient selection by CD73 status in this trial.", "provenance": "Abstract read in full; patient numbers in escalation and expansion with the three tumour types, the absence of dose-limiting toxicities, the common adverse events, the sustained decreases in soluble and cell-surface CD73 with reduced tumour enzymatic activity, and all four response figures including the zero percent in escalation as reported", "quantitativeExtraction": "extracted" }, "L255": { "id": "L255", "year": 2024, "topic": "CD39/CD73 where verified", "title": "NSGO-OV-UMB1/ENGOT-OV30: A phase II study of durvalumab in combination with the anti-CD73 monoclonal antibody oleclumab in patients with relapsed ovarian cancer", "url": "https://doi.org/10.1016/j.ygyno.2024.06.017", "studyType": "Phase II open-label non-randomised study in 25 patients with CD73-positive relapsed epithelial ovarian cancer receiving anti-CD73 antibody with anti-PD-L1, with disease control rate at 16 weeks as the primary endpoint and archival PD-L1 and CD8 immunohistochemistry, Gynecologic Oncology 188:103-110", "diseaseContext": "Ovarian (HGSC)", "useInModel": "Tests the obvious rescue for the preceding record's negative - select patients whose tumours express the target - and the result stays modest. Twenty-five patients with CD73-positive relapsed disease received the combination, 22 were evaluable, and the disease control rate at 16 weeks was 27 percent with median progression-free survival of 2.7 months and median overall survival of 8.4 months. CD8 infiltration and tumour PD-L1 expression were present in partially overlapping sets covering 74 percent of samples. Two uses for this atlas. Biomarker selection on the target did not convert the axis into a benefit, which closes off the first explanation anyone would reach for - and it matters because this project will be tempted to propose exactly that kind of selection from a mechanism. And the partially overlapping distribution of two immune markers in three quarters of samples is a reminder that patients selected on one marker are heterogeneous on others, so a single-marker selection is not a homogeneous population.", "limit": "Twenty-five patients, single-arm and non-randomised, so there is no control for what the combination's components contribute or for what this population would do untreated - a 27 percent disease control rate at 16 weeks in relapsed ovarian cancer is not interpretable without a comparator. Progression-free survival of 2.7 months is short enough to be consistent with no effect. CD73 positivity is defined by the trial's own assay and threshold, which are not extracted here. Archival rather than contemporaneous tissue for the immune markers.", "provenance": "Abstract read in full; the design and selection criterion, both patient counts, the dosing, the disease control rate with both survival medians and their confidence intervals, and the partially overlapping marker distribution with its percentage as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "atp-probe-threshold", "atp-apyrase-response" ] }, { "id": "I101", "name": "Reactive oxygen/nitrogen species", "category": "Chemistry", "whereToCheck": "Local short-range production sites", "states": [ "Species", "production", "scavenging" ], "behaviors": [ "Oxidative damage and signaling", "nitric oxide context" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "functional-no-consumption" ], "priorResearch": { "path": "simulation/data/profiles/reactive-oxygen-nitrogen-species.json", "summary": "The row whose inventory entry gives a location rather than a tissue - local short-range production sites - and the records justify it while supplying the atlas's first usable rate constant. Nitric oxide is consumed in tissue first order in itself and first order in oxygen, with a rate constant of 4.0 plus or minus 0.3 times ten to the third per molar per second, so its flux across a vessel wall is around fivefold greater at zero oxygen than at 150 micromolar and its effective diffusion distance lengthens significantly below 25 micromolar (L257). That makes one of the atlas's fields set the geometry of another. At the other extreme of range, peroxynitrite and reactive oxygen species from myeloid-derived suppressor cells nitrate tyrosines in the T cell receptor and CD8 complex during direct cell-cell contact, blinding those T cells to their specific antigen while leaving non-specific responsiveness intact (L256). And hydrogen peroxide crosses membranes by simple lipid diffusion rather than through any transporter (L258).", "stateAxes": [ { "axis": "Nitric oxide context, with a rate constant and a coupled range", "whatToMeasure": "Oxygen alongside nitric oxide, because oxygen sets the range. For a constant endothelial surface concentration, flux out of the adventitial surface at zero oxygen was around fivefold that at 150 micromolar; consumption is first order in nitric oxide and first order in oxygen with a rate constant of 4.0 plus or minus 0.3 times ten to the third per molar per second; and simulation on those kinetics gives a significantly longer effective diffusion distance at or below 25 micromolar oxygen than at 200.", "interpretationLimit": "Aortic wall in a purpose-built setup, not a drawn environment, so transferring the constant is a labelled transfer - with the mitigation the atlas has used before, that a reaction rate constant travels between tissues better than an architecture does. The diffusion distances are simulated from the measured kinetics rather than measured, and no distance in micrometres is extracted. Healthy tissue.", "evidence": [ "L257" ] }, { "axis": "Oxidative damage, at contact range, breaking recognition", "whatToMeasure": "Whether the receptor has been chemically modified, which no abundance reports. Myeloid-derived suppressor cells nitrate tyrosines in a T cell receptor and CD8 complex through hyperproduction of reactive oxygen species and peroxynitrite during direct cell-cell contact; the T cells then cannot bind peptide-MHC dimers or respond to their specific peptide while retaining responsiveness to non-specific stimulation.", "interpretationLimit": "Mouse models with dimer binding as the readout and no human tissue. No peroxynitrite concentration, no nitration stoichiometry and no measured distance - contact dependence gives a range of roughly one cell diameter by inference. The nitration sites are modelled rather than identified. Reversibility and timescale are not addressed, which matters because a permanent modification and a transient one call for different interventions.", "evidence": [ "L256" ] }, { "axis": "Species, and whether membranes contain them", "whatToMeasure": "Which species is being discussed, since they differ in whether a membrane stops them. Hydrogen peroxide crosses the human red blood cell membrane mainly by simple diffusion through the lipid fraction: unchanged in cells lacking urea transporter B or the Rh ammonia transporters, lower in Gaucher disease cells accumulating membrane sphingolipids, and raised by hexanol fluidisation, with aquaporin water efflux unaffected as a control.", "interpretationLimit": "Red blood cells, which have an unusual membrane and a strong antioxidant defence, so the conclusion needs checking before transfer to nucleated cells. No permeability coefficient is extracted - the results are comparisons between conditions. Gaucher cells differ in morphology and deformability as well as lipid content, and hexanol is blunt. What the atlas gains is a mechanism: this species needs no transporter, and its permeability depends on lipid composition, which no marker panel predicts.", "evidence": [ "L258" ] }, { "axis": "Production and scavenging", "whatToMeasure": "Two of the three states the inventory names, and neither is served. No production rate for any species by any family in any environment, and no scavenging capacity, redox ratio, glutathione or NADH measurement anywhere - which the mitochondria row already recorded while noting that this row was unwritten and would pair with it.", "interpretationLimit": "The absence is structural rather than incidental. These species are consumed as fast as they are made, so a concentration without a production and a scavenging term is close to meaningless - and the one quantitative result the row holds is a consumption constant rather than a production rate. The pairing the mitochondria row anticipated therefore does not happen: that row has no redox measurement and this one has no production rate, so the two gaps meet without closing.", "evidence": [] } ], "records": { "L256": { "id": "L256", "year": 2007, "topic": "Oxidative damage and signaling", "title": "Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer", "url": "https://doi.org/10.1038/nm1609", "studyType": "In vivo models of myeloid-derived suppressor cell-induced tolerance with peptide-MHC dimer binding assays, tyrosine nitration of the T cell receptor and CD8 complex, contact dependence testing, and molecular modelling of nitration sites, Nature Medicine 13(7):828-835", "diseaseContext": "Shared cancer", "useInModel": "A way for a target to be present and unreachable, with no abundance changing anywhere - and a demonstration that this row's species act at contact range. Myeloid-derived suppressor cells disrupt the binding of specific peptide-MHC dimers to CD8-expressing T cells by nitrating tyrosines in a T cell receptor and CD8 complex. The consequence is precise: those T cells cannot bind peptide-MHC or respond to their specific peptide, while retaining the ability to respond to non-specific stimulation. So the cell is not suppressed, it is blinded to its antigen. The nitration is induced through hyperproduction of reactive oxygen species and peroxynitrite during direct cell-cell contact, which is the inventory's local short-range production site demonstrated rather than assumed. Two uses. The atlas's address class rests on antigen density and on specificity, and this is a mechanism by which the antigen is present, the receptor is present, and recognition fails for chemical reasons that no marker panel would detect - a failure of a kind the project has not recorded. And it is an interaction whose range is a cell diameter, which means it cannot be represented as a field at all.", "limit": "In vivo mouse models with peptide-MHC dimer binding as the readout, so this is a mechanism in a model system and no human tissue appears. No peroxynitrite concentration, no nitration stoichiometry and no distance over which it operates are given - contact dependence is established qualitatively, so the atlas gains a range of about one cell diameter by inference rather than a measured length. The specific nitration sites are suggested by molecular modelling rather than identified experimentally. Whether the modification is reversible, and on what timescale, is not addressed - which matters, because a permanent change and a transient one imply different interventions.", "provenance": "Abstract read in full; the disruption of peptide-MHC dimer binding through tyrosine nitration of the receptor-CD8 complex, the retention of responsiveness to non-specific stimulation, the requirement for direct cell-cell contact with reactive oxygen species and peroxynitrite hyperproduction, and the modelling of nitration sites as reported", "quantitativeExtraction": "extracted" }, "L257": { "id": "L257", "year": 2010, "topic": "Nitric oxide context", "title": "Oxygen regulates the effective diffusion distance of nitric oxide in the aortic wall", "url": "https://doi.org/10.1016/j.freeradbiomed.2009.11.024", "studyType": "Direct measurement of nitric oxide diffusion flux across the aortic wall at a range of oxygen concentrations, with reaction order and rate constant determination and computer simulation of the resulting concentration distributions, Free Radical Biology and Medicine 48(4):554-559", "diseaseContext": "Healthy reference; vascular wall", "useInModel": "The atlas's first bimolecular rate constant, and a statement that one of its fields sets the geometry of another. For a constant nitric oxide concentration at the endothelial surface, the flux out of the adventitial surface at zero oxygen was around fivefold greater than at 150 micromolar oxygen - so nitric oxide is consumed in the wall in an oxygen-dependent way. The kinetics are given explicitly: consumption is first order in nitric oxide and first order in oxygen, with a rate constant of 4.0 plus or minus 0.3 times ten to the third per molar per second. Simulation then shows the consequence - the concentration distribution changes substantially with oxygen, and the effective diffusion distance at low oxygen, at or below 25 micromolar, is significantly longer than at 200 micromolar. Three uses. This is a parameter the project can carry as written, with units and an uncertainty, which almost nothing else in the atlas is. It makes two of the atlas's Chemistry rows coupled in a specific way: the range over which one species signals is set by the concentration of another, so the fields cannot be computed independently and then added. And it supplies a mechanism for a physiological effect - dilating vessels during hypoxia by extending nitric oxide's reach - which is a coupling with a direction and a sign.", "limit": "Aortic wall rather than any drawn environment, in a purpose-built experimental setup, so the rate constant is a property of this tissue preparation and its transfer to tumour or brain tissue is untested - the atlas has warned elsewhere against exactly that kind of transfer, with the qualification that a reaction rate constant travels better than an architecture does. The effective diffusion distances are from computer simulation on the measured kinetics rather than measured directly, and no distance in micrometres is extracted here. Healthy tissue, and oxygen concentrations spanning a range chosen for the experiment.", "provenance": "Abstract read in full; the approximately fivefold flux difference between zero and 150 micromolar oxygen, both reaction orders, the rate constant with its stated uncertainty, and the simulated lengthening of effective diffusion distance at or below 25 micromolar against 200 micromolar as reported", "quantitativeExtraction": "extracted" }, "L258": { "id": "L258", "year": 2025, "topic": "Species", "title": "Hydrogen peroxide diffusion across the red blood cell membrane occurs mainly by simple diffusion through the lipid fraction", "url": "https://doi.org/10.1016/j.freeradbiomed.2024.11.031", "studyType": "Permeability measurement in human red blood cells lacking urea transporter B or Rh ammonia transporters, in cells from patients with Gaucher disease accumulating membrane sphingolipids, and in normal cells treated with hexanol to fluidise the lipid fraction, with aquaporin-mediated water efflux as a control, Free Radical Biology and Medicine 226:389-396", "diseaseContext": "Healthy reference; Gaucher disease as a membrane-composition comparison", "useInModel": "Settles whether this row's most diffusible species respects compartment boundaries, and the answer is that it largely does not. Hydrogen peroxide crosses the human red blood cell membrane mainly by simple diffusion through the lipid fraction: permeability was unchanged in cells lacking urea transporter B or the Rh ammonia transporters, was lower in cells from patients with Gaucher disease whose membranes accumulate sphingolipids, and rose when normal cells were treated with hexanol to fluidise the lipid - while hexanol had no effect on aquaporin-mediated water efflux, which is the control that makes the lipid interpretation specific. Two uses. A simulation can treat hydrogen peroxide as crossing membranes without a transporter, which distinguishes it sharply from every other species in this category and from the nutrients and ions in the neighbouring rows, all of which need one. And the permeability depends on membrane lipid composition rather than on protein expression, so it is a parameter no marker panel in this atlas could predict - and one that differs between cell types for reasons the atlas does not record anywhere.", "limit": "Red blood cells throughout, which have an unusual membrane and an unusually strong antioxidant defence, so the permeability conclusion should not be transferred to nucleated cells without checking. No permeability coefficient is extracted into this atlas by this record - the results are comparisons between conditions, so what is held is the mechanism and not a number. Gaucher disease cells differ in morphology and deformability as well as lipid content, and hexanol is a blunt intervention. The earlier finding that this permeability is independent of aquaporins 1 and 3 is cited by the authors from their own prior work rather than repeated here.", "provenance": "Abstract read in full; the null results for both transporter-deficient cell types, the lower permeability in Gaucher disease cells with the stated sphingolipid accumulation, the increase on hexanol treatment, and the aquaporin water-efflux control as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "functional-no-consumption" ] }, { "id": "I102", "name": "Hormones and neurotransmitters", "category": "Chemistry", "whereToCheck": "Systemic inputs and local innervation", "states": [ "Receptor status", "pulsatility" ], "behaviors": [ "Androgen/estrogen", "catecholamines", "glutamate", "context" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "variation-leptin" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "variation-leptin" ], "priorResearch": { "path": "simulation/data/profiles/hormones-and-neurotransmitters.json", "summary": "The last Chemistry row, and the one that supplies the mechanism behind a finding the project has been accumulating without explaining. The inventory names pulsatility as a state, and for this category it is not a refinement but the physiology: the same ligand at the same concentration, delivered continuously or in hourly pulses for the same 12 hours, suppressed one gonadotropin transcript to 48 percent of control or stimulated it more than fourfold depending only on the schedule - while a second transcript rose equally either way and a third ignored both (L259). An entire drug class exists because continuous agonist exposure inverts a pulsatile signal. The clinical question then got tested twice at scale in the same disease, and the answer depends on the disease state: intermittent androgen deprivation was non-inferior with six quality-of-life benefits in non-metastatic recurrence (L260) and statistically inconclusive with the point estimate favouring continuous therapy in metastatic disease (L261).", "stateAxes": [ { "axis": "Pulsatility, which is the signal rather than a detail of it", "whatToMeasure": "The delivery pattern, separately from the concentration, because they are independent variables. At one concentration over one duration, continuous input produced a brief episode of secretion then a return to unstimulated levels while pulses were each responded to; alpha subunit messenger RNA rose 1.6-fold continuous against 1.7-fold pulsatile, FSH beta was suppressed to 48 percent continuous and stimulated over fourfold by pulses, and LH beta responded to neither. Episodic input is stated to be necessary for maintaining secretion.", "interpretationLimit": "Dispersed rat pituitary in perifusion - an isolated endocrine tissue rather than a microenvironment, carried for the principle. One concentration, one pulse interval of an hour and one 12-hour window, all chosen, so the row supplies no frequency dependence and no interval at which the inversion sets in. Messenger RNA rather than protein or function, and from 1990, with no modern equivalent in the atlas that varies the interval systematically.", "evidence": [ "L259" ] }, { "axis": "Receptor status, and the schedule question answered by disease state", "whatToMeasure": "The disease state as well as the schedule, since it decides the answer. In non-metastatic disease with rising PSA after radiotherapy, 1,386 patients gave median survival 8.8 years intermittent against 9.1 continuous with 268 against 256 deaths, no adverse event difference and potential benefits across six quality-of-life domains. In newly diagnosed metastatic hormone-sensitive disease, 1,535 analysed patients gave 5.1 against 5.8 years, hazard ratio 1.10 with a 90 percent interval of 0.99 to 1.23 against a boundary of 1.20, which the authors call statistically inconclusive.", "interpretationLimit": "One is a non-inferiority result, so it establishes the absence of a demonstrated deficit rather than a benefit, with the point estimate still favouring continuous therapy. The other is explicitly inconclusive, its interval admitting both no difference and a deficit past the boundary - the atlas should not report it as either a win or a loss. The metastatic trial analysed half of those enrolled, since randomisation required a PSA response, so its population is hormone-responsive by selection. Off-periods in both were PSA-adaptive rather than fixed, so the interval is not a parameter either trial tested.", "evidence": [ "L260", "L261" ] }, { "axis": "An off-period is not an off-state", "whatToMeasure": "Whether the withdrawn variable actually returns. On the intermittent arm, full testosterone recovery occurred in 35 percent of patients and recovery to the trial-entry threshold in 79 percent - so for roughly two thirds the hormone never fully came back, across 8-month cycles.", "interpretationLimit": "Measured in one trial in one axis, where the suppressing agent has a long pharmacological tail and the patients are older men after radiotherapy - so incomplete recovery has causes specific to this setting and should not be assumed general. But it is the only place in the atlas where the question was asked at all, and every schedule argument the project holds assumes the answer is yes.", "evidence": [ "L260" ] }, { "axis": "Catecholamines, glutamate and context", "whatToMeasure": "Three of the four behaviours the inventory names, of which one is served at second hand and two not at all. Glutamate appears only as clearance capacity: the astroglial transporter GLT-1 falls 71 percent in ALS motor cortex and spinal cord while the other astroglial transporter is unchanged. Catecholamines have no record. Context - the inventory's own term for whether a systemic input is locally modified - has none either.", "interpretationLimit": "A transporter loss is not a concentration, and the atlas has no glutamate level in any compartment in any environment, so the one neurotransmitter it touches is represented by its removal machinery. For catecholamines the absence is notable given that adrenergic signalling in cancer is an active field. And no record anywhere establishes whether a systemic hormone concentration differs from the local one in any drawn environment, which is what the inventory means by context and what the nutrient row showed matters for metabolites.", "evidence": [ "L194" ] } ], "records": { "L194": { "id": "L194", "year": 1995, "topic": "Glutamate uptake", "title": "Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis", "url": "https://doi.org/10.1002/ana.410380114", "studyType": "Immunoblot and immunocytochemistry for three glutamate transporter subtypes with subtype-specific C-terminal antipeptide antibodies, across brain regions of ALS patients and age- and postmortem-delay-matched controls, Annals of Neurology 38(1):73-84", "diseaseContext": "ALS", "useInModel": "The atlas's first glutamate uptake measurement, and it is selective in a way that matters more than its size. GLT-1, the astroglial transporter, was decreased 71 percent in ALS motor cortex and also in spinal cord, with a dramatic 90 percent loss in roughly a quarter of motor cortex specimens. The other astroglial transporter, GLAST, showed no appreciable change. The neuronal transporter EAAC1 fell only 20 percent, which the authors attribute to loss of cortical motor neurons rather than to transporter downregulation. And glial fibrillary acidic protein, the marker used to identify and to call astrocytes reactive, was not changed. So this is not astrocyte loss and not generalised astrocyte failure: one transporter of two in the same cell collapses while the cell's identity marker holds steady. Three consequences for a simulation. Glutamate clearance is a parameter this family can now be given a number for in one environment. The loss is subtype-resolved, so a single uptake term is wrong. And a panel reading GFAP would register nothing at all while the function it is meant to report had fallen by three quarters.", "limit": "Post-mortem immunoreactive protein, so this is transporter abundance and not transport rate - no uptake velocity, Km or Vmax is measured, and the atlas therefore has a percentage rather than a flux. Sporadic ALS at end stage, so whether the loss causes degeneration or follows it is not addressed by this design; the authors offer the causal direction as a hypothesis supported by separate experimental models. Percentages are group comparisons against matched controls, with the quarter of specimens showing 90 percent loss reported as a subset rather than a defined subgroup. Antibody-based quantification across regions.", "provenance": "Abstract read in full; all four protein comparisons with their percentages, the subset of motor cortex specimens, the absence of change in GLAST and GFAP, and the authors' own reading of the EAAC1 change as reported", "quantitativeExtraction": "extracted" }, "L259": { "id": "L259", "year": 1990, "topic": "Pulsatility", "title": "Divergent responses of gonadotropin subunit messenger RNAs to continuous versus pulsatile gonadotropin-releasing hormone in vitro", "url": "https://doi.org/10.1210/mend-4-4-557", "studyType": "Dispersed rat pituitary perifusion with gonadotropin-releasing hormone at 10 nanomolar delivered either as a continuous infusion or as hourly pulses over 12 hours, with secretion sampled every 5 minutes and subunit messenger RNA measured at the end, Molecular Endocrinology 4(4):557-564", "diseaseContext": "Healthy reference", "useInModel": "The cleanest demonstration in this atlas that schedule is a signal in its own right, and it comes with a magnitude. The same ligand at the same concentration was given two ways for the same duration. Secretion looked similar in outline - cells responded to each pulse, while continuous delivery produced only a brief episode of release before returning to unstimulated levels - but the transcriptional responses diverged sharply and gene by gene. Alpha subunit messenger RNA rose about equally either way, 1.6-fold on continuous and 1.7-fold on pulsatile delivery. FSH beta messenger RNA was suppressed to 48 percent of control by continuous delivery and stimulated more than fourfold by pulses. LH beta messenger RNA did not respond to either. The authors' framing is the general statement: episodic input is necessary for the maintenance of secretion. Three uses. The project has collected several instances of exposure being non-monotonic in time and treated them as a peculiarity of particular systems; here it is the physiology of an axis, and the divergence from identical total exposure is roughly eightfold on one transcript. The selectivity matters as much as the size: one gene inverts, one is indifferent to schedule, and one does not respond at all, so schedule-dependence is a property of a readout and not of a cell. And this is the mechanism behind a whole drug class, since continuous agonist exposure suppresses an axis that pulses stimulate.", "limit": "Dispersed rat pituitary cells in perifusion, so this is an isolated endocrine tissue and not a microenvironment - the atlas carries it for the principle rather than for any drawn environment. One concentration, one pulse interval of an hour and one 12-hour window, all experimental choices, so nothing here gives the frequency dependence or the interval at which the inversion appears. Messenger RNA rather than protein or function. From 1990, and the atlas holds no modern equivalent that varies the interval systematically.", "provenance": "Abstract read in full; the concentration, both delivery modes and the duration, the described secretion patterns, and all three transcript responses with their fold changes and the 48 percent figure as reported, with the authors' opening statement about episodic input", "quantitativeExtraction": "extracted" }, "L260": { "id": "L260", "year": 2012, "topic": "Receptor status", "title": "Intermittent androgen suppression for rising PSA level after radiotherapy", "url": "https://doi.org/10.1056/NEJMoa1201546", "studyType": "Randomised non-inferiority trial in 1,386 patients with prostate-specific antigen above 3 nanograms per millilitre more than a year after primary or salvage radiotherapy, assigned to intermittent androgen deprivation in 8-month cycles with off-periods set by PSA, or to continuous therapy, with overall survival as the primary endpoint, New England Journal of Medicine 367(10):895-903", "diseaseContext": "Prostate", "useInModel": "The fourth randomised test in this atlas of whether an intermittent schedule helps, and the first in which it clearly did not hurt. Of 1,386 patients, 690 received intermittent and 696 continuous therapy over a median 6.9 years; median overall survival was 8.8 years with intermittent against 9.1 with continuous, with 268 deaths against 256 and no significant difference in adverse events. Intermittent therapy gave potential benefits in physical function, fatigue, urinary problems, hot flashes, libido and erectile function - six domains, which is the strongest quality-of-life case for an intermittent schedule the atlas holds. The detail that matters most for this project is quieter: full testosterone recovery occurred in 35 percent of patients on the intermittent arm, and recovery to the trial-entry threshold in 79 percent. So the off-period is not an off-state. Every schedule argument the project has assembled assumes a drug-free interval restores the baseline, and in the best-measured case roughly two thirds of patients never fully recovered the hormone whose withdrawal was the point of the interval.", "limit": "Non-metastatic disease defined by a rising PSA after radiotherapy, which is the setting where the result is most favourable - the companion record in metastatic disease comes out differently, and the two should always be read together. A non-inferiority design, so the conclusion is the absence of a demonstrated deficit rather than a benefit, and the point estimate still favours continuous therapy by 0.3 years. Quality-of-life benefits are reported as potential across six domains without magnitudes extracted here. Off-periods were determined by PSA rather than by a fixed schedule, so the interval is a response-adaptive variable and not a parameter.", "provenance": "Abstract read in full; the enrolment and both arm sizes, the follow-up duration, both median survivals and both death counts, the absence of an adverse event difference, all six quality-of-life domains, and both testosterone recovery fractions as reported", "quantitativeExtraction": "extracted" }, "L261": { "id": "L261", "year": 2013, "topic": "Receptor status", "title": "Intermittent versus continuous androgen deprivation in prostate cancer", "url": "https://doi.org/10.1056/NEJMoa1212299", "studyType": "Randomised non-inferiority trial in newly diagnosed metastatic hormone-sensitive prostate cancer: 3,040 enrolled, 1,535 analysed after a 7-month induction, assigned 765 to continuous and 770 to intermittent androgen deprivation, with a one-sided non-inferiority boundary at a hazard ratio of 1.20 and quality of life as a coprimary objective, New England Journal of Medicine 368(14):1314-1325", "diseaseContext": "Prostate", "useInModel": "The fifth randomised test, in the same disease and on the same axis as the fourth, and it reaches the opposite conclusion - which is the finding. The trial's stated hypothesis is the one the project keeps meeting: replacing androgens before progression was hypothesised to prolong androgen dependence, the same resistance-delaying logic as the melanoma schedule work. Over a median 9.8 years, median survival was 5.8 years on continuous therapy against 5.1 on intermittent, hazard ratio for death with intermittent 1.10 with a 90 percent confidence interval of 0.99 to 1.23 - which does not exclude the pre-specified boundary of 1.20, so the authors state plainly that the findings were statistically inconclusive. Intermittent therapy was associated with better erectile function and mental health. Read with the companion trial in non-metastatic disease, where intermittent therapy was non-inferior with benefits across six quality-of-life domains, the atlas's schedule question acquires its answer: the determining variable is the disease state, not the schedule principle. Same drug class, same axis, same intervention, and the conclusion flips with the extent of disease.", "limit": "Statistically inconclusive is the authors' own characterisation and the atlas should carry it exactly: the confidence interval includes both no difference and a deficit beyond the non-inferiority boundary, so the trial neither establishes equivalence nor demonstrates harm. Of 3,040 enrolled only 1,535 were analysed, since randomisation required a PSA response to induction - so this is a selected, hormone-responsive population. Quality-of-life advantages are reported for two domains here against six in the non-metastatic trial, which is itself a difference between the settings. The intermittent arm's off-periods and the resulting exposure are not extracted.", "provenance": "Abstract read in full; the stated hypothesis, the induction and randomisation design with the enrolment and analysed numbers, both arm sizes, the follow-up, both median survivals, the hazard ratio with its 90 percent interval and the pre-specified boundary, the two quality-of-life advantages, and the authors' statement that the findings were inconclusive as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I103", "name": "Microorganisms and microbial products", "category": "External", "whereToCheck": "Mucosal/luminal sites; other sites only if validated", "states": [ "Species", "viability", "contamination controls" ], "behaviors": [ "Barrier crossing", "metabolites", "immune effects" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "bacteria-pdac-load" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "bacteria-pdac-load", "bacteria-detection-tumor", "bacteria-detection-control" ], "priorResearch": { "path": "simulation/data/profiles/microorganisms-and-microbial-products.json", "summary": "The first External row, and the one whose inventory entry was a warning rather than a description: mucosal and luminal sites, other sites only if validated, with contamination controls listed as a state to resolve. The field then supplied the test case. Re-analysis of a large study correlating microbes with 33 cancer types found millions of false positive bacterial reads because most sequences called bacterial were human, and a data transformation that created a distinct signature for each tumour type even for microbes with no reads at all - with more than a dozen downstream studies likely invalid (L262). An analysis of over 5,700 cancer genomes concluded most detected sequences are artefacts, while three associations survive: Helicobacter pylori in gastric carcinoma, Fusobacterium nucleatum in colorectal cancer and human papillomavirus in cervical malignancy (L263). Against that short list, one mechanism is strong: bacteria inactivate gemcitabine through their own cytidine deaminase, abrogated by an antibiotic, in tumours 76 percent of which carry bacteria (L264).", "stateAxes": [ { "axis": "Contamination controls, which this row treats as the primary state", "whatToMeasure": "The controls, before anything else. Re-analysis of a large study found two fundamental flaws: database and method errors produced millions of false positive bacterial reads, largely because most sequences identified as bacteria were human; and a raw-data transformation created an artificial signature even for microbes with no reads detected, which the machine-learning classifiers then used. Either flaw invalidates the results, the classifiers are described as entirely wrong, and more than a dozen further studies using the same data are likely invalid. A subsequent analysis of more than 5,700 cancer genomes found most detected sequences to be artefacts.", "interpretationLimit": "These are re-analyses and reassessments rather than new measurements, so they establish that particular findings are unsupported rather than that tumours contain no microbes - a distinction this row keeps deliberately. The downstream invalidation is inferred from shared data rather than demonstrated study by study. The 5,700-genome analysis is cited by a two-page reassessment and is not itself read into this atlas.", "evidence": [ "L262", "L263" ] }, { "axis": "Species, as a short validated list rather than a composition", "whatToMeasure": "Specific organism-and-environment pairs with independent evidence. The reassessment names three that survive: Helicobacter pylori in gastric carcinoma, Fusobacterium nucleatum in colorectal cancer, and human papillomavirus in cervical malignancy. The large survey separately reports that where intratumour bacteria are present they are mostly intracellular, in both cancer and immune cells, across 1,526 tumours in seven cancer types.", "interpretationLimit": "The surviving list is asserted as robust in a short reassessment without its supporting evidence summarised, so each pair would need its own record before the atlas could use it quantitatively - and two of the three are drawn environments where this row consequently holds a name and no number. The survey's composition claims predate the field's reckoning and are treated here as unvalidated rather than refuted; its localisation claim is the part this row uses, and no abundance per tumour is held anywhere.", "evidence": [ "L263", "L265" ] }, { "axis": "Metabolites, and a drug destroyed on arrival", "whatToMeasure": "What the organism does to molecules the host did not make. Bacteria metabolise gemcitabine into its inactive form through a long isoform of bacterial cytidine deaminase, found primarily in Gammaproteobacteria; in a colon cancer mouse model resistance was induced by intratumour Gammaproteobacteria, depended on that enzyme, and was abrogated by ciprofloxacin; and 86 of 113 human pancreatic tumours were bacteria-positive, mainly Gammaproteobacteria.", "interpretationLimit": "Mechanism and rescue in mouse colon cancer; the pancreatic link is a prevalence survey plus a hypothesis the authors label as such, with no human resistance outcome. The 76 percent is a detection result from 2017, before the field's contamination reckoning, and its controls are not extracted here - which this row's other records make a live concern. No bacterial load, enzyme activity or local drug concentration, so a mechanism with no quantity at any step.", "evidence": [ "L264" ] }, { "axis": "Barrier crossing, immune effects, and viability", "whatToMeasure": "Three things the inventory names and this row cannot serve. Barrier crossing has no record - nothing measures an organism or product traversing an epithelium or endothelium in any drawn environment. Immune effects appear only as a noted correlation with immunotherapy response in a survey whose composition data this row treats as unvalidated, and as improved response prediction after decontamination, which is a statistical result rather than a mechanism. Viability is not addressed at all: every measurement here is of nucleic acid, which does not distinguish a living organism from its residue.", "interpretationLimit": "The viability gap is the one that matters most and the inventory named it. Sequence detection cannot tell a colonising population from dead material or from contamination, and the row's central mechanism requires living bacteria expressing an enzyme - so the evidence for presence and the evidence for activity are of different kinds and only the second is mechanistic.", "evidence": [ "L266" ] } ], "records": { "L262": { "id": "L262", "year": 2023, "topic": "Contamination controls", "title": "Major data analysis errors invalidate cancer microbiome findings", "url": "https://doi.org/10.1128/mbio.01607-23", "studyType": "Re-analysis of the data from a large-scale study reporting correlations between microbial organisms and 33 cancer types and near-perfect machine-learning classifiers, identifying errors in the reference database, the computational methods and the data transformation, mBio 14(5):e0160723", "diseaseContext": "Shared cancer across 33 types", "useInModel": "The inventory told this row to carry contamination controls and to accept sites other than mucosal and luminal ones only if validated. This record is why. Re-analysis of a large study found at least two fundamental flaws. Errors in the genome database and the associated computational methods produced millions of false positive bacterial reads across all samples, largely because most sequences identified as bacteria were in fact human. And errors in transforming the raw data created an artificial signature even for microbes with no reads detected at all, tagging each tumour type with a distinct signal that the machine-learning programmes then used to build an apparently accurate classifier. Either flaw invalidates the results; the re-analysis concludes the microbiome-based cancer classifiers are entirely wrong, and that the same data have since affected more than a dozen further published studies whose results are likely invalid too. For this atlas the lesson generalises past microbiology. A signal measured near the detection limit will be dominated by contamination and by processing artefacts unless the controls are reported as part of the value - and a classifier's accuracy is not evidence that its features are real, since here the features were absent and the accuracy was high.", "limit": "A re-analysis rather than new measurement, so it establishes that particular findings are unsupported rather than that tumours contain no microbes - the distinction matters and the atlas should keep it. It addresses one dataset and the studies built on it, not the field. Its claim that more than a dozen downstream studies are likely invalid is an inference from shared data rather than a re-analysis of each. And it says nothing about which associations do survive, which the companion record in this row supplies.", "provenance": "Abstract read in full; both named flaws with their stated causes - human sequences misidentified as bacterial, and a transformation artefact affecting microbes with zero reads - the conclusion that the classifiers are entirely wrong, and the stated downstream effect on more than a dozen studies as reported", "quantitativeExtraction": "extracted" }, "L263": { "id": "L263", "year": 2025, "topic": "Species", "title": "Reassessment of microbial DNA in cancer genomes: addressing contamination controversies", "url": "https://doi.org/10.1097/ms9.0000000000004087", "studyType": "Short reassessment of the tumour microbiome literature following an analysis of more than 5,700 cancer genomes, with recommendations on methodological standards, Annals of Medicine and Surgery 87:9085-9086", "diseaseContext": "Shared cancer; Gastric / GEJ and Colorectal for the surviving associations", "useInModel": "Supplies the short list this row has to be written on. Following an analysis of more than 5,700 cancer genomes showing that most detected microbial sequences reflect artefacts, the reassessment states that enthusiasm for a universal tumour microbiome must be tempered while robust associations remain in specific cancers - naming Helicobacter pylori in gastric carcinoma, Fusobacterium nucleatum in colorectal cancer, and human papillomavirus in cervical malignancy. Two of those three are drawn environments in this atlas. It also names what rigorous practice requires: robust negative controls, contamination-aware pipelines and transparent reporting. For the project this converts the inventory's instruction into a usable rule. The row is not about a tumour microbiome in general; it is about a small number of organism-and-environment pairs with independent evidence, and anything else should be treated as unvalidated until its controls are shown.", "limit": "A two-page reassessment rather than primary data, so it is carried for the list and the standards it names rather than as a measurement - and the 5,700-genome analysis it cites is not itself read into this atlas. The surviving associations are asserted as robust without the supporting evidence being summarised here, so each would need its own record before the atlas could use it quantitatively. No abundances, no prevalences and no effect sizes. Published in 2025, so the position may move again.", "provenance": "Abstract read in full; the stated finding that most detected sequences in more than 5,700 cancer genomes are artefacts, all three named surviving associations with their cancers, and all three recommended methodological standards as reported", "quantitativeExtraction": "extracted" }, "L264": { "id": "L264", "year": 2017, "topic": "Metabolites", "title": "Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine", "url": "https://doi.org/10.1126/science.aah5043", "studyType": "Colon cancer models with bacterial metabolism of gemcitabine, dependence on a long isoform of bacterial cytidine deaminase, antibiotic co-treatment in mice, and bacterial detection in 113 human pancreatic ductal adenocarcinomas, Science 357(6356):1156-1160", "diseaseContext": "Pancreatic (PDAC); Colorectal", "useInModel": "A drug destroyed at its destination by an enzyme that is not the host's - a failure mode the atlas's delivery chain does not have. Bacteria metabolise gemcitabine into its inactive form, and the metabolism depends on expression of a long isoform of the bacterial enzyme cytidine deaminase, seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intratumour Gammaproteobacteria, was dependent on that bacterial enzyme, and was abrogated by co-treatment with ciprofloxacin. In human tissue, 86 of 113 pancreatic ductal adenocarcinomas - 76 percent - were positive for bacteria, mainly Gammaproteobacteria. Three uses. The atlas's chain has six stages concerned with a molecule reaching its target and one noted missing stage about whether the machinery at the destination can handle it; this is a seventh problem, that something at the destination may consume the drug first, with its own genome and its own enzymology. The dependency is genetic and the rescue is an existing antibiotic, which makes it one of the better-specified interventions in the project. And the 76 percent prevalence is a human number in a drawn environment, which this row otherwise struggles to supply.", "limit": "The mechanism and the antibiotic rescue are mouse colon cancer models, and the pancreatic connection is a prevalence survey plus a hypothesis - the authors say consistent with this possibility, and no human resistance outcome is tested. Bacterial positivity in 76 percent of tumours is a detection result, and this row's other records establish how easily such detection is contaminated; the comparison tissue and controls for that survey are not extracted here. No bacterial load, no enzyme activity and no local gemcitabine concentration, so the atlas holds a mechanism with no quantity at any step. Published in 2017, before the field's contamination reckoning.", "provenance": "Abstract read in full; the inactivation product named, the dependence on the long cytidine deaminase isoform and its taxonomic distribution, all three elements of the mouse result including the ciprofloxacin rescue, and the 86 of 113 human prevalence figure as reported with the authors' own hedging", "quantitativeExtraction": "extracted" }, "L265": { "id": "L265", "year": 2020, "topic": "Species", "title": "The human tumor microbiome is composed of tumor type-specific intracellular bacteria", "url": "https://doi.org/10.1126/science.aay9189", "studyType": "Comprehensive analysis of 1,526 tumours and their adjacent normal tissues across seven cancer types - breast, lung, ovary, pancreas, melanoma, bone and brain - with bacterial localisation, Science 368(6494):973-980", "diseaseContext": "Breast; Lung (NSCLC); Ovarian (HGSC); Pancreatic (PDAC); Melanoma (cutaneous); Glioblastoma", "useInModel": "The largest survey the row can draw on, and the one whose claims the atlas has to hold carefully given what follows it. Across 1,526 tumours and adjacent normal tissues in seven cancer types, each tumour type was reported to have a distinct microbiome composition, with breast cancer particularly rich and diverse. The localisation claim is the one most useful here and least dependent on composition: the intratumour bacteria are mostly intracellular, present in both cancer cells and immune cells. Correlations were noted with tumour type and subtype, patients' smoking status and response to immunotherapy. The authors state the problem this row cannot escape - characterising the tumour microbiome has remained challenging because of its low biomass. For the atlas the usable content is that if organisms are present they are largely inside host cells rather than in the interstitium, which puts them in a different compartment from every other External component and means they are not a field.", "limit": "A low-biomass sequencing survey published before the field's contamination reckoning, and this row holds the record showing that a large contemporaneous study's composition findings were artefactual. This study reports its own controls, which the atlas has not read, so its composition claims should be treated as unvalidated here rather than as either confirmed or refuted - the reassessment record's position is that a universal tumour microbiome must be tempered while specific associations survive, and none of the three it names is from this survey. The correlations with smoking status and immunotherapy response are associations in a survey with no effect sizes extracted. No abundance per tumour is held.", "provenance": "Abstract read in full; the sample and cancer-type counts, the stated distinctness of composition by tumour type and the breast observation, the intracellular localisation in both cancer and immune cells, the three noted correlations, and the authors' statement about low biomass as reported", "quantitativeExtraction": "extracted" }, "L266": { "id": "L266", "year": 2023, "topic": "Contamination controls", "title": "Contamination source modeling with SCRuB improves cancer phenotype prediction from microbiome data", "url": "https://doi.org/10.1038/s41587-023-01696-w", "studyType": "Probabilistic in silico decontamination method using information shared across multiple samples and controls, validated in data-driven simulations and induced-contamination experiments across ecosystems, data types and sequencing depths, with application to melanoma treatment-response prediction, Nature Biotechnology 41(12):1820-1828", "diseaseContext": "Melanoma (cutaneous); shared cancer", "useInModel": "The remedy for this row's central problem, with a number attached. Existing in silico decontamination uses controls but does not exploit information shared across samples, and cannot handle taxa that only partly originate in contamination or biological material leaking into the controls. This method models the contamination source probabilistically across samples and controls, and in simulations and induced-contamination experiments it outperformed existing approaches by an average of 15 to 20 times. Applied to tumour microbiome data it improved prediction of host phenotypes, most notably treatment response in melanoma patients. Two uses. It is the one record in this row that turns the inventory's demand for contamination controls into something executable - a pipeline rather than an exhortation. And the two failure modes it names are general: partial contamination of a taxon and leakage of signal into the control are exactly the problems that make a near-detection-limit measurement hard anywhere, not only in sequencing.", "limit": "A methods paper, so its 15 to 20 fold advantage is over other decontamination algorithms on simulated and induced-contamination data rather than a statement about truth in real tumours - better decontamination does not establish that what survives is real. The improvement in melanoma treatment-response prediction is a prediction accuracy result on existing data, not a validated biological finding. It cannot recover signal that was never measured, so it does not address the other row's finding that most sequences called bacterial were human. No abundance or prevalence for any organism in any environment.", "provenance": "Abstract read in full; the two stated shortcomings of existing methods, the probabilistic approach described, the 15 to 20 fold average improvement with its validation settings, and the melanoma treatment-response application as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "bacteria-detection-tumor", "bacteria-detection-control" ] }, { "id": "I104", "name": "Interstitial fluid and CSF routes", "category": "External", "whereToCheck": "Tissue and CNS boundaries", "states": [ "Pressure", "composition", "direction" ], "behaviors": [ "Convection", "drainage", "dilution", "clearance" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "mri-csf-volume" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "mri-csf-volume" ], "priorResearch": { "path": "simulation/data/profiles/interstitial-fluid-and-csf-routes.json", "summary": "The compartment everything else in this atlas moves through, and the row where it stops being a fixed geometry. Natural sleep or anaesthesia are associated with a 60 percent increase in the interstitial space in live mice, with a striking increase in convective exchange of cerebrospinal with interstitial fluid and an increased rate of beta-amyloid clearance (L267). Drainage has a route and a destination, and ablating it separates two of the states the inventory asks for: dural lymphatic vessels carry absorbed fluid to deep cervical nodes through skull-base foramina, and in animals lacking them macromolecule clearance was attenuated and nodal transport abolished while interstitial pressure and water content were unchanged (L268). Set against that, the atlas's own delivery chain has this same compartment in tumours as diffusion-only, with pressures of 75 to 130 millimetres of mercury against 8 to 13 in normal tissue and the lymphatics mechanically compressed - so the two environments are in opposite transport regimes for a stated reason.", "stateAxes": [ { "axis": "Composition and volume, which are not fixed", "whatToMeasure": "The volume fraction, as a state rather than a constant. Natural sleep or anaesthesia were associated with a 60 percent increase in interstitial space in live mice, assessed by real-time tetramethylammonium diffusion with two-photon imaging, with a striking increase in convective exchange of cerebrospinal with interstitial fluid and an increased beta-amyloid clearance rate. Composition is separately established as differing from plasma: absolute concentrations of more than 118 metabolites in tumour interstitial fluid differ from circulation and depend on tumour type, anatomical location and diet.", "interpretationLimit": "The 60 percent is a change in an effective volume fraction inferred from a small cation's diffusion under a transport model, not a directly observed space, in healthy mice - and sleep and anaesthesia are grouped together, leaving the trigger unresolved. Brain only, so nothing says any other interstitium behaves this way. The composition data are murine, terminal and from two tumour types, and this atlas holds the dataset's existence rather than its values.", "evidence": [ "L267", "L244" ] }, { "axis": "Drainage, and its dissociation from pressure", "whatToMeasure": "Solute clearance and fluid balance separately, because removing the route changes one and not the other. Dural lymphatic vessels absorb cerebrospinal fluid from the subarachnoid space and brain interstitial fluid and transport it to deep cervical nodes through skull-base foramina; in animals with complete aplasia of those vessels, macromolecule clearance from the brain was attenuated and transport to the nodes abolished, while brain interstitial pressure and water content were unaffected.", "interpretationLimit": "Mouse and healthy, with attenuation reported as a direction and no drainage flux - the same gap the atlas's existing dural lymphatic record has. The aplasia is developmental, so the unchanged pressure could be adaptation rather than independence. The interstitium-to-subarachnoid leg is attributed to the glymphatic system without being tested here, and clearance is measured for tracers rather than for any endogenous species the atlas carries.", "evidence": [ "L268", "L101" ] }, { "axis": "Pressure and direction, opposite in two environments", "whatToMeasure": "Whether drainage is working, since that decides the regime. In tumour interstitium, failed lymphatic drainage lets pressure rise until it approaches microvascular pressure and the inward gradient disappears - 8 to 13 millimetres of mercury by catheter in normal mouse pancreas against 75 to 130 in autochthonous tumours, uniform across the interior and falling steeply at the margin, with solid stress from proliferating cells compressing the lymphatics. In brain with drainage intact, convective exchange is present and state-dependent.", "interpretationLimit": "The pressures are held in the atlas's delivery chain from murine measurements, and the dispute over whether solid stress or fluid pressure is the compressing quantity was resolved in the atlas towards solid stress - which the atlas also records as having pressures for the consequence and, until recently, nothing for the cause. The brain and tumour comparison is across species-matched models but not across one experiment, so the opposite regimes are an inference from two literatures rather than a measured contrast.", "evidence": [ "Q02", "V43", "V44" ] }, { "axis": "Clearance and dilution", "whatToMeasure": "The rate at which a species leaves, which the atlas holds for one compartment and not for this one. Cerebrospinal fluid has turnover parameters for almost 200 human proteins and an allometric rate constant for amyloid-beta 40; interstitial fluid has concentrations and no turnover at all. Dilution - the inventory's own term - has no record anywhere.", "interpretationLimit": "The cerebrospinal turnover figures describe a sampleable compartment downstream of the interstitium, so they bound interstitial clearance without measuring it. Nothing in the atlas gives an interstitial clearance rate for any species in any environment, and for dilution there is not even a method named - which matters because every concentration the project holds for this compartment is a steady-state value whose production and removal terms are both unknown.", "evidence": [ "L211", "L212" ] } ], "records": { "L101": { "id": "L101", "year": 2015, "topic": "Transport", "title": "Structural and functional features of central nervous system lymphatic vessels", "url": "https://doi.org/10.1038/nature14432", "studyType": "Discovery and functional characterisation of dural sinus lymphatic vessels in mouse, Nature 523(7560):337-341", "diseaseContext": "Healthy reference", "useInModel": "Supplies the drainage route for the one compartment where the atlas had explicitly ruled out the peripheral one. The central nervous system was held to lack a classical lymphatic drainage system. Functional lymphatic vessels were found lining the dural sinuses, expressing all the molecular hallmarks of lymphatic endothelium, able to carry both fluid and immune cells from the cerebrospinal fluid, and connected to the deep cervical lymph nodes - their unique location having impeded discovery and sustained the assumption of absence. This matters because the atlas has pointed four times at a lymphoid compartment outside the drawn environments and resolved it twice: tertiary lymphoid structures put it inside peripheral tumours, and CCR7-dependent dendritic trafficking supplies the route to a draining node - with the explicit caveat, recorded when that route was written, that brain drainage differs and the peripheral journey could not be assumed there. This is the brain route, with a named destination.", "limit": "Mouse, healthy, and an anatomical and functional characterisation rather than a measurement of flux - no drainage rate, transit time or cell flux to the cervical nodes is given. It establishes that the route exists and carries fluid and cells, not its capacity, and nothing here concerns a disease state or the drawn neurodegenerative environments. The deep cervical lymph node remains outside the drawn set, so the atlas again knows where material goes without being able to represent the destination.", "provenance": "Abstract read in full; the dural sinus location, lymphatic hallmarks, carriage of fluid and immune cells from cerebrospinal fluid, and the connection to deep cervical lymph nodes as reported", "quantitativeExtraction": "extracted" }, "L211": { "id": "L211", "year": 2019, "topic": "Transport", "title": "In Vivo Large-Scale Mapping of Protein Turnover in Human Cerebrospinal Fluid", "url": "https://doi.org/10.1021/acs.analchem.9b03328", "studyType": "Metabolic labelling with sequential ventricular cerebrospinal fluid sampling in patients, proteome-wide and targeted, with mathematical modelling to derive per-protein turnover parameters, Analytical Chemistry 91(24):15500-15508", "diseaseContext": "Healthy reference; patients with ventricular access", "useInModel": "The single most useful methodological record in this atlas for its largest structural gap. The project's recurring complaint is that it holds exchanges without fluxes - five metabolite hand-offs between adjacent cells, none with a transfer rate. This work determined turnover parameters for almost 200 proteins in human ventricular cerebrospinal fluid, where a handful were known before, covering many neuron-biology and immune-related proteins including biomarkers and drug targets, and it reports a significant relationship between a protein's turnover and its tissue of origin. The requirement is stated plainly: sequential sample collection. That is why this compartment has rates and the atlas's other compartments do not - cerebrospinal fluid can be sampled repeatedly in the same person and interstitial fluid cannot. So the atlas's missing rates are not missing because rates are unmeasurable; they are missing because most of its compartments cannot be sampled twice. This row is the exception, and the relationship between turnover and origin means a protein's rate here carries information about where it came from.", "limit": "Ventricular cerebrospinal fluid from patients who had ventricular access, so the population is clinically selected and the compartment is not lumbar fluid, where most clinical biomarkers are measured. A methods paper: the turnover parameters are its product and no individual value is extracted into this atlas, so what is held is the existence and the method rather than any number. Turnover in a fluid compartment combines synthesis, entry, clearance and bulk flow, so a per-protein rate is not a secretion rate for this family. Nothing about disease.", "provenance": "Abstract read in full; the count of almost 200 proteins against a handful previously known, the classes of protein covered, the reported relationship between turnover and protein origin, and the stated requirement for sequential sampling as reported", "quantitativeExtraction": "extracted" }, "L212": { "id": "L212", "year": 2013, "topic": "Transport", "title": "Cerebrospinal fluid beta-amyloid turnover in the mouse, dog, monkey and human evaluated by systematic quantitative analyses", "url": "https://doi.org/10.1159/000341217", "studyType": "Pharmacokinetic and pharmacodynamic modelling of cerebrospinal fluid amyloid-beta dynamics after beta- or gamma-secretase inhibition, pooling in-house and published data across four species, Neurodegenerative Diseases 12(1):36-50", "diseaseContext": "Alzheimer's", "useInModel": "The atlas's first scaling law, written as an equation, and a species comparison with a number on it. The turnover rate constant for cerebrospinal fluid amyloid-beta 40 follows allometry as kout equal to 0.395 times body weight to the power -0.351. And the relationship to bulk fluid turnover changes with size: in rodents the amyloid-beta 40 rate constant is roughly twofold higher than the turnover of the fluid itself, while in higher species the two are comparable. Three uses. This is a parameter a simulation can actually carry, with an explicit dependence on body mass rather than a single value per species. It gives the project an instance of what cross-species transfer looks like when somebody quantifies it instead of cautioning about it - the scaling holds, and a derived ratio does not, which is a more useful statement than either a warning or a blanket assumption. And it bears directly on the atlas's amyloid row, since the slow turnover in these compartments is given as the reason pharmacodynamic readouts for secretase inhibitors are hard to interpret.", "limit": "Modelled rate constants derived from pooled dynamic data after pharmacological inhibition, so these are parameters of a fitted model rather than directly measured fluxes, and they describe amyloid-beta 40 specifically rather than the family's secretory output. Public-domain data pooled with in-house data across four species brings heterogeneous designs. An allometric exponent fitted across four species rests on few points. The comparison to fluid turnover uses literature values for that turnover, which this atlas does not independently hold - so the twofold statement depends on a number not recorded here.", "provenance": "Abstract read in full; the allometric equation with its coefficient and exponent as printed, the twofold relationship in rodents against comparability in higher species, the four species pooled, and the authors' stated motivation about slow turnover complicating interpretation as reported", "quantitativeExtraction": "extracted" }, "L244": { "id": "L244", "year": 2019, "topic": "Available", "title": "Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability", "url": "https://doi.org/10.7554/eLife.44235", "studyType": "Quantitative metabolomics measuring absolute concentrations of more than 118 metabolites in plasma and in tumour interstitial fluid, compared between autochthonous and transplant models of murine pancreatic and lung adenocarcinoma and across diets, eLife 8:e44235", "diseaseContext": "Pancreatic (PDAC); Lung (NSCLC)", "useInModel": "The single largest ingestion opportunity the atlas has found, and it corrects an assumption the project has been carrying. Absolute concentrations were measured for more than 118 metabolites in tumour interstitial fluid - the extracellular fluid that perfuses tumours, and the compartment in which every metabolite hand-off this atlas records takes place. Three findings. The nutrients available to tumours differ from those present in circulation, so plasma is not a proxy for the interstitium and the atlas should not treat a serum value as a local one. Interstitial nutrient levels differed between autochthonous and transplant models of the same disease, which is a warning about every transplant-model number the atlas holds. And tumour type, anatomical location and animal diet each affected local availability - so a nutrient concentration is not a property of a disease but of a disease in a place under a feeding regimen. The atlas has repeatedly recorded that its metabolite exchange terms have no flux; what it had not noticed is that they have no concentration either, and this supplies concentrations for more than a hundred of them in two drawn environments.", "limit": "Murine, and terminal: interstitial fluid is obtained from excised tumours, so this is a destructive single-timepoint measurement and gives concentrations rather than rates - it does not supply the fluxes the atlas lacks, only the other half of what a flux calculation needs. Two tumour types. The comparison showing that transplant and autochthonous models differ is itself the reason to be careful transferring these values to human disease, which is untested here. Diet effects mean the numbers are conditional on husbandry. No individual metabolite concentration is extracted into this atlas by this record, so what is held is the existence, the method and the three determinants.", "provenance": "Abstract read in full; the count of more than 118 metabolites and both compartments measured, the difference between interstitial fluid and plasma, the autochthonous against transplant comparison, and all three stated determinants of local availability as reported", "quantitativeExtraction": "extracted" }, "L267": { "id": "L267", "year": 2013, "topic": "Convection", "title": "Sleep drives metabolite clearance from the adult brain", "url": "https://doi.org/10.1126/science.1241224", "studyType": "Real-time assessment of tetramethylammonium diffusion with two-photon imaging in live mice across natural sleep, anaesthesia and wakefulness, with beta-amyloid clearance rate measured, Science 342(6156):373-377", "diseaseContext": "Healthy reference; Alzheimer's as the stated relevance", "useInModel": "The compartment this atlas's entire delivery chain diffuses through turns out to be a state variable, and the change is large. Natural sleep or anaesthesia were associated with a 60 percent increase in the interstitial space, measured in live mice by real-time tetramethylammonium diffusion with two-photon imaging - producing a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid, and in turn an increased rate of beta-amyloid clearance during sleep. Three uses. The project has been treating the interstitium as a fixed geometry to be characterised once; its volume fraction moves by well over half with behavioural state, which means every diffusion and clearance term computed in it inherits that state. It is the second independent brain measurement the atlas holds that changes with sleep, after synaptic density by tracer binding moving with one night of deprivation - so the project's caution that a measurement moves with the state of the subject is now supported twice in the same organ by unrelated methods. And the mechanism is convective rather than diffusive, which sits directly against what the atlas's delivery chain concludes for tumour interstitium.", "limit": "Live mice, healthy, with the interstitial volume inferred from the diffusion behaviour of a small cation rather than measured geometrically - so 60 percent is a change in an effective volume fraction under a transport model, not a directly observed space. Sleep and anaesthesia are grouped as associated with the same change, which is convenient for measurement and leaves the physiological trigger unresolved. The amyloid clearance result is a rate change without the rate extracted here, and the relevance to Alzheimer's is the authors' framing rather than a measurement in disease. Brain only: nothing establishes that any other interstitium behaves this way.", "provenance": "Abstract read in full; both measurement methods, the grouping of natural sleep with anaesthesia, the 60 percent interstitial space increase, the stated increase in convective cerebrospinal-to-interstitial exchange, and the increased beta-amyloid clearance rate as reported", "quantitativeExtraction": "extracted" }, "L268": { "id": "L268", "year": 2015, "topic": "Drainage", "title": "A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules", "url": "https://doi.org/10.1084/jem.20142290", "studyType": "Identification of a dural lymphatic network in mouse brain with tracing of cerebrospinal and interstitial fluid absorption and transport to deep cervical lymph nodes, plus a transgenic VEGF-C/D trap model with complete aplasia of dural lymphatic vessels, Journal of Experimental Medicine 212(7):991-999", "diseaseContext": "Healthy reference", "useInModel": "The functional ablation that the atlas's existing drainage record does not have, and it yields a dissociation. The atlas already holds the discovery of dural sinus lymphatic vessels connected to the deep cervical lymph nodes, as an anatomical and functional characterisation with no flux. This companion work adds the removal experiment: dural lymphatic vessels absorb cerebrospinal fluid from the adjacent subarachnoid space and brain interstitial fluid by way of the glymphatic system, and transport it to deep cervical nodes through foramina at the base of the skull. In a transgenic model with complete aplasia of those vessels, macromolecule clearance from the brain was attenuated and transport from the subarachnoid space to the deep cervical nodes was abrogated - and, the authors say surprisingly, brain interstitial fluid pressure and water content were unaffected. That is the useful part for this row. The inventory asks it to resolve pressure, composition and direction, and this says they are not one variable: abolishing the route that clears solutes left the fluid balance unchanged. A model that treats interstitial pressure as the readout for drainage would have registered nothing.", "limit": "Mouse and healthy, with clearance attenuation reported as a direction rather than a rate - so still no drainage flux, which is the quantity the atlas's existing record also lacks. The aplasia is developmental, so compensation over development cannot be excluded and the unchanged pressure may reflect adaptation rather than independence. The route from interstitium to subarachnoid space is attributed to the glymphatic system, which this record does not itself test. Macromolecule clearance is measured for tracers rather than for any endogenous species the atlas carries.", "provenance": "Abstract read in full; the absorption of cerebrospinal and interstitial fluid, the route to deep cervical nodes through skull-base foramina, the aplasia model's attenuated macromolecule clearance and abrogated nodal transport, and the authors' own surprise at unchanged interstitial pressure and water content as reported", "quantitativeExtraction": "extracted" }, "Q02": { "id": "Q02", "year": 2012, "topic": "Transport comparator", "title": "Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma", "url": "https://pubmed.ncbi.nlm.nih.gov/22439937/", "studyType": "Autochthonous KPC/KC mouse pancreatic cancer with in vivo pressure catheter, vessel morphometry and drug-delivery imaging, Cancer Cell 21(3):418-429", "diseaseContext": "Pancreatic", "useInModel": "Gives the pressure that explains why pancreatic vessels are shut, and the size of the delivery gain from opening them. Interstitial fluid pressure measured by catheter was 8-13 mmHg in normal pancreas, mean 10.4 across 8 animals, against 75-130 mmHg in autochthonous PDA, mean 99 in 7 KPC tumours and 87 in 4 KC tumours. That exceeds typical capillary pressure of 15-40 mmHg and overlaps arteriolar pressure of 40-80, which is the mechanical reason the vessels are collapsed rather than absent. Hyaluronan is identified as the determinant: 3 mg/ml of it more than doubled the baseline pressure of carcinoma cells engrafted in collagen alone. A single intravenous dose of the hyaluronidase PEGPH20 brought pressure to 16 mmHg in KC and 22 mmHg in KPC tumours at 24 hours, statistically indistinguishable from normal pancreas, and produced a more than 6.5-fold increase in doxorubicin fluorescence in the tumour. Vessel number did not change - only diameter - so the gain came from reopening existing vessels, not from new ones. With gemcitabine, median survival went from 55.5 days to 91.5 days; the enzyme alone reached 63 days and was not significant.", "limit": "Mouse, pancreatic, small groups: 14 to 16 animals per survival arm and 4 to 8 per pressure measurement. The mechanism is formally disputed - two commentaries in the same journal argue that the vessel compression is caused by solid stress rather than by interstitial fluid pressure, so the measured pressures stand while the causal account does not (L26). And the delivery gain did not translate: the clinical trial of the same enzyme is Q03.", "provenance": "Full text read; pressures, delivery fold-change and survival medians taken from results and figure legends", "quantitativeExtraction": "extracted" }, "V43": { "id": "V43", "year": 2004, "topic": "Transport", "title": "Cancer cells compress intratumour vessels", "url": "https://doi.org/10.1038/427695a", "studyType": "Mouse tumour imaging, Nature 427(6976):695", "diseaseContext": "Shared cancer", "useInModel": "Gives the mechanism for the vessel that is not there, and it is growth rather than failure to form. Proliferating tumour cells generate solid stress that compresses intratumoural vessels, lymphatics included - so the absent drainage that lets interstitial pressure rise toward microvascular pressure is a mechanical consequence of proliferation. That matters for the delivery chain this atlas has assembled: the second stage, where convection disappears, is caused by the first thing a tumour does. It also settles which way to read the recorded dispute over vessel collapse: a commentary argues that hyaluronan compresses pancreatic vessels through solid stress rather than interstitial fluid pressure, and this record supplies solid stress from an independent source, so the atlas should carry solid stress as the compressing quantity and interstitial pressure as its consequence.", "limit": "Mouse tumour models in a brief report. Solid stress is not measured in any drawn environment here, and compression is inferred from vessel geometry rather than from a measured force - so the mechanism is identified and the quantity is absent, which is the same position the atlas is in for the pressures it does hold.", "provenance": "Re-extracted from the record's own screened content. The proliferation-generated solid stress, the inclusion of lymphatics among the compressed vessels, and the inference of compression from geometry as reported. The reading of the vessel-collapse dispute is this atlas's own", "quantitativeExtraction": "extracted" }, "V44": { "id": "V44", "year": 2004, "topic": "Transport", "title": "High interstitial fluid pressure - an obstacle in cancer therapy", "url": "https://doi.org/10.1038/nrc1456", "studyType": "Review, Nat Rev Cancer 4(10):806-813", "diseaseContext": "Shared cancer", "useInModel": "Explains why nothing moves by convection inside a tumour, which is the step between the junction row's entry problem and the matrix's own geometry. Without lymphatic drainage, fluid entering from leaky vessels has nowhere to go, so pressure rises until it approaches microvascular pressure and the gradient that would carry a large molecule into tissue disappears. The spatial description matters as much: pressure is reported as uniform across the tumour interior and falling steeply at the margin, so the gradient and the exit are both at the rim. Taken with the junction row, the atlas can now name the limiting step at each stage of delivery - permeability limits entry and puts tissue-surface concentration one hundred to one thousand times below plasma, and once inside there is no convection, so transport is diffusion alone through a matrix whose pore geometry the atlas does not measure.", "limit": "A review. It explains why the pressures measured in breast and pancreatic tumours matter for delivery and does not measure them, and the spatial profile is a general description rather than a per-environment map. It also predates the dispute recorded elsewhere in this atlas over whether interstitial fluid pressure or solid stress is the quantity that collapses vessels, and its framing assumes the former.", "provenance": "Re-extracted from the record's own screened content. The drainage argument, the approach of interstitial to microvascular pressure, the loss of the convective gradient, and the uniform-interior-steep-margin profile as reported. The assembly of the delivery chain across rows is this atlas's own", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I105", "name": "Mechanical and thermal conditions", "category": "External", "whereToCheck": "All modeled regions", "states": [ "Stress", "strain", "stiffness", "temperature" ], "behaviors": [ "Cell and molecular response", "distinguish culture from in vivo" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "recovered-stiffness-fibroglandular", "recovered-stiffness-fatty" ], "priorResearch": { "path": "simulation/data/profiles/mechanical-and-thermal-conditions.json", "summary": "The row the inventory told to distinguish culture from in vivo, and the answer is sharper than a caution. Natural extracellular matrices are viscoelastic and relax under stress; the hydrogels used for three-dimensional culture are typically elastic. Tuning relaxation rate independently of elastic modulus, degradation and ligand density, cell spreading, proliferation and osteogenic differentiation were all enhanced by faster relaxation, and stem cells in rapidly relaxing gels at a 17 kilopascal initial modulus built a mineralised, bone-like matrix (L269). So a stiffness is not a mechanical specification, and every elastic modulus in this atlas is half of one. Against that, the row supplies human in vivo stiffness for the first time: breast fibroglandular tissue at 2.95 plus or minus 0.43 kilopascals and fatty at 1.85 plus or minus 0.32, with reference ranges (L270), and brain stiffness varying by region across 96 adults with deep structures stiffer than cortex (L271). Temperature, the row's other named state, has no record anywhere.", "stateAxes": [ { "axis": "Stiffness, which is half a specification", "whatToMeasure": "The elastic modulus and the stress relaxation rate, as two variables. Natural matrices are viscoelastic while culture hydrogels are typically elastic; tuning relaxation independently of modulus, degradation and ligand density, faster relaxation enhanced spreading, proliferation and osteogenic differentiation, and at a 17 kilopascal initial modulus rapidly relaxing gels produced a mineralised collagen-1-rich matrix resembling bone. In people, breast fibroglandular tissue is 2.95 plus or minus 0.43 kilopascals and fatty tissue 1.85 plus or minus 0.32, with reference ranges of 2.17 to 3.77 and 1.30 to 2.44, and brain stiffness differs by region with deep structures above lobar ones.", "interpretationLimit": "The relaxation finding is engineered gels and one lineage in culture, so it establishes that the variable matters and not any tissue's value - and no relaxation time exists in this atlas for any tissue. Both human measurements are normal tissue rather than disease, from 48 and 96 people at single centres; elastography reports a shear modulus at a driving frequency, and the brain figures come from a virtual elastography inferred from diffusion imaging, which its authors call preliminary. So the atlas gains human baselines by compartment and region, and still cannot specify a substrate the way the culture result says it must.", "evidence": [ "L269", "L270", "L271" ] }, { "axis": "Distinguish culture from in vivo", "whatToMeasure": "Whether the substrate differs from tissue in the property that decides the outcome, not only in magnitude. It does: natural matrices relax and culture gels typically do not, and relaxation rate changed fate at fixed modulus. The magnitude gap is now also numerical - human breast parenchyma is 1.30 to 3.77 kilopascals across both compartments, against a 17 kilopascal gel in which stem cells built bone-like matrix and culture plastic orders of magnitude above either.", "interpretationLimit": "The comparison across those three figures is assembled by this profile from two records and common knowledge of culture plastic, not measured in one study - the atlas should treat the ordering as sound and the arithmetic as indicative. More importantly, the instruction cannot be fully obeyed: distinguishing culture from in vivo requires knowing the in vivo relaxation time, and the atlas has none, so for now it can say the substrate is wrong and not by how much.", "evidence": [ "L269", "L270" ] }, { "axis": "Stress and strain", "whatToMeasure": "The forces the atlas already holds for tumours, cited here because this row is their subject: solid stress from proliferating cells compressing vessels and lymphatics, interstitial pressures of 75 to 130 millimetres of mercury against 8 to 13 in normal tissue, arrest of migrating cells at 10 percent of the nuclear cross-section, and cell-generated stress under confinement with a passive phase from compression of the cell body and nucleus and an active contractile phase relieved by blebbing.", "interpretationLimit": "All of it is held in other rows and none of it is in units of force: the atlas has pressures for the consequence of solid stress and, since the cytoskeleton row, a structure for its cause without a magnitude - no pascals, no confinement threshold, no transition timing. And a force computed with an elastic analysis on a dissipative material may be misinterpreted, which this row's relaxation finding now shows is not a measurement nicety but a statement about tissue.", "evidence": [ "Q02", "L178", "L234", "L235" ] }, { "axis": "Temperature", "whatToMeasure": "The inventory names it as a state and nothing in this atlas measures it, in any family or environment. The absence is not quite passive: the atlas's own breast reoxygenation record manipulated temperature, raising tissue oxygen tension from an average median of 3.2 to 19.2 millimetres of mercury with neoadjuvant chemotherapy combined with hyperthermia - so the project holds an intervention that changes temperature, a measured consequence of it, and no temperature.", "interpretationLimit": "Because the two treatments were combined in that record, neither the thermal nor the chemotherapeutic contribution can be separated - the atlas already notes this. What it means for this row is that temperature appears in the project as an unmeasured confounder inside one of its better human results, which is worse than a clean absence.", "evidence": [ "L239" ] } ], "records": { "L178": { "id": "L178", "year": 2013, "topic": "Thickness and gaps", "title": "Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force", "url": "https://doi.org/10.1083/jcb.201210152", "studyType": "Migration quantified in MMP-degradable collagen lattices and non-degradable substrates of varying porosity, with nuclear deformation measured to the point of physical arrest, Journal of Cell Biology 201(7):1069-1084", "diseaseContext": "Shared cancer; healthy reference", "useInModel": "The atlas's first hard geometric threshold, and it is cell-type-specific. Migration independent of matrix metalloproteinases declined as a linear function of pore size and with deformation of the nucleus, with arrest reached at 10 percent of the nuclear cross section - 7 square micrometres for tumour cells, 4 for T cells, 2 for neutrophils. Residual migration under space restriction depended on MMP-dependent cleavage enlarging pore diameters and on integrin- and actomyosin-dependent force that jointly propelled the nucleus. Three things follow. The project has recorded local mechanisms without length scales repeatedly; here is a threshold with numbers and a linear relationship above it, so a model can interpolate rather than guess. The limiting structure is the nucleus, which means the hardest constraint in the Structures category is set by a component of the Intracellular category. And proteolysis is a modulator rather than a gate: migration happens without it and declines with pore size, while enzymes extend the range by widening pores - so blocking proteases shifts a threshold rather than closing a door.", "limit": "Engineered collagen lattices and synthetic porous substrates, not basement membrane and not tissue - so the thresholds are properties of cells moving through characterised pore geometries rather than measurements of any real interface. Basement membrane is a dense sheet rather than a porous lattice, so these numbers describe interstitial passage better than they describe crossing this family. The values are cross-sectional areas at arrest in specific cell types under specific conditions, and nuclear deformability varies with lamin composition and cell state, which this does not survey. Nothing here measures a pore size in any drawn environment.", "provenance": "Abstract read in full; the experimental systems, the linear dependence on pore size, the arrest criterion at 10 percent of nuclear cross section with all three cell-type values, and the roles of proteolysis and force generation as modulators as reported", "quantitativeExtraction": "extracted" }, "L234": { "id": "L234", "year": 2026, "topic": "Force", "title": "CFM: confinement force microscopy - a dynamic, precise and stable microconfiner for traction force microscopy in spatial confinement", "url": "https://doi.org/10.1038/s41592-026-03216-5", "studyType": "Microconfiner platform for live-cell imaging with programmable control of confinement level, timing and frequency while measuring traction forces on the microenvironment, with ROCK and myosin II inhibition, Nature Methods 23(11):2066-2076", "diseaseContext": "Healthy reference; shared cancer as the stated motivation", "useInModel": "Supplies the cause-side of a force the atlas has only ever held as a consequence. The delivery chain records interstitial pressures of 75 to 130 millimetres of mercury in tumours and names the compressing quantity as solid stress generated by proliferating cells, with the explicit note that the atlas holds pressures for the consequence and nothing for the cause. This measures the cause, and finds it has two phases. Under confinement a cell shows first a rapid passive stress rise, from compression of the cell body and nucleus against the substrate, and then an active stress increase associated with enhanced contractility, intracellular pressure buildup and bleb formation. Bleb expansion partially relieves that pressure and reduces the stress the cell imposes on its surroundings. ROCK and myosin II inhibition each reduce stress generation, with distinct effects on blebbing. Three uses. The passive phase is mechanically the same event the nucleus row records as damaging the genome, so one compression produces a force outward and DNA damage inward - the same confinement appearing in two of the atlas's rows with different readouts. Blebbing is a negative-feedback term on cell-generated stress, which the atlas's solid stress account does not have. And the two inhibitors make the active phase a target rather than a property.", "limit": "A methods paper in engineered confinement, so the result is a structure and not a magnitude: no stress in pascals, no confinement height at which each phase begins, and no timing for the passive-to-active transition are extracted here. Cells on a substrate under a programmable confiner, which is not an interstitial matrix - the geometry the atlas actually needs is a pore network, whose dimensions it holds for no drawn environment. Reduce stress generation is a direction for both inhibitors without magnitudes. No disease context and no in vivo work.", "provenance": "Abstract read in full; the platform's programmable control, both phases with their stated causes, the pressure-relieving role of blebbing, and the effects of ROCK and myosin II inhibition including their distinct consequences for blebbing as reported", "quantitativeExtraction": "extracted" }, "L235": { "id": "L235", "year": 2026, "topic": "Force", "title": "Traction Force Microscopy for Viscoelastic Substrates: A Semi-Analytical Method", "url": "https://doi.org/10.1002/advs.202522252", "studyType": "Semi-analytical two-dimensional viscoelastic traction force microscopy generalising the elastic Boussinesq framework to Generalized Maxwell substrates, applied to beating cardiomyocytes, epithelial cells and dermal fibroblasts on polyacrylamide and alginate hydrogels, Advanced Science 13:e22252", "diseaseContext": "Healthy reference", "useInModel": "A measurement-provenance caution about the quantity the companion record produces, and it is the strongest of its kind in the atlas because it says published values can be wrong rather than merely incomparable. Elastic formulations of traction force microscopy neglect viscous dissipation and can misinterpret cellular forces on viscoelastic substrates - and living tissue is viscoelastic. The generalisation finds two things that decide the answer: whether the cell engages the substrate elastically or viscoelastically depends on timescale matching between the loading rate and the substrate's relaxation times, and for the substrates analysed, viscoelastic traction magnitudes scale with the substrate's total dissipation rather than with individual relaxation times. So a traction force is not a property of the cell alone: it depends on how fast the cell pulls relative to how fast the material relaxes. For this atlas the instruction is concrete - any cell-generated force it ingests must carry the substrate model used to compute it, and a value obtained with an elastic formulation on a dissipative material should be treated as suspect rather than as a lower bound.", "limit": "A methods paper, so it supplies a framework and criteria rather than forces for any cell type in any disease - no magnitude is extracted here. Two-dimensional, on engineered hydrogels of finite thickness, with Generalized Maxwell substrates of one or two components; whether the scaling with total dissipation holds for tissue, which is neither two-dimensional nor a Maxwell material, is not established. The three cell types are a demonstration set. The criteria for when elastic treatment remains valid are derived within this framework, so they inherit its assumptions.", "provenance": "Abstract read in full; the stated misinterpretation risk on viscoelastic substrates, the dependence of regime on timescale matching, the scaling of magnitude with total dissipation rather than individual relaxation times, and the three cell types and two hydrogel systems as reported", "quantitativeExtraction": "extracted" }, "L239": { "id": "L239", "year": 2003, "topic": "Partial pressures", "title": "Ultrasound guided pO2 measurement of breast cancer reoxygenation after neoadjuvant chemotherapy and hyperthermia treatment", "url": "https://doi.org/10.1080/0265673031000121517", "studyType": "Ultrasound-guided Eppendorf polarographic oxygen probe measurement in 18 patients with stage IIB-III breast cancer, before and after neoadjuvant chemotherapy combined with hyperthermia, with colour Doppler used to avoid large vessels, International Journal of Hyperthermia 19(5):498-506", "diseaseContext": "Breast", "useInModel": "Bears directly on a disputed range the atlas has already flagged, and suggests the dispute is not a disagreement. The breast parameter set carries median tissue oxygen tension as a validation target of 23 to 28 millimetres of mercury from one source against 44 from another, labelled as a disputed range. In these 18 patients of the same stage and type the distribution was bimodal rather than uncertain: 11 of 18 were hypoxic by the conventional threshold of a median below 10 millimetres of mercury, averaging 3.2, while 7 had well-oxygenated tumours with a median of 48.3 - a fifteen- fold separation between two groups in one cohort. A population median between those two figures is the mean of a mixture, which is what the disputed range may be. The second finding is that the number moves under treatment: 8 of the hypoxic patients improved significantly, to 19.2 millimetres of mercury, while 3 stayed hypoxic at an average of 4.5. So this is a human in vivo parameter, in a drawn environment, with a before and after value - and the atlas should stop treating a single median as the quantity to reproduce.", "limit": "Eighteen patients, described by its own authors as preliminary, and the treatment is chemotherapy combined with hyperthermia rather than chemotherapy alone - so the reoxygenation cannot be attributed to either. Polarographic probe measurement samples tracks through the tumour rather than mapping it, which is the sparse-sampling problem the imaging literature raises, and the ultrasound guidance addresses electrode placement rather than coverage. The bimodality is an observation in one cohort and no mixture model is fitted. Whether the two groups differ in anything other than oxygenation is not established here.", "provenance": "Abstract read in full; the cohort size and stage, the hypoxia threshold used, both subgroup counts with their average and median values, the post-treatment value with its p value, and the three non-responding patients as reported", "quantitativeExtraction": "extracted" }, "L269": { "id": "L269", "year": 2016, "topic": "Distinguish culture from in vivo", "title": "Hydrogels with tunable stress relaxation regulate stem cell fate and activity", "url": "https://doi.org/10.1038/nmat4489", "studyType": "Materials approach tuning hydrogel stress relaxation rate independently of initial elastic modulus, degradation and cell-adhesion-ligand density, with three-dimensional culture of mesenchymal stem cells and mechanistic tests of adhesion-ligand binding, actomyosin contractility and ligand clustering, Nature Materials 15(3):326-334", "diseaseContext": "Healthy reference", "useInModel": "Answers the instruction this row was given and invalidates half the mechanical specifications in the atlas at the same time. Natural extracellular matrices are viscoelastic and exhibit stress relaxation; the hydrogels used as synthetic matrices for three-dimensional culture are typically elastic. Tuning the relaxation rate independently of the initial elastic modulus, the degradation rate and the adhesion-ligand density, the authors found cell spreading, proliferation and osteogenic differentiation of mesenchymal stem cells all enhanced in faster-relaxing gels - and strikingly, cells in rapidly relaxing gels with an initial elastic modulus of 17 kilopascals formed a mineralised, collagen-1-rich matrix resembling bone. The effects were mediated by adhesion-ligand binding, actomyosin contractility and mechanical clustering of adhesion ligands. Two consequences. A stiffness is not a mechanical specification: at a fixed modulus, the relaxation rate changed fate outright, so every elastic modulus this atlas holds - for basement membrane, for matrix, for any substrate - is half of what a model needs. And the instruction to distinguish culture from in vivo now has a mechanism rather than a caution: the standard culture substrate differs from tissue in precisely the property that is decisive, and in a direction nobody reports.", "limit": "Engineered hydrogels and mesenchymal stem cells in culture - so this establishes that relaxation rate matters, not what any tissue's relaxation rate is, and the atlas holds a relaxation time for no tissue in any environment. Osteogenic differentiation in a bone-forming lineage is the readout, so the generality of the direction to other cell types is untested here. Faster relaxing is reported comparatively without the relaxation times extracted, and the 17 kilopascal figure is the gel's initial elastic modulus rather than a tissue value. The clustering mechanism is identified as a mediator without a force or a cluster size.", "provenance": "Abstract read in full; the stated contrast between viscoelastic natural matrices and elastic culture hydrogels, the independent tuning of relaxation from modulus, degradation and ligand density, all three enhanced cell behaviours, the mineralised matrix at 17 kilopascals initial modulus, and all three named mediators as reported", "quantitativeExtraction": "extracted" }, "L270": { "id": "L270", "year": 2026, "topic": "Stiffness", "title": "Correlation Between Breast Parenchymal Stiffness Measured by 3T Magnetic Resonance Elastography and CT-Derived Hounsfield Units", "url": "https://doi.org/10.12659/MSM.952112", "studyType": "Single-centre study of 48 women aged 29 to 56 undergoing 3-tesla breast magnetic resonance elastography with a 19-centimetre pneumatic driver and non-contrast chest computed tomography within one month, with correlation, regression and tissue-specific reference analysis, Medical Science Monitor 32:e952112", "diseaseContext": "Breast", "useInModel": "A human in vivo stiffness in kilopascals, by tissue compartment, with reference ranges - in the environment that carries this atlas's parameter set. Fibroglandular tissue measured 2.95 plus or minus 0.43 kilopascals against 1.85 plus or minus 0.32 for fatty tissue, with reference ranges of 2.17 to 3.77 and 1.30 to 2.44 respectively. Stiffness correlated strongly with computed tomography attenuation at an r of 0.834, and a regression of stiffness on attenuation and age explained 70.1 percent of the variance. Three uses. The atlas has carried mechanical claims for several rows with a recorded caution that a stiffness without its method is uninterpretable; this is a non-invasive human measurement with its method, its driver and its field strength stated. It gives the culture comparison a number: normal breast parenchyma is single-digit kilopascals, against the 17 kilopascal gel in which stem cells built bone-like matrix and against culture plastic orders of magnitude above either. And because it is imaging, it could be repeated in the same patient, which makes it a mechanical measurement the project could in principle follow under treatment - where the atlas already knows the matrix obstacle changes.", "limit": "Forty-eight women at a single centre, aged 29 to 56, and normal parenchyma rather than tumour - so this is the baseline the environment's mechanics should be measured against and not a disease value. Elastography reports a shear modulus at the driving frequency, so it is a stiffness under a particular loading and not a complete mechanical description - which this row's companion record shows is the thing that matters, and no relaxation time is reported here. The correlation with computed tomography attenuation is a relationship between two imaging measures rather than a validation against mechanical testing. The regression's age term is small and fitted within a narrow age range.", "provenance": "Abstract read in full; the cohort and both modalities with field strength and driver, the correlation coefficient and its p value, the regression equation and its explained variance, both tissue stiffness means with standard deviations, and both reference ranges as reported", "quantitativeExtraction": "extracted" }, "L271": { "id": "L271", "year": 2026, "topic": "Stiffness", "title": "Measuring Brain Stiffness in Normal Adults According to Age and Sex Using Virtual MR Elastography: A Preliminary Study", "url": "https://doi.org/10.2463/mrms.mp.2025-0040", "studyType": "Retrospective study of 96 adults aged 31 to 80, 51 men and 45 women, with diffusion-weighted imaging at b values of 200 and 1500 converted to a virtual shear modulus and measured across 12 brain regions, Magnetic Resonance in Medical Sciences 25", "diseaseContext": "Healthy reference; relevant to Alzheimer's, ALS and frontotemporal dementia as the atlas's central nervous system environments", "useInModel": "A human in vivo mechanical measurement in the organ where this atlas's three neurodegenerative environments sit, and where almost every row has recorded holding nothing. Across 96 normal adults, brain stiffness showed regional differences, with higher shear modulus in deep structures - thalamus and basal ganglia - than in lobar regions, with age effects also detected. Two uses. It establishes that the quantity is obtainable non-invasively and regionally in people, which is what a central nervous system mechanical model would need, and the atlas has repeatedly recorded that its mechanical evidence is engineered substrates and mouse tissue. And the regional variation matters structurally: deep grey structures are stiffer than cortex, so a single brain stiffness is wrong in the same way a single tumour oxygen tension is - the project should carry a regional profile here as it has started to for sodium.", "limit": "Described by its authors as preliminary, retrospective, and based on a virtual elastography derived from diffusion-weighted imaging rather than on mechanical wave measurement - so the shear modulus is inferred from a diffusion contrast through a conversion, which is a longer inferential chain than conventional elastography and makes the absolute values method-dependent. No stiffness value for any region is extracted into this atlas by this record, only the pattern. Normal adults, so nothing about any disease state. The age effect's explained variance is small.", "provenance": "Abstract read in full; the cohort with its age and sex composition, the diffusion-weighted basis and both b values, the conversion to a virtual shear modulus, the 12 regions measured, and the finding of higher stiffness in deep structures than lobar regions with a detected age effect as reported", "quantitativeExtraction": "extracted" }, "Q02": { "id": "Q02", "year": 2012, "topic": "Transport comparator", "title": "Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma", "url": "https://pubmed.ncbi.nlm.nih.gov/22439937/", "studyType": "Autochthonous KPC/KC mouse pancreatic cancer with in vivo pressure catheter, vessel morphometry and drug-delivery imaging, Cancer Cell 21(3):418-429", "diseaseContext": "Pancreatic", "useInModel": "Gives the pressure that explains why pancreatic vessels are shut, and the size of the delivery gain from opening them. Interstitial fluid pressure measured by catheter was 8-13 mmHg in normal pancreas, mean 10.4 across 8 animals, against 75-130 mmHg in autochthonous PDA, mean 99 in 7 KPC tumours and 87 in 4 KC tumours. That exceeds typical capillary pressure of 15-40 mmHg and overlaps arteriolar pressure of 40-80, which is the mechanical reason the vessels are collapsed rather than absent. Hyaluronan is identified as the determinant: 3 mg/ml of it more than doubled the baseline pressure of carcinoma cells engrafted in collagen alone. A single intravenous dose of the hyaluronidase PEGPH20 brought pressure to 16 mmHg in KC and 22 mmHg in KPC tumours at 24 hours, statistically indistinguishable from normal pancreas, and produced a more than 6.5-fold increase in doxorubicin fluorescence in the tumour. Vessel number did not change - only diameter - so the gain came from reopening existing vessels, not from new ones. With gemcitabine, median survival went from 55.5 days to 91.5 days; the enzyme alone reached 63 days and was not significant.", "limit": "Mouse, pancreatic, small groups: 14 to 16 animals per survival arm and 4 to 8 per pressure measurement. The mechanism is formally disputed - two commentaries in the same journal argue that the vessel compression is caused by solid stress rather than by interstitial fluid pressure, so the measured pressures stand while the causal account does not (L26). And the delivery gain did not translate: the clinical trial of the same enzyme is Q03.", "provenance": "Full text read; pressures, delivery fold-change and survival medians taken from results and figure legends", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "recovered-stiffness-fibroglandular", "recovered-stiffness-fatty" ] }, { "id": "I106", "name": "Treatment molecules and formulations", "category": "External", "whereToCheck": "Blood; tissue; intracellular targets", "states": [ "Free", "bound", "degraded", "active metabolites" ], "behaviors": [ "Transport", "binding", "uptake", "clearance", "off-target exposure" ], "slots": { "size": { "status": "references available", "referenceIds": [ "recovered-doxorubicin-distance" ], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "references available", "referenceIds": [ "recovered-carboplatin-half-life" ], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "recovered-doxorubicin-distance", "recovered-carboplatin-half-life" ], "priorResearch": { "path": "simulation/data/profiles/treatment-molecules-and-formulations.json", "summary": "The row the whole delivery chain was built for, and it finally has a measured gradient. Doxorubicin concentration falls exponentially from tumour blood vessels, halving at about 40 to 50 micrometres, while viable cells sit 90 to 140 micrometres from the nearest vessel - so many are not exposed to detectable drug after a single injection, which is resistance with no resistance mechanism (L272). Penetration turns out to be a property of the molecule and the tissue together rather than of the tissue: two PARP inhibitors measured by validated quantitative imaging in the same tumour type distributed differently, niraparib homogeneously and at higher exposure than olaparib (L273). For the inventory's free and bound states the governing parameter is named, the mathematics established, and the values almost absent (L274) - and the lysosomal sink the atlas argued about is now quantified at 0.03 to 5.3 percent of tissue volume, mattering fourfold for one basic compound in spleen and 7 percent or less for most drugs (L275).", "stateAxes": [ { "axis": "Transport, with a decay length at last", "whatToMeasure": "Concentration against distance from the nearest vessel. Doxorubicin decreases exponentially from tumour vessels, halving at about 40 to 50 micrometres, with the mean vessel-to-hypoxia distance 90 to 140 micrometres in the same tumours and many viable cells not exposed to detectable drug after a single injection. Penetration differs between molecules: in one tumour type, niraparib distributed homogeneously with higher exposure than olaparib, by validated single-pixel quantitative imaging confirmed against bulk measurement.", "interpretationLimit": "Murine tumours and xenografts throughout. Doxorubicin can be imaged this way because it is intrinsically fluorescent, so the method does not generalise - quantitative mass spectrometry imaging does, and is targeted, so it requires knowing the analyte. A single injection rather than a clinical schedule, and detectable is assay-limited rather than zero. The half-distance belongs to this compound in these tumours and penetration is a drug property, so it must not be transferred. No absolute drug concentration in any tissue is ingested into this atlas by either record.", "evidence": [ "L272", "L273" ] }, { "axis": "Free versus bound", "whatToMeasure": "The unbound tissue concentration, and its ratio to unbound plasma, which the field names as the best indicator of the extent of tissue distribution. Blood may be a reasonable surrogate for passively permeable compounds; for the many compounds that are substrates of tissue uptake or efflux transporters, significant discrepancies between unbound blood and unbound tissue are expected. Three measurement routes exist - homogenates, slices and microdialysis - with the mathematics for rate and extent established.", "interpretationLimit": "The review's own assessment is that very few examples focus on tissue unbound drug concentration even in a preclinical setting, so the parameter is named, derivable and almost never measured - and this atlas holds no value for any compound in any tissue. From 2013, about drug discovery practice rather than any drawn environment, with the transporter-driven discrepancy treated as expected rather than systematically quantified.", "evidence": [ "L274" ] }, { "axis": "Bound, in a compartment the atlas had argued about", "whatToMeasure": "The sink's volume as well as its affinity. Lysosomal volume fractions across major rat tissues range from 0.03 percent in adipose to 5.3 percent in spleen; incorporating pH-driven trapping improved unbound partition predictions fourfold for nicotine in spleen, twofold in lung and kidney, 1.8-fold for quinidine in brain, and by 7 percent or less for most other drugs.", "interpretationLimit": "Rat tissues, estimated volume fractions from a marker lipid, and improvements in predicted rather than measured intracellular concentrations. No tumour is among the tissues characterised, which is where the atlas's dispute about lysosomal sequestration arose. What it settles is the general magnitude: the sink is specifiable and usually small, with exceptions confined to basic compounds of lower lipophilicity in lysosome-rich tissues - consistent with the atlas's reading that an intracellular sink matters only if it drains the source.", "evidence": [ "L275" ] }, { "axis": "Degraded, active metabolites, and off-target exposure", "whatToMeasure": "Three of the states and behaviours the inventory names, served unevenly. Degradation has one striking case and it is not the host's enzyme: a bacterial long-isoform cytidine deaminase inactivates gemcitabine inside tumours, with resistance abrogated by an antibiotic and 76 percent of human pancreatic tumours carrying such bacteria. Off-target exposure is served by records held elsewhere in the atlas - interstitial lung disease from a payload's reach, adjudicated in 381 cases among 2,801 treated patients, and three recorded off-target mechanisms. Active metabolites have no record at all.", "interpretationLimit": "The degradation case is mouse mechanism plus human prevalence and is the only degradation evidence this row has, which makes the atlas's coverage of this state accidental rather than systematic - host metabolism of drugs is enormous and almost entirely unread here. Active metabolites are named by the inventory and absent, which matters because the atlas holds a bladder residence record in which the measured species was an active metabolite.", "evidence": [ "L264", "L139" ] } ], "records": { "L139": { "id": "L139", "year": 2026, "topic": "Local toxicity", "title": "Real-world characteristics of trastuzumab deruxtecan-related interstitial lung disease in Japanese patients with breast cancer and gastric cancer", "url": "https://doi.org/10.1093/oncolo/oyag340", "studyType": "Post hoc analysis of independently adjudicated cases from all-patient post-marketing surveillance of 2,801 treated patients, The Oncologist 31:oyag340", "diseaseContext": "Breast cancer; gastric cancer", "useInModel": "Puts a number and a histology on the local toxicity the inventory asks for, and locates it in this family. Among 2,801 patients treated with trastuzumab deruxtecan - 1,731 breast, 1,070 gastric - 421 potential cases were reviewed and 381 were adjudicated as drug-related interstitial lung disease, 278 in breast and 103 in gastric cancer. The predominant imaging pattern was organising pneumonia at 67.7 percent, then hypersensitivity pneumonitis at 14.2 percent and diffuse alveolar damage at 12.6 percent. Most cases, 78.2 percent, were worst grade 1 or 2; grade 5 occurred in 30 patients, 7.9 percent of adjudicated cases, and diffuse alveolar damage was the pattern in 26 of those 30. Overall recovery was 83.5 percent. The timing matters as much as the rate: events occurred throughout observation including fatal cases beyond twelve months from initiation, with no specific onset window and no difference in time to onset across grades. So the hazard is flat rather than front-loaded, which means there is no early period after which exposure becomes safe - and the fatal subset is distinguished by a histological pattern that is specifically damage to the alveolar barrier this row describes.", "limit": "Post-marketing surveillance in Japanese patients, so neither the population nor the reporting is a trial cohort, and the percentages for pattern and grade are proportions of adjudicated cases rather than of all treated patients. Adjudication identifies drug-related disease without establishing the cellular mechanism, so attributing the damage to type 1 or type 2 cells specifically is an inference from the diffuse alveolar damage pattern and not a measurement. Smoking history in 28.3 percent is reported without being resolved as a risk factor here. Nothing in this record connects the toxicity to HER2 expression in lung tissue.", "provenance": "Abstract read in full; the treated and adjudicated counts by tumour type, all three imaging pattern proportions, the grade distribution, the grade 5 count with its pattern, the recovery rate, and the absence of an onset window as reported", "quantitativeExtraction": "extracted" }, "L264": { "id": "L264", "year": 2017, "topic": "Metabolites", "title": "Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine", "url": "https://doi.org/10.1126/science.aah5043", "studyType": "Colon cancer models with bacterial metabolism of gemcitabine, dependence on a long isoform of bacterial cytidine deaminase, antibiotic co-treatment in mice, and bacterial detection in 113 human pancreatic ductal adenocarcinomas, Science 357(6356):1156-1160", "diseaseContext": "Pancreatic (PDAC); Colorectal", "useInModel": "A drug destroyed at its destination by an enzyme that is not the host's - a failure mode the atlas's delivery chain does not have. Bacteria metabolise gemcitabine into its inactive form, and the metabolism depends on expression of a long isoform of the bacterial enzyme cytidine deaminase, seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intratumour Gammaproteobacteria, was dependent on that bacterial enzyme, and was abrogated by co-treatment with ciprofloxacin. In human tissue, 86 of 113 pancreatic ductal adenocarcinomas - 76 percent - were positive for bacteria, mainly Gammaproteobacteria. Three uses. The atlas's chain has six stages concerned with a molecule reaching its target and one noted missing stage about whether the machinery at the destination can handle it; this is a seventh problem, that something at the destination may consume the drug first, with its own genome and its own enzymology. The dependency is genetic and the rescue is an existing antibiotic, which makes it one of the better-specified interventions in the project. And the 76 percent prevalence is a human number in a drawn environment, which this row otherwise struggles to supply.", "limit": "The mechanism and the antibiotic rescue are mouse colon cancer models, and the pancreatic connection is a prevalence survey plus a hypothesis - the authors say consistent with this possibility, and no human resistance outcome is tested. Bacterial positivity in 76 percent of tumours is a detection result, and this row's other records establish how easily such detection is contaminated; the comparison tissue and controls for that survey are not extracted here. No bacterial load, no enzyme activity and no local gemcitabine concentration, so the atlas holds a mechanism with no quantity at any step. Published in 2017, before the field's contamination reckoning.", "provenance": "Abstract read in full; the inactivation product named, the dependence on the long cytidine deaminase isoform and its taxonomic distribution, all three elements of the mouse result including the ciprofloxacin rescue, and the 86 of 113 human prevalence figure as reported with the authors' own hedging", "quantitativeExtraction": "extracted" }, "L272": { "id": "L272", "year": 2005, "topic": "Transport", "title": "The distribution of the anticancer drug doxorubicin in relation to blood vessels in solid tumors", "url": "https://doi.org/10.1158/1078-0432.CCR-05-1664", "studyType": "Quantitative immunofluorescence of doxorubicin relative to CD31-identified blood vessels in murine 16C and EMT6 tumours and human PC-3 prostate xenografts, with hypoxic regions identified by injected EF5, Clinical Cancer Research 11(24):8782-8788", "diseaseContext": "Prostate; shared cancer", "useInModel": "The measured drug gradient the delivery chain has been reasoning about without. Doxorubicin concentration decreases exponentially with distance from tumour blood vessels, falling to half its perivascular value at about 40 to 50 micrometres; the mean distance from vessels to regions of hypoxia in the same tumours is 90 to 140 micrometres; and many viable tumour cells are not exposed to detectable drug after a single injection. The authors call limited distribution an important and neglected cause of clinical resistance that is amenable to modification. Three uses. The atlas's chain concludes that interstitial transport in tumours is diffusion alone and that the stage it diffuses through has no measured geometry; this measures the consequence directly - a decay length for the molecule itself. The geometric statement is the sharper one: with the drug halving in 40 to 50 micrometres and viable cells sitting 90 to 140 micrometres from the nearest vessel, a large fraction of the target population is beyond the drug's reach by construction, which is resistance without any resistance mechanism. And it is a length the project can compare against its own: this atlas already carries vessels about 109 micrometres apart in breast and an oxygen gradient falling more than half within 50 micrometres, so drug and oxygen decay on comparable scales and both are shorter than half the intervessel spacing.", "limit": "Murine tumours and a human xenograft, and doxorubicin is intrinsically fluorescent, which is why it can be imaged this way - the method does not generalise to most drugs, and the row's companion record shows what is needed instead. A single injection, so this is the distribution after one dose rather than at steady state under a clinical schedule. Detectable concentration is an assay-limited statement, not a statement about zero. The 40 to 50 micrometre half-distance is a fitted decay for this compound in these tumours and should not be transferred to another molecule, since penetration is a drug property. The comparison with the atlas's oxygen and vessel-spacing figures is this profile's synthesis across three records in three tissues, not a published result.", "provenance": "Abstract read in full; the exponential decay with the 40 to 50 micrometre half-distance, the 90 to 140 micrometre mean vessel-to-hypoxia distance, the statement that many viable cells see no detectable drug after a single injection, and the authors' conclusion about neglected resistance as reported", "quantitativeExtraction": "extracted" }, "L273": { "id": "L273", "year": 2020, "topic": "Transport", "title": "Quantitative determination of niraparib and olaparib tumor distribution by mass spectrometry imaging", "url": "https://doi.org/10.7150/ijbs.41395", "studyType": "Targeted mass spectrometry imaging with inorganic nanoparticle matrices, deuterated internal standard normalisation and a custom preprocessing pipeline for single-pixel absolute quantification of two PARP inhibitors in human ovarian tumours from treated mice, validated for precision, accuracy, linearity, repeatability and limit of detection, with LC-MS/MS confirmation, International Journal of Biological Sciences 16(8):1363-1375", "diseaseContext": "Ovarian (HGSC)", "useInModel": "Makes intratumoral penetration a measurable drug property rather than an inferred one, and shows two drugs of the same class differ in it. A quantitative imaging method was set up and validated for absolute single-pixel concentration, and the two PARP inhibitors behaved differently in the same tumour type: niraparib showed homogeneous distribution and higher tumour exposure than olaparib, with the imaging result confirmed by bulk mass spectrometry. Two uses. The atlas's address class lists penetration as one of six parameters and records it as computable in principle from a scaling law needing antigen concentration, affinity and internalisation rate, none of which the project holds - this is penetration measured directly instead, and spatially, which sidesteps the whole inference. And the finding that two agents against the same target distribute differently means penetration cannot be a property of the environment alone; it is a pairing of molecule and tissue, so the project needs it per compound and the chain's stages cannot be calibrated once and reused.", "limit": "Human ovarian tumours grown in treated mice, so the tissue is human and the pharmacokinetics are murine. Two compounds of one class, and the stated difference is in homogeneity and exposure without the concentrations extracted into this atlas - so the method's absolute values exist and none is held here. Targeted imaging requires knowing the analyte, which makes it a confirmation tool rather than a discovery one. The validation is analytical - precision, accuracy, linearity, repeatability, limit of detection - and says nothing about whether the measured distributions predict response.", "provenance": "Abstract read in full; the method's components and the five validation parameters, the comparison of the two inhibitors with niraparib's homogeneous distribution and higher exposure, and the LC-MS/MS confirmation as reported", "quantitativeExtraction": "extracted" }, "L274": { "id": "L274", "year": 2013, "topic": "Free versus bound", "title": "Insight into tissue unbound concentration: utility in drug discovery and development", "url": "https://doi.org/10.2174/1389200211314030008", "studyType": "Review of techniques for estimating tissue unbound drug concentration - homogenates, slices and microdialysis - with the mathematical expressions for the rate and extent of tissue distribution and the factors affecting unbound concentration, Current Drug Metabolism 14(3):324-340", "diseaseContext": "Healthy reference; drug discovery practice", "useInModel": "Names the parameter the inventory's first two states reduce to, and states how rarely it is measured. Under the free drug hypothesis the unbound concentration is the pharmacologically relevant one, and blood may be a reasonable surrogate for tissue for passively permeable compounds - but for the large number of compounds that are substrates of uptake or efflux transporters expressed in tissue, significant discrepancies are expected between unbound blood and unbound tissue concentrations. The ratio of unbound tissue to unbound plasma concentration is described as the best indicator of the extent of tissue distribution. And the review's own assessment is the part this atlas should carry: despite the technical advances it surveys, very few examples demonstrate a focus on tissue unbound drug concentrations in a preclinical setting. So the governing quantity for free and bound has a name, three measurement routes, an established mathematics, and almost no values - which is the same shape as several of this project's other gaps and unusual in having the theory fully worked out.", "limit": "A review from 2013, so it establishes the framework and the scarcity rather than supplying any value - no unbound concentration or partition coefficient for any compound in any tissue is extracted here. Its subject is drug discovery practice rather than any drawn environment, and none of the three techniques it surveys has been applied in this atlas. The free drug hypothesis is a hypothesis, and the review treats the transporter-driven discrepancy as expected rather than as systematically quantified.", "provenance": "Abstract read in full; the free drug hypothesis as stated, the conditions under which blood is a reasonable surrogate and where transporters break it, the unbound tissue-to-plasma ratio as the best indicator of extent, the three measurement techniques named, and the review's own statement that very few examples focus on tissue unbound concentration as reported", "quantitativeExtraction": "extracted" }, "L275": { "id": "L275", "year": 2021, "topic": "Bound", "title": "Extension of the mechanistic tissue distribution model of Rodgers and Rowland by systematic incorporation of lysosomal trapping: impact on unbound partition coefficient", "url": "https://doi.org/10.1124/dmd.120.000161", "studyType": "Validation of a lysosomal drug content prediction method across 41 compounds, estimation of lysosomal volume fraction for all major rat tissues using the lysosomal marker lipid bis(monoacylglycero)phosphate, and integration of pH-driven lysosomal trapping into an established mechanistic tissue distribution model, Drug Metabolism and Disposition 49(1):53-61", "diseaseContext": "Healthy reference", "useInModel": "Quantifies a compartment the atlas has argued about and settles the argument in the direction of the negative result. The endosome row holds two records disagreeing about whether lysosomal sequestration causes drug resistance, with the atlas's own reading that an intracellular sink matters only if it drains the source, and a note that no study tested both mechanisms in one system. This supplies the missing dimension - the size of the compartment. Lysosomal volume fractions were estimated for all major rat tissues and range from 0.03 percent in adipose to 5.3 percent in spleen. Integrating pH-driven trapping improved unbound partition predictions for lysosome-rich tissues: nicotine's rose fourfold in spleen and twofold in lung and kidney, quinidine's 1.8-fold in brain - and for most other drugs the effect was 7 percent or less. So the sink is real, specifiable and usually negligible, with the exceptions being basic compounds of lower lipophilicity in tissues that happen to be lysosome-rich. That is a rule the project can apply rather than a dispute it has to hold open.", "limit": "Rat tissues and a prediction-model exercise rather than measured intracellular drug concentrations - the volume fractions are estimated from a marker lipid and the partition improvements are improvements in predicted values against observed data, not direct measurements of lysosomal content in tissue. Forty-one compounds for the content-prediction validation. The model is a whole-body distribution framework, so its tissues are organs rather than any drawn environment, and no tumour appears. Whether the same volume fractions hold in human or in diseased tissue is untested, and tumours are not among the tissues characterised.", "provenance": "Abstract read in full; the 41-compound validation, the lysosomal volume fraction range from 0.03 percent in adipose to 5.3 percent in spleen, all three named compound-and-tissue improvements with their fold changes, and the statement that effects were 7 percent or less for most other drugs as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I107", "name": "Engineered therapeutic cells", "category": "External", "whereToCheck": "Selected immunotherapy modules", "states": [ "Viable", "activated", "proliferating", "exhausted" ], "behaviors": [ "Trafficking", "contact", "killing", "persistence" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "cart-p1-cd8", "cart-p1-cd4", "cart-p2-cd4" ], "priorResearch": { "path": "simulation/data/profiles/engineered-therapeutic-cells.json", "summary": "The row where the atlas's one quantified address-class parameter meets its opposite. That parameter is effector durability, recorded as mean specific lysis falling from 88.4 percent at day 7 to 8.6 percent at day 28 under continuous engager exposure and described as dominating this payload class. Here, CD19-directed CAR T cells given once remained detectable and functionally active more than ten years later, with sustained remission in both patients, a highly activated cytotoxic CD4 population dominating at late timepoints, and the clonal repertoire narrowing to a few clones (L276). Same payload category, three weeks against a decade, and the difference is how the cells are driven. Trafficking is also measurable in people: whole-body CD8 imaging across 23 patients and 251 lesions found uptake heterogeneous within patients as well as between them, with relapsing lesions consistently low and above-median pre-infusion uptake predicting longer time to progression (L277).", "stateAxes": [ { "axis": "Persistence, with an upper bound in people", "whatToMeasure": "Function over years, not weeks. CAR T cells were detectable more than ten years after a single infusion in two patients in continuous complete remission since 2010; a highly activated CD4 population emerged in both and dominated at later timepoints, showing cytotoxic characteristics with ongoing functional activation and proliferation on single-cell profiling; a gamma delta CAR T population expanded prominently in one patient alongside CD8 cells during the initial response; and the clonal repertoire stabilised around a small number of clones.", "interpretationLimit": "Two patients. This establishes that a decade of function is possible and says nothing about frequency. One disease, one antigen, and a liquid tumour - so none of it speaks to reaching cells through matrix. Detectability and proliferation are reported without cell numbers, so the atlas gains a timescale and not a density. Whether CD4 dominance causes the remission or follows it is unresolved, and the clonal narrowing is described without being linked to outcome.", "evidence": [ "L276" ] }, { "axis": "Trafficking, heterogeneous within a patient", "whatToMeasure": "Uptake per lesion, before and after infusion. Across 23 patients and 251 lesions, whole-body CD8 tracer uptake was heterogeneous between and within patients; higher pre-infusion tumour uptake was associated with higher post-infusion uptake at day 2; above-median pre-infusion uptake went with longer time to progression; and lesions that relapsed showed consistently low uptake. Normal-tissue uptake varied over time and no tracer-related side effects occurred.", "interpretationLimit": "Exploratory and single-arm with tracer distribution as the primary endpoint, so the outcome associations are secondary findings in 23 patients and not validated predictors. The tracer reports CD8 cells rather than the construct, so uptake mixes product with bystanders - a compartment measurement. Uptake is a signal rather than a cell density, with no cells per unit volume extracted, and varying normal-tissue uptake complicates the baseline.", "evidence": [ "L277" ] }, { "axis": "Exhausted, measured as function rather than phenotype", "whatToMeasure": "Lysis, not markers. The atlas's evidence for this state is the collapse of mean specific lysis from 88.4 percent at day 7 to 8.6 percent at day 28 under continuous engager exposure, with patients on 28-day continuous infusion showing declining T cell function - and the remedy recorded for that payload class being to stop dosing. Against it, this row's persistence record has cells still cytotoxic and proliferating after a decade following a single infusion.", "interpretationLimit": "The two sit at opposite ends and come from different platforms, different diseases and different measurement types - an in vitro lysis assay with a clinical correlate on one side, and single-cell profiling of two patients on the other. So the contrast is real as a bracket and is not a controlled comparison. Neither measures an exhaustion marker, which is the right way round for this atlas and means it holds no phenotype-to-function mapping for the state the inventory names.", "evidence": [ "L276" ] }, { "axis": "Viable, activated, proliferating, contact and killing", "whatToMeasure": "Five of the states and behaviours the inventory names, served only indirectly. Proliferation and activation appear as qualitative single-cell findings in the persistence record. Killing appears as the lysis figures held in the address class for an engager rather than for an engineered cell. Contact is not served at all - no contact duration, serial killing count or synapse measurement exists in this atlas for any effector. Viability of the infused product is not measured anywhere after infusion.", "interpretationLimit": "The gap that matters most is contact. The atlas holds a cell-based therapy's effect as a lysis percentage and never as an interaction - how long an effector dwells on a target, how many targets one cell kills, or how that depends on antigen density, which is itself one of six address-class parameters with no value. Without it the project cannot connect a cell count to a killing rate, which is the one calculation a cell-payload model most needs.", "evidence": [] } ], "records": { "L276": { "id": "L276", "year": 2022, "topic": "Persistence", "title": "Decade-long leukaemia remissions with persistence of CD4+ CAR T cells", "url": "https://doi.org/10.1038/s41586-021-04390-6", "studyType": "Longitudinal study of two patients with chronic lymphocytic leukaemia who achieved complete remission in 2010 after CD19-directed chimeric antigen receptor T cell infusion, with clonal repertoire tracking and single-cell profiling over more than ten years, Nature 602(7897):503-509", "diseaseContext": "Leukemia", "useInModel": "Sets the upper bound on effector persistence and shows it is a property of the platform rather than of the payload class. CAR T cells remained detectable more than ten years after a single infusion, with sustained remission in both patients. The atlas's address class holds effector durability as its only parameter with a magnitude, measured as mean specific lysis falling from 88.4 percent at day 7 to 8.6 percent at day 28 under continuous engager exposure, and records it as dominating that payload class. Both are engineered or recruited effectors against a B-cell antigen; one collapses in three weeks and the other works for a decade, and the difference is continuous exposure against a single infusion. So durability is not a fixed property of using cells as a payload - it is set by how the cells are driven, which connects this row to the project's schedule thread from a new direction. Two further findings matter for how the state should be represented. A highly activated CD4 population emerged in both patients and dominated at later timepoints, with cytotoxic characteristics and ongoing functional activation and proliferation on single-cell profiling - so the effector's identity changes over the course, and a gamma delta CAR T population expanded prominently in one patient alongside CD8 cells during the initial response. And the clonal repertoire stabilised, dominated by a small number of clones.", "limit": "Two patients, which is the central caveat - this establishes that decade-long functional persistence is possible and says nothing about how often it happens. One disease, one target antigen, and a liquid tumour, where the atlas's whole delivery chain problem of reaching cells through matrix does not arise; nothing here transfers to a solid environment. Detectable and ongoing proliferation are reported without cell numbers or fractions extracted, so the atlas gains a timescale and not a density. Whether the CD4 dominance is required for the remission or is a consequence of it is not established, and the clonal narrowing is described rather than linked to outcome.", "provenance": "Abstract read in full; the two patients and their 2010 remission, detectability beyond ten years with sustained remission, the emergence and late dominance of the activated CD4 population with its cytotoxic characteristics and continuing proliferation, the gamma delta expansion in one patient, and the clonal stabilisation around few clones as reported", "quantitativeExtraction": "extracted" }, "L277": { "id": "L277", "year": 2025, "topic": "Trafficking", "title": "Whole-body CD8+ T-cell PET imaging in patients with large B-cell lymphoma before and during CD19-directed CAR T-cell therapy: a phase 2 study", "url": "https://doi.org/10.1038/s41467-025-66767-9", "studyType": "Exploratory single-arm phase 2 trial using a zirconium-89-labelled one-armed anti-CD8-alpha antibody for whole-body positron emission tomography of CD8 T cells in 23 patients with relapsed or refractory large B-cell lymphoma, analysing 251 lesions before and after CAR T cell infusion, Nature Communications 16:11629", "diseaseContext": "Lymphoma", "useInModel": "Trafficking measured in patients, lesion by lesion, with an outcome link - and the variation is within patients rather than between them. Across 23 patients and 251 lesions, tracer uptake in normal tissues varied over time and tumour uptake was heterogeneous both between and within patients. Higher pre-infusion tumour uptake was associated with higher post-infusion uptake at day 2; above-median pre-infusion uptake was associated with a longer time to progression; and lesions that relapsed exhibited consistently low uptake. No tracer-related side effects occurred. Three uses. The atlas's recurring finding that a drawn environment splits into parts differing in kind now has an instance in the effector rather than in the tissue, at lesion resolution, in people, with relapse tracking the low-uptake lesions - so the unit of failure is a lesion and not a patient. The pre-infusion state constrains the post-infusion one, which makes existing infiltration a boundary condition on what the therapy can achieve rather than something the therapy establishes. And it is a whole-body, non-invasive, repeatable measurement of a cell population, which the project has wanted and has only ever had as tissue sections taken once.", "limit": "Exploratory, single-arm, with whole-body tracer distribution as the primary endpoint - so the associations with time to progression and relapse are secondary and exploratory in 23 patients, and should not be read as validated predictors. The tracer reports CD8 cells generally rather than the engineered cells specifically, so uptake mixes the product with pre-existing and bystander CD8 populations; this is a measurement of the compartment rather than of the construct. Uptake is a tracer signal rather than a cell density, and no cells per unit volume are extracted. Normal-tissue uptake varying over time complicates the baseline. One liquid-origin disease with nodal and extranodal lesions.", "provenance": "Abstract read in full; the tracer and modality, patient and lesion counts, the variation in normal tissue uptake over time, the heterogeneity between and within patients, the pre-to-post association at day 2, the absence of tracer-related side effects, the association of above-median pre-infusion uptake with longer time to progression, and the consistently low uptake in relapsing lesions as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "cart-p1-cd8", "cart-p1-cd4", "cart-p2-cd4" ] }, { "id": "I108", "name": "Anti-drug antibodies and drug complexes", "category": "External", "whereToCheck": "Treatment-exposed patients", "states": [ "Neutralizing", "non-neutralizing", "clearance-altering" ], "behaviors": [ "Exposure changes", "immunogenicity", "assay interference" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "ada-asthma-pooled-incidence" ], "priorResearch": { "path": "simulation/data/profiles/anti-drug-antibodies-and-drug-complexes.json", "summary": "The row whose inventory entry lists assay interference as a behaviour to resolve, and the evidence makes that the row's centre. Pooled anti-drug antibody incidence across 46 studies of six biologics was 2.91 percent, ranging from zero to 8.35 percent by agent, with neutralizing antibodies from zero to 10.74 percent (L278). For tumour necrosis factor inhibitors the antibodies are consistently associated with lower serum drug levels and reduced clinical response, and concomitant methotrexate lowers their prevalence - but the reviewers state that prevalence is not directly comparable across studies because of immunoassay heterogeneity (L279). The quantitative reason: across three iterations of one laboratory's own assay, sensitivity moved from 3,400 to 98 nanograms per millilitre, and from 6,900 to 46 for a companion assay (L280) - and the interference is structural, coming from the drug and from its soluble target (L281). Inside all of that sits a finding for the project's schedule thread: neutralizing antibodies were more common on the every-8-week arm than the every-4-week one.", "stateAxes": [ { "axis": "Immunogenicity, with a pooled incidence", "whatToMeasure": "Incidence by agent, not by class. Across 46 studies of six biologics, treatment-emergent anti-drug antibody incidence was 2.91 percent with a 95 percent interval of 1.60 to 4.55: benralizumab 8.35 percent with a risk ratio of 4.9 against placebo, dupilumab 7.61, reslizumab 4.39, mepolizumab 3.63, tezepelumab 1.12 and omalizumab zero. Neutralizing antibody incidence ran from zero to 10.74 percent, highest for benralizumab at 7.12 - and higher on its every-8-week arm, 8.17 percent, than on its every-4-week arm at 5.81.", "interpretationLimit": "One disease and one broad drug class, with incidences pooled across heterogeneous assays - which this row's other records show is the central problem with any such pooling. The dosing-interval comparison is between arms within a meta-analysis rather than a randomised test with immunogenicity as its endpoint, and the two arms differ in total exposure as well as interval. Clinical consequences are not quantified in this record.", "evidence": [ "L278" ] }, { "axis": "Clearance-altering, with a settled direction for one class", "whatToMeasure": "Serum drug level alongside antibody status, because they move together. Across tumour necrosis factor inhibitor studies, anti-drug antibodies were consistently associated with lower serum drug levels and reduced clinical response; prevalence was highest with adalimumab, infliximab and golimumab and very low or absent with secukinumab and etanercept; and concomitant methotrexate was associated with lower prevalence, making immunogenicity a modifiable property of a regimen rather than a fixed property of a molecule.", "interpretationLimit": "A systematic review without meta-analysis, so these are consistent directions rather than pooled estimates - no concentration difference or response difference is extracted. One disease. The reviewers state that drug level and outcome data were limited or lacking for the interleukin-targeting classes, so the direction does not extend across the agents reviewed. The methotrexate association is observational and confounded by why it is prescribed.", "evidence": [ "L279" ] }, { "axis": "Assay interference, which the row treats as its primary state", "whatToMeasure": "The assay's sensitivity and drug tolerance, before the result. Neutralizing antibody assays are inherently prone to interference from the drug and from its soluble target, with acid dissociation of immune complexes and separation of antibody from circulating drug as the remedies. The magnitude: across three iterations of one laboratory's assay, sensitivity improved from 3,400 to 98 nanograms per millilitre and drug tolerance from 2.5 to between 4.8 and 5.6 nanomolar, with the companion assay improving from 6,900 to 46 nanograms per millilitre.", "interpretationLimit": "Both are methods papers, so the figures belong to those assays and what transfers is the magnitude of the dependence. Later versions being more sensitive does not establish that their rates are correct, since the comparison is against the laboratory's own earlier versions rather than a truth standard. The interference is established and its error magnitude is not quantified - the authors' own phrase is potentially resulting in erroneous results. No patient samples in either.", "evidence": [ "L280", "L281" ] }, { "axis": "Neutralizing against non-neutralizing, and drug complexes", "whatToMeasure": "Which of the two an antibody is, since only one abolishes activity - and the incidence data separate them, with neutralizing antibodies running from zero to 10.74 percent against a total incidence of 2.91 percent pooled. For drug complexes, what the immune complex then does: nothing in this row measures complex formation, size, clearance route or effector consequence.", "interpretationLimit": "The neutralizing figures come from the same pooled analysis and inherit its assay heterogeneity, and cell-based neutralization assays are the format most affected by drug and target interference - so the distinction the inventory asks for is measured by the least tolerant method. Antibody subclass, which largely determines whether a complex clears or activates effectors, is not reported anywhere in this row. The drug-complexes half of the row's title has no measurement at all.", "evidence": [ "L278", "L281" ] } ], "records": { "L278": { "id": "L278", "year": 2023, "topic": "Immunogenicity", "title": "Incidence of Anti-Drug Antibodies to Monoclonal Antibodies in Asthma: A Systematic Review and Meta-Analysis", "url": "https://doi.org/10.1016/j.jaip.2022.12.046", "studyType": "Systematic review and meta-analysis of 46 randomised controlled trials, open-label extensions and non-randomised studies of six biologics approved for asthma, with treatment-emergent anti-drug antibody incidence and prevalence as primary outcomes, Journal of Allergy and Clinical Immunology: In Practice 11(5):1475-1484.e20", "diseaseContext": "Asthma; relevant to this atlas as the only pooled immunogenicity incidence it holds", "useInModel": "The quantified baseline for this row, and inside it a finding the project's schedule thread had not considered. Across 46 studies, anti-drug antibody incidence over follow-up was 2.91 percent with a 95 percent interval of 1.60 to 4.55 - highest with benralizumab at 8.35 percent, a risk ratio of 4.9 against placebo, and lowest with omalizumab at zero; dupilumab 7.61, reslizumab 4.39, mepolizumab 3.63 and tezepelumab 1.12 percent. Neutralizing antibody incidence ranged from zero to 10.74 percent, highest for benralizumab at 7.12. The finding that matters beyond this row: neutralizing antibody incidence was higher on the every-8-week benralizumab arm, 8.17 percent, than on the every-4-week arm at 5.81. A longer dosing interval produced more neutralizing antibodies. This project has assembled five randomised tests of whether intermittent dosing helps and has treated the question as being about efficacy and resistance; here is a mechanism by which a longer interval can be worse that none of them measured - the gaps between doses are when an immune response can be mounted against the agent. Any schedule a simulation proposes therefore has an immunogenicity cost that scales the wrong way.", "limit": "One disease and one drug class, and the dosing-interval comparison is between arms of benralizumab studies rather than a randomised test of interval with immunogenicity as an endpoint - so it is an association within a meta-analysis and the two arms differ in total exposure as well as in interval. Incidence figures are pooled across heterogeneous assays, which the companion record in this row shows is the central problem with any such pooling. Clinical impact is not quantified here beyond incidence, so the atlas gains rates and not consequences from this record.", "provenance": "Abstract read in full; the study count, the pooled incidence with its confidence interval, all six drug-specific incidences, the benralizumab risk ratio against placebo, the neutralizing antibody range and its benralizumab value, and both dosing-interval neutralizing incidences as reported", "quantitativeExtraction": "extracted" }, "L279": { "id": "L279", "year": 2026, "topic": "Clearance-altering", "title": "Prevalence and clinical relevance of anti-drug antibodies in psoriatic arthritis: a systematic review", "url": "https://doi.org/10.1136/rmdopen-2026-007140", "studyType": "PRISMA-guided systematic review of 28 studies - 19 randomised controlled trials and 9 observational - reporting anti-drug antibody measurement in adults receiving biological disease-modifying antirheumatic drugs, with risk of bias assessed by Cochrane tools, RMD Open 12:e007140", "diseaseContext": "Psoriatic arthritis; relevant to this atlas for the direction of effect and the pooling limit", "useInModel": "Gives the inventory's clearance-altering state a consistent direction, a modifiable factor, and a warning that the literature cannot be combined. Across tumour necrosis factor inhibitor studies, anti-drug antibodies were consistently associated with lower serum drug levels and reduced clinical response - so for this class the state is real and its sign is settled. Concomitant methotrexate was associated with lower anti-drug antibody prevalence, which makes immunogenicity a modifiable property of a regimen rather than a fixed property of a molecule. Prevalence was highest with adalimumab, infliximab and golimumab, then ustekinumab, ixekizumab, certolizumab pegol and guselkumab, while secukinumab and etanercept showed very low or absent immunogenicity. And the reviewers' own limit is the part this atlas should carry hardest: prevalence varied widely between agents and across studies of the same agent, and was not directly comparable because of immunoassay heterogeneity. So a published immunogenicity rate is a property of the assay as much as of the patients - which is the same shape as the near-detection-limit problem this atlas recorded for the tumour microbiome, in a literature that looks far more settled.", "limit": "A systematic review without meta-analysis, so the associations are consistent directions across studies rather than pooled estimates - no hazard ratio, no concentration difference and no response difference is extracted. One disease. For the interleukin-17, interleukin-12/23 and interleukin-23 inhibitors the reviewers state that serum drug level and clinical outcome data were limited or lacking, so the direction established for tumour necrosis factor inhibitors does not extend across the classes reviewed. The methotrexate association is observational and confounded by why patients receive it.", "provenance": "Abstract read in full; the study composition, the stated non-comparability due to immunoassay heterogeneity, the full prevalence ordering across agents, the consistent association of antibodies with lower drug levels and reduced response for tumour necrosis factor inhibitors, the methotrexate association, and the stated absence of data for the interleukin-targeting classes as reported", "quantitativeExtraction": "extracted" }, "L280": { "id": "L280", "year": 2025, "topic": "Assay interference", "title": "Improving sensitivity and drug tolerance of assays for neutralizing anti-drug antibodies to semaglutide and native GLP-1", "url": "https://doi.org/10.1080/17576180.2025.2596576", "studyType": "Development and validation of two cell-based neutralizing antibody assays across three iterations, with platform optimisation, sample pre-treatment and altered control antibodies, Bioanalysis 17(18):1449-1460", "diseaseContext": "Healthy reference; bioanalytical method development", "useInModel": "Puts a number on how much an immunogenicity result depends on the assay rather than on the patient. Across three iterations of the same assay for neutralizing antibodies to one drug, sensitivity improved from 3,400 to 98 nanograms per millilitre - a factor of about 35 - and drug tolerance from 2.5 nanomolar to between 4.8 and 5.6 nanomolar. For the companion assay against the endogenous ligand, sensitivity improved from 6,900 to 46 nanograms per millilitre, a factor of about 150. The same samples run on the first and last versions would give different answers, and the gain came from the concentration of drug standard used for receptor activation, sample pre-treatment, and better understanding of the control antibody's binding properties. For this atlas the lesson is the quantitative form of a caution it has already recorded twice: an incidence measured near an assay's detection limit is a property of the assay, and here the limit moved by one to two orders of magnitude within one laboratory's own method development. Any anti-drug antibody rate the project ingests must carry the assay's sensitivity and drug tolerance, and rates from different assays should not be pooled - which the clinical review in this row says the literature does anyway.", "limit": "A methods paper on one drug and its endogenous counterpart, so the specific figures belong to those assays - what transfers is the magnitude of the dependence, not the values. Cell-based neutralizing assays, which are a subset of immunogenicity testing. Improvement is measured against the laboratory's own earlier versions rather than against a truth standard, so a later assay being more sensitive does not establish that its rate is correct. No patient samples or clinical incidences are reported.", "provenance": "Abstract read in full; the three iterations, both sensitivity improvements with their start and end values, both drug tolerance improvements with their antibody concentrations, and the three factors credited for the gains as reported", "quantitativeExtraction": "extracted" }, "L281": { "id": "L281", "year": 2019, "topic": "Assay interference", "title": "Approaches to improve drug tolerance and target tolerance in the assessment of neutralizing anti-drug antibodies", "url": "https://doi.org/10.4155/bio-2019-0184", "studyType": "Methodological study optimising acid pretreatment to dissociate antibody-drug immune complexes, with separation of neutralizing antibodies from circulating drug by removal or purification, in cell-based and non-cell-based assays, and an integrated strategy for simultaneous drug and soluble target tolerance, Bioanalysis 11(22):2061-2074", "diseaseContext": "Healthy reference; bioanalytical method development", "useInModel": "Names the two interferences and one of them is not obvious. Neutralizing antibody assays are described as inherently prone to interference from the drug and from its soluble target, potentially producing erroneous results - so the measurement is corrupted both by the agent being tested for antibodies and by the very molecule the agent was designed to bind. The remedy is mechanical: acid pretreatment to dissociate the antibody-drug immune complexes, then separation of the antibodies from circulating drug by removal or purification, with an integrated strategy to handle drug and soluble target together. Two uses for this atlas. The soluble target interference connects this row to the molecular rows, where shed and soluble forms of targets are recorded - those soluble forms are not only a sink for the drug but a confounder in the assay that would detect the immune response to it. And the word inherently is the right one for the project to carry: this is not a defect of particular assays but a structural property of measuring an antibody against a molecule that is still circulating, which is why the measurement needs a stated tolerance rather than a stated result.", "limit": "A methods paper, so it establishes the interference and the remedies without quantifying how wrong an untreated assay is - no error magnitude is reported, and potentially resulting in erroneous results is the authors' own hedge. Acid pretreatment conditions and separation approaches are optimised for the systems studied rather than generalised. Nothing here is a patient sample or a clinical incidence, and the soluble target interference is named as a general problem without any specific target's contribution being measured.", "provenance": "Abstract read in full; the two named sources of interference including the soluble target, the acid dissociation approach with subsequent separation by removal or purification, both assay formats addressed, and the integrated drug-and-target strategy as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [ "ada-asthma-pooled-incidence" ] }, { "id": "I109", "name": "Dead cells and necrotic regions", "category": "External", "whereToCheck": "Disease and treatment sites", "states": [ "Apoptotic", "necrotic", "cleared" ], "behaviors": [ "Debris", "diffusion obstacles", "inflammation", "histology bias" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "unknown", "referenceIds": [], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [], "priorResearch": { "path": "simulation/data/profiles/dead-cells-and-necrotic-regions.json", "summary": "The row three other rows pointed at before it was written, and the atlas recorded why: potassium released from necrosis suppresses T cell effector function, sodium imaging finds its highest concentration in necrotic areas, and extracellular ATP sits in the hundreds of micromolar in tumour interstitium against undetectable in healthy tissue. The inventory frames this row as debris, diffusion obstacles, inflammation and histology bias - something in the way - and on that evidence it is a chemical reservoir. This row adds the second mode: dead cells also act by being eaten. Efferocytosis induces a proangiogenic function in macrophages near vascular niches, remodels their chromatin and attenuates their interferon-gamma response, with the induced programme correlating with poor survival in human uveal melanoma (L282). And where the state has been measured against outcome, presence fails and extent works: in 343 clear cell renal carcinomas presence gave 64.6 percent accuracy and no independent significance, extent gave 74.5 percent and p equal to 0.029 (L283) - while in papillary disease the same measure is prognostic in one subtype and not the other (L284).", "stateAxes": [ { "axis": "Necrotic, where presence fails and extent works", "whatToMeasure": "The proportion, not the presence. In 343 consecutive clear cell renal carcinomas necrosis was present in 227 - 66 percent - and associated with more advanced disease, yet gave only 64.6 percent predictive accuracy for cancer-specific survival and was not retained as an independent factor at p equal to 0.299. Significant heterogeneity existed among the tumours that had it, with increasing extent tracking performance status, stage, grade, vascular invasion and sarcomatoid features; extent-based classification reached 74.5 percent accuracy and independence at p equal to 0.029, with a 20 percent cut-off proposed.", "interpretationLimit": "One tumour type, one centre, 2009, and necrosis scored histologically on sampled sections - so extent is a proportion of what was sampled rather than of the tumour, which this row's histology-bias record bears on directly. Accuracy figures are concordance in this cohort and will fall on external validation, and the 20 percent cut-off is a clinical convenience rather than a biological threshold.", "evidence": [ "L283" ] }, { "axis": "Cleared, and what clearing does to the clearer", "whatToMeasure": "The state of the macrophage after engulfment, graded by how much it has digested. Coupling single-cell transcriptomes to lysosomal acidification, a gene programme rose gradually with acidification; efferocytosis induced a proangiogenic function in macrophages spatially close to vascular niches, remodelled chromatin accessibility and attenuated the response to interferon-gamma; and the programme's expression correlated with poor survival in human uveal melanoma.", "interpretationLimit": "Murine melanoma for the mechanism with a human survival correlation for a gene score defined in the same work and not independently validated. Labelled apoptotic cells were supplied as cargo, which is not the apoptotic and necrotic mixture a tumour contains, and no engulfment rate, cargo count per macrophage or duration of the reprogrammed state is held. The proangiogenic effect is positional with no distance given, which matters because the atlas does hold signalling length scales to compare against.", "evidence": [ "L282" ] }, { "axis": "Histology bias, which the inventory named", "whatToMeasure": "Whether the variable in the record is there because it matters or because a template asked for it. A pathology reporting template for bone tumour biopsies recommends spontaneous tumour necrosis and mitotic rate - described as of unproven prognostic significance - while omitting cytologic anaplasia; and in 125 patients with high-grade osteosarcoma, severe anaplasia was independently associated with better overall and disease-free survival while mitotic rate and spontaneous necrosis had no prognostic impact after adjustment.", "interpretationLimit": "Osteosarcoma, outside the drawn set, retrospective, one cohort of 125 - so the negative findings are this cohort's and the template critique is an argument rather than a settled revision. And it concerns diagnostic biopsies, where sampling of necrosis is least reliable, while this row's positive prognostic findings are on resected renal specimens. The records therefore disagree across tumour type and specimen type, and the atlas should carry the specimen-dependence rather than a verdict.", "evidence": [ "L285" ] }, { "axis": "Apoptotic against necrotic, debris, diffusion obstacles and inflammation", "whatToMeasure": "Four things the inventory names and this row cannot separate or serve. The apoptotic-necrotic distinction is the one that should matter most, since clearance of apoptotic material reprogrammes macrophages towards suppression while necrotic rupture supplies suppressive ions and nucleotides - two different mechanisms from two modes of death - and the prognostic evidence scores histological necrosis without distinguishing them. Debris, diffusion obstacles and inflammation have no measurement at all: no particle load, no effect of necrotic regions on a measured diffusion coefficient, and no inflammatory consequence quantified.", "interpretationLimit": "The diffusion obstacle the inventory names is the one this atlas is best equipped to care about and least able to evaluate - the delivery chain's weakest stage is the geometry a molecule diffuses through, a drug halves within 40 to 50 micrometres of a vessel, and whether necrotic regions help or hinder that is unmeasured. Nothing in the atlas reports a diffusion coefficient, a porosity or a binding capacity for necrotic tissue, so a region occupying up to a fifth of a tumour is unrepresented in the transport account.", "evidence": [] } ], "records": { "L282": { "id": "L282", "year": 2026, "topic": "Cleared", "title": "Efferocytosis induces proangiogenic function and chromatin remodeling in tumor-associated macrophages", "url": "https://doi.org/10.1126/sciimmunol.aed1544", "studyType": "Single-cell transcriptomics coupled with lysosomal acidification tracked by a pH-sensitive dye to follow molecular dynamics after engulfment of labelled apoptotic cells, with a derived gene programme scored in a murine melanoma model and in human uveal melanoma, Science Immunology 11:eaed1544", "diseaseContext": "Melanoma (cutaneous); Uveal melanoma", "useInModel": "Turns clearance from a disposal process into an interaction that reprogrammes the clearing cell, and supplies the consequence this row most needed. Coupling single-cell transcriptomes to lysosomal acidification measured by a pH-sensitive dye, the authors defined a gene programme that rises gradually with dye intensity - so the state is graded by how much has been digested rather than by whether engulfment occurred. In murine melanoma, efferocytosis induced a proangiogenic function in macrophages that were spatially close to vascular niches; it remodelled chromatin accessibility, leading to an attenuated macrophage response to interferon-gamma; and in human uveal melanoma the programme's expression correlated with poor survival. Three uses. The atlas's three records pointing at this row all treat dead cells as a chemical source - potassium released, sodium concentrated, ATP abundant - and this adds the second mode: dead cells act by being eaten, and the eater changes. The attenuated interferon-gamma response matters specifically, since the atlas carries an interferon-gamma length scale of 30 to 40 micrometres as one of its few measured signalling ranges - the receiving cell's responsiveness is now known to depend on what it has recently digested. And it is a third instance of an environmental input setting a state in the nucleus row, after oxygen through clustered DNA breaks and methionine through a histone mark - the first where the input is an entire cell.", "limit": "A murine melanoma model for the mechanism, with human uveal melanoma contributing a survival correlation for a gene score rather than any measurement of efferocytosis itself - so the human arm is an association with a transcriptional proxy. The score is defined in this work and has no independent validation. Labelled apoptotic cells supplied as cargo, which is not the mixture of apoptotic and necrotic material a tumour contains, and no rate of engulfment, number of cargo cells per macrophage or duration of the reprogrammed state is extracted. The proangiogenic effect is positional and no distance is given.", "provenance": "Abstract read in full; the coupled transcriptomic and lysosomal acidification method, the gradual rise of the derived programme with dye intensity, the proangiogenic induction with its spatial proximity to vascular niches, the chromatin remodelling with the attenuated interferon-gamma response, and the survival correlation in human uveal melanoma as reported", "quantitativeExtraction": "extracted" }, "L283": { "id": "L283", "year": 2009, "topic": "Necrotic", "title": "Presence of tumor necrosis is not a significant predictor of survival in clear cell renal cell carcinoma: higher prognostic accuracy of extent based rather than presence/absence classification", "url": "https://doi.org/10.1016/j.juro.2008.11.098", "studyType": "Prospective study of the presence and extent of tumour necrosis against pathological features and cancer-specific survival in 343 consecutive patients with clear cell renal cell carcinoma, comparing presence-absence against extent-based classification, Journal of Urology 181(4):1558-1564", "diseaseContext": "Kidney", "useInModel": "A third family in which a binary state variable fails and a graded one works, with the accuracy gain measured. Necrosis was present in 227 of 343 tumours, 66 percent, and was associated with more advanced disease - but its predictive accuracy for cancer-specific survival was only 64.6 percent and presence was not retained as an independent prognostic factor on multivariate analysis, at p equal to 0.299. There was significant heterogeneity among the tumours that had necrosis, with increasing extent associated with poorer performance status, higher stage and grade, vascular invasion and sarcomatoid features. Extent-based classification predicted survival better than presence alone, 74.5 against 64.6 percent, and was retained as independent at p equal to 0.029, with a 20 percent cut-off proposed for clinical use. The atlas has recorded twice that a state measured across its range turns out to be graded rather than categorical - for motor neuron vulnerability and for astrocyte reactivity - and noted that in both cases the replacement was unspecified. Here the graded version exists, is quantified, and gains about ten percentage points of accuracy over the binary. That makes this the first instance where the project can see what the fix is worth.", "limit": "One tumour type and one centre, with necrosis assessed histologically on resected specimens - so the extent is a proportion of what the sections sampled rather than of the tumour, which this row's own histology-bias concern bears on directly. Predictive accuracy figures are concordance measures for this cohort and will shrink on external validation. The 20 percent cut-off is proposed for clinical convenience rather than derived as a biological threshold. Published in 2009, before much of the molecular subclassification of this disease.", "provenance": "Abstract read in full; the prospective design and cohort size, the 227 of 343 prevalence, the 64.6 percent accuracy and non-significant multivariate p value for presence, the stated heterogeneity and the associations of increasing extent, the 74.5 percent accuracy and p equal to 0.029 for extent-based classification, and the proposed 20 percent cut-off as reported", "quantitativeExtraction": "extracted" }, "L285": { "id": "L285", "year": 2017, "topic": "Histology bias", "title": "Cytologic anaplasia is a prognostic factor in osteosarcoma biopsies, but mitotic rate or extent of spontaneous tumor necrosis are not: a critique of the College of American Pathologists cancer template", "url": "https://doi.org/10.1038/modpathol.2016.163", "studyType": "Retrospective cohort of 125 patients with high-grade osteosarcoma evaluating diagnostic biopsy features against clinical outcome and neoadjuvant chemotherapy response, with multivariate Cox regression adjusted for established prognostic factors and logistic regression for good response, Modern Pathology 30(1):52-59", "diseaseContext": "Shared cancer; osteosarcoma, outside the drawn set", "useInModel": "Names the bias the inventory told this row to resolve, and locates it in a reporting standard rather than in an experiment. The current pathology template for bone tumour biopsies recommends reporting features of unproven prognostic significance, including spontaneous tumour necrosis and mitotic rate, while omitting the degree of cytologic anaplasia. In 125 patients with high-grade osteosarcoma, severe anaplasia was independently associated with increased overall and disease-free survival, while mitotic rate and spontaneous necrosis had no prognostic impact after controlling for confounders - and neither spontaneous necrosis nor anaplasia predicted a good histologic response to chemotherapy. For this atlas the general lesson is about where its own numbers come from. Most of what the project ingests as a tissue measurement was recorded because a template asked for it, and a template can ask for a variable with no demonstrated prognostic value while omitting one that has it. So the availability of a measurement in the record is not evidence that it matters, and the absence of one is not evidence that it does not.", "limit": "Osteosarcoma, which is not a drawn environment, and a retrospective single-cohort study of 125 patients - so the negative findings for necrosis and mitotic rate are this cohort's and the template critique is an argument rather than a consensus revision. Diagnostic biopsies rather than resections, which is the setting where sampling of necrosis is least reliable, and this row's companion records find necrosis extent prognostic in a different disease on resected material. So the records disagree across tumour types and specimen types, and the atlas should hold the specimen-dependence rather than a general verdict on necrosis as a prognostic variable.", "provenance": "Abstract read in full; the stated contents and omission of the reporting template, the cohort size, the independent association of severe anaplasia with both survival measures, the absence of prognostic impact for mitotic rate and spontaneous necrosis after adjustment, and the failure of either to predict chemotherapy response as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] }, { "id": "I110", "name": "Systemic boundary conditions", "category": "External", "whereToCheck": "Outside local region", "states": [ "Organ function", "age", "prior therapy", "circulation" ], "behaviors": [ "Incoming drug/cells/signals", "clearance", "replenishment" ], "slots": { "size": { "status": "unknown", "referenceIds": [], "gap": "State-specific geometry / dimensions remain unresolved unless explicitly measured; mass is not a diameter." }, "amount": { "status": "references available", "referenceIds": [ "nutrient-glucose-plasma", "nutrient-glutamine-plasma", "nutrient-arginine-plasma", "nutrient-tryptophan-plasma", "nutrient-alanine-plasma", "nutrient-cystine-plasma" ], "gap": "Local count, concentration or density requires a stated tissue volume, compartment and disease state." }, "timing": { "status": "unknown", "referenceIds": [], "gap": "State-specific activation, movement and interaction times remain unresolved; lifespan is a different quantity." } }, "referenceIds": [ "nutrient-glucose-plasma", "nutrient-glutamine-plasma", "nutrient-arginine-plasma", "nutrient-tryptophan-plasma", "nutrient-alanine-plasma", "nutrient-cystine-plasma" ], "priorResearch": { "path": "simulation/data/profiles/systemic-boundary-conditions.json", "summary": "The last of the 110 rows, and the one that sits outside everything the other 109 describe. Its subject is what enters the modelled region from elsewhere, and the evidence says those inputs can override the local mechanism. Checkpoint inhibition prolonged survival at a hazard ratio of 0.73 in patients under 65 and had no significant effect at 75 and over, across 10,291 patients in one disease (L287) - while 14,768 patients in another showed no age effect at all, with performance status instead predicting survival without predicting response (L288). Sarcopenia, defined by a chair stand above 16.7 seconds together with reduced muscle quantity, is associated with severe toxicity and mortality in those over 70 (L289). And a systemic cytotoxic given before a locoregional cell therapy decides whether the patient mounts an immune response against it: without lymphodepletion, anti-CAR humoral and cellular responses appeared in cerebrospinal fluid and blood; with it, none in cerebrospinal fluid (L286).", "stateAxes": [ { "axis": "Age, which decides whether a local mechanism pays off - in one disease", "whatToMeasure": "Age, against outcome, stratified. Across 17 randomised trials and 10,291 patients with non-small cell lung cancer, checkpoint inhibition prolonged overall survival at a hazard ratio of 0.73 with an interval of 0.66 to 0.81 under 65 and also in the 65 to 75 stratum, with no significant effect at 75 and over - attributed to immunosenescence. In 14,768 patients with hepatocellular carcinoma there was no significant evidence of an age effect on efficacy.", "interpretationLimit": "The two disagree, and the atlas holds both. The lung analysis uses published subgroups rather than individual patient data, so confounding with performance status, comorbidity and treatment intensity is inseparable, and an absent effect in the smallest and least-represented stratum is not evidence of none. The liver analysis dichotomises age as older against younger, which could miss a threshold effect above 75 by construction, and pools heterogeneous study designs. Disease is the obvious candidate stratifier and nothing here tests it.", "evidence": [ "L287", "L288" ] }, { "axis": "Organ function, and a dissociation worth keeping", "whatToMeasure": "Survival and response separately, because one boundary variable moves only the first. Performance status had no significant effect on objective response or progression-free survival in 14,768 patients - intervals crossing unity on both - while worse performance status went with worse overall survival at a hazard ratio of 1.52 from 1.26 to 1.84. Separately, sarcopenia defined as a chair stand above 16.7 seconds plus reduced muscle quantity or quality, severe when a timed up-and-go exceeds 13.5 seconds, was associated with severe treatment toxicity and mortality in adults over 70.", "interpretationLimit": "Performance status is a coarse ordinal scored by different observers across 111 studies. The sarcopenia analysis is a secondary observational analysis of 161 participants in a trial's usual care arm, with no effect sizes extracted - so the atlas holds a definition, two thresholds and a direction, and sarcopenia may mark disease burden rather than cause intolerance. Neither record measures an organ's function directly; both use whole-patient proxies for it.", "evidence": [ "L288", "L289" ] }, { "axis": "Prior therapy, engineered on purpose", "whatToMeasure": "What the preceding treatment did to the host's capacity to respond to the next one. In a phase I trial of CAR T cells infused weekly into the cerebral ventricles, patients who did not receive lymphodepletion developed anti-CAR humoral and cellular immune responses detectable in cerebrospinal fluid and peripheral blood, while patients receiving systemic lymphodepletion had no evidence of anti-CAR immunity in cerebrospinal fluid. Feasibility, safety and tolerability were met with one dose-limiting toxicity; 8 of 16 evaluable patients had radiographic size decreases and two met protocol response criteria.", "interpretationLimit": "A preprint and a phase I trial whose endpoints were feasibility and safety, so the response and survival figures are descriptive in 16 evaluable patients - and the 187-month ependymoma survival from diagnosis reflects an indolent course rather than a treatment effect. The lymphodepletion comparison is between those who did and did not receive it rather than randomised, so confounding by the reason for the choice cannot be excluded, and an absence of detectable anti-CAR immunity depends on an assay sensitivity not extracted here.", "evidence": [ "L286" ] }, { "axis": "Circulation, replenishment, and the incoming terms", "whatToMeasure": "The rates at which the region is supplied and drained from outside - which the inventory names and which this row holds only in fragments scattered through other rows. Body weight scales a clearance constant allometrically; a cerebrospinal compartment has turnover for almost 200 proteins; interstitial nutrient levels depend on animal diet; and the atlas's marrow rows describe where circulating cells are replenished from without any rate of replenishment.", "interpretationLimit": "Nothing in this row measures a circulation, a replenishment rate or an incoming flux. The fragments cited belong to other rows and were assembled for other purposes, so the inventory's three behaviours - incoming drug, cells and signals; clearance; replenishment - are the least served of any row in the atlas despite being the terms a bounded model most needs. A simulation of a local region requires values at its boundary, and this row establishes that those values matter without supplying one.", "evidence": [ "L212", "L211", "L244" ] } ], "records": { "L211": { "id": "L211", "year": 2019, "topic": "Transport", "title": "In Vivo Large-Scale Mapping of Protein Turnover in Human Cerebrospinal Fluid", "url": "https://doi.org/10.1021/acs.analchem.9b03328", "studyType": "Metabolic labelling with sequential ventricular cerebrospinal fluid sampling in patients, proteome-wide and targeted, with mathematical modelling to derive per-protein turnover parameters, Analytical Chemistry 91(24):15500-15508", "diseaseContext": "Healthy reference; patients with ventricular access", "useInModel": "The single most useful methodological record in this atlas for its largest structural gap. The project's recurring complaint is that it holds exchanges without fluxes - five metabolite hand-offs between adjacent cells, none with a transfer rate. This work determined turnover parameters for almost 200 proteins in human ventricular cerebrospinal fluid, where a handful were known before, covering many neuron-biology and immune-related proteins including biomarkers and drug targets, and it reports a significant relationship between a protein's turnover and its tissue of origin. The requirement is stated plainly: sequential sample collection. That is why this compartment has rates and the atlas's other compartments do not - cerebrospinal fluid can be sampled repeatedly in the same person and interstitial fluid cannot. So the atlas's missing rates are not missing because rates are unmeasurable; they are missing because most of its compartments cannot be sampled twice. This row is the exception, and the relationship between turnover and origin means a protein's rate here carries information about where it came from.", "limit": "Ventricular cerebrospinal fluid from patients who had ventricular access, so the population is clinically selected and the compartment is not lumbar fluid, where most clinical biomarkers are measured. A methods paper: the turnover parameters are its product and no individual value is extracted into this atlas, so what is held is the existence and the method rather than any number. Turnover in a fluid compartment combines synthesis, entry, clearance and bulk flow, so a per-protein rate is not a secretion rate for this family. Nothing about disease.", "provenance": "Abstract read in full; the count of almost 200 proteins against a handful previously known, the classes of protein covered, the reported relationship between turnover and protein origin, and the stated requirement for sequential sampling as reported", "quantitativeExtraction": "extracted" }, "L212": { "id": "L212", "year": 2013, "topic": "Transport", "title": "Cerebrospinal fluid beta-amyloid turnover in the mouse, dog, monkey and human evaluated by systematic quantitative analyses", "url": "https://doi.org/10.1159/000341217", "studyType": "Pharmacokinetic and pharmacodynamic modelling of cerebrospinal fluid amyloid-beta dynamics after beta- or gamma-secretase inhibition, pooling in-house and published data across four species, Neurodegenerative Diseases 12(1):36-50", "diseaseContext": "Alzheimer's", "useInModel": "The atlas's first scaling law, written as an equation, and a species comparison with a number on it. The turnover rate constant for cerebrospinal fluid amyloid-beta 40 follows allometry as kout equal to 0.395 times body weight to the power -0.351. And the relationship to bulk fluid turnover changes with size: in rodents the amyloid-beta 40 rate constant is roughly twofold higher than the turnover of the fluid itself, while in higher species the two are comparable. Three uses. This is a parameter a simulation can actually carry, with an explicit dependence on body mass rather than a single value per species. It gives the project an instance of what cross-species transfer looks like when somebody quantifies it instead of cautioning about it - the scaling holds, and a derived ratio does not, which is a more useful statement than either a warning or a blanket assumption. And it bears directly on the atlas's amyloid row, since the slow turnover in these compartments is given as the reason pharmacodynamic readouts for secretase inhibitors are hard to interpret.", "limit": "Modelled rate constants derived from pooled dynamic data after pharmacological inhibition, so these are parameters of a fitted model rather than directly measured fluxes, and they describe amyloid-beta 40 specifically rather than the family's secretory output. Public-domain data pooled with in-house data across four species brings heterogeneous designs. An allometric exponent fitted across four species rests on few points. The comparison to fluid turnover uses literature values for that turnover, which this atlas does not independently hold - so the twofold statement depends on a number not recorded here.", "provenance": "Abstract read in full; the allometric equation with its coefficient and exponent as printed, the twofold relationship in rodents against comparability in higher species, the four species pooled, and the authors' stated motivation about slow turnover complicating interpretation as reported", "quantitativeExtraction": "extracted" }, "L244": { "id": "L244", "year": 2019, "topic": "Available", "title": "Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability", "url": "https://doi.org/10.7554/eLife.44235", "studyType": "Quantitative metabolomics measuring absolute concentrations of more than 118 metabolites in plasma and in tumour interstitial fluid, compared between autochthonous and transplant models of murine pancreatic and lung adenocarcinoma and across diets, eLife 8:e44235", "diseaseContext": "Pancreatic (PDAC); Lung (NSCLC)", "useInModel": "The single largest ingestion opportunity the atlas has found, and it corrects an assumption the project has been carrying. Absolute concentrations were measured for more than 118 metabolites in tumour interstitial fluid - the extracellular fluid that perfuses tumours, and the compartment in which every metabolite hand-off this atlas records takes place. Three findings. The nutrients available to tumours differ from those present in circulation, so plasma is not a proxy for the interstitium and the atlas should not treat a serum value as a local one. Interstitial nutrient levels differed between autochthonous and transplant models of the same disease, which is a warning about every transplant-model number the atlas holds. And tumour type, anatomical location and animal diet each affected local availability - so a nutrient concentration is not a property of a disease but of a disease in a place under a feeding regimen. The atlas has repeatedly recorded that its metabolite exchange terms have no flux; what it had not noticed is that they have no concentration either, and this supplies concentrations for more than a hundred of them in two drawn environments.", "limit": "Murine, and terminal: interstitial fluid is obtained from excised tumours, so this is a destructive single-timepoint measurement and gives concentrations rather than rates - it does not supply the fluxes the atlas lacks, only the other half of what a flux calculation needs. Two tumour types. The comparison showing that transplant and autochthonous models differ is itself the reason to be careful transferring these values to human disease, which is untested here. Diet effects mean the numbers are conditional on husbandry. No individual metabolite concentration is extracted into this atlas by this record, so what is held is the existence, the method and the three determinants.", "provenance": "Abstract read in full; the count of more than 118 metabolites and both compartments measured, the difference between interstitial fluid and plasma, the autochthonous against transplant comparison, and all three stated determinants of local availability as reported", "quantitativeExtraction": "extracted" }, "L286": { "id": "L286", "year": 2026, "topic": "Prior therapy", "title": "Lymphodepletion mitigates anti-CAR immunity in pediatric and young adult patients with recurrent or refractory brain tumors: clinical trial results", "url": "https://doi.org/10.64898/2026.08.27.26361261", "studyType": "Phase I clinical trial of IL13BB-zeta CAR T cells infused weekly into the cerebral ventricles in paediatric and young adult patients with recurrent or refractory brain tumours, with anti-CAR humoral and cellular responses measured in cerebrospinal fluid and peripheral blood in patients with and without systemic lymphodepletion; preprint", "diseaseContext": "Glioblastoma; paediatric high-grade glioma and ependymoma", "useInModel": "A systemic intervention outside the modelled region decides whether a local therapy survives immunologically, and it closes a gap this atlas recorded as open. Patients who did not receive lymphodepletion developed anti-CAR humoral and cellular immune responses detectable in both cerebrospinal fluid and peripheral blood; patients who did receive systemic lymphodepletion had no evidence of anti-CAR immunity in cerebrospinal fluid. The anti-drug antibody row recorded that the atlas held no immunogenicity data for any engineered construct while holding effects that fade - and this is that measurement, in the compartment where the therapy acts. Three uses. The boundary condition here is not passive context but a deliberately engineered part of the treatment: a systemic cytotoxic given to change what the local region will do to the agent. Immunity against the construct is measurable in the local fluid, so the project can in principle carry it as a state rather than as a risk. And the trial itself is locoregional delivery repeated weekly into the ventricles, which is the atlas's delivery chain bypassed at stage one - and still the therapy needed a systemic intervention to work. Trial outcomes: feasibility, safety and tolerability were met with one dose-limiting toxicity, 8 of 16 evaluable patients had radiographic size decreases and two met protocol response criteria, with median survival for lymphodepleted patients of 20.5 months from diagnosis and 6.9 from treatment in midline glioma, and 187 months from diagnosis and 7.5 from treatment in ependymoma.", "limit": "A preprint, which the atlas should weight accordingly, and a phase I trial whose primary objectives were feasibility, safety and tolerability rather than efficacy - so the response and survival figures are descriptive in 16 evaluable patients and the 187-month ependymoma figure from diagnosis reflects an indolent course rather than a treatment effect. The lymphodepletion comparison is between patients who did and did not receive it rather than a randomised allocation, so confounding by why it was given cannot be excluded. Absence of cerebrospinal anti-CAR immunity is a negative detection result with the assay's sensitivity not extracted. Paediatric and young adult patients, and two tumour types.", "provenance": "Abstract read in full; the construct and the weekly intraventricular route, the met primary objectives with one dose-limiting toxicity, the 8 of 16 radiographic decreases and two protocol responses, both median survival pairs by tumour type, and the contrast in anti-CAR humoral and cellular responses between lymphodepleted and non-lymphodepleted patients in both compartments as reported", "quantitativeExtraction": "extracted" }, "L287": { "id": "L287", "year": 2024, "topic": "Age", "title": "Efficacy of immune checkpoint inhibitors for NSCLC in patients with different age: A systematic review and meta-analysis", "url": "https://doi.org/10.1016/j.asjsur.2024.03.145", "studyType": "Systematic review and meta-analysis of 17 randomised controlled trials comprising 10,291 patients with non-small cell lung cancer, comparing overall survival under immune checkpoint inhibition across three age strata, Asian Journal of Surgery 47(11):4691-4698", "diseaseContext": "Lung (NSCLC)", "useInModel": "A patient-level variable outside any modelled region decides whether a local immune intervention works, with a magnitude. Across 17 randomised trials and 10,291 patients, checkpoint inhibition significantly prolonged overall survival in patients under 65 at a hazard ratio of 0.73 with a 95 percent interval of 0.66 to 0.81, and in those aged 65 to 75 - and had no significant effect on overall survival in those aged 75 and over. The authors attribute the loss to immunosenescence, innate and adaptive immune dysregulation with age. For this project the lesson is structural and arrives in the last row by design: the atlas has spent 109 rows on what is inside the local region, and here a number recorded on a patient's chart determines whether the mechanism those rows describe produces a survival benefit at all. Age also appears repeatedly inside the atlas already - perivascular aquaporin-4 localisation tracks it, brain stiffness varies with it, and it is a term in this project's only human breast stiffness regression - so it is both a boundary condition and a modifier of the local variables.", "limit": "Trial-level meta-analysis with age as a stratification of published subgroups rather than individual patient data, so the strata are as the trials defined them and confounding with performance status, comorbidity and treatment intensity cannot be separated. Absence of a significant effect in the oldest group is not evidence of no effect - that stratum is the smallest and the least well represented in trials. One disease and one drug class, and the immunosenescence attribution is the authors' interpretation rather than anything measured here. The companion record in this row finds no age effect in a different disease.", "provenance": "Abstract read in full; the trial and patient counts, the hazard ratio with its interval for the under-65 stratum, the benefit in the 65 to 75 stratum, the absence of a significant overall survival effect at 75 and over, and the authors' attribution to immunosenescence as reported", "quantitativeExtraction": "extracted" }, "L288": { "id": "L288", "year": 2024, "topic": "Organ function", "title": "The effect of age, sex, and Eastern Cooperative Oncology Group performance status on the efficacy and safety of immune checkpoint inhibitors in patients with hepatocellular carcinoma", "url": "https://doi.org/10.1080/14737140.2024.2341723", "studyType": "Meta-analysis of 111 studies comprising 14,768 patients with hepatocellular carcinoma, evaluating age, sex and performance status against objective response, progression-free survival and overall survival under immune checkpoint inhibition, Expert Review of Anticancer Therapy 24(5):303-312", "diseaseContext": "Liver (HCC & CRC mets)", "useInModel": "Disagrees with the companion record about the same boundary variable, and the atlas should hold both. Across 111 studies and 14,768 patients with hepatocellular carcinoma, there was no significant evidence of an effect of age or of sex on the efficacy of checkpoint inhibition - against 10,291 lung cancer patients in whom the benefit disappeared above 75. What did matter was performance status: it had no significant effect on objective response or progression-free survival, with odds and hazard ratios whose intervals cross unity, while patients with worse performance status had worse overall survival at a hazard ratio of 1.52 with an interval of 1.26 to 1.84. The authors conclude that therapy should not be restricted by age or sex while worse performance status may warrant closer monitoring. Two uses. The disagreement about age is a candidate for the resolution the dead-cell row demonstrated - stratification by disease rather than better measurement - and nothing in this atlas settles it. And the dissociation within this record is the more useful finding: performance status predicts survival without predicting response or progression, so it is acting on whether a patient lives rather than on whether the drug works, which are different quantities a model should not merge.", "limit": "A large meta-analysis of heterogeneous studies including single-arm and observational designs, so the pooled estimates mix evidence of very different quality - and no significant evidence of an effect in a pooled analysis is weaker than a demonstrated absence. Performance status is a coarse clinical ordinal recorded by different observers across 111 studies. Age and sex comparisons are dichotomised as older against younger and male against female, so a threshold effect like the one reported in lung cancer above 75 could be missed by construction. One disease, one drug class.", "provenance": "Abstract read in full; the study and patient counts, the absence of significant age or sex effects on efficacy, the null results for performance status on objective response and progression-free survival with their intervals, the overall survival hazard ratio of 1.52 with its interval, and the authors' conclusion about not restricting by age or sex as reported", "quantitativeExtraction": "extracted" }, "L289": { "id": "L289", "year": 2026, "topic": "Organ function", "title": "Sarcopenia Is Associated With Severe Treatment Toxicity and Mortality in Older Adults With Advanced Cancer: A Secondary Analysis", "url": "https://doi.org/10.1002/jcsm.70388", "studyType": "Secondary analysis of 161 participants in the usual care arm of a randomised geriatric assessment trial - adults aged 70 and over with advanced cancer starting a new regimen, recruited from community oncology practices - with sarcopenia defined by reduced strength plus reduced muscle quantity or quality on baseline standard-of-care computed tomography, Journal of Cachexia, Sarcopenia and Muscle 17:e70388", "diseaseContext": "Shared cancer; older adults with advanced disease", "useInModel": "A boundary condition measured at the bedside, with operational thresholds, predicting toxicity and death. Sarcopenia was defined as reduced strength - a chair stand time above 16.7 seconds for five rises - together with either reduced muscle quantity by skeletal muscle index on routine computed tomography or reduced muscle quality, and classed as severe when impaired physical performance was also present, a timed up-and-go above 13.5 seconds. So defined, it was associated with severe treatment toxicity and with mortality in adults aged 70 and over starting a new regimen. Two uses. The authors note that most published work measures muscle quantity alone in patients under 70, so this is the combination of strength and quantity in the population actually treated - a correction of a literature's habit rather than a new variable. And the thresholds are the most accessible numbers in this entire atlas: a chair and a stopwatch against the mass spectrometry, elastography and isotope infusion the other 109 rows depend on. If a bedside measure predicts who is harmed by treatment, a simulation that models only the local region is answering a narrower question than the clinical one.", "limit": "A secondary analysis of 161 participants in the usual care arm of a trial designed for something else, so this is observational within a randomised study and the associations are not causal - sarcopenia may mark disease burden rather than cause intolerance. Mixed advanced cancers rather than any drawn environment. The effect sizes are not extracted here, so the atlas holds the definition, the thresholds and the direction without magnitudes. Computed tomography was standard of care, so muscle quantity is measured on scans acquired for other purposes with the variability that implies.", "provenance": "Abstract read in full; the design and cohort, the composite definition with the chair stand threshold of 16.7 seconds and the timed up-and-go threshold of 13.5 seconds for severity, the stated association with severe treatment toxicity and mortality, and the authors' observation that most prior work measures quantity alone in patients under 70 as reported", "quantitativeExtraction": "extracted" } }, "boundary": "Existing family research, carried forward with its original interpretation limits. This is not a fresh verification of every claim or a set of simulation defaults." }, "otherReferenceIds": [] } ], "references": [ { "id": "hatton-55", "family": "I001", "source": "hatton", "locator": "UniqueID 55", "population": "Capillary EnCs", "tissue": "Eyes; Head · Retina; Vascular; Blood.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 400.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 317.0, 835.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 36600000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 400.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 36600000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 400.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 29300000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Adamson, 1993; Aird, 2007; Pries, 2000; Crapo, 1982; Hogan, 1986.", "amount": "Nagra, 2017; Panda-Jonas, 1994; Kolb, 1995; Nittala, 2018; Grover, 2010; Kryczka, 2014;Nickla, 2010; Freitas, 1999; Greer, 2004, p777." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-527", "family": "I001", "source": "hatton", "locator": "UniqueID 527", "population": "Capillary EnCs", "tissue": "Lungs; Pulmonary · Vascular; Lungs", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 632.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 429.0, 835.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 69100000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 632.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 61700000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 632.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 30900000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Crapo, 1982; Hogan, 1986.", "amount": "Crapo, 1982; Stone, 1992a; Snyder, 1975, (ICRP-23, p 172)." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-547", "family": "I004", "source": "hatton", "locator": "UniqueID 547", "population": "Capillary EnCs-L", "tissue": "Heart · Vascular; Lymphatics.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 400.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 317.0, 835.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 5420000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 400.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 4110000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 400.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2300000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Adamson, 1993; Aird, 2007; Pries, 2000; Crapo, 1982; Hogan, 1986.", "amount": "Freitas, 1999; Bergmann, 2015; Pinto, 2016." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-580", "family": "I004", "source": "hatton", "locator": "UniqueID 580", "population": "Capillary EnCs-L", "tissue": "Lymph Nodes · Vascular; Lymphatics.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 400.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 317.0, 835.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1460000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 400.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1270000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 400.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 780000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Adamson, 1993; Aird, 2007; Pries, 2000; Crapo, 1982; Hogan, 1986.", "amount": "Fletcher, 2011b; Freitas, 1999; Hirosue, 2015; Fletcher, 2011a; Willard-Mack, 2006." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-153", "family": "I005", "source": "hatton", "locator": "UniqueID 153", "population": "Pericytes / Vascular Mural Cells (vSMCs)", "tissue": "Central Nervous System (CNS), Brain · Vascular; Cerebrum", "match": "Related pooled identity; subtype unresolved", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 366.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 285.0, 460.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 9430000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 366.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 8460000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 366.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 8520000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Gordon, 2011; Ribatti, 2015; Siegel, 1996, in Greger, 1996, p 1942-43; Grant, 2019; Mangialardi, 2016; Mills, 2013; Brown, 2019; Alarcon-Martinez, 2018; Trost, 2016.", "amount": "Castro Dias, 2019; Hall, 2014; Pardridge, 1999; Murray, 2017; Mills, 2013; Armulik, 2011; Cipolla, 2009; Geevarghese, 2014; Shepro, 1993." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-528", "family": "I005", "source": "hatton", "locator": "UniqueID 528", "population": "Pericytes / Vascular Mural Cells (vSMCs)", "tissue": "Lungs; Pulmonary · Vascular; Lungs", "match": "Related pooled identity; subtype unresolved", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 366.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 285.0, 460.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 9870000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 366.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 8820000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 366.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 4410000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Gordon, 2011; Ribatti, 2015; Siegel, 1996, in Greger, 1996, p 1942-43; Grant, 2019; Mangialardi, 2016; Mills, 2013; Brown, 2019; Alarcon-Martinez, 2018; Trost, 2016.", "amount": "Barron, 2016; Kato, 2018; Armulik, 2011." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. 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Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. 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Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-562", "family": "I008", "source": "hatton", "locator": "UniqueID 562", "population": "Red Blood Cells (RBCs)", "tissue": "Blood, Intravascular · Blood; Intravascular, Circulating.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 97.9, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 66.6, 133.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 25700000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 97.9, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 19200000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 97.9, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 11700000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Greer, 2004, p217; Kaushansky, 2010, p418; d'Onofrio, 1995; Snyder, 1975; Prall, 1998; Grover, 2011; Norouzi, 2017.", "amount": "Snyder, 1975, p94; Kaushansky, 2010, p 335; Guyton, 2006, p419; Boron, 2009, p453; McPherson, 2011." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-564", "family": "I009", "source": "hatton", "locator": "UniqueID 564", "population": "Platelets", "tissue": "Blood, Intravascular · Blood; Intravascular, Circulating.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 9.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 6.4799999999999995, 12.3 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1300000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 9.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 969000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 9.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 591000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Kaushansky, 2010, p1735; Greer, 2004, p6, 619; Zipursky, 1976; Norouzi, 2017; Schmoeller, 2017; Korniluk, 2019.", "amount": "Kaushansky, 2010, p17; Snyder, 1975, p38, 33, 105; Freitas, 1999, p247." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-520", "family": "I011", "source": "hatton", "locator": "UniqueID 520", "population": "Lymphocyte T-Cells; Cytotoxic (CD8)", "tissue": "Lungs; Bronchial Tree · Blood; Tissue Resident; Bronchial Tissue; Lamina Propria.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 108.0, 135.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 932000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 832000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 416000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Schmid-schonbein, 1980; Downey, 1990; Kaushansky, 2010, p1079; Milo, 2015, p44; Kaushansky, 2016, p1138,39; Zipursky, 1976; Norouzi, 2017.", "amount": "Ekberg-Jansson, 1999; Pabst, 1995." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-532", "family": "I011", "source": "hatton", "locator": "UniqueID 532", "population": "Lymphocyte T-Cells; Cytotoxic (CD8)", "tissue": "Lungs; Pulmonary · Blood; Tissue Resident.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 108.0, 135.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 3540000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 3170000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1580000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Schmid-schonbein, 1980; Downey, 1990; Kaushansky, 2010, p1079; Milo, 2015, p44; Kaushansky, 2016, p1138,39; Zipursky, 1976; Norouzi, 2017.", "amount": "Ganusov, 2007; Crapo, 1982; Pabst, 1995; Apostoaei, 2012; Semenzato, 1996; del Mar Valenzuela-Membrives, 2016." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-1179", "family": "I011", "source": "hatton", "locator": "UniqueID 1179", "population": "Lymphocyte T-Cells; Cytotoxic (CD8)", "tissue": "Breast, female · Blood; Tissue Resident; Lobules", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1270000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Schmid-schonbein, 1980; Downey, 1990; Kaushansky, 2010, p1079; Milo, 2015, p44; Kaushansky, 2016, p1138,39; Zipursky, 1976; Norouzi, 2017.", "amount": "Degnim, 2014; Kim, 2020; Erdag, 2012; Li, 2019; Li, 2020." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-521", "family": "I012", "source": "hatton", "locator": "UniqueID 521", "population": "Lymphocyte T-Cells; Helper (CD4)", "tissue": "Lungs; Bronchial Tree · Blood; Tissue Resident; Bronchial Tissue; Lamina Propria.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 108.0, 135.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 932000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 832000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 416000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Schmid-schonbein, 1980; Downey, 1990; Kaushansky, 2010, p1079; Milo, 2015, p44; Kaushansky, 2016, p1138,39; Zipursky, 1976; Norouzi, 2017.", "amount": "Ekberg-Jansson, 1999; Pabst, 1995." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-531", "family": "I012", "source": "hatton", "locator": "UniqueID 531", "population": "Lymphocyte T-Cells; Helper (CD4)", "tissue": "Lungs; Pulmonary · Blood; Tissue Resident.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 108.0, 135.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 5770000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 5160000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2580000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Schmid-schonbein, 1980; Downey, 1990; Kaushansky, 2010, p1079; Milo, 2015, p44; Kaushansky, 2016, p1138,39; Zipursky, 1976; Norouzi, 2017.", "amount": "Ganusov, 2007; Crapo, 1982; Pabst, 1995; Apostoaei, 2012; Semenzato, 1996; del Mar Valenzuela-Membrives, 2016." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-1178", "family": "I012", "source": "hatton", "locator": "UniqueID 1178", "population": "Lymphocyte T-Cells; Helper (CD4)", "tissue": "Breast, female · Blood; Tissue Resident; Lobules", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 179000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Schmid-schonbein, 1980; Downey, 1990; Kaushansky, 2010, p1079; Milo, 2015, p44; Kaushansky, 2016, p1138,39; Zipursky, 1976; Norouzi, 2017.", "amount": "Degnim, 2014; Kim, 2020; Erdag, 2012; Li, 2019; Li, 2020." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-707", "family": "I014", "source": "hatton", "locator": "UniqueID 707", "population": "Lymphocyte T-Cells; gamma delta ", "tissue": "GastroIntestinal Tract (GIT) · Blood; Tissue Resident; Intraepithelial; Small Intestines", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 108.0, 135.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 11300000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 10400000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 6420000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Schmid-schonbein, 1980; Downey, 1990; Kaushansky, 2010, p1079; Milo, 2015, p44; Kaushansky, 2016, p1138,39; Zipursky, 1976; Norouzi, 2017.", "amount": "Cellier, 1998; Westermann, 1992; Cheroutre, 2011; Mayassi, 2018; Ganusov, 2007." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-572", "family": "I016", "source": "hatton", "locator": "UniqueID 572", "population": "NK Lymphocytes; Natural Killer Cells", "tissue": "Blood, Intravascular · Blood; Intravascular, Circulating.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 258.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 194.0, 335.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2470000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 258.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1840000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 258.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1120000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Greer, 2004, p511; Zipursky, 1976; Norouzi, 2017.", "amount": "Kaushansky, 2010, p14, 17; Apostoaei, 2012, p 16; Morbach, 2010; Ruschil, 2020; Kokuina, 2019." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-536", "family": "I016", "source": "hatton", "locator": "UniqueID 536", "population": "NK Lymphocytes; Natural Killer Cells", "tissue": "Lungs; Pulmonary · Blood; Tissue Resident.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 258.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 194.0, 335.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 3210000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 258.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2870000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 258.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1430000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Greer, 2004, p511; Zipursky, 1976; Norouzi, 2017.", "amount": "Ganusov, 2007; Crapo, 1982; Pabst, 1995; Apostoaei, 2012; Semenzato, 1996; del Mar Valenzuela-Membrives, 2016." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-571", "family": "I018", "source": "hatton", "locator": "UniqueID 571", "population": "Lymphocyte B-Cells", "tissue": "Blood, Intravascular · Blood; Intravascular, Circulating.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 108.0, 135.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1430000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1070000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 650000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Schmid-schonbein, 1980; Downey, 1990; Kaushansky, 2010, p1079; Milo, 2015, p44; Kaushansky, 2016, p1138,39; Zipursky, 1976; Norouzi, 2017.", "amount": "Kaushansky, 2010, p14, 17; Apostoaei, 2012, p 16; Morbach, 2010; Ruschil, 2020; Kokuina, 2019." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-535", "family": "I018", "source": "hatton", "locator": "UniqueID 535", "population": "Lymphocyte B-Cells", "tissue": "Lungs; Pulmonary · Blood; Tissue Resident.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 108.0, 135.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 962000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 860000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 125.00000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 430000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Schmid-schonbein, 1980; Downey, 1990; Kaushansky, 2010, p1079; Milo, 2015, p44; Kaushansky, 2016, p1138,39; Zipursky, 1976; Norouzi, 2017.", "amount": "Ganusov, 2007; Crapo, 1982; Pabst, 1995; Apostoaei, 2012; Semenzato, 1996; del Mar Valenzuela-Membrives, 2016." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-573", "family": "I019", "source": "hatton", "locator": "UniqueID 573", "population": "Plasma Cells (Lymphoid cells)", "tissue": "Blood, Intravascular · Blood; Intravascular, Circulating.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 800.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 174.0, 1909.9999999999998 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 30000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 800.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 22400000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 800.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 13600000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Kaushansky, 2010, p33, 1082; Zipursky, 1976; Norouzi, 2017.", "amount": "Apostoaei, 2012, p 16, 27; Morbach, 2010; Ruschil, 2020; Kokuina, 2019." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-584", "family": "I019", "source": "hatton", "locator": "UniqueID 584", "population": "Plasma Cells (Lymphoid cells)", "tissue": "Lymph Nodes · Blood Organ, Tissue Resident.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 800.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 174.0, 1909.9999999999998 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 5700000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 800.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 4940000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 800.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 3040000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Kaushansky, 2010, p33, 1082; Zipursky, 1976; Norouzi, 2017.", "amount": "Pabst, 2008; Kaushansky, 2010; Greer, 2004; Shander, 2014; Nunez, 2016; Joling, 1994; Apostoaei, 2012, p34." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-586", "family": "I020", "source": "hatton", "locator": "UniqueID 586", "population": "Dendritic Cells", "tissue": "Lymph Nodes · Blood Organ, Tissue Resident.", "match": "Related pooled identity; subtype unresolved", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1450.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 664.0, 2240.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 6670000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1450.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 5780000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1450.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 3560000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Dumortier, 2005; Wi_niewski, 2014.", "amount": "Kumar, 2015; Hirosue, 2015; Fletcher, 2011a; Willard-Mack, 2006; Bode, 2008." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-1177", "family": "I020", "source": "hatton", "locator": "UniqueID 1177", "population": "Dendritic Cells", "tissue": "Breast, female · Blood; Tissue Resident; Lobules", "match": "Related pooled identity; subtype unresolved", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1740.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 110000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Graw, 2012; Dumortier, 2005; Wisniewski, 2014.", "amount": "Degnim, 2014; Kim, 2020; Erdag, 2012; Li, 2019; Li, 2020." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-574", "family": "I022", "source": "hatton", "locator": "UniqueID 574", "population": "Monocytes", "tissue": "Blood, Intravascular · Blood; Intravascular, Circulating.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 357.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 209.0, 560.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1560000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 357.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1160000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 357.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 709000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Downey, 1990; Schmid-schonbein, 1980; Kaushansky, 2010, p989; Zipursky, 1976.", "amount": "Kaushansky, 2010, p14, 17; Greer, 2004, p 356; Swirski, 2009; Shander, 2014." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-575", "family": "I022", "source": "hatton", "locator": "UniqueID 575", "population": "Monocytes; marginating pool", "tissue": "Blood, Intravascular · Blood; Intravascular, Marginating pool", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 357.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 209.0, 560.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2040000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 357.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1520000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 357.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 927000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Downey, 1990; Schmid-schonbein, 1980; Kaushansky, 2010, p989; Zipursky, 1976.", "amount": "Kaushansky, 2010, p14, 17; Greer, 2004, p 356; Swirski, 2009; Shander, 2014." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-529", "family": "I023", "source": "hatton", "locator": "UniqueID 529", "population": "Alveolar Macrophages", "tissue": "Lungs; Pulmonary · Blood; Tissue Resident; Lungs.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 3310.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 1000.0000000000001, 5640.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 23000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 3310.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 20600000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 3310.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 10300000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Crapo, 1982; Krombach, 1997; Stone, 1992a.", "amount": "Crapo, 1982; Krombach, 1997; Stone, 1992b." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-732", "family": "I023", "source": "hatton", "locator": "UniqueID 732", "population": "Kupffer Cells (Liver macrophages)", "tissue": "Liver · Blood; Tissue Resident; Sinuses", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 4000.0000000000005, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 1870.0, 4420.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 48000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 4000.0000000000005, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 37300000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 4000.0000000000005, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 22100000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Freitas, 2003.", "amount": "Shander, 2014; Malarkey, 2005; Nenseter, 1992; Widmann, 1972; Freitas, 1999; Wisse, 1996; Greger, 1996, p1369." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-566", "family": "I026", "source": "hatton", "locator": "UniqueID 566", "population": "Neutrophils; circulating", "tissue": "Blood, Intravascular · Blood; Intravascular, Circulating.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 320.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 170.0, 574.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 22900000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 320.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 17100000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 320.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 10400000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Downey, 1990; Schmid-schonbein, 1980; Fawcett, 1994, p118-123; Ross, 2006, p171; Kaushansky, 2010, p893; Greer, 2013, Table 7.3 [e-book, p287, pdf p329]; Milo, 2015, p44; Zipursky, 1976; Norouzi, 2017.", "amount": "Kaushansky, 2010, p14, 17; Greer, 2004, p284, 285, 287; Snyder, 1975." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-567", "family": "I026", "source": "hatton", "locator": "UniqueID 567", "population": "Neutrophils; marginating pool", "tissue": "Blood, Intravascular · Blood; Intravascular, Marginating pool", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 320.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 170.0, 574.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 5010000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 320.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 3730000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 320.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2280000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Downey, 1990; Schmid-schonbein, 1980; Fawcett, 1994, p118-123; Ross, 2006, p171; Kaushansky, 2010, p893; Greer, 2013, Table 7.3 [e-book, p287, pdf p329]; Milo, 2015, p44; Zipursky, 1976; Norouzi, 2017.", "amount": "Kaushansky, 2010; Peters, 1992; MacNee, 1993; Greer, 2004." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-423", "family": "I026", "source": "hatton", "locator": "UniqueID 423", "population": "Neutrophil (post mitotic mature marrow storage pool)", "tissue": "Skeleton Red-bone-marrow · Blood Organ, Tissue Resident.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 320.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 170.0, 574.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 136000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 320.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 104000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 320.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 73100000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Downey, 1990; Schmid-schonbein, 1980; Fawcett, 1994, p118-123; Ross, 2006, p171; Kaushansky, 2010, p893; Greer, 2013, Table 7.3 [e-book, p287, pdf p329]; Milo, 2015, p44; Zipursky, 1976; Norouzi, 2017.", "amount": "Kaushansky, 2010, p30, 60, 893; Greer, 2004, p17; Kaushansky, 2016, ebook p32, 75, 941." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-113", "family": "I027", "source": "hatton", "locator": "UniqueID 113", "population": "Mast Cells", "tissue": "Salivary glands; Head · Blood; Tissue Resident; Salivary glands", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1500.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 408.0, 3000.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 336000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1500.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 277000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1500.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 174000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Bradding, 2009; Schulman, 1983; Ross, 2006, p169-171; Greer, 2004, p336; Jamur, 2001", "amount": "Jaafari-Ashkavandi, 2014; Snyder, 1975." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-530", "family": "I027", "source": "hatton", "locator": "UniqueID 530", "population": "Mast Cells", "tissue": "Lungs; Pulmonary · Blood; Tissue Resident; Lungs", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1500.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 408.0, 3000.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 12000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1500.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 10700000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1500.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 5360000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Bradding, 2009; Schulman, 1983; Ross, 2006, p169-171; Greer, 2004, p336; Jamur, 2001; Levine, 1982.", "amount": "Craig, 1986; Crapo, 1982." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-568", "family": "I028", "source": "hatton", "locator": "UniqueID 568", "population": "Eosinophils, Circulating", "tissue": "Blood, Intravascular · Blood; Intravascular, Circulating.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 400.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 170.0, 574.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1040000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 400.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 775000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 400.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 473000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Downey, 1990; Schmid-schonbein, 1980; Fawcett, 1994, p118-123; Kaushansky, 2010, p876; Greer, 2004, p271, Table 10.3; Zipursky, 1976; Norouzi, 2017.", "amount": "Kaushansky, 2010, p14, 17." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-569", "family": "I028", "source": "hatton", "locator": "UniqueID 569", "population": "Basophils (blood / marrow)", "tissue": "Blood, Intravascular · Blood; Intravascular, Circulating.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 375.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 194.0, 655.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 208000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 375.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 155000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 375.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 94500000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Ross, 2006, p169-171; Greer, 2004, p336.", "amount": "Kaushansky, 2010, p14, 17." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-156", "family": "I029", "source": "hatton", "locator": "UniqueID 156", "population": "Microglial Cells", "tissue": "Central Nervous System (CNS), Brain · Blood; Tissue Resident; Cerebrum", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1580.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 438.0, 5500.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 3390000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1580.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 3040000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1580.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 3060000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Abdolhoseini, 2019; York, 2018; Kozlowski, 2012; Kettenmann, 2011; Vela, 1995; Greer, 2004, p353.", "amount": "Lyck, 2009; Pelvig, 2008; Azevedo, 2009; Valentin, 2003." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-157", "family": "I029", "source": "hatton", "locator": "UniqueID 157", "population": "Microglial Cells", "tissue": "Central Nervous System (CNS), Brain · Blood; Tissue Resident; Cerebellum", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1580.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 438.0, 5500.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 463000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1580.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 415000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1580.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 418000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Abdolhoseini, 2019; York, 2019; Kozlowski, 2012; Kettenmann, 2011; Vela, 1995; Greer, 2004, p353.", "amount": "Vela, 1995; Lyck, 2009; Pelvig, 2008; Azevedo, 2009; Valentin, 2003." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-158", "family": "I029", "source": "hatton", "locator": "UniqueID 158", "population": "Microglial Cells", "tissue": "Central Nervous System (CNS), Brain · Blood; Tissue Resident; Rest of Brain (RoB)", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1580.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 438.0, 5500.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 313000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1580.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 281000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1580.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 283000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Abdolhoseini, 2019; York, 2019; Kozlowski, 2012; Kettenmann, 2011; Vela, 1995; Greer, 2004, p353.", "amount": "Lyck, 2009; Pelvig, 2008; Azevedo, 2009; Valentin, 2003." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-112", "family": "I031", "source": "hatton", "locator": "UniqueID 112", "population": "Fibroblasts", "tissue": "Salivary glands; Head · Salivary glands", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1500.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 240.0, 3700.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2060000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1500.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1700000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1500.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1070000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Milo, 2015; Agley, 2013; Townsley, 2012; Freitas, 1999; Squier, 1990; Crapo, 1982; Mitsui, 1976.", "amount": "Lee, 2012; Tandler, 2006; Anzi, 2018; Tandler, 1993; Snyder, 1975." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-526", "family": "I031", "source": "hatton", "locator": "UniqueID 526", "population": "Fibroblasts", "tissue": "Lungs; Pulmonary · Aveolar Tissue", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1180.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 119.0, 1690.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 46100000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1180.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 41200000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1180.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 20600000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Crapo, 1982; Townsley, 2012.", "amount": "Crapo, 1982." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-350", "family": "I032", "source": "hatton", "locator": "UniqueID 350", "population": "Adipocyte, White", "tissue": "Peripheral Nervous System (PNS) · Interstitial Adipose Tissue; PNS", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 121000.00000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 17100.0, 185000.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1240000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 121000.00000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1150000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 121000.00000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 972000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Hirsch, 1968; Salans, 1973; Sjostrom, 1971; Eto, 2009; Snyder, 1975, p44.", "amount": "Ross, 2006, p342; Fawcett, 1994, p337; Barkmeier, 2000; Verheijen, 2003; Mitchell, 1945; Forbes, 1953; Forbes, 1956." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-451", "family": "I032", "source": "hatton", "locator": "UniqueID 451", "population": "Adipocyte, Brown", "tissue": "Adipose Tissue; Visceral Parenchyma · Visceral; Brown Adipose, ~0.85kg of 4.0kg; mostly subclavicle, cervical, and paravertebral", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 5430.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 476.0, 30500.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 140000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 5430.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 221000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 5430.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 84000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "De Matteis, 2002a; de Jong, 2019, Stock, 2003.", "amount": "Leitner, 2017; Sacks, 2013." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-454", "family": "I032", "source": "hatton", "locator": "UniqueID 454", "population": "Supra adventitial-adipose stromal cells (SA-ASC). ", "tissue": "Adipose Tissue; Stroma · Vascular", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 366.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 110.0, 550.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 35300000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 366.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 45600000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 366.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 18900000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Debnath, 2019; Liu, 2016; Sarigil, 2018.", "amount": "Eto, 2009; Zimmerlin, 2009; Zimmerlin, 2013." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-459", "family": "I032", "source": "hatton", "locator": "UniqueID 459", "population": "Adipose-derived stromal cells", "tissue": "Adipose Tissue; Stroma · Peri-adipocyte connective tissue", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 2200.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 1959.9999999999998, 3930.0000000000005 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 45000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 2200.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 58200000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 2200.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 24100000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Brohem, 2013; Zhang, 2018; Chun, 2012; Milo, 2015; Mitsui, 1976.", "amount": "Eto, 2009; Brohem, 2013; Zhang, 2018; Chun, 2012." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-405", "family": "I033", "source": "hatton", "locator": "UniqueID 405", "population": "Marrow Reticular Cells", "tissue": "Skeleton Red-bone-marrow · Stromal cells only (non-structural, non-adipose tissue); mass at ~5% of 1.17kg", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1500.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 240.0, 3700.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 8460000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1500.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 6500000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1500.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 4550000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Milo, 2015; Agley, 2013; Townsley, 2012; Freitas, 1999; Squier, 1990; Crapo, 1982; Mitsui, 1976.", "amount": "Harrison, 1962; Kaushansky, 2010; Greer, 2004." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-406", "family": "I033", "source": "hatton", "locator": "UniqueID 406", "population": "CAR Cells (CXCL12-abundant Reticular Cells)", "tissue": "Skeleton Red-bone-marrow · Vascular; Stromal cells only (non-structural, non-adipose tissue); mass at ~5% of 1.17kg", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1050.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 240.0, 3700.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 14600000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1050.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 11300000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1050.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 7880000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Gomariz, 2018; Milo, 2015; Agley, 2013; Townsley, 2012; Freitas, 1999; Squier, 1990; Crapo, 1982; Mitsui, 1976.", "amount": "Sacchetti, 2007; Galan-Diez, 2018; Gomariz, 2018; Weiss, 1976; Kaushansky, 2010, p45; Greer, 2004; Snyder, 1975; Valentin, 2003." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-407", "family": "I033", "source": "hatton", "locator": "UniqueID 407", "population": "CAR/LepR+ Cells (CAR and Leptin Receptor Cells)", "tissue": "Skeleton Red-bone-marrow · Vascular; Stromal cells only (non-structural, non-adipose tissue); mass at ~5% of 1.17kg", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1050.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 240.0, 3700.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 300000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1050.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 231000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1050.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 162000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Gomariz, 2018; Milo, 2015; Agley, 2013; Townsley, 2012; Freitas, 1999; Squier, 1990; Crapo, 1982; Mitsui, 1976.", "amount": "Zhou, 2014; Sacchetti, 2007; Galan-Diez, 2018; Weiss, 1976; Kaushansky, 2010, p45; Greer, 2004; Snyder, 1975; Valentin, 2003.." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-409", "family": "I033", "source": "hatton", "locator": "UniqueID 409", "population": "Bone Marrow Stromal Cells [BMSCs]", "tissue": "Skeleton Red-bone-marrow · Blood Organ, Tissue Resident.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 337.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 110.0, 550.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2170000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 337.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1670000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 337.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1170000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Liu, 2016; Sarigil, 2018.", "amount": "Kumagai, 2018." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-376", "family": "I034", "source": "hatton", "locator": "UniqueID 376", "population": "Osteocytes", "tissue": "Skeleton Bone · Bone Matrix", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 400.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 190.0, 553.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 76100000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 400.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 55400000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 400.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 31800000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Sugawara, 2005; Dong, 2014a; Dong, 2014b; Carter, 2013; Carter, 2014.", "amount": "Valentin, 2003; Hekimsoy, 2008; Franz-Odendaal, 2006; Hobdell and Howe, 1971; Mullender, 1996; Shander, 2014, (updated edition, 2020, added references from correspondence with Stripolli [Bianconi, 2013, Author]; Carter, 2013; Carter, 2014; Dong, 2014a; Dong, 2014b; Hesse, 2014; Buenzli, 2015); Smith, 1995." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-378", "family": "I034", "source": "hatton", "locator": "UniqueID 378", "population": "Osteoblasts", "tissue": "Skeleton Bone · Bone Matrix", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 6500.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 1750.0, 14900.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 4400000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 6500.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 3200000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 6500.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1840000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Zouani, 2013; Pilia, 2013; Docheva, 2008; Pautke, 2004; Tanaka-Kamioka, 1998; Milo, 2015; Martin, 1995.", "amount": "Hekimsoy, 2008; Downey, 2006; Ross, 2006, p209; Fawcett, 1994, p204-207; Shander, 2014; Franz-Odendaal, 2006." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-379", "family": "I034", "source": "hatton", "locator": "UniqueID 379", "population": "Bone Lining Cells (quiescent Osteoblasts)", "tissue": "Skeleton Bone · Bone Matrix", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 931.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 211.0, 1850.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1760000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 931.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1280000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 931.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 736000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Baylink, 1971; Zallone, 1977; Menton, 1984.", "amount": "Hekimsoy, 2008; Downey, 2006; Ross, 2006, p209; Fawcett, 1994, p204-207; Shander, 2014; Franz-Odendaal, 2006." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-382", "family": "I035", "source": "hatton", "locator": "UniqueID 382", "population": "Osteoclasts (Bone Macrophages)", "tissue": "Skeleton Bone · Blood; Tissue Resident; Skeleton Bone.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 65000.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 16400.0, 495000.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 880000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 65000.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 640000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 65000.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 368000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Downey, 2006; Crowl, 2006; Fawcett, 1994; Greer, 2004, p.353-357.", "amount": "Hekimsoy, 2008; Downey, 2006; Ross, 2006, p209; Fawcett, 1994, p204-207; Shander, 2014; Franz-Odendaal, 2006." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-195", "family": "I036", "source": "hatton", "locator": "UniqueID 195", "population": "Schwann Cells", "tissue": "Peripheral Nervous System (PNS) · Cranial Nerves", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 21900.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 1160.0, 49300.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 7820000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 21900.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 7010000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 21900.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 7070000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Sharma, 2009; Teixeira, 2016; Snaidero, 2014. ", "amount": "Teixeira, 2016; Snaidero, 2014. " }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-251", "family": "I036", "source": "hatton", "locator": "UniqueID 251", "population": "Remak Schwann Cells", "tissue": "Peripheral Nervous System (PNS) · Cranial Nerves", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1760.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 1670.0, 2780.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 5380000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1760.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 4980000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1760.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 4220000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Gomez-Sanchez, 2017; Teixeira, 2016; Thomas, 1963; Poitelon, 2020; Kunze, 1974 (Sharma, 1974); Ugrenovic, 2016; Snaidero, 2014. ", "amount": "Kunze, 1974 (Sharma, 1974); Teixeira, 2016; Hoffman, 1961." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-1", "family": "I037", "source": "hatton", "locator": "UniqueID 1", "population": "Striated Muscle (Fast, Slow, Intermediate mix)", "tissue": "Ears; Head; Skeletal Muscles · Ear, Inner", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 295000.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 131000.0, 613000.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 4550.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 185000.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 4550.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 116000.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 4550.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Blevins 1968; Ross 2006; Buytaert 2011; Hain 2019; Wojciechowski 2020; Mukerji 2010; Suzuka 1984", "amount": "Blevins 1968; Ross 2006; Buytaert 2011; Hain 2019; Wojciechowski 2020; Mukerji 2010; Suzuka 1984" }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-906", "family": "I037", "source": "hatton", "locator": "UniqueID 906", "population": "Satellite cells (myogenic progenitor cells)", "tissue": "Skeletal Muscle Tissue; Distributed Support Cells · Muscle, skeletal", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 188.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 124.00000000000001, 251.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 27600000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 188.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 17300000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 188.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 10900000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Roth, 2001; Roth, 2000; Yin, 2013.", "amount": "Fujimaki, 2013; Robinson, 2011; Burdzinska, 2009; Shander, 2014; Snyder, 1975; Johns, 2014; Gamrin, 1996; Kuhn, 1999; Liu, 2009." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-672", "family": "I038", "source": "hatton", "locator": "UniqueID 672", "population": "Gastro-Intestinal myocytes; Smooth Muscle Myocytes", "tissue": "GastroIntestinal Tract (GIT) · Small Intestines; Muscle, smooth", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 9330.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 1040.0, 11700.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 5220000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 9330.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 4820000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 9330.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2970000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Ross, 2006, p300; Fawcett, 1994, p260; Berne, 2006; Tortora, 2009, p330; Portincasa, 2004; Ruegg, 1996; Greger, 1996; Guyton, 2006; Sacks, 1982; Lieber, 1992; Klein-Breteler, 1999; Kokshenev, 2014; Siebert, 2015; Zipursky, 1976; Norouzi, 2017; Prall, 1998; Sarigil, 2018; Snyder, 1975.", "amount": "Snyder, 1975, p134-144; Valentin, 2003; Chen, 2017; Ross, 2006; Lukaski, 2005; Flear, 1965." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-838", "family": "I038", "source": "hatton", "locator": "UniqueID 838", "population": "Detrusor Myocytes, Bladder Smooth Muscle Myocytes", "tissue": "Urinary bladder · Detrusor Muscle; Muscularis Inner Longitudinal Layer", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 9330.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 1040.0, 11700.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 868000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 9330.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 772000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 9330.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 482000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Ross, 2006, p300; Fawcett, 1994, p260; Berne, 2006; Tortora, 2009, p330; Portincasa, 2004; Siegel, 1996; Greger, 1996; Ruegg, 1996; Greger, 1996; Guyton, 2006; Sacks, 1982; Lieber, 1992; Klein-Breteler, 1999; Kokshenev, 2014; Siebert, 2015; Zipursky, 1976; Norouzi, 2017; Prall, 1998; Sarigil, 2018; Snyder, 1975.", "amount": "Bolla, 2020; Ross, 2006, p684-685; Snyder, 1975, p179; Keshtkar, 2006." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-892", "family": "I039", "source": "hatton", "locator": "UniqueID 892", "population": "Basal EpC, Prostate", "tissue": "Prostate · Prostate", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 433.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 159.0, 566.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 289000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Dermer, 1978; McNeal, 1965; McNeal, 1988; Packer, 2017; Henry, 2018; Stone, 1977; McNeal, 1981; Amin, 2010.", "amount": "Benninghoff, 1993; Robinson, 2017; McNeal, 1988; Henry, 2018; Packer, 2016; El-Alfy, 2000; Snyder, 1975; Zaichick, 2011; Alberts, 2007." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-896", "family": "I039", "source": "hatton", "locator": "UniqueID 896", "population": "Acinar Cells; Prostate; Luminal EpC, seminal fluid component secretion", "tissue": "Prostate · Prostate", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1400.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 743.0, 1990.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 501000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Henry, 2018; Amin, 2010; Stone, 1977.", "amount": "Benninghoff, 1993; Robinson, 2017; McNeal, 1988; Henry, 2018; Packer, 2016; El-Alfy, 2000; Snyder, 1975; Zaichick, 2011; Alberts, 2007." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-1112", "family": "I040", "source": "hatton", "locator": "UniqueID 1112", "population": "Luminal Ductal Cells ER+ (EpC)", "tissue": "Breast, female · Lactiferous ducts; Primary mammary ducts; female", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1060.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 615000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Hassiotou, 2013; Honeth, 2015; Butcher, 2009; Russo, 1988; Gudjonsson, 2002.", "amount": "Ramsay, 2005; Hassiotou, 2013; Carter, 2017; Shoker, 1999; Beha, 2012; Inman, 2015; Cristea, 2018; Valentin, 2003; Snyder, 1975; Katch, 1980; Moffat, 1996." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-1113", "family": "I040", "source": "hatton", "locator": "UniqueID 1113", "population": "Luminal Ductal Cells ER- (EpC)", "tissue": "Breast, female · Lactiferous ducts; Primary mammary ducts; female", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1060.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 8430000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Hassiotou, 2013; Honeth, 2015; Butcher, 2009; Russo, 1988; Gudjonsson, 2002.", "amount": "Ramsay, 2005; Hassiotou, 2013; Carter, 2017; Shoker, 1999; Beha, 2012; Inman, 2015; Cristea, 2018; Valentin, 2003; Snyder, 1975; Katch, 1980; Moffat, 1996." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-1114", "family": "I040", "source": "hatton", "locator": "UniqueID 1114", "population": "Myoepithelial cells; Ductal; Spindle-Fusiform; (MyoEpCs)", "tissue": "Breast, female · Lactiferous ducts; Primary mammary ducts", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 796.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 9050000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Hassiotou, 2013; Gudjonsson, 2005; Carter, 2017.", "amount": "Ramsay, 2005; Hassiotou, 2013; Carter, 2017; Shoker, 1999; Beha, 2012; Inman, 2015; Cristea, 2018; Valentin, 2003; Snyder, 1975; Katch, 1980; Moffat, 1996." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-1143", "family": "I040", "source": "hatton", "locator": "UniqueID 1143", "population": "Alveolar Lactocytes ER+", "tissue": "Breast, female · Type 1 Lobule; LDUs", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 2060.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 33600000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Hassiotou, 2013; Sternlicht, 2006b; Watson, 2008; Russo, 2001; Russo, 2004; Russo, 1988.", "amount": "Russo, 1988; Russo, 1992; Naccarato, 2003; Pandya, 2011; Bistoni, 2015; Honeth, 2015; Hassiotou, 2013; Aranda-Gutierrez, 2022." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-524", "family": "I041", "source": "hatton", "locator": "UniqueID 524", "population": "Alveolar Type 1 (Type I Pneumocytes)", "tissue": "Lungs; Pulmonary · Aveolar Tissue", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1830.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 1010.0, 2530.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 19300000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1830.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 17200000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1830.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 8620000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Crapo, 1982; Stone, 1992a.", "amount": "Crapo, 1982; Stone, 1992a." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-525", "family": "I041", "source": "hatton", "locator": "UniqueID 525", "population": "Alveolar Type 2 (Type II Pneumocytes)", "tissue": "Lungs; Pulmonary · Aveolar Tissue", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 827.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 647.0, 1570.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 35000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 827.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 31200000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 827.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 15600000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Crapo, 1982; Stone, 1992a.", "amount": "Crapo, 1982; Stone, 1992a." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-510", "family": "I042", "source": "hatton", "locator": "UniqueID 510", "population": "Ciliated Epithelial Cells; Respiratory Tract", "tissue": "Lungs; Bronchial Tree · Bronchial Tissue; Bronchi", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1320.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 950.0, 1580.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 4590000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1320.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 4100000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1320.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2050000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Mercer, 1994; Bianconi, 2013.", "amount": "Bianconi, 2013; Mercer, 1994." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-513", "family": "I042", "source": "hatton", "locator": "UniqueID 513", "population": "Basal Epithelial Cells; Respiratory Tract", "tissue": "Lungs; Bronchial Tree · Bronchial Tissue; Bronchi", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 528.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 528.0, 686.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 4330000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 528.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 3870000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 528.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1940000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Mercer, 1994; Bianconi, 2013.", "amount": "Bianconi, 2013; Mercer, 1994." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-516", "family": "I042", "source": "hatton", "locator": "UniqueID 516", "population": "Clara Cells, Lungs, Bronchioles (secretes Clara cell 10-kDa secretory protein (CCSP))", "tissue": "Lungs; Bronchial Tree · Bronchial Tissue; Bronchioles", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 422.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 309.0, 703.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2300000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 422.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2060000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 422.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1030000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Mercer, 1994; Bianconi, 2013.", "amount": "Mercer, 1994; Bianconi, 2013, Mercer, 1991." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-517", "family": "I043", "source": "hatton", "locator": "UniqueID 517", "population": "Pulmonary Neuroendocrine Cells (PNECs)", "tissue": "Lungs; Bronchial Tree · Bronchial Tissue; Bronchioles", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1050.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 415.0, 1630.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 66700000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1050.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 59600000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1050.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 29800000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Weichselbaum, 2005; Mercer, 1994.", "amount": "Weichselbaum, 2005; Snyder, 1975." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-673", "family": "I044", "source": "hatton", "locator": "UniqueID 673", "population": "Colonocytes, surface", "tissue": "GastroIntestinal Tract (GIT) · Large intestine", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1030.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 338.0, 2120.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 3860000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1030.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 3750000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1030.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2190000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "See Enterocyte villi cell references.", "amount": "Kamra, 2005; Snyder, 1975, (ICRP-23), p142; Qi, 2008; Fawcett, 1994, p637; Sandle, 1998; Boron, 2009; Shander, 2014; Kim, 2010; Schneider, 2018." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-674", "family": "I044", "source": "hatton", "locator": "UniqueID 674", "population": "Colonocytes, crypt", "tissue": "GastroIntestinal Tract (GIT) · Large intestine", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 671.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 338.0, 2120.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 38700000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 671.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 37700000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 671.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 22000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "See Enterocyte crypt cell reference.", "amount": "Kamra, 2005; Snyder, 1975, (ICRP-23), p142; Qi, 2008; Fawcett, 1994, p637; Sandle, 1998; Boron, 2009; Shander, 2014; Kim, 2010; Schneider, 2018." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-655", "family": "I045", "source": "hatton", "locator": "UniqueID 655", "population": "Paneth Cells; Small intestine lysozyme secreting cell", "tissue": "GastroIntestinal Tract (GIT) · Small intestine", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 671.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 338.0, 2120.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 18800000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 671.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 17300000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 671.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 10700000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Gassler, 2017; See Enterocyte crypt cell reference.", "amount": "Dutton, 2019; Snyder, 1975; Fawcett, 1994; Marsh, 1969." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-656", "family": "I045", "source": "hatton", "locator": "UniqueID 656", "population": "Enteroendocrine Cells [EECs]; Small intestine mucosa, villa and crypt ", "tissue": "GastroIntestinal Tract (GIT) · Small intestine", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1030.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 338.0, 2120.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 200000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1030.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 185000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1030.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 114000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "See Enterocyte villi cell references.", "amount": "Latorre, 2016; Dutton, 2019; Snyder, 1975; Fawcett, 1994; Marsh, 1969." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-665", "family": "I045", "source": "hatton", "locator": "UniqueID 665", "population": "Crypt Stem Cells", "tissue": "GastroIntestinal Tract (GIT) · Small intestine", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 453.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 270.0, 636.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 433000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 453.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 400000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 453.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 247000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Meran, 2017; Barker, 2007; Barker, 2009; Cheng, 1974a; Cheng, 1974b.", "amount": "de Santa Barbara, 2003; Baker, 2014; Fawcett, 1994; Snyder, 1975; Marsh, 1969." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-478", "family": "I046", "source": "hatton", "locator": "UniqueID 478", "population": "Melanocytes", "tissue": "Skin · Hair Follicles", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1510.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 821.0, 2970.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 5920000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1510.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 4130000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1510.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1470000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Ishida, 1987; Toyoda, 1998.", "amount": "Slominski, 2005; Commo, 2000; Cichorek, 2013; Fawcett, 1994, p544-545; Columbo, 2011." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-482", "family": "I047", "source": "hatton", "locator": "UniqueID 482", "population": "Epidermal Basal Keratinocytes", "tissue": "Skin · Epidermal", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 548.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 231.0, 1070.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 25300000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 548.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 17600000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 548.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 6290000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Kanitakis, 2002; Bauer, 2001; Fawcett, 1994, p525-530.", "amount": "Cichorek, 2013." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-483", "family": "I047", "source": "hatton", "locator": "UniqueID 483", "population": "Epidermal Keratinocytes (nucleated)", "tissue": "Skin · Epidermal", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 820.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 540.0, 1220.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 87300000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 820.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 60800000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 820.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 21700000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Bauer, 2001; Fawcett, 1994, p525-530; Kanitakis, 2002; Ipponjima, 2020; Koehler, 2011.", "amount": "Snyder, 1975; Fawcett, 1994; Bauer, 2001; Kanitakis, 2002; Bianconi, 2013; Hoath, 2003; Ghadially, 2012; Cichorek, 2013; Szabo, 1967; Ishida, 1987; Haass, 2005." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-484", "family": "I047", "source": "hatton", "locator": "UniqueID 484", "population": "Epidermal Corneocytes (non-nucleated)", "tissue": "Skin · Epidermal", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 250.00000000000003, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 211.0, 413.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 32900000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 250.00000000000003, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 22900000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 250.00000000000003, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 8170000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Stucker, 2015; Richter, 2001; Riethmuller, 2018; O'Lenick, 2011; Ipponjima, 2020.", "amount": "Bianconi, 2013; Hoath, 2003; Snyder, 1975; Valentin, 2003." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-806", "family": "I048", "source": "hatton", "locator": "UniqueID 806", "population": "Transitional Epithelial Cells (Urothelium)", "tissue": "Kidneys · Kidney Papillary Ducts, Calyx, and Pelvis", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 16500.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 5520.0, 29900.000000000004 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 3260000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 16500.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2890000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 16500.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1890000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Khandelwal, 2009; Keshtkar, 2007; Lewis, 2000; Lewis, 1990; Krstic, 1985.", "amount": "Fawcett, 1994; Gandhi, 2019; Krishnaveni, 2014; Jona, 1936." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-808", "family": "I048", "source": "hatton", "locator": "UniqueID 808", "population": "Transitional Epithelial Basal Cells (Urothelium)", "tissue": "Kidneys · Kidney Papillary Ducts, Calyx, and Pelvis", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 655.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 132.0, 1210.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 19800000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 655.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 17500000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 655.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 11500000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Hicks, 1975; Keshtkar, 2007; Lewis, 2000; Lewis and Hanrahan, 1990; Khandelwal, 2009; Krstic, 1985.", "amount": "Fawcett, 1994; Gandhi, 2019; Krishnaveni, 2014; Jona, 1936." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-783", "family": "I049", "source": "hatton", "locator": "UniqueID 783", "population": "Proximal Tubule Cells, Kidneys", "tissue": "Kidneys · Proximal Tubules", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 3630.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 2260.0, 4250.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 11000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 3630.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 9750000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 3630.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 6380000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Morgado, 1990.", "amount": "Layton, 2019; Singh, 2019; Tisher, 1978; Nyengaard, 1992; Basgen, 1994; Fawcett, 1994; Fulladosa, 2003; Hoy, Bertram, 2003; Puelles, 2011; Puelles, 2012." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-790", "family": "I049", "source": "hatton", "locator": "UniqueID 790", "population": "Thick Ascending Loop (TAL) of Henle Cells, Kidneys", "tissue": "Kidneys · Kidney Loop of Henle Tubules", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1210.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 853.0, 1770.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 12900000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1210.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 11400000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1210.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 7490000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Morgado, 1990; Welling, 1978.", "amount": "Layton, 2019; Singh, 2019; Tisher, 1978; Nyengaard, 1992; Basgen, 1994; Fawcett, 1994; Fulladosa, 2003; Hoy, Bertram, 2003; Puelles, 2011; Puelles, 2012." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-795", "family": "I049", "source": "hatton", "locator": "UniqueID 795", "population": "Distal Convoluted Tubule Cells; kidneys", "tissue": "Kidneys · Distal Tubules", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1210.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 853.0, 1770.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2610000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1210.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2310000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1210.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1510000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Tisher, 1968; Bloom and Fawcett, 1994; Zhai, 2006; Kumaran, 2020.", "amount": "Roy, 2015; Clark, 2018; Layton, 2019; Singh, 2019; Fawcett, 1994, p742-743; Tisher, 1978; Nyengaard, 1992; Basgen, 1994; Fulladosa, 2003; Hoy, 2003; Puelles, 2011; Puelles, 2012." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-799", "family": "I049", "source": "hatton", "locator": "UniqueID 799", "population": "Cortical Collecting Tubule/Duct [CCD] Principal Cells; Kidney", "tissue": "Kidneys · Collecting Tubules", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1210.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 853.0, 1770.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1670000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1210.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1480000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1210.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 970000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Madsen, 1988; Tisher, 1968; Morgado, 1990; Bloom and Fawcett, 1994; Zhai, 2006; Kumaran, 2020; Myers, 1966.", "amount": "Roy, 2015; Verlander, 1998; Clark, 2018; Layton, 2019; Singh, 2019; Fawcett, 1994, p742-743; Tisher, 1978; Nyengaard, 1992; Basgen, 1994; Fulladosa, 2003; Hoy, 2003; Puelles, 2011; Puelles, 2012." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-781", "family": "I050", "source": "hatton", "locator": "UniqueID 781", "population": "Glomerular Podocytes; Kidneys", "tissue": "Kidneys · Glomeruli", "match": "Related pooled identity; subtype unresolved", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1160.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 537.0, 1560.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1440000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1160.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1270000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1160.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 834000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Morgado, 1990; Savage, 2007.", "amount": "Steffes, 2001; Puelles, 2015; Tisher, 1978; Nyengaard, 1992; Basgen, 1994; Fawcett, 1994; Fulladosa, 2003; Hoy, 2003; Puelles, 2011; Puelles, 2012." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-782", "family": "I050", "source": "hatton", "locator": "UniqueID 782", "population": "Intraglomerular Mesangial cells [Pericytes / macrophages], Kidneys", "tissue": "Kidneys · Vascular; Glomeruli", "match": "Related pooled identity; subtype unresolved", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 366.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 275.0, 610.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2750000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 366.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2440000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 366.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1590000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Gordon, 2011; Ribatti, 2015; Siegel, 1996, in Greger, 1996, p 1942-43; Grant, 2019; Mangialardi, 2016; Mills, 2013; Brown, 2019; Alarcon-Martinez, 2018; Trost, 2016; Gonlusen, 2001.", "amount": "Steffes, 2001; Tisher, 1978; Nyengaard, 1992; Basgen, 1994; Fawcett, 1994; Fulladosa, 2003; Hoy, 2003; Puelles, 2011; Puelles, 2012." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-794", "family": "I050", "source": "hatton", "locator": "UniqueID 794", "population": "Extraglomerular Mesangial Cells [Pericytes / macrophages], Kidneys", "tissue": "Kidneys · Vascular; Distal Tubules", "match": "Related pooled identity; subtype unresolved", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 366.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 133.0, 460.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 71000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 366.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 63000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 366.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 41200000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Gordon, 2011; Ribatti, 2015; Siegel, 1996, in Greger, 1996, p 1942-43; Grant, 2019; Mangialardi, 2016; Mills, 2013; Brown, 2019; Alarcon-Martinez, 2018; Trost, 2016.", "amount": "Christensen, 1975; Cangiotti, 2018; Biava, 1966; Tisher, 1978; Nyengaard, 1992; Basgen, 1994; Fawcett, 1994; Fulladosa, 2003; Hoy, 2003; Puelles, 2011; Puelles, 2012." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-1237", "family": "I051", "source": "hatton", "locator": "UniqueID 1237", "population": "Luminal Epithelial Cells (LEs)", "tissue": "Uterus · Endometrium", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1000.0000000000001, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 521000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Chumduri, 2021; Niklaus, 2001; Sarani, 1999.", "amount": "Snyder, 1975; Schwalm, 1966; Fawcett, 1994; Goldstuck, 2018, Lv, 2022." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-1238", "family": "I051", "source": "hatton", "locator": "UniqueID 1238", "population": "Glandular Epithelial Cells (GEs)", "tissue": "Uterus · Endometrium", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1110.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 979000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": null, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": null, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Johannisson, 1987; Niklaus, 2001; Sarani, 1999; Chumduri, 2021.", "amount": "Kelleher, 2019; Wang, 2007, Johannisson, 1987; Cousins, 2022; Snyder, 1975; Schwalm, 1966; Fawcett, 1994; Goldstuck, 2018, Lv, 2022." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-408", "family": "I054", "source": "hatton", "locator": "UniqueID 408", "population": "Pluripotent Hematopoietic Stem Cells (P-HSCs), Marrow located ", "tissue": "Skeleton Red-bone-marrow · Blood Organ, Tissue Resident.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 180.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 121.0, 287.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 35300000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 180.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 27200000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 180.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 19000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Ogawa, 2013; Orlic, 1994; Acar, 2015; Zhang, 2019.", "amount": "Rebolj, 2018; Kim, 2013; Kaushansky, 2010; Greer, 2004; Nombela-Arrieta, 2017; Fawcett, 1994; Ogawa, 2013." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-413", "family": "I055", "source": "hatton", "locator": "UniqueID 413", "population": "Pronormoblast (Proerythroblasts; nucleated RBC precursors, bone marrow)", "tissue": "Skeleton Red-bone-marrow · Blood Organ, Tissue Resident.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 954.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 586.0, 1420.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 7500000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 954.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 5770000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 954.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 4040000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Kaushansky, 2010; Greer, 2004; Zipursky, 1976; Levine, 1982.", "amount": "Kaushansky, 2010, p30, 60, 412, 893; Greer, 2004, p17; Kaushansky, 2016, ebook p75 and p482." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-416", "family": "I055", "source": "hatton", "locator": "UniqueID 416", "population": "Orthochromatic normoblasts (Orthochromatic erythroblasts)", "tissue": "Skeleton Red-bone-marrow · Blood Organ, Tissue Resident.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 240.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 140.0, 473.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 29700000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 240.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 22800000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 240.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 16000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Kaushansky, 2010; Greer, 2004; Zipursky, 1976; Levine, 1982.", "amount": "Kaushansky, 2010, p30, 60, 412, 893; Greer, 2004, p17; Kaushansky, 2016, ebook p75 and p482." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-434", "family": "I055", "source": "hatton", "locator": "UniqueID 434", "population": "Megakaryocytes, Stage I - thrombocytic Series", "tissue": "Skeleton Red-bone-marrow · Blood Organ, Tissue Resident.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 1090.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 121.99999999999999, 5470.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 104000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 1090.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 79700000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 1090.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 55800000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Levine, 1982; Kaushansky, 2010; Greer, 2004; Greer, 2013; Milo, 2015; Zipursky, 1976; Norouzi, 2017.", "amount": "Kaushansky, 2010; Greer, 2004; Finch, 1977; Levine, 1982; Branehog, 1975." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-437", "family": "I055", "source": "hatton", "locator": "UniqueID 437", "population": "Megakaryocytes, Stage IV - thrombocytic Series", "tissue": "Skeleton Red-bone-marrow · Blood Organ, Tissue Resident.", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 28600.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 12400.0, 85500.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 81900000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 28600.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 63000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 28600.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 44100000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Levine, 1982; Kaushansky, 2010; Greer, 2004; Greer, 2013; Milo, 2015; Zipursky, 1976; Norouzi, 2017.", "amount": "Kaushansky, 2010; Greer, 2004; Finch, 1977; Levine, 1982; Branehog, 1975." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-116", "family": "I056", "source": "hatton", "locator": "UniqueID 116", "population": "Pyramidal Neurons; Cerebral Cortex", "tissue": "Central Nervous System (CNS), Brain · Cerebral Cortex Neurons; Non Motor Cortex", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 41000.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 2610.0, 2130000.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 14500000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 41000.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 12600000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 41000.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 13500000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Azevedo, 2009; Snyder, 1975; Valentin, 2003; Shander, 2014; Lyck, 2009; Pakkenberg, 1997; Pelvig, 2008; Kanari, 2019; Wang, 2018a; Wells, 2005; Everall, 1993; Pakkenberg, 2003; Rivara, 2003; Liewald, 2014; Wegiel, 2018; Zhou, 2013; Chudler, 2020; Tang, 2003; Sepehrband, 2016; Catani, 2002; Catani, 2008; Catani, 2012.", "amount": "Azevedo, 2009; Lyck, 2009; Pakkenberg, 1997; Pelvig, 2008; Wang, 2018a; Kanari, 2019; Shander, 2014." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-115", "family": "I057", "source": "hatton", "locator": "UniqueID 115", "population": "Interneurons; Cerebral Cortex", "tissue": "Central Nervous System (CNS), Brain · Cerebral Cortex Neurons", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 5170.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 3280.0, 5930.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2550000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 5170.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2220000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 5170.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 2390000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Rakic, 1972; Fishell, 2020; Lim, 2018", "amount": "Azevedo, 2009; Lyck, 2009; Pakkenberg, 1997; Pelvig, 2008; Wang, 2018; Kanari, 2019; Shander, 2014." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-123", "family": "I059", "source": "hatton", "locator": "UniqueID 123", "population": "Astrocytes", "tissue": "Central Nervous System (CNS), Brain · Cerebral Cortex Glia (not including microglial)", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 15600.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 12300.0, 18800.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 7800000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 15600.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 4800000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 15600.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 6300000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Chvatal, 2007; Oberheim, 2009; Rajkowska, 2007.", "amount": "Pelvig, 2008; Walloe, 2014; Oberheim, 2009." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-122", "family": "I060", "source": "hatton", "locator": "UniqueID 122", "population": "Oligodendrocytes", "tissue": "Central Nervous System (CNS), Brain · Cerebral Cortex Glia (not including microglial)", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 4600.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 2220.0, 6020.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 28800000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 4600.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 21000000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 4600.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 24900000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Bakiri, 2011; Orthmann-Murphy, 2020; Osterhout, 1999; Snyder, 1975; Valentin, 2003 (Woodard, 1986); Alberts, 2007; Pelvig, 2008; Tang, 2003.", "amount": "Pelvig, 2008; Walloe, 2014; Azevedo, 2009." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-138", "family": "I060", "source": "hatton", "locator": "UniqueID 138", "population": "Oligodendrocytes", "tissue": "Central Nervous System (CNS), Brain · Cerebellum Glia (not including microglial)", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 4600.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 2260.0, 6300.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 1010000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 4600.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 908000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 4600.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 915000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Bakiri, 2011; Orthmann-Murphy, 2020; Osterhout, 1999; Snyder, 1975; Valentin, 2003 (Woodard, 1986); Alberts, 2007; Pelvig, 2008; Tang, 2003.", "amount": "Bahney, 2018; Heck, 2002; Andersen, 1992; Pelvig, 2008; Bakiri, 2011." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-124", "family": "I062", "source": "hatton", "locator": "UniqueID 124", "population": "Ependymocytes; Ependymal ciliated epithelium", "tissue": "Central Nervous System (CNS), Brain · Cerebrum; Lateral Ventricles", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 2150.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 1900.0, 2590.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 61600000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 2150.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 55300000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 2150.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 55700000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Vidovic, 2018; Jimenez, 2014.", "amount": "Lamers, 2010; Chilamkurthy, 2019; Doetsch, 1997." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "hatton-126", "family": "I062", "source": "hatton", "locator": "UniqueID 126", "population": "Choroidal Plexus Epithelial Cells", "tissue": "Central Nervous System (CNS), Brain · Cerebrum; Lateral Ventricles", "match": "Stated subset only", "host": "human reference models", "models": { "male": { "size": { "label": "Cell mass (not diameter)", "value": 3560.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": [ 1060.0, 3560.0 ], "boundsKind": "Source low–high mass range, not CI" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 182000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "female": { "size": { "label": "Cell mass (not diameter)", "value": 3560.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 163000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } }, "child": { "size": { "label": "Cell mass (not diameter)", "value": 3560.0, "unit": "pg/cell", "statistic": "Source mean-size estimate", "bounds": null, "boundsKind": "Model-specific range not supplied" }, "amount": { "label": "Count in the stated tissue/compartment", "value": 164000000.0, "unit": "cells", "statistic": "Source reference-body estimate", "bounds": null, "boundsKind": "Not supplied" } } }, "underlyingReferences": { "size": "Faure, 2003; Strazielle, 2000; Sturrock, 1979.", "amount": "Faure, 2003; Strazielle, 2000; Lamers, 2010; Chilamkurthy, 2019; Doetsch, 1997." }, "limits": "Normal-reference synthesis, potentially including extrapolation. Counts are whole stated compartments, not cells per mm³ or disease abundance. Cell mass includes the source-defined cell; it is not a soma diameter. No timing is supplied by this row." }, { "id": "sender-I008-erythrocytes", "family": "I008", "source": "sender", "locator": "Results_summary cell 7, output 2: Erythrocytes", "population": "Erythrocytes", "tissue": "Reference-body synthesis; see named population and source methods", "host": "human reference synthesis", "match": "Stated subset only", "models": { "all": { "timing": { "label": "Mean lifespan / turnover timescale", "value": 119.0, "unit": "days", "statistic": "Source synthesis estimate", "bounds": [ 116.0, 122.0 ], "boundsKind": "Author-reported uncertainty bounds (not observed minimum–maximum)" } } }, "limits": "Cell replacement timescale, not activation, division, transit or interaction duration. Neutrophil estimate includes marrow pools; it is not circulating residence time. Rodent estimates are not human defaults." }, { "id": "sender-I026-neutrophils", "family": "I026", "source": "sender", "locator": "Results_summary cell 7, output 2: Neutrophils", "population": "Neutrophils", "tissue": "Reference-body synthesis; see named population and source methods", "host": "human reference synthesis", "match": "Stated subset only", "models": { "all": { "timing": { "label": "Mean lifespan / turnover timescale", "value": 6.6, "unit": "days", "statistic": "Source synthesis estimate", "bounds": [ 6.4, 6.8 ], "boundsKind": "Author-reported uncertainty bounds (not observed minimum–maximum)" } } }, "limits": "Cell replacement timescale, not activation, division, transit or interaction duration. Neutrophil estimate includes marrow pools; it is not circulating residence time. Rodent estimates are not human defaults." }, { "id": "sender-I022-monocytes", "family": "I022", "source": "sender", "locator": "Results_summary cell 7, output 2: Monocytes", "population": "Monocytes", "tissue": "Reference-body synthesis; see named population and source methods", "host": "human reference synthesis", "match": "Stated subset only", "models": { "all": { "timing": { "label": "Mean lifespan / turnover timescale", "value": 3.5, "unit": "days", "statistic": "Source synthesis estimate", "bounds": [ 3.0, 4.1 ], "boundsKind": "Author-reported uncertainty bounds (not observed minimum–maximum)" } } }, "limits": "Cell replacement timescale, not activation, division, transit or interaction duration. Neutrophil estimate includes marrow pools; it is not circulating residence time. Rodent estimates are not human defaults." }, { "id": "sender-I011-mature-t-cells", "family": "I011", "source": "sender", "locator": "Results_summary cell 7, output 2: Mature T cells", "population": "Mature T cells", "tissue": "Reference-body synthesis; see named population and source methods", "host": "human reference synthesis", "match": "Pooled parent population; not subtype-specific", "models": { "all": { "timing": { "label": "Mean lifespan / turnover timescale", "value": 320.0, "unit": "days", "statistic": "Source synthesis estimate", "bounds": [ 240.0, 430.0 ], "boundsKind": "Author-reported uncertainty bounds (not observed minimum–maximum)" } } }, "limits": "Cell replacement timescale, not activation, division, transit or interaction duration. Neutrophil estimate includes marrow pools; it is not circulating residence time. Rodent estimates are not human defaults." }, { "id": "sender-I012-mature-t-cells", "family": "I012", "source": "sender", "locator": "Results_summary cell 7, output 2: Mature T cells", "population": "Mature T cells", "tissue": "Reference-body synthesis; see named population and source methods", "host": "human reference synthesis", "match": "Pooled parent population; not subtype-specific", "models": { "all": { "timing": { "label": "Mean lifespan / turnover timescale", "value": 320.0, "unit": "days", "statistic": "Source synthesis estimate", "bounds": [ 240.0, 430.0 ], "boundsKind": "Author-reported uncertainty bounds (not observed minimum–maximum)" } } }, "limits": "Cell replacement timescale, not activation, division, transit or interaction duration. Neutrophil estimate includes marrow pools; it is not circulating residence time. Rodent estimates are not human defaults." }, { "id": "sender-I018-mature-b-cells", "family": "I018", "source": "sender", "locator": "Results_summary cell 7, output 2: Mature B cells", "population": "Mature B cells", "tissue": "Reference-body synthesis; see named population and source methods", "host": "human reference synthesis", "match": "Stated subset only", "models": { "all": { "timing": { "label": "Mean lifespan / turnover timescale", "value": 63.0, "unit": "days", "statistic": "Source synthesis estimate", "bounds": [ 52.0, 76.0 ], "boundsKind": "Author-reported uncertainty bounds (not observed minimum–maximum)" } } }, "limits": "Cell replacement timescale, not activation, division, transit or interaction duration. Neutrophil estimate includes marrow pools; it is not circulating residence time. Rodent estimates are not human defaults." }, { "id": "sender-I031-dermal-fibroblasts", "family": "I031", "source": "sender", "locator": "Results_summary cell 7, output 2: Dermal fibroblasts", "population": "Dermal fibroblasts", "tissue": "Reference-body synthesis; see named population and source methods", "host": "rodent-derived timing reference", "match": "Stated subset only", "models": { "all": { "timing": { "label": "Mean lifespan / turnover timescale", "value": 140.0, "unit": "days", "statistic": "Source synthesis estimate", "bounds": [ 120.0, 160.0 ], "boundsKind": "Author-reported uncertainty bounds (not observed minimum–maximum)" } } }, "limits": "Cell replacement timescale, not activation, division, transit or interaction duration. Neutrophil estimate includes marrow pools; it is not circulating residence time. Rodent estimates are not human defaults." }, { "id": "sender-I047-epidermal-cells", "family": "I047", "source": "sender", "locator": "Results_summary cell 7, output 2: Epidermal cells", "population": "Epidermal cells", "tissue": "Reference-body synthesis; see named population and source methods", "host": "human reference synthesis", "match": "Stated subset only", "models": { "all": { "timing": { "label": "Mean lifespan / turnover timescale", "value": 31.0, "unit": "days", "statistic": "Source synthesis estimate", "bounds": [ 27.0, 35.0 ], "boundsKind": "Author-reported uncertainty bounds (not observed minimum–maximum)" } } }, "limits": "Cell replacement timescale, not activation, division, transit or interaction duration. Neutrophil estimate includes marrow pools; it is not circulating residence time. Rodent estimates are not human defaults." }, { "id": "sender-I041-alveolar-epithelial-cells", "family": "I041", "source": "sender", "locator": "Results_summary cell 7, output 2: Alveolar epithelial cells", "population": "Alveolar epithelial cells", "tissue": "Reference-body synthesis; see named population and source methods", "host": "rodent-derived timing reference", "match": "Stated subset only", "models": { "all": { "timing": { "label": "Mean lifespan / turnover timescale", "value": 32.0, "unit": "days", "statistic": "Source synthesis estimate", "bounds": [ 29.0, 36.0 ], "boundsKind": "Author-reported uncertainty bounds (not observed minimum–maximum)" } } }, "limits": "Cell replacement timescale, not activation, division, transit or interaction duration. Neutrophil estimate includes marrow pools; it is not circulating residence time. Rodent estimates are not human defaults." }, { "id": "sender-I042-bronchial-epithelial-cells", "family": "I042", "source": "sender", "locator": "Results_summary cell 7, output 2: Bronchial epithelial cells", "population": "Bronchial epithelial cells", "tissue": "Reference-body synthesis; see named population and source methods", "host": "human reference synthesis", "match": "Stated subset only", "models": { "all": { "timing": { "label": "Mean lifespan / turnover timescale", "value": 139.0, "unit": "days", "statistic": "Source synthesis estimate", "bounds": [ 109.0, 180.0 ], "boundsKind": "Author-reported uncertainty bounds (not observed minimum–maximum)" } } }, "limits": "Cell replacement timescale, not activation, division, transit or interaction duration. Neutrophil estimate includes marrow pools; it is not circulating residence time. Rodent estimates are not human defaults." }, { "id": "sender-I023-alveolar-macrophages", "family": "I023", "source": "sender", "locator": "Results_summary cell 7, output 2: Alveolar macrophages", "population": "Alveolar macrophages", "tissue": "Reference-body synthesis; see named population and source methods", "host": "human reference synthesis", "match": "Stated subset only", "models": { "all": { "timing": { "label": "Mean lifespan / turnover timescale", "value": 165.0, "unit": "days", "statistic": "Source synthesis estimate", "bounds": [ 97.0, 280.0 ], "boundsKind": "Author-reported uncertainty bounds (not observed minimum–maximum)" } } }, "limits": "Cell replacement timescale, not activation, division, transit or interaction duration. Neutrophil estimate includes marrow pools; it is not circulating residence time. Rodent estimates are not human defaults." }, { "id": "sender-I001-endothelial-cells", "family": "I001", "source": "sender", "locator": "Results_summary cell 7, output 2: Endothelial cells", "population": "Endothelial cells", "tissue": "Reference-body synthesis; see named population and source methods", "host": "human reference synthesis", "match": "Pooled parent population; not subtype-specific", "models": { "all": { "timing": { "label": "Mean lifespan / turnover timescale", "value": 2300.0, "unit": "days", "statistic": "Source synthesis estimate", "bounds": [ 1100.0, 3500.0 ], "boundsKind": "Author-reported uncertainty bounds (not observed minimum–maximum)" } } }, "limits": "Cell replacement timescale, not activation, division, transit or interaction duration. Neutrophil estimate includes marrow pools; it is not circulating residence time. Rodent estimates are not human defaults." }, { "id": "sender-I002-endothelial-cells", "family": "I002", "source": "sender", "locator": "Results_summary cell 7, output 2: Endothelial cells", "population": "Endothelial cells", "tissue": "Reference-body synthesis; see named population and source methods", "host": "human reference synthesis", "match": "Pooled parent population; not subtype-specific", "models": { "all": { "timing": { "label": "Mean lifespan / turnover timescale", "value": 2300.0, "unit": "days", "statistic": "Source synthesis estimate", "bounds": [ 1100.0, 3500.0 ], "boundsKind": "Author-reported uncertainty bounds (not observed minimum–maximum)" } } }, "limits": "Cell replacement timescale, not activation, division, transit or interaction duration. Neutrophil estimate includes marrow pools; it is not circulating residence time. Rodent estimates are not human defaults." }, { "id": "sender-I003-endothelial-cells", "family": "I003", "source": "sender", "locator": "Results_summary cell 7, output 2: Endothelial cells", "population": "Endothelial cells", "tissue": "Reference-body synthesis; see named population and source methods", "host": "human reference synthesis", "match": "Pooled parent population; not subtype-specific", "models": { "all": { "timing": { "label": "Mean lifespan / turnover timescale", "value": 2300.0, "unit": "days", "statistic": "Source synthesis estimate", "bounds": [ 1100.0, 3500.0 ], "boundsKind": "Author-reported uncertainty bounds (not observed minimum–maximum)" } } }, "limits": "Cell replacement timescale, not activation, division, transit or interaction duration. Neutrophil estimate includes marrow pools; it is not circulating residence time. Rodent estimates are not human defaults." }, { "id": "sender-I004-endothelial-cells", "family": "I004", "source": "sender", "locator": "Results_summary cell 7, output 2: Endothelial cells", "population": "Endothelial cells", "tissue": "Reference-body synthesis; see named population and source methods", "host": "human reference synthesis", "match": "Pooled parent population; not subtype-specific", "models": { "all": { "timing": { "label": "Mean lifespan / turnover timescale", "value": 2300.0, "unit": "days", "statistic": "Source synthesis estimate", "bounds": [ 1100.0, 3500.0 ], "boundsKind": "Author-reported uncertainty bounds (not observed minimum–maximum)" } } }, "limits": "Cell replacement timescale, not activation, division, transit or interaction duration. Neutrophil estimate includes marrow pools; it is not circulating residence time. Rodent estimates are not human defaults." }, { "id": "sender-I045-small-intestine-epithelia", "family": "I045", "source": "sender", "locator": "Results_summary cell 7, output 2: Small intestine epithelia", "population": "Small intestine epithelia", "tissue": "Reference-body synthesis; see named population and source methods", "host": "human reference synthesis", "match": "Pooled parent population; not subtype-specific", "models": { "all": { "timing": { "label": "Mean lifespan / turnover timescale", "value": 2.8, "unit": "days", "statistic": "Source synthesis estimate", "bounds": [ 2.1, 3.5 ], "boundsKind": "Author-reported uncertainty bounds (not observed minimum–maximum)" } } }, "limits": "Cell replacement timescale, not activation, division, transit or interaction duration. Neutrophil estimate includes marrow pools; it is not circulating residence time. Rodent estimates are not human defaults." }, { "id": "sender-I044-colon-epithelia", "family": "I044", "source": "sender", "locator": "Results_summary cell 7, output 2: Colon epithelia", "population": "Colon epithelia", "tissue": "Reference-body synthesis; see named population and source methods", "host": "human reference synthesis", "match": "Pooled parent population; not subtype-specific", "models": { "all": { "timing": { "label": "Mean lifespan / turnover timescale", "value": 2.8, "unit": "days", "statistic": "Source synthesis estimate", "bounds": [ 2.3, 3.3 ], "boundsKind": "Author-reported uncertainty bounds (not observed minimum–maximum)" } } }, "limits": "Cell replacement timescale, not activation, division, transit or interaction duration. Neutrophil estimate includes marrow pools; it is not circulating residence time. Rodent estimates are not human defaults." }, { "id": "sender-I032-adipocytes", "family": "I032", "source": "sender", "locator": "Results_summary cell 7, output 2: Adipocytes", "population": "Adipocytes", "tissue": "Reference-body synthesis; see named population and source methods", "host": "human reference synthesis", "match": "Stated subset only", "models": { "all": { "timing": { "label": "Mean lifespan / turnover timescale", "value": 4000.0, "unit": "days", "statistic": "Source synthesis estimate", "bounds": [ 1000.0, 7000.0 ], "boundsKind": "Author-reported uncertainty bounds (not observed minimum–maximum)" } } }, "limits": "Cell replacement timescale, not activation, division, transit or interaction duration. Neutrophil estimate includes marrow pools; it is not circulating residence time. Rodent estimates are not human defaults." }, { "id": "sender-I037-myocytes", "family": "I037", "source": "sender", "locator": "Results_summary cell 7, output 2: Myocytes", "population": "Myocytes", "tissue": "Reference-body synthesis; see named population and source methods", "host": "human reference synthesis", "match": "Pooled parent population; not subtype-specific", "models": { "all": { "timing": { "label": "Mean lifespan / turnover timescale", "value": 18000.0, "unit": "days", "statistic": "Source synthesis estimate", "bounds": [ 11000.0, 25000.0 ], "boundsKind": "Author-reported uncertainty bounds (not observed minimum–maximum)" } } }, "limits": "Cell replacement timescale, not activation, division, transit or interaction duration. Neutrophil estimate includes marrow pools; it is not circulating residence time. Rodent estimates are not human defaults." }, { "id": "tcell-133", "family": "I011", "source": "tcell", "locator": "Table 1, volumes calculated from R0", "population": "Naïve CD8+", "tissue": "Human peripheral blood; activation in culture for 7–8 days", "host": "human cells in vitro", "match": "Specific measured state", "models": { "all": { "size": { "label": "Cell volume from spherical diameter", "value": 194.3, "unit": "µm³", "statistic": "Measured mean", "bounds": [ 164.5, 224.10000000000002 ], "boundsKind": "Mean ± SD, not observed range" } } }, "sampleSize": 133, "limits": "Volume, not diameter. SD describes cell variability; n counts cells, not donors. Culture activation duration is not cell lifespan." }, { "id": "tcell-97", "family": "I011", "source": "tcell", "locator": "Table 1, volumes calculated from R0", "population": "Activated CD8+", "tissue": "Human peripheral blood; activation in culture for 7–8 days", "host": "human cells in vitro", "match": "Specific measured state", "models": { "all": { "size": { "label": "Cell volume from spherical diameter", "value": 856.5, "unit": "µm³", "statistic": "Measured mean", "bounds": [ 551.4, 1161.6 ], "boundsKind": "Mean ± SD, not observed range" } } }, "sampleSize": 97, "limits": "Volume, not diameter. SD describes cell variability; n counts cells, not donors. Culture activation duration is not cell lifespan." }, { "id": "afm-pitch", "family": "I085", "locator": "Figure 1", "models": { "all": { "size": { "label": "Spiral pitch", "value": 99, "unit": "nm", "statistic": "Reported fit mean", "bounds": [ 79, 119 ], "boundsKind": "Mean ± reported 20 nm spread; not full range" } } }, "source": "afm", "population": "LMW Aβ1–42 spiral fibrils", "tissue": "Mica in liquid; phosphate 10 mM, pH 7.4; NaCl 100 mM; room temperature", "host": "in vitro", "match": "Specific assay, not brain-tissue baseline", "limits": "Do not transfer to tissue concentrations or total fibril length. Table 1 fit parameters have no CI; S5 is a separate exploratory trace." }, { "id": "afm-step", "family": "I085", "locator": "Table 1", "models": { "all": { "size": { "label": "Growth-step size", "value": 62, "unit": "nm", "statistic": "Exponential-fit parameter", "bounds": null, "boundsKind": "Not supplied" } } }, "source": "afm", "population": "LMW Aβ1–42 spiral fibrils", "tissue": "Mica in liquid; phosphate 10 mM, pH 7.4; NaCl 100 mM; room temperature", "host": "in vitro", "match": "Specific assay, not brain-tissue baseline", "limits": "Do not transfer to tissue concentrations or total fibril length. Table 1 fit parameters have no CI; S5 is a separate exploratory trace." }, { "id": "afm-dwell", "family": "I085", "locator": "Table 1", "models": { "all": { "timing": { "label": "Dwell time", "value": 29, "unit": "s", "statistic": "Exponential-fit parameter", "bounds": null, "boundsKind": "Not supplied" } } }, "source": "afm", "population": "LMW Aβ1–42 spiral fibrils", "tissue": "Mica in liquid; phosphate 10 mM, pH 7.4; NaCl 100 mM; room temperature", "host": "in vitro", "match": "Specific assay, not brain-tissue baseline", "limits": "Do not transfer to tissue concentrations or total fibril length. Table 1 fit parameters have no CI; S5 is a separate exploratory trace." }, { "id": "afm-growth", "family": "I085", "locator": "Table 1", "models": { "all": { "timing": { "label": "Growth-step duration", "value": 42, "unit": "s", "statistic": "Exponential-fit parameter", "bounds": null, "boundsKind": "Not supplied" } } }, "source": "afm", "population": "LMW Aβ1–42 spiral fibrils", "tissue": "Mica in liquid; phosphate 10 mM, pH 7.4; NaCl 100 mM; room temperature", "host": "in vitro", "match": "Specific assay, not brain-tissue baseline", "limits": "Do not transfer to tissue concentrations or total fibril length. Table 1 fit parameters have no CI; S5 is a separate exploratory trace." }, { "id": "afm-abeta", "family": "I085", "locator": "Methods", "models": { "all": { "amount": { "label": "Aβ1–42 assay concentration", "value": 2.5, "unit": "µM", "statistic": "Protocol setting", "bounds": null, "boundsKind": "Not supplied" } } }, "source": "afm", "population": "LMW Aβ1–42 spiral fibrils", "tissue": "Mica in liquid; phosphate 10 mM, pH 7.4; NaCl 100 mM; room temperature", "host": "in vitro", "match": "Specific assay, not brain-tissue baseline", "limits": "Do not transfer to tissue concentrations or total fibril length. Table 1 fit parameters have no CI; S5 is a separate exploratory trace." }, { "id": "afm-salt", "family": "I099", "locator": "Methods", "models": { "all": { "amount": { "label": "NaCl assay concentration", "value": 100, "unit": "mM", "statistic": "Protocol setting", "bounds": null, "boundsKind": "Not supplied" } } }, "source": "afm", "population": "LMW Aβ1–42 spiral fibrils", "tissue": "Mica in liquid; phosphate 10 mM, pH 7.4; NaCl 100 mM; room temperature", "host": "in vitro", "match": "Specific assay, not brain-tissue baseline", "limits": "Do not transfer to tissue concentrations or total fibril length. Table 1 fit parameters have no CI; S5 is a separate exploratory trace." }, { "id": "armstrong-albumin", "family": "I010", "source": "armstrong", "locator": "Table 3, human serum albumin", "population": "Human serum albumin", "host": "human protein reference", "tissue": "Aqueous hydrodynamic reference", "match": "Named carrier only", "limits": "Equivalent hydrodynamic radius, not geometric diameter or plasma abundance.", "models": { "all": { "size": { "label": "Hydrodynamic radius", "value": 3.51, "unit": "nm", "statistic": "Author-calculated reference estimate", "bounds": null, "boundsKind": "Not supplied" } } } }, { "id": "armstrong-transferrin", "family": "I010", "source": "armstrong", "locator": "Table 3, transferrin", "population": "Transferrin", "host": "human protein reference", "tissue": "Aqueous hydrodynamic reference", "match": "Named carrier only", "limits": "Equivalent hydrodynamic radius; no local concentration or transport time supplied.", "models": { "all": { "size": { "label": "Hydrodynamic radius", "value": 3.72, "unit": "nm", "statistic": "Author-calculated reference estimate", "bounds": null, "boundsKind": "Not supplied" } } } }, { "id": "armstrong-fibrinogen", "family": "I077", "source": "armstrong", "locator": "Table 3, fibrinogen; intrinsic-viscosity calculation", "population": "Fibrinogen", "host": "human protein reference", "tissue": "Aqueous hydrodynamic reference", "match": "Soluble fibrinogen only", "limits": "Not fibrin-fiber geometry. Method matters: Table 4 separately gives 8.83 nm from diffusion; these are not uncertainty bounds.", "models": { "all": { "size": { "label": "Hydrodynamic radius from intrinsic viscosity", "value": 10.95, "unit": "nm", "statistic": "Author-calculated reference estimate", "bounds": null, "boundsKind": "Not supplied; method-dependent estimates not pooled" } } } }, { "id": "xu-treg-count", "family": "I013", "source": "xu", "locator": "Table 1, number of Treg cells per microliter", "population": "Circulating regulatory T cells", "host": "healthy human cohort", "tissue": "Peripheral blood; 196 Han Chinese adults, Shanxi; ages 20–70; fasting collection", "match": "Study-defined circulating subset", "limits": "Blood count, not tissue density or suppressive activity. Cohort, age and assay affect transferability. SD 15 cells/µL; mean 95% CI 29–33; these differ from the displayed reference interval.", "models": { "all": { "amount": { "label": "Circulating Treg count", "value": 31, "unit": "cells/µL", "statistic": "Cohort mean", "bounds": [ 5, 64 ], "boundsKind": "Source reference interval, 2.5th–97.5th percentiles; not mean CI" } } } }, { "id": "rayat-gbm", "family": "I065", "source": "rayat", "locator": "Abstract, 25 normal adult postmortem biopsies", "population": "Glomerular basement membrane", "host": "human postmortem tissue", "tissue": "Indian adults, ages 18–58; 16 men and 9 women; TEM, 50 orthogonal intercepts per case", "match": "Kidney glomerular membrane only", "limits": "Method- and tissue-specific thickness. Not other basement membranes or a universal diagnostic threshold.", "models": { "all": { "size": { "label": "Glomerular basement membrane thickness", "value": 321, "unit": "nm", "statistic": "Reported mean of per-case harmonic thickness estimates", "bounds": [ 293, 349 ], "boundsKind": "Mean ± SD (28 nm), not observed minimum–maximum" } } } }, { "id": "grant-collagen-length", "family": "I066", "source": "grant", "locator": "Introduction, monomer dimensions; reference 7", "population": "Type I collagen monomer (tropocollagen)", "host": "molecular structural reference", "tissue": "Monomer within the collagen hierarchy", "match": "Monomer, not a fibril or fiber", "limits": "Approximate structural scale cited by the authors, not a newly measured mean. Tissue fiber length and fibril diameter remain unknown.", "models": { "all": { "size": { "label": "Tropocollagen length", "value": 300, "unit": "nm", "statistic": "Approximate documented structural length", "bounds": null, "boundsKind": "Not supplied" } } } }, { "id": "grant-collagen-width", "family": "I066", "source": "grant", "locator": "Introduction, 15 Å monomer diameter; reference 7", "population": "Type I collagen monomer (tropocollagen)", "host": "molecular structural reference", "tissue": "Monomer within the collagen hierarchy", "match": "Monomer, not a fibril or fiber", "limits": "Unit conversion only: 15 Å = 1.5 nm. Hydrated fibrils and tissue fibers have different dimensions.", "models": { "all": { "size": { "label": "Tropocollagen diameter", "value": 1.5, "unit": "nm", "statistic": "Approximate documented structural diameter", "bounds": null, "boundsKind": "Not supplied" } } } }, { "id": "synovial-ha", "family": "I067", "source": "synovial", "locator": "Results 3.1, Figure 2; one sample per donor", "population": "Hyaluronan", "host": "human cadaveric donor samples", "tissue": "Knee synovial fluid; 33 donors without knee injury/pathology; donor age 60 ± 14 years", "match": "Synovial-fluid hyaluronan only", "limits": "Reported SD 2.05 mg/mL is separate from the observed range. This is not tumor-matrix concentration or a polymer-length distribution.", "models": { "all": { "amount": { "label": "Hyaluronan concentration", "value": 2.66, "unit": "mg/mL", "statistic": "Donor cohort mean", "bounds": [ 0.44, 10.13 ], "boundsKind": "Observed sample minimum–maximum, not confidence interval" } } } }, { "id": "grenier-ev", "family": "I084", "source": "grenier", "locator": "Figure 1a–b and accompanying results", "population": "Enriched plasma extracellular vesicles", "host": "healthy human donor plasma", "tissue": "35 donors aged 20–85; two-part enrichment; ZetaView nanoparticle tracking", "match": "Method-defined EV-enriched particle fraction", "limits": "Isolation and detection affect counts and size; not all circulating vesicles. The ± quantities are preserved as reported; SD versus SEM was not verified, so no sampling distribution is assigned.", "models": { "all": { "size": { "label": "Particle diameter", "value": 129.6, "unit": "nm", "statistic": "Reported cohort average", "bounds": [ 127.5, 131.7 ], "boundsKind": "Average ± reported 2.1 nm; spread definition unresolved" }, "amount": { "label": "Particle concentration per plasma volume", "value": 1400000000, "unit": "particles/mL plasma", "statistic": "Reported cohort average", "bounds": [ 1230000000, 1570000000 ], "boundsKind": "Average ± reported 170,000,000; spread definition unresolved" } } } }, { "id": "iborra-mitochondria", "family": "I090", "source": "iborra", "locator": "Table 1 (length and mtDNA); abstract/results (RNA residence)", "population": "Mitochondrial network and mitochondrial genomes", "host": "human ECV304/T-24 cell line in vitro", "tissue": "Fluorescently labeled mitochondria in cultured cells", "match": "Specific cell line; not healthy tissue average", "limits": "600 µm is total mitochondrial length per cell, not one organelle. Table reports ±124; spread definition remains unresolved. DNA copies are not organelle counts. RNA residence is not mitochondrial lifespan.", "models": { "all": { "size": { "label": "Total mitochondrial length per cell", "value": 600, "unit": "µm/cell", "statistic": "Reported mean, 50 cells", "bounds": [ 476, 724 ], "boundsKind": "Mean ± reported 124 µm; spread definition unresolved" }, "amount": { "label": "Mitochondrial DNA copies per cell", "value": 3500, "unit": "mtDNA molecules/cell", "statistic": "Gel-electrophoresis estimate", "bounds": null, "boundsKind": "Not supplied" }, "timing": { "label": "New mitochondrial RNA residence half-time in a focus", "value": 43, "unit": "min", "statistic": "Approximate kinetic estimate", "bounds": null, "boundsKind": "Not supplied" } } } }, { "id": "lysosome-untreated", "family": "I092", "source": "lysosome", "locator": "Measurement of Lysosome Diameter, Figure 2A", "population": "Untreated-cell lysosomes", "host": "monkey BS-C-1 cells in vitro", "tissue": "Kidney epithelial cell line; confocal microscopy; 50 lysosomes in 3 cells", "match": "Untreated assay reference", "limits": "Median, not mean. Authors identify likely overestimation: approximately 300 nm optical resolution misses smaller lysosomes. Not a human lysosome default; endosome measurements remain missing.", "models": { "all": { "size": { "label": "Apparent lysosome diameter", "value": 520, "unit": "nm", "statistic": "Measured median", "bounds": null, "boundsKind": "Not supplied; optical resolution is not an uncertainty interval" } } } }, { "id": "unconventional-inkt", "family": "I015", "source": "unconventional", "population": "iNKT cells", "host": "healthy human blood", "tissue": "Age 18–35 subgroup of the European adult cohort", "locator": "Results, age 18–35 subgroup; Table 3", "match": "Named population and source conditions only", "limits": "Age-specific blood count; not tissue abundance or all-age mean.", "models": { "all": { "amount": { "label": "Absolute blood count", "value": 2, "unit": "cells/µL", "statistic": "Subgroup median", "bounds": [ 0.1, 63.5 ], "boundsKind": "Reported observed minimum–maximum" } } } }, { "id": "unconventional-mait", "family": "I015", "source": "unconventional", "population": "MAIT cells", "host": "healthy human blood", "tissue": "Age 18–35 subgroup of the European adult cohort", "locator": "Results, age 18–35 subgroup; Table 3", "match": "Named population and source conditions only", "limits": "Age-specific blood count; not tissue abundance or all-age mean.", "models": { "all": { "amount": { "label": "Absolute blood count", "value": 71, "unit": "cells/µL", "statistic": "Subgroup median", "bounds": [ 10, 183 ], "boundsKind": "Reported observed minimum–maximum" } } } }, { "id": "ilc-ilc1", "family": "I017", "source": "ilc", "population": "ILC1", "host": "healthy human blood", "tissue": "Adults, n=30; flow cytometry", "locator": "Table 1, adult row", "match": "Named population and source conditions only", "limits": "Units are cells/mL, not cells/µL. Tissue abundance remains unknown.", "models": { "all": { "amount": { "label": "Absolute blood count", "value": 468, "unit": "cells/mL", "statistic": "Median", "bounds": [ 249, 1218 ], "boundsKind": "10th–90th percentiles; not full range or CI" } } } }, { "id": "ilc-ilc2", "family": "I017", "source": "ilc", "population": "ILC2", "host": "healthy human blood", "tissue": "Adults, n=30; flow cytometry", "locator": "Table 1, adult row", "match": "Named population and source conditions only", "limits": "Units are cells/mL, not cells/µL. Tissue abundance remains unknown.", "models": { "all": { "amount": { "label": "Absolute blood count", "value": 585, "unit": "cells/mL", "statistic": "Median", "bounds": [ 153, 1566 ], "boundsKind": "10th–90th percentiles; not full range or CI" } } } }, { "id": "ilc-ilc3", "family": "I017", "source": "ilc", "population": "ILC3", "host": "healthy human blood", "tissue": "Adults, n=30; flow cytometry", "locator": "Table 1, adult row", "match": "Named population and source conditions only", "limits": "Units are cells/mL, not cells/µL. Tissue abundance remains unknown.", "models": { "all": { "amount": { "label": "Absolute blood count", "value": 513, "unit": "cells/mL", "statistic": "Median", "bounds": [ 180, 2186 ], "boundsKind": "10th–90th percentiles; not full range or CI" } } } }, { "id": "held-synaptic-vesicles", "family": "I069", "source": "held", "population": "Synaptic vesicles", "host": "mouse neuronal culture", "tissue": "Primary hippocampal neurons; cryo-electron tomography", "locator": "Figure 2C; Results, synaptic ultrastructure", "match": "Named population and source conditions only", "limits": "Counts can underestimate the whole terminal because some tomograms omit part of it. No human or neuromuscular-junction default.", "models": { "all": { "size": { "label": "Synaptic vesicle diameter", "value": 48.7, "unit": "nm", "statistic": "Reported mean", "bounds": null, "boundsKind": "Not supplied" }, "amount": { "label": "Vesicles in captured presynaptic terminals", "value": 94, "unit": "vesicles/terminal", "statistic": "Reported mean; incomplete field of view", "bounds": null, "boundsKind": "Not supplied" } } } }, { "id": "held-synaptic-cleft", "family": "I069", "source": "held", "population": "Synaptic cleft", "host": "mouse neuronal culture", "tissue": "Primary hippocampal neurons; cryo-electron tomography", "locator": "Figure 2C; Results, synaptic ultrastructure", "match": "Named population and source conditions only", "limits": "Width is a geometric reference, not neurotransmission time. Human transfer remains unresolved.", "models": { "all": { "size": { "label": "Synaptic cleft width", "value": 24.4, "unit": "nm", "statistic": "Reported mean", "bounds": null, "boundsKind": "Not supplied" } } } }, { "id": "variation-il6", "family": "I074", "source": "variation", "population": "IL-6", "host": "healthy human serum", "tissue": "12 volunteers, weekly sampling for six weeks; ELISA", "locator": "Table 1", "match": "Named population and source conditions only", "limits": "Within-person CV 21.5%; between-person CV 26.4%. These are variability coefficients, not bounds or local tissue concentrations.", "models": { "all": { "amount": { "label": "Serum concentration", "value": 0.961, "unit": "pg/mL", "statistic": "Reported mean", "bounds": null, "boundsKind": "Not supplied" } } } }, { "id": "variation-mip1b", "family": "I075", "source": "variation", "population": "MIP-1β / CCL4", "host": "healthy human serum", "tissue": "12 volunteers, weekly sampling for six weeks; ELISA", "locator": "Table 1", "match": "Named population and source conditions only", "limits": "Within-person CV 20%; between-person CV 57%. These are variability coefficients, not bounds or local tissue concentrations.", "models": { "all": { "amount": { "label": "Serum concentration", "value": 101, "unit": "pg/mL", "statistic": "Reported mean", "bounds": null, "boundsKind": "Not supplied" } } } }, { "id": "variation-leptin", "family": "I102", "source": "variation", "population": "Leptin", "host": "healthy human serum", "tissue": "12 volunteers, weekly sampling for six weeks; ELISA", "locator": "Table 1", "match": "Named population and source conditions only", "limits": "Within-person CV 31%; between-person CV 68%. These are variability coefficients, not bounds or local tissue concentrations.", "models": { "all": { "amount": { "label": "Serum concentration", "value": 7.66, "unit": "ng/mL", "statistic": "Reported mean", "bounds": null, "boundsKind": "Not supplied" } } } }, { "id": "auwera-plasma-dna", "family": "I083", "source": "auwera", "population": "Circulating total plasma DNA", "host": "healthy human controls", "tissue": "20 controls; quantitative PCR", "locator": "Results, plasma total DNA; Figure 1", "match": "Named population and source conditions only", "limits": "Method-dependent recovered DNA. Reported zero does not establish molecular absence. Not a measure of DAMP signaling or tumor-derived fraction.", "models": { "all": { "amount": { "label": "Plasma DNA concentration", "value": 4, "unit": "ng/mL", "statistic": "Median", "bounds": [ 0, 17 ], "boundsKind": "Reported observed minimum–maximum" } } } }, { "id": "minflux-kinesin", "family": "I094", "source": "minflux", "population": "Kinesin-1 motor construct", "host": "Drosophila motor in fixed-cell assay", "tissue": "Purified DmKHC(1–421); preserved microtubules; saturating ATP >1 mM", "locator": "Figure 1I–J, motor-PAINT experiment", "match": "Named population and source conditions only", "limits": "Fixed-cell assay, not live-cell baseline. Step SEM 0.09 nm differs from the displayed SD. Timing depends on ATP; no whole-organelle transport model is implied.", "models": { "all": { "size": { "label": "Motor displacement per step", "value": 7.8, "unit": "nm", "statistic": "Gaussian-fit mean", "bounds": [ 5.1, 10.5 ], "boundsKind": "Mean ± SD (2.7 nm), not full range" }, "timing": { "label": "Interstep dwell time", "value": 30.8, "unit": "ms", "statistic": "Average from two-exponential convolution fit", "bounds": null, "boundsKind": "Not supplied" } } } }, { "id": "mri-csf-volume", "family": "I104", "source": "csf", "population": "Cerebrospinal fluid", "host": "healthy human volunteers", "tissue": "15 adults; brain and spinal-axis MRI segmentation", "locator": "Results and Discussion, total CSF volume", "match": "Named population and source conditions only", "limits": "Whole CNS compartment volume, not interstitial volume, production rate or turnover. Segmentation method affects estimates.", "models": { "all": { "amount": { "label": "Total cranial and spinal CSF volume", "value": 263, "unit": "mL", "statistic": "Reported cohort mean", "bounds": null, "boundsKind": "Not supplied" } } } }, { "id": "recovered-pbr-postmenopausal-females", "family": "I064", "source": "L177", "population": "postmenopausal females", "tissue": "Sublingual microvessels, 4–25 µm calibre; 22 participants overall; pre-supplementation", "host": "human in vivo", "match": "Specific measured context; not a family-wide default", "locator": "Abstract", "models": { "all": { "size": { "label": "Perfused boundary region (inverse proxy; NOT glycocalyx thickness)", "value": 2.11, "unit": "µm", "statistic": "Reported group mean", "bounds": [ 1.97, 2.25 ], "boundsKind": "Mean ± reported spread; SD/SEM definition not reverified" } } }, "limits": "Larger PBR indicates a thinner glycocalyx. Do not use this value as layer thickness. Small post hoc older-adult cohort; not tumor vessels or reference-body estimates." }, { "id": "recovered-pbr-older-males", "family": "I064", "source": "L177", "population": "older males", "tissue": "Sublingual microvessels, 4–25 µm calibre; 22 participants overall; pre-supplementation", "host": "human in vivo", "match": "Specific measured context; not a family-wide default", "locator": "Abstract", "models": { "all": { "size": { "label": "Perfused boundary region (inverse proxy; NOT glycocalyx thickness)", "value": 1.97, "unit": "µm", "statistic": "Reported group mean", "bounds": [ 1.84, 2.1 ], "boundsKind": "Mean ± reported spread; SD/SEM definition not reverified" } } }, "limits": "Larger PBR indicates a thinner glycocalyx. Do not use this value as layer thickness. Small post hoc older-adult cohort; not tumor vessels or reference-body estimates." }, { "id": "recovered-oxygen-hypoxic", "family": "I096", "source": "L239", "population": "hypoxic breast tumors (n=11)", "tissue": "Stage IIB–III breast cancer; before chemotherapy plus hyperthermia; Eppendorf polarographic probe", "host": "human in vivo", "match": "Specific measured context; not a family-wide default", "locator": "Abstract", "models": { "all": { "amount": { "label": "Tissue oxygen partial pressure (not concentration)", "value": 3.2, "unit": "mmHg", "statistic": "Average of patient median pO₂ values", "bounds": null, "boundsKind": "Not reported in the inspected abstract" } } }, "limits": "18 patients overall. Keep the two pretreatment subgroups separate; do not average them into a universal baseline. Probe tracks do not map whole-tumor oxygen. Spread and CO₂ remain unresolved." }, { "id": "recovered-oxygen-well-oxygenated", "family": "I096", "source": "L239", "population": "well-oxygenated breast tumors (n=7)", "tissue": "Stage IIB–III breast cancer; before chemotherapy plus hyperthermia; Eppendorf polarographic probe", "host": "human in vivo", "match": "Specific measured context; not a family-wide default", "locator": "Abstract", "models": { "all": { "amount": { "label": "Tissue oxygen partial pressure (not concentration)", "value": 48.3, "unit": "mmHg", "statistic": "Reported subgroup median pO₂", "bounds": null, "boundsKind": "Not reported in the inspected abstract" } } }, "limits": "18 patients overall. Keep the two pretreatment subgroups separate; do not average them into a universal baseline. Probe tracks do not map whole-tumor oxygen. Spread and CO₂ remain unresolved." }, { "id": "recovered-stiffness-fibroglandular", "family": "I105", "source": "L270", "population": "fibroglandular breast parenchyma (n=28)", "tissue": "Normal parenchyma; women aged 29–56; 3T MR elastography, 19 cm pneumatic driver", "host": "human in vivo", "match": "Specific measured context; not a family-wide default", "locator": "Tables 1 and 3; Results", "models": { "all": { "property": { "label": "MRE tissue stiffness", "value": 2.95, "unit": "kPa", "statistic": "Measured mean; SD 0.43 kPa", "bounds": [ 2.17, 3.77 ], "boundsKind": "Reported distribution-based 2.5th–97.5th percentiles; not CI" } } }, "limits": "Single center, 48 women total. Method-specific normal tissue reference; not tumor stiffness or a complete mechanical model. Relaxation time unresolved." }, { "id": "recovered-stiffness-fatty", "family": "I105", "source": "L270", "population": "fatty breast parenchyma (n=20)", "tissue": "Normal parenchyma; women aged 29–56; 3T MR elastography, 19 cm pneumatic driver", "host": "human in vivo", "match": "Specific measured context; not a family-wide default", "locator": "Tables 1 and 3; Results", "models": { "all": { "property": { "label": "MRE tissue stiffness", "value": 1.85, "unit": "kPa", "statistic": "Measured mean; SD 0.32 kPa", "bounds": [ 1.3, 2.44 ], "boundsKind": "Reported distribution-based 2.5th–97.5th percentiles; not CI" } } }, "limits": "Single center, 48 women total. Method-specific normal tissue reference; not tumor stiffness or a complete mechanical model. Relaxation time unresolved." }, { "id": "recovered-doxorubicin-distance", "family": "I106", "source": "L272", "population": "Doxorubicin in 16C, EMT6 and PC-3 tumors", "tissue": "Mouse tumors and human PC-3 xenografts; single IV administration; drug fluorescence relative to CD31 vessels", "host": "mouse in vivo / human xenograft", "match": "Specific measured context; not a family-wide default", "locator": "Abstract and Figure 3 / Table 1 discussion", "models": { "all": { "size": { "label": "Drug penetration half-distance (not molecular size)", "value": null, "unit": "µm", "statistic": "No pooled mean imported", "bounds": [ 40, 50 ], "boundsKind": "Approximate reported range across tumor models; not CI" } } }, "limits": "Range-only reference; no midpoint invented. Specific compound, tumor models and single-dose experiment; not a human or general-drug default." }, { "id": "recovered-carboplatin-half-life", "family": "I106", "source": "oguri", "population": "Intact carboplatin in cancer-patient plasma", "tissue": "Single IV infusion; 375 and 450 mg/m² biphasic profiles; carboplatin-specific HPLC", "host": "human in vivo", "match": "Specific measured context; not a family-wide default", "locator": "Abstract", "models": { "all": { "timing": { "label": "Plasma elimination half-life, second phase", "value": 2.2, "unit": "h", "statistic": "Reported elimination half-life", "bounds": null, "boundsKind": "Not reported in the inspected abstract" } } }, "limits": "Parent drug, not total platinum. Sample size, infusion duration and uncertainty not verified from abstract. Not tumor exposure or a universal drug half-life. Reuses the existing Studies pharmacokinetic reference." }, { "id": "functional-permeability-cationized-bsa", "family": "I063", "source": "V24", "population": "Cationized bovine serum albumin; pI 8.6–9.1", "tissue": "LS174T colon-cancer xenograft; dorsal skinfold chamber; fluorescent protein after IV injection", "host": "SCID mouse / human xenograft", "match": "Context-specific functional reference; not a family-wide default", "locator": "Results, Figures 1–2; atlas V24", "models": { "all": { "property": { "label": "Effective transvascular permeability", "value": 4.25e-07, "unit": "cm/s", "statistic": "Reported median, inferred from fluorescence and pharmacokinetics", "bounds": [ 3.99e-07, 4.51e-07 ], "boundsKind": "Median ± standard error of median; not observed range or CI" } } }, "limits": "Whole vessel-barrier readout, not isolated junction conductance. Modified protein, one tumor model; charge modification also changes chemistry and clearance. Not a human baseline." }, { "id": "functional-permeability-anionized-bsa", "family": "I063", "source": "V24", "population": "Anionized bovine serum albumin; pI approximately 2.0", "tissue": "LS174T colon-cancer xenograft; dorsal skinfold chamber; fluorescent protein after IV injection", "host": "SCID mouse / human xenograft", "match": "Context-specific functional reference; not a family-wide default", "locator": "Results, Figures 1–2; atlas V24", "models": { "all": { "property": { "label": "Effective transvascular permeability", "value": 1.11e-07, "unit": "cm/s", "statistic": "Reported median, inferred from fluorescence and pharmacokinetics", "bounds": [ 6.7e-08, 1.55e-07 ], "boundsKind": "Median ± standard error of median; not observed range or CI" } } }, "limits": "Whole vessel-barrier readout, not isolated junction conductance. Modified protein, one tumor model; charge modification also changes chemistry and clearance. Not a human baseline." }, { "id": "functional-permeability-cationized-igg", "family": "I063", "source": "V24", "population": "Cationized IgG; pI 8.6–9.3", "tissue": "LS174T colon-cancer xenograft; dorsal skinfold chamber; fluorescent protein after IV injection", "host": "SCID mouse / human xenograft", "match": "Context-specific functional reference; not a family-wide default", "locator": "Results, Figures 1–2; atlas V24", "models": { "all": { "property": { "label": "Effective transvascular permeability", "value": 4.65e-07, "unit": "cm/s", "statistic": "Reported median, inferred from fluorescence and pharmacokinetics", "bounds": [ 4.36e-07, 4.94e-07 ], "boundsKind": "Median ± standard error of median; not observed range or CI" } } }, "limits": "Whole vessel-barrier readout, not isolated junction conductance. Modified protein, one tumor model; charge modification also changes chemistry and clearance. Not a human baseline." }, { "id": "functional-permeability-anionized-igg", "family": "I063", "source": "V24", "population": "Anionized IgG; pI 3.0–3.9", "tissue": "LS174T colon-cancer xenograft; dorsal skinfold chamber; fluorescent protein after IV injection", "host": "SCID mouse / human xenograft", "match": "Context-specific functional reference; not a family-wide default", "locator": "Results, Figures 1–2; atlas V24", "models": { "all": { "property": { "label": "Effective transvascular permeability", "value": 1.93e-07, "unit": "cm/s", "statistic": "Reported median, inferred from fluorescence and pharmacokinetics", "bounds": [ 1.52e-07, 2.34e-07 ], "boundsKind": "Median ± standard error of median; not observed range or CI" } } }, "limits": "Whole vessel-barrier readout, not isolated junction conductance. Modified protein, one tumor model; charge modification also changes chemistry and clearance. Not a human baseline." }, { "id": "functional-ctl-killing", "family": "I081", "source": "L30", "population": "Virus-specific cytotoxic T lymphocytes", "tissue": "Herpesvirus/poxvirus infection systems; two-photon imaging and model-estimated per-cell rates", "host": "mouse tissue; in vivo and explanted-node imaging", "match": "Context-specific functional reference; not a family-wide default", "locator": "Summary and Results; atlas L30", "models": { "all": { "property": { "label": "Per-capita target-cell killing rate", "value": null, "unit": "targets/CTL/day", "statistic": "Reported range of average rates across experimental systems", "bounds": [ 2, 16 ], "boundsKind": "Cross-system range; not individual-cell variation, SD or CI" } } }, "limits": "No pooled midpoint. Not an engager or tumor killing rate, and not a duration per killing event. Target recognition and cooperation matter; do not convert the range to a random distribution." }, { "id": "functional-hybridoma-density", "family": "I091", "source": "L222", "population": "Membrane-associated antibody on 9E10 cells", "tissue": "Mouse 9E10 hybridoma; 40 pL droplets; FRET assay at 37 °C; 60-minute observation", "host": "engineered mouse hybridoma in vitro", "match": "Context-specific functional reference; not a family-wide default", "locator": "Results / Figure 2D; atlas L222", "models": { "all": { "property": { "label": "Membrane-associated antibody surface density", "value": 100, "unit": "antibodies/µm²", "statistic": "Approximate reported density", "bounds": null, "boundsKind": "Not reported for this quantity" } } }, "limits": "Whole-cell output-associated readout, not ER/Golgi abundance or human plasma-cell baseline. No density-specific uncertainty reported. Recycling versus stable surface association unresolved." }, { "id": "functional-hybridoma-bound-count", "family": "I091", "source": "L222", "population": "Membrane-associated antibody on 9E10 cells", "tissue": "Mouse 9E10 hybridoma; 40 pL droplets; FRET assay at 37 °C; 60-minute observation", "host": "engineered mouse hybridoma in vitro", "match": "Context-specific functional reference; not a family-wide default", "locator": "Results / Figure 2D; Quantification and statistical analysis; atlas L222", "models": { "all": { "property": { "label": "Membrane-associated antibodies per cell", "value": 78000, "unit": "antibodies/cell", "statistic": "Reported mean", "bounds": [ 55000, 101000 ], "boundsKind": "Mean ± SD; not observed range or CI" } } }, "limits": "Same assay as the density record, not independent evidence. Membrane-bound fraction is not secreted output. Secretion normalization deferred: Results and Discussion report different secreted totals (about 800,000 versus 190,000), requiring reconciliation before calibration." }, { "id": "functional-no-consumption", "family": "I101", "source": "L257", "population": "NO consumption in isolated aortic wall", "tissue": "Electrochemical diffusion-flux assay at 37 °C; rate estimated at 50, 100 and 150 µM oxygen; n=6", "host": "isolated aortic wall; species not verified in this pass", "match": "Context-specific functional reference; not a family-wide default", "locator": "Results and Figure 3; atlas L257", "models": { "all": { "property": { "label": "Second-order NO consumption rate constant", "value": 4000, "unit": "M⁻¹ s⁻¹", "statistic": "Model-estimated mean", "bounds": [ 3700, 4300 ], "boundsKind": "Mean ± standard error; not SD or CI" } } }, "limits": "First order in NO and oxygen. Aortic preparation-specific estimate, not a universal chemical constant or measured diffusion distance. Model assumptions and host matching must be reviewed before transfer to tumor or brain tissue." }, { "id": "geometry-tau-phf-wide", "family": "I086", "source": "A06", "population": "Paired helical tau filaments", "tissue": "Sarkosyl-insoluble cerebral-cortex extract from one 74-year-old woman with Alzheimer disease; negative-stain electron microscopy", "host": "human postmortem preparation", "match": "Specific measured context; not a family-wide default", "locator": "Neuropathological characteristics; Figure 1c", "models": { "all": { "size": { "label": "Width at widest part", "value": 30, "unit": "nm", "statistic": "Approximate reported dimension", "bounds": null, "boundsKind": "Uncertainty not reported" } } }, "limits": "Width and crossover spacing are separate from total filament length. No growth timing or tissue concentration. One donor; no universal tau or in-vivo default. Source approximately 300 Å converted using 1 Å = 0.1 nm." }, { "id": "geometry-tau-phf-narrow", "family": "I086", "source": "A06", "population": "Paired helical tau filaments", "tissue": "Sarkosyl-insoluble cerebral-cortex extract from one 74-year-old woman with Alzheimer disease; negative-stain electron microscopy", "host": "human postmortem preparation", "match": "Specific measured context; not a family-wide default", "locator": "Neuropathological characteristics; Figure 1c", "models": { "all": { "size": { "label": "Width at narrowest part", "value": null, "unit": "nm", "statistic": "Reported interval; central estimate unavailable", "bounds": [ 10, 15 ], "boundsKind": "Reported dimensional interval; not SD or CI" } } }, "limits": "Width and crossover spacing are separate from total filament length. No growth timing or tissue concentration. One donor; no universal tau or in-vivo default. Source 100–150 Å converted using 1 Å = 0.1 nm." }, { "id": "geometry-tau-phf-crossover", "family": "I086", "source": "A06", "population": "Paired helical tau filaments", "tissue": "Sarkosyl-insoluble cerebral-cortex extract from one 74-year-old woman with Alzheimer disease; negative-stain electron microscopy", "host": "human postmortem preparation", "match": "Specific measured context; not a family-wide default", "locator": "Neuropathological characteristics; Figure 1c", "models": { "all": { "size": { "label": "Longitudinal crossover spacing", "value": null, "unit": "nm", "statistic": "Reported interval; central estimate unavailable", "bounds": [ 65, 80 ], "boundsKind": "Reported dimensional interval; not SD or CI" } } }, "limits": "Width and crossover spacing are separate from total filament length. No growth timing or tissue concentration. One donor; no universal tau or in-vivo default. Source 650–800 Å converted using 1 Å = 0.1 nm." }, { "id": "geometry-tau-sf-width", "family": "I086", "source": "A06", "population": "Straight tau filaments", "tissue": "Sarkosyl-insoluble cerebral-cortex extract from one 74-year-old woman with Alzheimer disease; negative-stain electron microscopy", "host": "human postmortem preparation", "match": "Specific measured context; not a family-wide default", "locator": "Neuropathological characteristics; Figure 1c", "models": { "all": { "size": { "label": "Projected filament width", "value": 15, "unit": "nm", "statistic": "Approximate reported dimension", "bounds": null, "boundsKind": "Uncertainty not reported" } } }, "limits": "Width and crossover spacing are separate from total filament length. No growth timing or tissue concentration. One donor; no universal tau or in-vivo default. Source approximately 150 Å converted using 1 Å = 0.1 nm." }, { "id": "geometry-tau-sf-crossover", "family": "I086", "source": "A06", "population": "Straight tau filaments", "tissue": "Sarkosyl-insoluble cerebral-cortex extract from one 74-year-old woman with Alzheimer disease; negative-stain electron microscopy", "host": "human postmortem preparation", "match": "Specific measured context; not a family-wide default", "locator": "Neuropathological characteristics; Figure 1c", "models": { "all": { "size": { "label": "Longitudinal crossover spacing", "value": null, "unit": "nm", "statistic": "Reported interval; central estimate unavailable", "bounds": [ 70, 90 ], "boundsKind": "Reported dimensional interval; not SD or CI" } } }, "limits": "Width and crossover spacing are separate from total filament length. No growth timing or tissue concentration. One donor; no universal tau or in-vivo default. Source 700–900 Å converted using 1 Å = 0.1 nm." }, { "id": "geometry-tdp-width", "family": "I087", "source": "L53", "population": "Pathological TDP-43 filaments", "tissue": "Cortical extracts from two people with ALS and FTLD; immunogold negative-stain EM", "host": "human postmortem preparation", "match": "Specific measured context; not a family-wide default", "locator": "Extraction of pathological TDP-43; Figure 1", "models": { "all": { "size": { "label": "Projected filament width", "value": null, "unit": "nm", "statistic": "Reported interval; no pooled mean", "bounds": [ 10, 15 ], "boundsKind": "Reported projected-width interval; not SD or CI" } } }, "limits": "No midpoint or total length inferred. Extracted pathological filaments, not soluble TDP-43 or all TDP-43 proteinopathies." }, { "id": "geometry-tdp-rise", "family": "I087", "source": "L53", "population": "Pathological TDP-43 filament core", "tissue": "Frontal and motor cortex from individual 1; frontal cortex from individual 2; cryo-EM reconstruction", "host": "human postmortem preparation", "match": "Specific measured context; not a family-wide default", "locator": "Structure determination", "models": { "all": { "size": { "label": "Axial separation between stacked molecules", "value": 0.48, "unit": "nm", "statistic": "Approximate structural spacing", "bounds": null, "boundsKind": "Not supplied" } } }, "limits": "Source approximately 4.8 Å converted to 0.48 nm. Axial spacing is not filament diameter, growth-step size or total length. Static reconstruction gives no growth rate." }, { "id": "geometry-opc-movement", "family": "I061", "source": "L203", "population": "NG2-positive oligodendrocyte progenitors", "tissue": "Adult mouse somatosensory cortex; longitudinal two-photon imaging; 318 cells in 5 mice", "host": "mouse in vivo", "match": "Specific measured context; not a family-wide default", "locator": "NG2+ cells migrate continuously; Figure 2b–d", "models": { "all": { "property": { "label": "Average daily somatic movement", "value": 2.1, "unit": "µm/day", "statistic": "Reported mean", "bounds": [ 2.0, 2.2 ], "boundsKind": "Mean ± reported 0.1; SD/SEM definition not verified in this pass" } } }, "limits": "Daily movement, not instantaneous speed or net displacement. Cells from five mice are not independent animals. No human transfer or trajectory distribution inferred." }, { "id": "geometry-opc-cycle", "family": "I061", "source": "L203", "population": "Repeatedly dividing NG2-positive progenitors", "tissue": "Adult mouse somatosensory cortex; longitudinal two-photon imaging; n=97 cells", "host": "mouse in vivo", "match": "Specific measured context; not a family-wide default", "locator": "NG2+ cells directly differentiate; Figure 7a–c", "models": { "all": { "timing": { "label": "Cell-cycle interval in cells with repeated divisions", "value": 18.5, "unit": "days", "statistic": "Reported average", "bounds": [ 17.5, 19.5 ], "boundsKind": "Mean ± reported 1 day; SD/SEM definition not verified in this pass" } } }, "limits": "Selected dividing cells, not every progenitor or a population lifespan. Cell-cycle intervals varied; no probability distribution or activation time inferred." }, { "id": "geometry-ph-control-intratumor", "family": "I098", "source": "L249", "population": "Untreated control window-chamber tumors (n=4)", "tissue": "MDA-MB-231 tumor constructs in mouse dorsal skin-fold windows; SNARF-1 fluorescence ratio imaging", "host": "mouse host / human tumor construct", "match": "Specific measured context; not a family-wide default", "locator": "Table 1C, control column; Figure 5; window-chamber methods", "models": { "all": { "property": { "label": "Intratumoral extracellular pH", "value": 7.0, "unit": "pH units", "statistic": "Reported mean", "bounds": [ 6.96, 7.04 ], "boundsKind": "Mean ± SE; not observed range or CI" } } }, "limits": "Control arm, Table 1C. Logarithmic pH, not proton or lactate concentration. Distant region is within this preparation, not a universal healthy baseline; keep separate from MRS measurements and treatment effects." }, { "id": "geometry-ph-control-distant", "family": "I098", "source": "L249", "population": "Untreated control window-chamber tumors (n=4)", "tissue": "MDA-MB-231 tumor constructs in mouse dorsal skin-fold windows; SNARF-1 fluorescence ratio imaging", "host": "mouse host / human tumor construct", "match": "Specific measured context; not a family-wide default", "locator": "Table 1C, control column; Figure 5; window-chamber methods", "models": { "all": { "property": { "label": "Distant-region extracellular pH", "value": 7.11, "unit": "pH units", "statistic": "Reported mean", "bounds": [ 7.08, 7.14 ], "boundsKind": "Mean ± SE; not observed range or CI" } } }, "limits": "Control arm, Table 1C. Logarithmic pH, not proton or lactate concentration. Distant region is within this preparation, not a universal healthy baseline; keep separate from MRS measurements and treatment effects." }, { "id": "abundance-progranulin-noncarriers", "family": "I088", "source": "L56", "population": "Three family members without the GRN c.813_816del deletion", "tissue": "Human plasma; family study, commercial AdipoGen Human Progranulin ELISA", "host": "human family cohort", "match": "Genotype-specific observed range; not a population average", "locator": "Results, page 1104; Figure 1A", "models": { "all": { "amount": { "label": "Plasma progranulin concentration", "value": null, "unit": "ng/mL", "statistic": "Reported observed range; mean not supplied", "bounds": [ 125, 143 ], "boundsKind": "Observed range across three individuals; not confidence interval" } } }, "limits": "No pooled mean imported. Small related cohort; plasma is not brain interstitial fluid. Homozygous siblings were below detection (<0.6 ng/mL), not measured zero; that censored result is not assigned a baseline. No SOD1 or C9orf72 abundance, protein dimensions or turnover inferred." }, { "id": "abundance-progranulin-heterozygotes", "family": "I088", "source": "L56", "population": "Three heterozygous GRN c.813_816del family members", "tissue": "Human plasma; family study, commercial AdipoGen Human Progranulin ELISA", "host": "human family cohort", "match": "Genotype-specific observed range; not a population average", "locator": "Results, page 1104; Figure 1A", "models": { "all": { "amount": { "label": "Plasma progranulin concentration", "value": null, "unit": "ng/mL", "statistic": "Reported observed range; mean not supplied", "bounds": [ 33, 48 ], "boundsKind": "Observed range across three individuals; not confidence interval" } } }, "limits": "No pooled mean imported. Small related cohort; plasma is not brain interstitial fluid. Homozygous siblings were below detection (<0.6 ng/mL), not measured zero; that censored result is not assigned a baseline. No SOD1 or C9orf72 abundance, protein dimensions or turnover inferred." }, { "id": "abundance-tcr-wildtype-cd4", "family": "I079", "source": "T34", "population": "Wild-type mouse CD4+ T cells", "tissue": "Peripheral lymph-node cells; quantitative flow cytometry with calibrated bead standards", "host": "mouse", "match": "Specific measured cell population; not human or engager-binding default", "locator": "Results, page 74; Figure 3C", "models": { "all": { "amount": { "label": "TCR molecules per cell", "value": 40000, "unit": "molecules/cell", "statistic": "Approximate reported count; no uncertainty extracted", "bounds": null, "boundsKind": "Not reported for this approximate textual estimate" } } }, "limits": "TCR receptor count, not CD3 subunit count or accessible engager sites. No human tissue density, activation threshold, receptor turnover or binding kinetics inferred. Do not substitute the commonly cited 30,000 count or low-response thresholds for this measured wild-type population." }, { "id": "surface-p53-kms26", "family": "I078", "source": "T04", "population": "KMS26 cancer cells with endogenous TP53 R175H and HLA-A*02:01", "tissue": "Cultured cancer cells; mass spectrometry compared with heavy isotope-labeled controls", "host": "human-derived cells in vitro", "match": "Specific measured cell system; not a patient or family-wide baseline", "locator": "Results: detection of p53 R175H peptide; table S1 cited in text", "models": { "all": { "amount": { "label": "p53 R175H / HLA-A*02:01 surface complexes", "value": 2.4, "unit": "copies/cell", "statistic": "Reported population-average estimate", "bounds": null, "boundsKind": "Uncertainty not extracted for this reported estimate" } } }, "limits": "Fractional copies are population averages, not fractional molecules on individual cells. No single-cell distribution, uncertainty or patient-tumor abundance inferred. Specific peptide and HLA allele; not total p53 or total HLA. No pooled mean across cell lines or activation threshold imported." }, { "id": "surface-p53-kle", "family": "I078", "source": "T04", "population": "KLE cancer cells with endogenous TP53 R175H and HLA-A*02:01", "tissue": "Cultured cancer cells; mass spectrometry compared with heavy isotope-labeled controls", "host": "human-derived cells in vitro", "match": "Specific measured cell system; not a patient or family-wide baseline", "locator": "Results: detection of p53 R175H peptide; table S1 cited in text", "models": { "all": { "amount": { "label": "p53 R175H / HLA-A*02:01 surface complexes", "value": 1.3, "unit": "copies/cell", "statistic": "Reported population-average estimate", "bounds": null, "boundsKind": "Uncertainty not extracted for this reported estimate" } } }, "limits": "Fractional copies are population averages, not fractional molecules on individual cells. No single-cell distribution, uncertainty or patient-tumor abundance inferred. Specific peptide and HLA allele; not total p53 or total HLA. No pooled mean across cell lines or activation threshold imported." }, { "id": "surface-p53-tyk-nu", "family": "I078", "source": "T04", "population": "TYK-nu cancer cells with endogenous TP53 R175H and HLA-A*02:01", "tissue": "Cultured cancer cells; mass spectrometry compared with heavy isotope-labeled controls", "host": "human-derived cells in vitro", "match": "Specific measured cell system; not a patient or family-wide baseline", "locator": "Results: detection of p53 R175H peptide; table S1 cited in text", "models": { "all": { "amount": { "label": "p53 R175H / HLA-A*02:01 surface complexes", "value": 1.5, "unit": "copies/cell", "statistic": "Reported population-average estimate", "bounds": null, "boundsKind": "Uncertainty not extracted for this reported estimate" } } }, "limits": "Fractional copies are population averages, not fractional molecules on individual cells. No single-cell distribution, uncertainty or patient-tumor abundance inferred. Specific peptide and HLA allele; not total p53 or total HLA. No pooled mean across cell lines or activation threshold imported." }, { "id": "surface-pdl1-raji-high", "family": "I080", "source": "T35", "population": "Engineered PD-L1 high Raji B cells", "tissue": "Intact-cell PD-1/CD28 signaling assay with PD-1-expressing Jurkat T cells", "host": "human-derived cells in vitro", "match": "Specific measured cell system; not a patient or family-wide baseline", "locator": "Intact-cell Results; Figure 4A (high) and Figure S14A (low)", "models": { "all": { "amount": { "label": "PD-L1 surface density", "value": 86, "unit": "molecules/µm²", "statistic": "Approximate reported density", "bounds": null, "boundsKind": "Uncertainty not extracted for this reported estimate" } } }, "limits": "Engineered expression states, not native Raji or patient tissue averages. High and low lines are separate conditions, not uncertainty bounds. No PD-1 density, receptor dimensions, binding kinetics or in-vivo baseline inferred. Two- and ten-minute assay observations are not fitted biological timescales." }, { "id": "surface-pdl1-raji-low", "family": "I080", "source": "T35", "population": "Engineered PD-L1 low Raji B cells", "tissue": "Intact-cell PD-1/CD28 signaling assay with PD-1-expressing Jurkat T cells", "host": "human-derived cells in vitro", "match": "Specific measured cell system; not a patient or family-wide baseline", "locator": "Intact-cell Results; Figure 4A (high) and Figure S14A (low)", "models": { "all": { "amount": { "label": "PD-L1 surface density", "value": 16, "unit": "molecules/µm²", "statistic": "Approximate reported density", "bounds": null, "boundsKind": "Uncertainty not extracted for this reported estimate" } } }, "limits": "Engineered expression states, not native Raji or patient tissue averages. High and low lines are separate conditions, not uncertainty bounds. No PD-1 density, receptor dimensions, binding kinetics or in-vivo baseline inferred. Two- and ten-minute assay observations are not fitted biological timescales." }, { "id": "surface-lamin-a549-ratio", "family": "I089", "source": "L214", "population": "Wild-type A549 lung carcinoma cells", "tissue": "Nuclear lamins measured by mass spectrometry; calibration of immunoblot and immunofluorescence", "host": "human-derived cells in vitro", "match": "Specific measured cell system; not a patient or family-wide baseline", "locator": "Results: 3D migration is biphasic in lamin-A levels; Figure 1Cii", "models": { "all": { "property": { "label": "Lamin-A:B stoichiometric ratio", "value": 2.3, "unit": "ratio", "statistic": "Reported mean ratio", "bounds": null, "boundsKind": "Uncertainty not extracted for this reported estimate" } } }, "limits": "Ratio is not absolute lamin abundance, nuclear size, stiffness or repair time. The paper reports approximately 20% single-cell coefficient of variation for wild-type lamin ratios across cell types; no numerical bounds are inferred for this mass-spectrometry mean. Prior calibration is attributed by the authors to Swift et al. (2013b)." }, { "id": "nutrient-glucose-tif", "family": "I097", "source": "L244", "population": "Glucose in tumor fluid", "tissue": "Autochthonous pancreatic ductal adenocarcinoma-bearing mice; tumor fluid; LC/MS stable isotope dilution", "host": "mouse, terminal sampling", "match": "Specific tumor-bearing cohort and compartment; not a human or healthy reference", "locator": "elife-44235-fig2-figsupp6-data1-v2.xlsx, Figure 2 source data 4, BC3:BC9; Figure 2 and supplement 6", "models": { "all": { "amount": { "label": "Glucose concentration", "value": 4320.0, "unit": "µM", "statistic": "Arithmetic mean calculated from source samples (n=7); rounded to 3 significant figures", "bounds": [ 808.0, 10100.0 ], "boundsKind": "Observed sample minimum–maximum; not confidence interval or measurement error" } } }, "sampleSize": 7, "observations": [ { "sample": "922_TIF", "cell": "BC3", "value": 3818.196238 }, { "sample": "5197_TIF", "cell": "BC4", "value": 10096.15621 }, { "sample": "172_TIF", "cell": "BC5", "value": 4129.382096 }, { "sample": "142_TIF", "cell": "BC6", "value": 3961.808317 }, { "sample": "1339_TIF", "cell": "BC7", "value": 4600.147418 }, { "sample": "268_TIF", "cell": "BC8", "value": 808.175768 }, { "sample": "AL1_TIF", "cell": "BC9", "value": 2851.431134 } ], "missingObservations": [], "limits": "Tumor fluid and plasma are separate cohorts (7 and 18 samples before missingness), not a fully paired comparison. Harvest time was not fixed; feeding and circadian variation remain. Extraction delay may affect concentrations. No consumption, secretion, transport rates or random distribution inferred. Lipids, molecular dimensions and kinetics remain unresolved. No missing values in the selected cells." }, { "id": "nutrient-glucose-plasma", "family": "I110", "source": "L244", "population": "Glucose in plasma", "tissue": "Autochthonous pancreatic ductal adenocarcinoma-bearing mice; plasma; LC/MS stable isotope dilution", "host": "mouse, terminal sampling", "match": "Specific tumor-bearing cohort and compartment; not a human or healthy reference", "locator": "elife-44235-fig2-figsupp6-data1-v2.xlsx, Figure 2 source data 4, BC11:BC28; Figure 2 and supplement 6", "models": { "all": { "amount": { "label": "Glucose concentration", "value": 8220.0, "unit": "µM", "statistic": "Arithmetic mean calculated from source samples (n=18); rounded to 3 significant figures", "bounds": [ 3450.0, 16700.0 ], "boundsKind": "Observed sample minimum–maximum; not confidence interval or measurement error" } } }, "sampleSize": 18, "observations": [ { "sample": "922_Plasma", "cell": "BC11", "value": 11088.48631 }, { "sample": "58_Plasma", "cell": "BC12", "value": 8367.216535 }, { "sample": "5197_Plasma", "cell": "BC13", "value": 16734.63795 }, { "sample": "172_Plasma", "cell": "BC14", "value": 4450.094009 }, { "sample": "142_Plasma", "cell": "BC15", "value": 8787.822492 }, { "sample": "268_Plasma", "cell": "BC16", "value": 3449.912959 }, { "sample": "AL1_Plasma", "cell": "BC17", "value": 8749.439029 }, { "sample": "X2_Plasma", "cell": "BC18", "value": 4002.853021 }, { "sample": "X3_Plasma", "cell": "BC19", "value": 5578.993884 }, { "sample": "X4_Plasma", "cell": "BC20", "value": 11606.52422 }, { "sample": "3731_Plasma", "cell": "BC21", "value": 5860.013315 }, { "sample": "4198_Plasma", "cell": "BC22", "value": 9328.640526 }, { "sample": "4300_Plasma", "cell": "BC23", "value": 5338.077993 }, { "sample": "A0_Plasma", "cell": "BC24", "value": 10180.03101 }, { "sample": "A1_Plasma", "cell": "BC25", "value": 11014.42155 }, { "sample": "B0_Plasma", "cell": "BC26", "value": 10688.9855 }, { "sample": "B1_Plasma", "cell": "BC27", "value": 5663.797756 }, { "sample": "B2_Plasma", "cell": "BC28", "value": 7065.157769 } ], "missingObservations": [], "limits": "Tumor fluid and plasma are separate cohorts (7 and 18 samples before missingness), not a fully paired comparison. Harvest time was not fixed; feeding and circadian variation remain. Extraction delay may affect concentrations. No consumption, secretion, transport rates or random distribution inferred. Lipids, molecular dimensions and kinetics remain unresolved. No missing values in the selected cells." }, { "id": "nutrient-glutamine-tif", "family": "I097", "source": "L244", "population": "Glutamine in tumor fluid", "tissue": "Autochthonous pancreatic ductal adenocarcinoma-bearing mice; tumor fluid; LC/MS stable isotope dilution", "host": "mouse, terminal sampling", "match": "Specific tumor-bearing cohort and compartment; not a human or healthy reference", "locator": "elife-44235-fig2-figsupp6-data1-v2.xlsx, Figure 2 source data 4, BD3:BD9; Figure 2 and supplement 6", "models": { "all": { "amount": { "label": "Glutamine concentration", "value": 821.0, "unit": "µM", "statistic": "Arithmetic mean calculated from source samples (n=7); rounded to 3 significant figures", "bounds": [ 434.0, 1330.0 ], "boundsKind": "Observed sample minimum–maximum; not confidence interval or measurement error" } } }, "sampleSize": 7, "observations": [ { "sample": "922_TIF", "cell": "BD3", "value": 784.0826622 }, { "sample": "5197_TIF", "cell": "BD4", "value": 933.8126417 }, { "sample": "172_TIF", "cell": "BD5", "value": 849.3976736 }, { "sample": "142_TIF", "cell": "BD6", "value": 1329.218605 }, { "sample": "1339_TIF", "cell": "BD7", "value": 606.9140814 }, { "sample": "268_TIF", "cell": "BD8", "value": 434.4065702 }, { "sample": "AL1_TIF", "cell": "BD9", "value": 808.9145226 } ], "missingObservations": [], "limits": "Tumor fluid and plasma are separate cohorts (7 and 18 samples before missingness), not a fully paired comparison. Harvest time was not fixed; feeding and circadian variation remain. Extraction delay may affect concentrations. No consumption, secretion, transport rates or random distribution inferred. Lipids, molecular dimensions and kinetics remain unresolved. No missing values in the selected cells." }, { "id": "nutrient-glutamine-plasma", "family": "I110", "source": "L244", "population": "Glutamine in plasma", "tissue": "Autochthonous pancreatic ductal adenocarcinoma-bearing mice; plasma; LC/MS stable isotope dilution", "host": "mouse, terminal sampling", "match": "Specific tumor-bearing cohort and compartment; not a human or healthy reference", "locator": "elife-44235-fig2-figsupp6-data1-v2.xlsx, Figure 2 source data 4, BD11:BD28; Figure 2 and supplement 6", "models": { "all": { "amount": { "label": "Glutamine concentration", "value": 850.0, "unit": "µM", "statistic": "Arithmetic mean calculated from source samples (n=18); rounded to 3 significant figures", "bounds": [ 470.0, 1380.0 ], "boundsKind": "Observed sample minimum–maximum; not confidence interval or measurement error" } } }, "sampleSize": 18, "observations": [ { "sample": "922_Plasma", "cell": "BD11", "value": 809.8507141 }, { "sample": "58_Plasma", "cell": "BD12", "value": 1298.730111 }, { "sample": "5197_Plasma", "cell": "BD13", "value": 767.6734611 }, { "sample": "172_Plasma", "cell": "BD14", "value": 534.2129188 }, { "sample": "142_Plasma", "cell": "BD15", "value": 1343.523627 }, { "sample": "268_Plasma", "cell": "BD16", "value": 647.3864408 }, { "sample": "AL1_Plasma", "cell": "BD17", "value": 1379.737511 }, { "sample": "X2_Plasma", "cell": "BD18", "value": 470.1843747 }, { "sample": "X3_Plasma", "cell": "BD19", "value": 722.492578 }, { "sample": "X4_Plasma", "cell": "BD20", "value": 629.2090152 }, { "sample": "3731_Plasma", "cell": "BD21", "value": 1083.324672 }, { "sample": "4198_Plasma", "cell": "BD22", "value": 697.7422529 }, { "sample": "4300_Plasma", "cell": "BD23", "value": 1261.756602 }, { "sample": "A0_Plasma", "cell": "BD24", "value": 552.0578182 }, { "sample": "A1_Plasma", "cell": "BD25", "value": 656.5093089 }, { "sample": "B0_Plasma", "cell": "BD26", "value": 804.9568229 }, { "sample": "B1_Plasma", "cell": "BD27", "value": 941.6643572 }, { "sample": "B2_Plasma", "cell": "BD28", "value": 695.1514906 } ], "missingObservations": [], "limits": "Tumor fluid and plasma are separate cohorts (7 and 18 samples before missingness), not a fully paired comparison. Harvest time was not fixed; feeding and circadian variation remain. Extraction delay may affect concentrations. No consumption, secretion, transport rates or random distribution inferred. Lipids, molecular dimensions and kinetics remain unresolved. No missing values in the selected cells." }, { "id": "nutrient-arginine-tif", "family": "I097", "source": "L244", "population": "Arginine in tumor fluid", "tissue": "Autochthonous pancreatic ductal adenocarcinoma-bearing mice; tumor fluid; LC/MS stable isotope dilution", "host": "mouse, terminal sampling", "match": "Specific tumor-bearing cohort and compartment; not a human or healthy reference", "locator": "elife-44235-fig2-figsupp6-data1-v2.xlsx, Figure 2 source data 4, BL3:BL9; Figure 2 and supplement 6", "models": { "all": { "amount": { "label": "Arginine concentration", "value": 2.12, "unit": "µM", "statistic": "Arithmetic mean calculated from source samples (n=7); rounded to 3 significant figures", "bounds": [ 0.874, 5.19 ], "boundsKind": "Observed sample minimum–maximum; not confidence interval or measurement error" } } }, "sampleSize": 7, "observations": [ { "sample": "922_TIF", "cell": "BL3", "value": 3.050101311 }, { "sample": "5197_TIF", "cell": "BL4", "value": 5.185003645 }, { "sample": "172_TIF", "cell": "BL5", "value": 0.874305399 }, { "sample": "142_TIF", "cell": "BL6", "value": 1.061648904 }, { "sample": "1339_TIF", "cell": "BL7", "value": 2.059540072 }, { "sample": "268_TIF", "cell": "BL8", "value": 1.598560239 }, { "sample": "AL1_TIF", "cell": "BL9", "value": 1.004387528 } ], "missingObservations": [], "limits": "Tumor fluid and plasma are separate cohorts (7 and 18 samples before missingness), not a fully paired comparison. Harvest time was not fixed; feeding and circadian variation remain. Extraction delay may affect concentrations. No consumption, secretion, transport rates or random distribution inferred. Lipids, molecular dimensions and kinetics remain unresolved. No missing values in the selected cells." }, { "id": "nutrient-arginine-plasma", "family": "I110", "source": "L244", "population": "Arginine in plasma", "tissue": "Autochthonous pancreatic ductal adenocarcinoma-bearing mice; plasma; LC/MS stable isotope dilution", "host": "mouse, terminal sampling", "match": "Specific tumor-bearing cohort and compartment; not a human or healthy reference", "locator": "elife-44235-fig2-figsupp6-data1-v2.xlsx, Figure 2 source data 4, BL11:BL28; Figure 2 and supplement 6", "models": { "all": { "amount": { "label": "Arginine concentration", "value": 130.0, "unit": "µM", "statistic": "Arithmetic mean calculated from source samples (n=18); rounded to 3 significant figures", "bounds": [ 50.9, 234.0 ], "boundsKind": "Observed sample minimum–maximum; not confidence interval or measurement error" } } }, "sampleSize": 18, "observations": [ { "sample": "922_Plasma", "cell": "BL11", "value": 148.7824863 }, { "sample": "58_Plasma", "cell": "BL12", "value": 144.5451687 }, { "sample": "5197_Plasma", "cell": "BL13", "value": 144.517793 }, { "sample": "172_Plasma", "cell": "BL14", "value": 50.85454898 }, { "sample": "142_Plasma", "cell": "BL15", "value": 52.29013489 }, { "sample": "268_Plasma", "cell": "BL16", "value": 57.15668733 }, { "sample": "AL1_Plasma", "cell": "BL17", "value": 79.11539179 }, { "sample": "X2_Plasma", "cell": "BL18", "value": 123.697469 }, { "sample": "X3_Plasma", "cell": "BL19", "value": 136.0309152 }, { "sample": "X4_Plasma", "cell": "BL20", "value": 234.1710539 }, { "sample": "3731_Plasma", "cell": "BL21", "value": 144.7357197 }, { "sample": "4198_Plasma", "cell": "BL22", "value": 125.953668 }, { "sample": "4300_Plasma", "cell": "BL23", "value": 162.9087998 }, { "sample": "A0_Plasma", "cell": "BL24", "value": 107.8200086 }, { "sample": "A1_Plasma", "cell": "BL25", "value": 200.3116279 }, { "sample": "B0_Plasma", "cell": "BL26", "value": 145.992975 }, { "sample": "B1_Plasma", "cell": "BL27", "value": 163.1760116 }, { "sample": "B2_Plasma", "cell": "BL28", "value": 112.894061 } ], "missingObservations": [], "limits": "Tumor fluid and plasma are separate cohorts (7 and 18 samples before missingness), not a fully paired comparison. Harvest time was not fixed; feeding and circadian variation remain. Extraction delay may affect concentrations. No consumption, secretion, transport rates or random distribution inferred. Lipids, molecular dimensions and kinetics remain unresolved. No missing values in the selected cells." }, { "id": "nutrient-tryptophan-tif", "family": "I097", "source": "L244", "population": "Tryptophan in tumor fluid", "tissue": "Autochthonous pancreatic ductal adenocarcinoma-bearing mice; tumor fluid; LC/MS stable isotope dilution", "host": "mouse, terminal sampling", "match": "Specific tumor-bearing cohort and compartment; not a human or healthy reference", "locator": "elife-44235-fig2-figsupp6-data1-v2.xlsx, Figure 2 source data 4, AV3:AV9; Figure 2 and supplement 6", "models": { "all": { "amount": { "label": "Tryptophan concentration", "value": 30.9, "unit": "µM", "statistic": "Arithmetic mean calculated from source samples (n=7); rounded to 3 significant figures", "bounds": [ 18.4, 71.3 ], "boundsKind": "Observed sample minimum–maximum; not confidence interval or measurement error" } } }, "sampleSize": 7, "observations": [ { "sample": "922_TIF", "cell": "AV3", "value": 37.27371774 }, { "sample": "5197_TIF", "cell": "AV4", "value": 71.34529685 }, { "sample": "172_TIF", "cell": "AV5", "value": 20.97763717 }, { "sample": "142_TIF", "cell": "AV6", "value": 22.29288117 }, { "sample": "1339_TIF", "cell": "AV7", "value": 24.14678102 }, { "sample": "268_TIF", "cell": "AV8", "value": 18.42597769 }, { "sample": "AL1_TIF", "cell": "AV9", "value": 22.13730643 } ], "missingObservations": [], "limits": "Tumor fluid and plasma are separate cohorts (7 and 18 samples before missingness), not a fully paired comparison. Harvest time was not fixed; feeding and circadian variation remain. Extraction delay may affect concentrations. No consumption, secretion, transport rates or random distribution inferred. Lipids, molecular dimensions and kinetics remain unresolved. No missing values in the selected cells." }, { "id": "nutrient-tryptophan-plasma", "family": "I110", "source": "L244", "population": "Tryptophan in plasma", "tissue": "Autochthonous pancreatic ductal adenocarcinoma-bearing mice; plasma; LC/MS stable isotope dilution", "host": "mouse, terminal sampling", "match": "Specific tumor-bearing cohort and compartment; not a human or healthy reference", "locator": "elife-44235-fig2-figsupp6-data1-v2.xlsx, Figure 2 source data 4, AV11:AV28; Figure 2 and supplement 6", "models": { "all": { "amount": { "label": "Tryptophan concentration", "value": 82.1, "unit": "µM", "statistic": "Arithmetic mean calculated from source samples (n=18); rounded to 3 significant figures", "bounds": [ 27.9, 151.0 ], "boundsKind": "Observed sample minimum–maximum; not confidence interval or measurement error" } } }, "sampleSize": 18, "observations": [ { "sample": "922_Plasma", "cell": "AV11", "value": 70.44210276 }, { "sample": "58_Plasma", "cell": "AV12", "value": 86.54312477 }, { "sample": "5197_Plasma", "cell": "AV13", "value": 98.10378201 }, { "sample": "172_Plasma", "cell": "AV14", "value": 27.91903709 }, { "sample": "142_Plasma", "cell": "AV15", "value": 27.92682089 }, { "sample": "268_Plasma", "cell": "AV16", "value": 51.32861279 }, { "sample": "AL1_Plasma", "cell": "AV17", "value": 60.00859653 }, { "sample": "X2_Plasma", "cell": "AV18", "value": 69.05304448 }, { "sample": "X3_Plasma", "cell": "AV19", "value": 99.28200855 }, { "sample": "X4_Plasma", "cell": "AV20", "value": 134.8076633 }, { "sample": "3731_Plasma", "cell": "AV21", "value": 66.94244518 }, { "sample": "4198_Plasma", "cell": "AV22", "value": 76.35089825 }, { "sample": "4300_Plasma", "cell": "AV23", "value": 67.12594675 }, { "sample": "A0_Plasma", "cell": "AV24", "value": 69.47738756 }, { "sample": "A1_Plasma", "cell": "AV25", "value": 89.63768318 }, { "sample": "B0_Plasma", "cell": "AV26", "value": 81.89705754 }, { "sample": "B1_Plasma", "cell": "AV27", "value": 149.8867235 }, { "sample": "B2_Plasma", "cell": "AV28", "value": 150.5304214 } ], "missingObservations": [], "limits": "Tumor fluid and plasma are separate cohorts (7 and 18 samples before missingness), not a fully paired comparison. Harvest time was not fixed; feeding and circadian variation remain. Extraction delay may affect concentrations. No consumption, secretion, transport rates or random distribution inferred. Lipids, molecular dimensions and kinetics remain unresolved. No missing values in the selected cells." }, { "id": "nutrient-alanine-tif", "family": "I097", "source": "L244", "population": "Alanine in tumor fluid", "tissue": "Autochthonous pancreatic ductal adenocarcinoma-bearing mice; tumor fluid; LC/MS stable isotope dilution", "host": "mouse, terminal sampling", "match": "Specific tumor-bearing cohort and compartment; not a human or healthy reference", "locator": "elife-44235-fig2-figsupp6-data1-v2.xlsx, Figure 2 source data 4, BB3:BB9; Figure 2 and supplement 6", "models": { "all": { "amount": { "label": "Alanine concentration", "value": 1120.0, "unit": "µM", "statistic": "Arithmetic mean calculated from source samples (n=7); rounded to 3 significant figures", "bounds": [ 637.0, 1460.0 ], "boundsKind": "Observed sample minimum–maximum; not confidence interval or measurement error" } } }, "sampleSize": 7, "observations": [ { "sample": "922_TIF", "cell": "BB3", "value": 1217.552669 }, { "sample": "5197_TIF", "cell": "BB4", "value": 1091.463322 }, { "sample": "172_TIF", "cell": "BB5", "value": 1457.96729 }, { "sample": "142_TIF", "cell": "BB6", "value": 1423.766564 }, { "sample": "1339_TIF", "cell": "BB7", "value": 778.7132058 }, { "sample": "268_TIF", "cell": "BB8", "value": 637.0859691 }, { "sample": "AL1_TIF", "cell": "BB9", "value": 1247.0075 } ], "missingObservations": [], "limits": "Tumor fluid and plasma are separate cohorts (7 and 18 samples before missingness), not a fully paired comparison. Harvest time was not fixed; feeding and circadian variation remain. Extraction delay may affect concentrations. No consumption, secretion, transport rates or random distribution inferred. Lipids, molecular dimensions and kinetics remain unresolved. No missing values in the selected cells." }, { "id": "nutrient-alanine-plasma", "family": "I110", "source": "L244", "population": "Alanine in plasma", "tissue": "Autochthonous pancreatic ductal adenocarcinoma-bearing mice; plasma; LC/MS stable isotope dilution", "host": "mouse, terminal sampling", "match": "Specific tumor-bearing cohort and compartment; not a human or healthy reference", "locator": "elife-44235-fig2-figsupp6-data1-v2.xlsx, Figure 2 source data 4, BB11:BB28; Figure 2 and supplement 6", "models": { "all": { "amount": { "label": "Alanine concentration", "value": 847.0, "unit": "µM", "statistic": "Arithmetic mean calculated from source samples (n=18); rounded to 3 significant figures", "bounds": [ 412.0, 1540.0 ], "boundsKind": "Observed sample minimum–maximum; not confidence interval or measurement error" } } }, "sampleSize": 18, "observations": [ { "sample": "922_Plasma", "cell": "BB11", "value": 708.4766732 }, { "sample": "58_Plasma", "cell": "BB12", "value": 793.7125724 }, { "sample": "5197_Plasma", "cell": "BB13", "value": 462.8607379 }, { "sample": "172_Plasma", "cell": "BB14", "value": 580.1783001 }, { "sample": "142_Plasma", "cell": "BB15", "value": 933.1493426 }, { "sample": "268_Plasma", "cell": "BB16", "value": 411.6127221 }, { "sample": "AL1_Plasma", "cell": "BB17", "value": 1273.681078 }, { "sample": "X2_Plasma", "cell": "BB18", "value": 540.6679642 }, { "sample": "X3_Plasma", "cell": "BB19", "value": 713.7316541 }, { "sample": "X4_Plasma", "cell": "BB20", "value": 790.1442387 }, { "sample": "3731_Plasma", "cell": "BB21", "value": 1538.567224 }, { "sample": "4198_Plasma", "cell": "BB22", "value": 668.4429368 }, { "sample": "4300_Plasma", "cell": "BB23", "value": 1059.25792 }, { "sample": "A0_Plasma", "cell": "BB24", "value": 616.9596605 }, { "sample": "A1_Plasma", "cell": "BB25", "value": 756.0284423 }, { "sample": "B0_Plasma", "cell": "BB26", "value": 1068.926156 }, { "sample": "B1_Plasma", "cell": "BB27", "value": 1378.809399 }, { "sample": "B2_Plasma", "cell": "BB28", "value": 954.1500306 } ], "missingObservations": [], "limits": "Tumor fluid and plasma are separate cohorts (7 and 18 samples before missingness), not a fully paired comparison. Harvest time was not fixed; feeding and circadian variation remain. Extraction delay may affect concentrations. No consumption, secretion, transport rates or random distribution inferred. Lipids, molecular dimensions and kinetics remain unresolved. No missing values in the selected cells." }, { "id": "nutrient-cystine-tif", "family": "I097", "source": "L244", "population": "Cystine in tumor fluid", "tissue": "Autochthonous pancreatic ductal adenocarcinoma-bearing mice; tumor fluid; LC/MS stable isotope dilution", "host": "mouse, terminal sampling", "match": "Specific tumor-bearing cohort and compartment; not a human or healthy reference", "locator": "elife-44235-fig2-figsupp6-data1-v2.xlsx, Figure 2 source data 4, BI3:BI9; Figure 2 and supplement 6", "models": { "all": { "amount": { "label": "Cystine concentration", "value": 50.6, "unit": "µM", "statistic": "Arithmetic mean calculated from source samples (n=7); rounded to 3 significant figures", "bounds": [ 16.1, 111.0 ], "boundsKind": "Observed sample minimum–maximum; not confidence interval or measurement error" } } }, "sampleSize": 7, "observations": [ { "sample": "922_TIF", "cell": "BI3", "value": 67.67039586 }, { "sample": "5197_TIF", "cell": "BI4", "value": 110.5816766 }, { "sample": "172_TIF", "cell": "BI5", "value": 16.05272458 }, { "sample": "142_TIF", "cell": "BI6", "value": 32.36616798 }, { "sample": "1339_TIF", "cell": "BI7", "value": 47.4052264 }, { "sample": "268_TIF", "cell": "BI8", "value": 32.87421016 }, { "sample": "AL1_TIF", "cell": "BI9", "value": 46.92109548 } ], "missingObservations": [], "limits": "Tumor fluid and plasma are separate cohorts (7 and 18 samples before missingness), not a fully paired comparison. Harvest time was not fixed; feeding and circadian variation remain. Extraction delay may affect concentrations. No consumption, secretion, transport rates or random distribution inferred. Lipids, molecular dimensions and kinetics remain unresolved. No missing values in the selected cells." }, { "id": "nutrient-cystine-plasma", "family": "I110", "source": "L244", "population": "Cystine in plasma", "tissue": "Autochthonous pancreatic ductal adenocarcinoma-bearing mice; plasma; LC/MS stable isotope dilution", "host": "mouse, terminal sampling", "match": "Specific tumor-bearing cohort and compartment; not a human or healthy reference", "locator": "elife-44235-fig2-figsupp6-data1-v2.xlsx, Figure 2 source data 4, BI11:BI28; Figure 2 and supplement 6", "models": { "all": { "amount": { "label": "Cystine concentration", "value": 95.4, "unit": "µM", "statistic": "Arithmetic mean calculated from source samples (n=17); rounded to 3 significant figures", "bounds": [ 29.9, 153.0 ], "boundsKind": "Observed sample minimum–maximum; not confidence interval or measurement error" } } }, "sampleSize": 17, "observations": [ { "sample": "922_Plasma", "cell": "BI11", "value": 150.3679462 }, { "sample": "58_Plasma", "cell": "BI12", "value": 153.3738799 }, { "sample": "5197_Plasma", "cell": "BI13", "value": 79.11850665 }, { "sample": "142_Plasma", "cell": "BI15", "value": 137.2282013 }, { "sample": "268_Plasma", "cell": "BI16", "value": 63.75149901 }, { "sample": "AL1_Plasma", "cell": "BI17", "value": 80.02623838 }, { "sample": "X2_Plasma", "cell": "BI18", "value": 80.96965056 }, { "sample": "X3_Plasma", "cell": "BI19", "value": 135.3288814 }, { "sample": "X4_Plasma", "cell": "BI20", "value": 133.2988241 }, { "sample": "3731_Plasma", "cell": "BI21", "value": 86.34924958 }, { "sample": "4198_Plasma", "cell": "BI22", "value": 29.94784796 }, { "sample": "4300_Plasma", "cell": "BI23", "value": 52.29083553 }, { "sample": "A0_Plasma", "cell": "BI24", "value": 56.37094368 }, { "sample": "A1_Plasma", "cell": "BI25", "value": 85.85677445 }, { "sample": "B0_Plasma", "cell": "BI26", "value": 122.0882013 }, { "sample": "B1_Plasma", "cell": "BI27", "value": 114.4542796 }, { "sample": "B2_Plasma", "cell": "BI28", "value": 60.80388529 } ], "missingObservations": [ { "sample": "172_Plasma", "cell": "BI14" } ], "limits": "Tumor fluid and plasma are separate cohorts (7 and 18 samples before missingness), not a fully paired comparison. Harvest time was not fixed; feeding and circadian variation remain. Extraction delay may affect concentrations. No consumption, secretion, transport rates or random distribution inferred. Lipids, molecular dimensions and kinetics remain unresolved. Missing source value: 172_Plasma; n=17 rather than 18. No zero imputed." }, { "id": "mechanics-tgfb-llc-helix", "family": "I073", "source": "L13", "population": "Latent TGF-beta1 large complex (LLC), alpha1 helix unfolding", "tissue": "CHO-produced extracellular matrix; AFM pulling at 200 nm/s, approximately 10,000 pN/s", "host": "human recombinant components expressed in hamster cells; in vitro", "match": "Domain-filtered event-population peak; not a family average", "locator": "Results: Mechanical Activation of TGF-beta1 from the ECM; Figure 6E", "models": { "all": { "size": { "label": "Unfolding contour-length increment", "value": 11.4, "unit": "nm", "statistic": "Reported event-population peak", "bounds": null, "boundsKind": "Peak uncertainty unresolved" }, "property": { "label": "Corresponding unfolding force", "value": 51.2, "unit": "pN", "statistic": "Reported event-population peak", "bounds": null, "boundsKind": "Peak uncertainty unresolved" } } }, "limits": "Extension is not resting molecular diameter. Loading-rate-dependent force is not a universal activation threshold. No timing, concentration or random distribution inferred." }, { "id": "mechanics-tgfb-llc-straitjacket", "family": "I073", "source": "L13", "population": "Same LLC assay; whole straitjacket unfolding", "tissue": "Same CHO-matrix AFM conditions as mechanics-tgfb-llc-helix", "host": "human recombinant components expressed in hamster cells; in vitro", "match": "Separate domain-filtered event population", "locator": "Results: Mechanical Activation; Figure 6E", "models": { "all": { "size": { "label": "Unfolding contour-length increment", "value": 18.3, "unit": "nm", "statistic": "Reported event-population peak", "bounds": null, "boundsKind": "Peak uncertainty unresolved" }, "property": { "label": "Corresponding unfolding force", "value": 38.6, "unit": "pN", "statistic": "Reported event-population peak", "bounds": null, "boundsKind": "Peak uncertainty unresolved" } } }, "limits": "Distinct event types are not uncertainty bounds. Extension is not resting diameter; force is assay-dependent. Amount and timing remain unknown." }, { "id": "mechanics-all-marrow-repopulation", "family": "I053", "source": "H04", "population": "Chemotherapy-resistant patient-derived acute lymphoblastic leukemia cells", "tissue": "Bone marrow after 28-day dexamethasone, vincristine and doxorubicin induction", "host": "human pediatric leukemia xenografts in NSG mice", "match": "Post-treatment repopulation window; not untreated cell-cycle duration", "locator": "Results: A leukemia xenograft model of induction chemotherapy; final paragraph", "models": { "all": { "timing": { "label": "Marrow repopulation after end of induction", "value": null, "unit": "days", "statistic": "Reported window; no average supplied", "bounds": [ 7, 28 ], "boundsKind": "Reported post-treatment interval, not a confidence interval" } } }, "limits": "Time zero is the end of induction, not transplantation or treatment start. No midpoint, human relapse prediction, doubling time or growth-rate constant inferred. Sample-level variation and lineage-specific intervals remain unresolved; size and local abundance remain unknown." }, { "id": "controls-pvm-vehicle", "family": "I030", "source": "L102", "population": "Perivascular macrophages: vehicle arm", "tissue": "Brain perivascular space; sequential green/red dextran labeling", "host": "TgCRND8 mice, age 5 months at first injection", "match": "Labeling-based turnover proxy; not absolute cell abundance", "locator": "Results: Chitin Administration; Figure 3A–B; Methods: Stimulation of Perivascular Macrophage Turnover", "sampleSize": 4, "models": { "all": { "property": { "label": "Singly red-labeled macrophages", "value": 32.7, "unit": "%", "statistic": "Reported mean; n=4 mice per arm", "bounds": [ 30.3, 35.1 ], "boundsKind": "Mean ± standard error of the mean; not population range" } } }, "limits": "Injections 14 days apart; endpoint 14 days after second injection. Chitin: 5 micrograms per injection; vehicle: PBS. Label fraction is not a daily turnover rate, lifespan or amyloid clearance rate. No human extrapolation or random distribution inferred." }, { "id": "controls-pvm-chitin", "family": "I030", "source": "L102", "population": "Perivascular macrophages: chitin arm", "tissue": "Brain perivascular space; sequential green/red dextran labeling", "host": "TgCRND8 mice, age 5 months at first injection", "match": "Labeling-based turnover proxy; not absolute cell abundance", "locator": "Results: Chitin Administration; Figure 3A–B; Methods: Stimulation of Perivascular Macrophage Turnover", "sampleSize": 4, "models": { "all": { "property": { "label": "Singly red-labeled macrophages", "value": 48.3, "unit": "%", "statistic": "Reported mean; n=4 mice per arm", "bounds": [ 42.4, 54.2 ], "boundsKind": "Mean ± standard error of the mean; not population range" } } }, "limits": "Injections 14 days apart; endpoint 14 days after second injection. Chitin: 5 micrograms per injection; vehicle: PBS. Label fraction is not a daily turnover rate, lifespan or amyloid clearance rate. No human extrapolation or random distribution inferred." }, { "id": "controls-mt1-control", "family": "I082", "source": "L28", "population": "HT-1080 cells: control siRNA", "tissue": "Chick chorioallantoic membrane (CAM), 3-day endpoint", "host": "Human fibrosarcoma cells on chick CAM", "match": "Functional invasion assay; not enzyme amount or dimensions", "locator": "Figure 6C caption", "sampleSize": 3, "models": { "all": { "property": { "label": "Cells invading across CAM surface", "value": 24, "unit": "%", "statistic": "Reported mean; n=3 experiments", "bounds": [ 17, 31 ], "boundsKind": "Mean ± one standard deviation; not confidence interval" } } }, "limits": "Control, silencing and rescue are separate experimental states. Not the human dermal-explant assay in Figure 6D. No enzyme concentration, catalytic rate, molecular size or lifetime inferred." }, { "id": "controls-mt1-silenced", "family": "I082", "source": "L28", "population": "HT-1080 cells: MT1-MMP siRNA", "tissue": "Chick chorioallantoic membrane (CAM), 3-day endpoint", "host": "Human fibrosarcoma cells on chick CAM", "match": "Functional invasion assay; not enzyme amount or dimensions", "locator": "Figure 6C caption", "sampleSize": 3, "models": { "all": { "property": { "label": "Cells invading across CAM surface", "value": 1, "unit": "%", "statistic": "Reported mean; n=3 experiments", "bounds": [ 0, 2 ], "boundsKind": "Mean ± one standard deviation; not confidence interval" } } }, "limits": "Control, silencing and rescue are separate experimental states. Not the human dermal-explant assay in Figure 6D. No enzyme concentration, catalytic rate, molecular size or lifetime inferred." }, { "id": "controls-mt1-rescue", "family": "I082", "source": "L28", "population": "HT-1080 cells: MT1-MMP siRNA plus mouse MT1-MMP expression vector", "tissue": "Chick chorioallantoic membrane (CAM), 3-day endpoint", "host": "Human fibrosarcoma cells on chick CAM", "match": "Functional invasion assay; not enzyme amount or dimensions", "locator": "Figure 6C caption", "sampleSize": 3, "models": { "all": { "property": { "label": "Cells invading across CAM surface", "value": 25, "unit": "%", "statistic": "Reported mean; n=3 experiments", "bounds": [ 22, 28 ], "boundsKind": "Mean ± one standard deviation; not confidence interval" } } }, "limits": "Control, silencing and rescue are separate experimental states. Not the human dermal-explant assay in Figure 6D. No enzyme concentration, catalytic rate, molecular size or lifetime inferred." }, { "id": "axonal-vivo-intermediate", "family": "I058", "source": "L233", "population": "HC555-labeled retrograde carriers after intramuscular injection; intermediate component", "tissue": "Wild-type mouse, intact sciatic nerve", "host": "Wild-type mouse, intact sciatic nerve", "match": "Fitted moving-speed component; not an overall transport mean", "locator": "Figure 1E–F and accompanying Results; Tracking and Data Quantification", "models": { "all": { "property": { "label": "Retrograde cargo speed: intermediate component", "value": 1, "unit": "µm/s", "statistic": "Reported Gaussian-component center", "bounds": null, "boundsKind": "Component width and center uncertainty not extracted" } } }, "limits": "Mixed motor/sensory axons; not motor-neuron-exclusive. 258 carriers, 44 axons, five experiments. No human extrapolation, transit time or random distribution inferred. Paused/slow component and weighting are not imported; these records do not reconstruct the full speed distribution." }, { "id": "axonal-vivo-fast", "family": "I058", "source": "L233", "population": "HC555-labeled retrograde carriers after intramuscular injection; fast component", "tissue": "Wild-type mouse, intact sciatic nerve", "host": "Wild-type mouse, intact sciatic nerve", "match": "Fitted moving-speed component; not an overall transport mean", "locator": "Figure 1E–F and accompanying Results; Tracking and Data Quantification", "models": { "all": { "property": { "label": "Retrograde cargo speed: fast component", "value": 1.66, "unit": "µm/s", "statistic": "Reported Gaussian-component center", "bounds": null, "boundsKind": "Component width and center uncertainty not extracted" } } }, "limits": "Mixed motor/sensory axons; not motor-neuron-exclusive. 258 carriers, 44 axons, five experiments. No human extrapolation, transit time or random distribution inferred. Paused/slow component and weighting are not imported; these records do not reconstruct the full speed distribution." }, { "id": "axonal-vitro-intermediate", "family": "I058", "source": "L233", "population": "HC555-labeled retrograde carriers in cultured motor neurons; intermediate component", "tissue": "Mouse primary motor-neuron culture", "host": "Mouse primary motor-neuron culture", "match": "Fitted moving-speed component; not an overall transport mean", "locator": "Figure 1E–F and accompanying Results; Tracking and Data Quantification", "models": { "all": { "property": { "label": "Retrograde cargo speed: intermediate component", "value": 0.53, "unit": "µm/s", "statistic": "Reported Gaussian-component center", "bounds": null, "boundsKind": "Component width and center uncertainty not extracted" } } }, "limits": "383 carriers, 32 axons, five cultures. Culture and intact nerve are separate settings. No human extrapolation, transit time or random distribution inferred. Paused/slow component and weighting are not imported; these records do not reconstruct the full speed distribution." }, { "id": "axonal-vitro-fast", "family": "I058", "source": "L233", "population": "HC555-labeled retrograde carriers in cultured motor neurons; fast component", "tissue": "Mouse primary motor-neuron culture", "host": "Mouse primary motor-neuron culture", "match": "Fitted moving-speed component; not an overall transport mean", "locator": "Figure 1E–F and accompanying Results; Tracking and Data Quantification", "models": { "all": { "property": { "label": "Retrograde cargo speed: fast component", "value": 0.95, "unit": "µm/s", "statistic": "Reported Gaussian-component center", "bounds": null, "boundsKind": "Component width and center uncertainty not extracted" } } }, "limits": "383 carriers, 32 axons, five cultures. Culture and intact nerve are separate settings. No human extrapolation, transit time or random distribution inferred. Paused/slow component and weighting are not imported; these records do not reconstruct the full speed distribution." }, { "id": "pdgf-hs-strong-binding-fragments", "family": "I071", "source": "L18", "population": "Strongly PDGF-BB-binding heparan-sulfate SAS fragments", "tissue": "Pig intestinal mucosa-derived heparan sulfate; isolated fragments on a PDGF-BB affinity column", "host": "Porcine material in a cell-free biochemical assay", "match": "Matrix-binding partner of the PDGF axis; not PDGF protein size", "locator": "Results accompanying Figure 5B–C: strongly binding SAS fraction", "models": { "all": { "property": { "label": "Saccharide count of strongly binding HS fragments", "value": null, "unit": "saccharide residues", "statistic": "Reported fraction range; no mean supplied", "bounds": [ 12, 18 ], "boundsKind": "Size range in the selected experimental fraction, not a confidence interval" } } }, "limits": "The input pool was approximately 8–18 residues; the strong-binding fraction eluted at 0.45 M NaCl. Thus 18 is not a biological maximum. SAS contains sulfated domains separated by N-acetylated units. This is not PDGF diameter, a whole HS-chain length, a dissociation constant or a physiological salt concentration. No midpoint, nanometre conversion or random distribution inferred. PDGF abundance and kinetics remain unknown." }, { "id": "cart-p1-cd8", "family": "I107", "source": "L276", "population": "Patient 1: CD8+ CAR T cells", "tissue": "Peripheral blood at 1.8 months after infusion; CD3+CAR+ gate", "host": "Human CLL, selected long-term remission cases", "match": "Patient-specific post-treatment composition, not a population baseline", "locator": "CyTOF reveals CD8+, gamma-delta and CD4+ CAR T cells; Figure 2a–c", "models": { "all": { "property": { "label": "CD8+ fraction of CAR T cells", "value": 29.3, "unit": "%", "statistic": "Reported single-patient time-point fraction; not a mean", "bounds": null, "boundsKind": "Uncertainty and population range not reported for this fraction" } } }, "limits": "Two selected long-term responders in the study; each reference is one patient at the stated time. CyTOF composition is not an absolute cell count or tissue concentration. Sampling time is not cell lifespan. No pooled average, confidence interval or random distribution inferred. Cell size, absolute abundance and biological timing remain unresolved." }, { "id": "cart-p1-cd4", "family": "I107", "source": "L276", "population": "Patient 1: CD4+ CAR T cells", "tissue": "Peripheral blood at 1.4 years after infusion; CD3+CAR+ gate", "host": "Human CLL, selected long-term remission cases", "match": "Patient-specific post-treatment composition, not a population baseline", "locator": "CyTOF reveals CD8+, gamma-delta and CD4+ CAR T cells; Figure 2a–c", "models": { "all": { "property": { "label": "CD4+ fraction of CAR T cells", "value": 97.5, "unit": "%", "statistic": "Reported single-patient time-point fraction; not a mean", "bounds": null, "boundsKind": "Uncertainty and population range not reported for this fraction" } } }, "limits": "Two selected long-term responders in the study; each reference is one patient at the stated time. CyTOF composition is not an absolute cell count or tissue concentration. Sampling time is not cell lifespan. No pooled average, confidence interval or random distribution inferred. Cell size, absolute abundance and biological timing remain unresolved." }, { "id": "cart-p2-cd4", "family": "I107", "source": "L276", "population": "Patient 2: CD4+ CAR T cells", "tissue": "Peripheral blood at 7.2 years after infusion; CD3+CAR+ gate", "host": "Human CLL, selected long-term remission cases", "match": "Patient-specific post-treatment composition, not a population baseline", "locator": "CyTOF reveals CD8+, gamma-delta and CD4+ CAR T cells; Figure 2a–c", "models": { "all": { "property": { "label": "CD4+ fraction of CAR T cells", "value": 97.6, "unit": "%", "statistic": "Reported single-patient time-point fraction; not a mean", "bounds": null, "boundsKind": "Uncertainty and population range not reported for this fraction" } } }, "limits": "Two selected long-term responders in the study; each reference is one patient at the stated time. CyTOF composition is not an absolute cell count or tissue concentration. Sampling time is not cell lifespan. No pooled average, confidence interval or random distribution inferred. Cell size, absolute abundance and biological timing remain unresolved." }, { "id": "adhesion-hev-rolling", "family": "I068", "source": "V38", "population": "Lymphocytes rolling along MECA-79-positive tumor-associated HEVs", "tissue": "MCAprog tumors under combined anti-PD-1/anti-CTLA-4 checkpoint blockade", "host": "Mouse tumor model, intravital imaging", "match": "Functional adhesion readout under treatment, not adhesion-molecule abundance", "locator": "Figure 4E and accompanying Results: lymphocyte tethering, rolling and sticking", "models": { "all": { "property": { "label": "Lymphocyte rolling fraction", "value": 40, "unit": "%", "statistic": "Approximately 40%; author-rounded reported fraction", "bounds": null, "boundsKind": "Uncertainty interval and observed range not extracted" } } }, "limits": "The matched MECA-79-negative non-HEV vessels had less than 10% rolling; this is a one-sided comparator, not exactly 10% or an uncertainty bound. Fraction of observed lymphocytes, not absolute entry flux, crossing probability or rolling velocity. No molecular size, local adhesion-molecule density or step duration inferred. Mouse treatment setting, not a healthy or human baseline." }, { "id": "axonopathy-endplate", "family": "I070", "source": "L112", "population": "Denervated neuromuscular end-plates", "tissue": "Neuromuscular junctions; mice aged 47 days", "host": "SOD1-G93A transgenic mouse ALS model", "match": "Axonal pathology reference; not myelin thickness or a healthy baseline", "locator": "Abstract: spatiotemporal pathological analysis", "models": { "all": { "property": { "label": "Denervated neuromuscular end-plates fraction", "value": 40, "unit": "%", "statistic": "Reported age-specific pathological fraction; aggregation statistic unspecified", "bounds": null, "boundsKind": "Uncertainty interval and observed range not extracted" } } }, "limits": "Age is a sampling condition, not an axonal lifespan or degeneration rate. These two fractions concern different anatomical populations; do not interpolate them as a single trajectory. Sample count and uncertainty for these fractions are not supplied by the abstract. The accompanying single human autopsy does not establish these percentages in humans. Myelin thickness, axon diameter, g-ratio, absolute density and conduction timing remain unresolved." }, { "id": "axonopathy-ventral-root", "family": "I070", "source": "L112", "population": "Lost ventral root axons", "tissue": "Ventral roots; mice aged 80 days", "host": "SOD1-G93A transgenic mouse ALS model", "match": "Axonal pathology reference; not myelin thickness or a healthy baseline", "locator": "Abstract: spatiotemporal pathological analysis", "models": { "all": { "property": { "label": "Lost ventral root axons fraction", "value": 60, "unit": "%", "statistic": "Reported age-specific pathological fraction; aggregation statistic unspecified", "bounds": null, "boundsKind": "Uncertainty interval and observed range not extracted" } } }, "limits": "Age is a sampling condition, not an axonal lifespan or degeneration rate. These two fractions concern different anatomical populations; do not interpolate them as a single trajectory. Sample count and uncertainty for these fractions are not supplied by the abstract. The accompanying single human autopsy does not establish these percentages in humans. Myelin thickness, axon diameter, g-ratio, absolute density and conduction timing remain unresolved." }, { "id": "fibroblast-section-count", "family": "I007", "source": "V47", "population": "Col1a1-CreERT2 tdTomato-positive perivascular fibroblasts", "host": "Adult mouse, uninjured spinal cord", "match": "Reporter-labeled subset; not all fibroblasts", "tissue": "Transverse spinal cord sections, 20 µm thick", "locator": "Figure 2c caption and targeting Results", "sampleSize": 7, "models": { "all": { "amount": { "label": "Labeled fibroblasts per section", "value": 6.9, "unit": "cells/section", "statistic": "Reported mean", "bounds": [ 5.3, 8.5 ], "boundsKind": "Mean ± standard deviation, not observed range or confidence interval" } } }, "limits": "n=7 animals, not seven sections. Count depends on reporter recombination and section geometry. Incomplete labeling; do not correct to total cells or convert to cells/mm³ without additional data. Section thickness is not cell size. Human abundance, cell dimensions and timing remain unknown." }, { "id": "fibroblast-distribution-arterioles", "family": "I007", "source": "V47", "population": "Col1a1-CreERT2 tdTomato-positive perivascular fibroblasts", "host": "Adult mouse, uninjured spinal cord", "match": "Reporter-labeled subset; not all fibroblasts", "tissue": "Thoracic spinal cord, 500-µm-thick segments; volumetric imaging", "locator": "Anatomical distribution Results; Figure 3 and Extended Data Figure 1", "models": { "all": { "property": { "label": "Labeled fibroblasts associated with arterioles", "value": 26.1, "unit": "%", "statistic": "Reported mean", "bounds": [ 24.3, 27.9 ], "boundsKind": "Mean ± standard deviation, not observed range or confidence interval" } } }, "limits": "Denominator is reporter-labeled fibroblasts. Arteriolar category includes higher-order penetrating arterioles and branches. Fractions are not vessel coverage or cells per vessel. Do not force the reported means to sum to 100% or interpret SD as a sampling distribution. Sample count for this extraction unresolved." }, { "id": "fibroblast-distribution-venules", "family": "I007", "source": "V47", "population": "Col1a1-CreERT2 tdTomato-positive perivascular fibroblasts", "host": "Adult mouse, uninjured spinal cord", "match": "Reporter-labeled subset; not all fibroblasts", "tissue": "Thoracic spinal cord, 500-µm-thick segments; volumetric imaging", "locator": "Anatomical distribution Results; Figure 3 and Extended Data Figure 1", "models": { "all": { "property": { "label": "Labeled fibroblasts associated with venules", "value": 73.3, "unit": "%", "statistic": "Reported mean", "bounds": [ 70.6, 76.0 ], "boundsKind": "Mean ± standard deviation, not observed range or confidence interval" } } }, "limits": "Denominator is reporter-labeled fibroblasts. Arteriolar category includes higher-order penetrating arterioles and branches. Fractions are not vessel coverage or cells per vessel. Do not force the reported means to sum to 100% or interpret SD as a sampling distribution. Sample count for this extraction unresolved." }, { "id": "ada-asthma-pooled-incidence", "family": "I108", "source": "L278", "population": "Asthma participants receiving the six reviewed biologics", "tissue": "Clinical studies with heterogeneous ADA assays and follow-up", "host": "Human asthma; systematic review and meta-analysis", "match": "Treatment-emergent clinical incidence; not antibody amount", "locator": "Abstract, pooled ADA incidence over follow-up", "models": { "all": { "property": { "label": "Participants developing anti-drug antibodies", "value": 2.91, "unit": "%", "statistic": "Pooled incidence over study follow-up", "bounds": [ 1.6, 4.55 ], "boundsKind": "95% confidence interval for pooled incidence; not individual variability" } } }, "limits": "46 studies met review eligibility; this is not the participant count or necessarily the number contributing to this estimate. Follow-up and assays differ. Not an annual rate, antibody concentration, neutralizing-antibody incidence or probability for a specific drug or patient. No clearance effect, size or formation time inferred." }, { "id": "ang-tie2-mrna-ang1", "family": "I072", "source": "L16", "population": "Ang1 relative to Tie2 transcripts", "tissue": "Cultured human dermal blood microvascular endothelial cells (BECs)", "host": "Human cells in vitro", "match": "Transcriptional expression reference; not protein stoichiometry", "locator": "Results: Ang2 regulates endothelial integrity independently of Tie2; Figure 1h and cited reference 31", "models": { "all": { "property": { "label": "Ang1/Tie2 mRNA ratio", "value": 0.01, "unit": "ratio", "statistic": "Author-reported transcript ratio; averaging method unspecified", "bounds": null, "boundsKind": "Uncertainty and observed range not supplied for this ratio" } } }, "limits": "Reported alongside mRNA profiling and Q-RT–PCR; the text cites an earlier study (reference 31). No new reanalysis of that study. Transcript ratios are not secreted ligand concentrations, receptor occupancy, protein ratios or binding constants. No mean, variability or random distribution inferred. Culture context does not establish tissue or disease abundance. Size, absolute amount and interaction timing remain unresolved." }, { "id": "ang-tie2-mrna-ang2", "family": "I072", "source": "L16", "population": "Ang2 relative to Tie2 transcripts", "tissue": "Cultured human dermal blood microvascular endothelial cells (BECs)", "host": "Human cells in vitro", "match": "Transcriptional expression reference; not protein stoichiometry", "locator": "Results: Ang2 regulates endothelial integrity independently of Tie2; Figure 1h and cited reference 31", "models": { "all": { "property": { "label": "Ang2/Tie2 mRNA ratio", "value": 6.8, "unit": "ratio", "statistic": "Author-reported transcript ratio; averaging method unspecified", "bounds": null, "boundsKind": "Uncertainty and observed range not supplied for this ratio" } } }, "limits": "Reported alongside mRNA profiling and Q-RT–PCR; the text cites an earlier study (reference 31). No new reanalysis of that study. Transcript ratios are not secreted ligand concentrations, receptor occupancy, protein ratios or binding constants. No mean, variability or random distribution inferred. Culture context does not establish tissue or disease abundance. Size, absolute amount and interaction timing remain unresolved." }, { "id": "lymphoma-abca3-release", "family": "I052", "source": "L44", "population": "Balm-3, Su-DHL-4 and OCI-Ly1 lymphoma cell models", "tissue": "Culture supernatants after 48 h; two independent ABCA3 shRNA constructs", "host": "Human cell lines in vitro", "match": "Context-specific lymphoma functional reference", "locator": "Results: Enhanced CDC efficacy; Figure 6B–C", "models": { "all": { "property": { "label": "Reduction in exosome release after ABCA3 silencing", "value": 50, "unit": "%", "statistic": "Approximately half; author-reported summary, not an exact mean", "bounds": null, "boundsKind": "Uncertainty and observed range not extracted" } } }, "limits": "Release assessed by whole exosomal protein and flotillin-2 Western blot. Approximate summary across cell models, not three independent numerical estimates. Absolute untreated release rate, particle count, antigen density and line-specific uncertainty remain unextracted. A perturbation response, not a baseline secretion rate." }, { "id": "lymphoma-rituximab-bound", "family": "I052", "source": "L44", "population": "Lymphoma patients receiving first R-CHOP course", "tissue": "Plasma sampled 3 h after the end of a 375 mg/m² rituximab infusion", "host": "Human treated-patient samples", "match": "Context-specific lymphoma functional reference", "locator": "Results: Lymphoma-derived exosomes bind antibody; Figure 2C", "models": { "all": { "property": { "label": "Measured plasma rituximab associated with exosomes", "value": 50, "unit": "%", "statistic": "Approximately half; author-reported summary, not an exact mean", "bounds": null, "boundsKind": "Uncertainty and observed range not extracted" } } }, "limits": "Anti-idiotype MB2A4 ELISA detects soluble and membrane-bound rituximab. Approximate author summary; sample count and dispersion not extracted here. Post-infusion fraction, not antibody concentration, binding affinity, clearance rate or untreated state. Sampling time is not binding kinetics." }, { "family": "I103", "source": "L264", "host": "Human surgical tissue", "match": "Specific pancreatic-tissue cohort; not a universal microbial baseline", "locator": "Results accompanying Figure 4A, Figure S13 and Table S6", "population": "Bacteria-colonized pancreatic ductal adenocarcinoma samples", "tissue": "Resected human PDAC; bacterial 16S rDNA qPCR", "id": "bacteria-pdac-load", "models": { "all": { "amount": { "label": "Human cells per estimated bacterium", "value": 146, "unit": "human cells/bacterium", "statistic": "Author-estimated average ratio in bacteria-positive tumors", "bounds": [ 53, 201 ], "boundsKind": "Author-reported 95% confidence interval; not between-tumor range" } } }, "limits": "Assumes 8 pg DNA per cancer cell. Retains the original inverse ratio; not a direct microscopy count or viable-cell density. Positive tumors only, not all PDAC or healthy tissue. Species, size, growth timing and spatial distribution unresolved. Low-biomass contamination controls remain necessary; see existing L262 research." }, { "family": "I103", "source": "L264", "host": "Human surgical tissue", "match": "Specific pancreatic-tissue cohort; not a universal microbial baseline", "locator": "Results accompanying Figure 4A, Figure S13 and Table S6", "population": "Resected human PDAC samples", "tissue": "Pancreatic tissue; bacterial 16S rDNA qPCR", "id": "bacteria-detection-tumor", "sampleSize": 113, "observations": { "positiveSamples": 86, "testedSamples": 113 }, "models": { "all": { "property": { "label": "Samples with detectable bacterial DNA", "value": 76, "unit": "%", "statistic": "Author-reported detection fraction", "bounds": null, "boundsKind": "Confidence interval not extracted" } } }, "limits": "86/113 tissue samples. Detection prevalence, not bacterial load or viable-cell fraction. Non-detection is not proof of zero bacteria. No distribution or patient-specific default inferred." }, { "family": "I103", "source": "L264", "host": "Human surgical tissue", "match": "Specific pancreatic-tissue cohort; not a universal microbial baseline", "locator": "Results accompanying Figure 4A, Figure S13 and Table S6", "population": "Normal pancreas from organ donors", "tissue": "Pancreatic tissue; bacterial 16S rDNA qPCR", "id": "bacteria-detection-control", "sampleSize": 20, "observations": { "positiveSamples": 3, "testedSamples": 20 }, "models": { "all": { "property": { "label": "Samples with detectable bacterial DNA", "value": 15, "unit": "%", "statistic": "Author-reported detection fraction", "bounds": null, "boundsKind": "Confidence interval not extracted" } } }, "limits": "3/20 tissue samples. Detection prevalence, not bacterial load or viable-cell fraction. Non-detection is not proof of zero bacteria. No distribution or patient-specific default inferred." }, { "family": "I100", "source": "L253", "host": "Mouse xenograft experiment with human reporter cells", "match": "Assay-specific reference, not a tissue concentration baseline", "id": "atp-probe-threshold", "population": "HEK293-pmeLUC extracellular ATP reporter", "tissue": "Healthy nude-mouse tissue compared with tumor sites", "locator": "Results, discussion following Figure 3", "models": { "all": { "property": { "label": "Approximate ATP detection threshold of the probe", "value": null, "unit": "µM", "statistic": "Reported assay threshold range; no central estimate", "bounds": [ 1, 5 ], "boundsKind": "Approximate detection threshold, not biological variability or CI" } } }, "limits": "Healthy-tissue ATP was below detection, not zero. Tumor levels were described as hundreds of micromolar or higher; no precise mean is imported. Signal saturation above 700 µM is not a tumor upper bound. This is assay sensitivity, not ATP abundance." }, { "family": "I100", "source": "L253", "host": "Mouse xenograft experiment with human reporter cells", "match": "Assay-specific reference, not a tissue concentration baseline", "id": "atp-apyrase-response", "population": "MZ2-MEL melanoma with HEK293-pmeLUC reporters", "tissue": "Nude-mouse tumor; apyrase 20 U in 40 µL, four days after reporter inoculation", "locator": "Results and Figure 6C", "sampleSize": 4, "models": { "all": { "property": { "label": "Luminescence reduction after apyrase", "value": 50, "unit": "%", "statistic": "Approximately 50%; author summary of averaged mouse measurements", "bounds": null, "boundsKind": "Dispersion not extracted" } } }, "limits": "Photon signal, not a calibrated percent ATP reduction. Signal returned to its earlier level within two days; this is not a half-life. Vehicle injection increased signal, attributed to injury. Absolute concentration, hydrolysis rate and recovery-time uncertainty remain unresolved." }, { "id": "pdc-induced-il10", "family": "I021", "source": "L105", "host": "Human ovarian-carcinoma ascites cells in vitro", "match": "Induced T-cell response; not pDC abundance or direct secretion", "population": "Autologous ascites T cells stimulated by CD40L-activated, antigen-loaded plasmacytoid dendritic cells", "tissue": "Culture: 500,000 T cells/mL and 10,000 dendritic cells/mL; two stimulation rounds; HLA-A2-specific Her-2/neu peptides", "locator": "Results: distinct T-cell activation; Figure 1B and caption", "sampleSize": 4, "models": { "all": { "property": { "label": "Induced T-cell IL-10 in culture supernatant", "value": 221, "unit": "pg/mL", "statistic": "Reported 221 ± 53; central-summary statistic not independently resolved", "bounds": [ 168, 274 ], "boundsKind": "Reported center ± 53; spread definition unresolved, not an inferred CI or full range" } } }, "limits": "ELISA endpoint. Figure reports n=4; replicate unit not resolved here. Without CD40L activation, IL-10 was reported below 30 pg/mL, not zero or exactly 30. This is a T-cell culture response, not pDC IL-10 secretion, type I interferon output, tissue concentration or per-cell rate. Cell densities are protocol settings. Size, abundance and kinetics remain unresolved." } ], "audit": { "inventoryFamilies": 110, "familiesWithReferences": 104, "familiesWithPriorResearch": 110, "unknownSlots": 173, "selectedHattonRows": 103, "sourceHattonRows": 1264, "unselectedSourceRows": 1161 } }