| | """Curated biological building blocks for procedural scenario generation.
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| |
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| | Provides tissue-specific cell types, disease profiles, pathway libraries,
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| | regulatory network templates, and perturbation effect profiles. The
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| | procedural generator composes these into complete ``Scenario`` objects
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| | with fully populated ``LatentBiologicalState``.
|
| | """
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| |
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| | from __future__ import annotations
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| |
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| | from dataclasses import dataclass, field
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| | from typing import Any, Dict, List, Optional, Tuple
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| |
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| |
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| |
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| |
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| |
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| | @dataclass
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| | class CellTypeTemplate:
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| | name: str
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| | marker_genes: List[str]
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| | proportion_range: Tuple[float, float] = (0.05, 0.30)
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| | states: List[str] = field(default_factory=lambda: ["quiescent"])
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| | disease_responsive: bool = False
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| | response_range: Tuple[float, float] = (0.5, 1.5)
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| |
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| |
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| | TISSUE_CELL_TYPES: Dict[str, List[CellTypeTemplate]] = {
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| | "heart": [
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| | CellTypeTemplate("cardiomyocyte", ["TNNT2", "MYH7", "ACTC1"], (0.25, 0.40), ["contractile", "stressed"]),
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| | CellTypeTemplate("cardiac_fibroblast", ["COL1A1", "DCN", "LUM"], (0.15, 0.30), ["quiescent", "activated"], True, (1.1, 1.8)),
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| | CellTypeTemplate("endothelial", ["PECAM1", "VWF", "CDH5"], (0.10, 0.20), ["quiescent"]),
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| | CellTypeTemplate("macrophage", ["CD68", "CD163", "CSF1R"], (0.05, 0.15), ["quiescent", "activated", "inflammatory"], True, (1.2, 2.0)),
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| | CellTypeTemplate("smooth_muscle", ["ACTA2", "MYH11", "TAGLN"], (0.08, 0.18), ["quiescent"]),
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| | CellTypeTemplate("pericyte", ["PDGFRB", "RGS5", "NOTCH3"], (0.03, 0.10), ["quiescent"]),
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| | ],
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| | "lung": [
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| | CellTypeTemplate("AT2", ["SFTPC", "SFTPB", "ABCA3"], (0.15, 0.25), ["normal", "stressed"]),
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| | CellTypeTemplate("AT1", ["AGER", "PDPN", "CAV1"], (0.10, 0.18), ["normal"]),
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| | CellTypeTemplate("alveolar_macrophage", ["MARCO", "FABP4", "MCEMP1"], (0.10, 0.20), ["resident", "activated"]),
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| | CellTypeTemplate("fibroblast", ["COL1A1", "COL3A1", "POSTN"], (0.12, 0.25), ["quiescent", "activated"], True, (1.2, 2.0)),
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| | CellTypeTemplate("endothelial", ["PECAM1", "CLDN5", "VWF"], (0.08, 0.15), ["quiescent"]),
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| | CellTypeTemplate("T_cell", ["CD3D", "CD3E", "IL7R"], (0.08, 0.18), ["quiescent", "activated"]),
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| | CellTypeTemplate("ciliated", ["FOXJ1", "DNAH5", "TPPP3"], (0.05, 0.12), ["normal"]),
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| | ],
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| | "brain": [
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| | CellTypeTemplate("excitatory_neuron", ["SLC17A7", "CAMK2A", "NRGN"], (0.25, 0.40), ["normal", "stressed"]),
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| | CellTypeTemplate("inhibitory_neuron", ["GAD1", "GAD2", "SLC32A1"], (0.12, 0.22), ["normal"]),
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| | CellTypeTemplate("astrocyte", ["GFAP", "AQP4", "SLC1A3"], (0.10, 0.20), ["quiescent", "activated"], True, (1.2, 1.8)),
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| | CellTypeTemplate("microglia", ["CX3CR1", "P2RY12", "TMEM119"], (0.05, 0.12), ["homeostatic", "activated", "inflammatory"], True, (1.3, 2.5)),
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| | CellTypeTemplate("oligodendrocyte", ["MBP", "PLP1", "MOG"], (0.10, 0.18), ["myelinating"]),
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| | CellTypeTemplate("OPC", ["PDGFRA", "CSPG4", "OLIG2"], (0.03, 0.08), ["progenitor"]),
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| | CellTypeTemplate("endothelial", ["CLDN5", "FLT1", "PECAM1"], (0.03, 0.08), ["quiescent"]),
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| | ],
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| | "liver": [
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| | CellTypeTemplate("hepatocyte", ["ALB", "APOB", "CYP3A4"], (0.55, 0.70), ["normal", "stressed"]),
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| | CellTypeTemplate("cholangiocyte", ["KRT19", "KRT7", "EPCAM"], (0.05, 0.10), ["normal"]),
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| | CellTypeTemplate("kupffer_cell", ["CD68", "CLEC4F", "MARCO"], (0.08, 0.15), ["quiescent", "activated", "inflammatory"], True, (1.2, 2.0)),
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| | CellTypeTemplate("stellate_cell", ["ACTA2", "LRAT", "PDGFRB"], (0.05, 0.12), ["quiescent", "activated"], True, (1.3, 2.0)),
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| | CellTypeTemplate("endothelial", ["PECAM1", "LYVE1", "STAB2"], (0.05, 0.10), ["quiescent"]),
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| | CellTypeTemplate("NK_cell", ["NKG7", "GNLY", "KLRD1"], (0.03, 0.08), ["quiescent", "activated"]),
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| | ],
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| | "bone_marrow": [
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| | CellTypeTemplate("HSC", ["CD34", "KIT", "THY1"], (0.03, 0.08), ["stem"]),
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| | CellTypeTemplate("CMP", ["CD34", "FLT3"], (0.08, 0.15), ["progenitor"]),
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| | CellTypeTemplate("GMP", ["CSF3R", "CEBPA"], (0.08, 0.15), ["progenitor"]),
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| | CellTypeTemplate("MEP", ["GATA1", "KLF1"], (0.06, 0.12), ["progenitor"]),
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| | CellTypeTemplate("erythrocyte", ["HBA1", "HBB", "GYPA"], (0.15, 0.25), ["mature"]),
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| | CellTypeTemplate("neutrophil", ["ELANE", "MPO", "CTSG"], (0.12, 0.22), ["mature"]),
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| | CellTypeTemplate("monocyte", ["CD14", "CSF1R", "FCGR3A"], (0.10, 0.18), ["mature"]),
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| | CellTypeTemplate("megakaryocyte", ["ITGA2B", "GP1BA", "PF4"], (0.05, 0.12), ["mature"]),
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| | ],
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| | "kidney": [
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| | CellTypeTemplate("proximal_tubule", ["SLC34A1", "LRP2", "CUBN"], (0.30, 0.45), ["normal", "stressed"]),
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| | CellTypeTemplate("distal_tubule", ["SLC12A3", "CALB1"], (0.10, 0.18), ["normal"]),
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| | CellTypeTemplate("collecting_duct", ["AQP2", "FXYD4"], (0.08, 0.15), ["normal"]),
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| | CellTypeTemplate("podocyte", ["NPHS1", "NPHS2", "WT1"], (0.05, 0.10), ["normal", "stressed"]),
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| | CellTypeTemplate("endothelial", ["PECAM1", "EMCN", "FLT1"], (0.05, 0.12), ["quiescent"]),
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| | CellTypeTemplate("macrophage", ["CD68", "CD163", "CSF1R"], (0.05, 0.10), ["quiescent", "inflammatory"], True, (1.3, 2.0)),
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| | CellTypeTemplate("fibroblast", ["COL1A1", "PDGFRA", "DCN"], (0.05, 0.12), ["quiescent", "activated"], True, (1.2, 1.8)),
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| | ],
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| | "colon": [
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| | CellTypeTemplate("colonocyte", ["CA2", "AQP8", "SLC26A3"], (0.25, 0.40), ["normal", "stressed"]),
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| | CellTypeTemplate("goblet_cell", ["MUC2", "TFF3", "FCGBP"], (0.10, 0.18), ["secretory"]),
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| | CellTypeTemplate("stem_cell", ["LGR5", "ASCL2", "OLFM4"], (0.05, 0.10), ["stem"]),
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| | CellTypeTemplate("T_cell", ["CD3D", "CD3E", "IL7R"], (0.10, 0.18), ["quiescent", "activated"]),
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| | CellTypeTemplate("macrophage", ["CD68", "CD163", "CSF1R"], (0.05, 0.12), ["quiescent", "inflammatory"], True, (1.3, 2.0)),
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| | CellTypeTemplate("fibroblast", ["COL1A1", "COL3A1", "VIM"], (0.08, 0.15), ["quiescent", "activated"], True, (1.2, 1.8)),
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| | CellTypeTemplate("endothelial", ["PECAM1", "VWF", "CDH5"], (0.05, 0.10), ["quiescent"]),
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| | ],
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| | "pancreas": [
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| | CellTypeTemplate("beta_cell", ["INS", "MAFA", "NKX6-1"], (0.25, 0.40), ["normal", "stressed"], True, (0.4, 0.8)),
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| | CellTypeTemplate("alpha_cell", ["GCG", "ARX", "IRX2"], (0.15, 0.25), ["normal"]),
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| | CellTypeTemplate("delta_cell", ["SST", "HHEX"], (0.05, 0.10), ["normal"]),
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| | CellTypeTemplate("ductal", ["KRT19", "SOX9", "CFTR"], (0.10, 0.18), ["normal"]),
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| | CellTypeTemplate("acinar", ["PRSS1", "CPA1", "CELA3A"], (0.10, 0.20), ["normal"]),
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| | CellTypeTemplate("stellate", ["ACTA2", "PDGFRA", "COL1A1"], (0.05, 0.10), ["quiescent", "activated"], True, (1.2, 1.8)),
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| | CellTypeTemplate("macrophage", ["CD68", "CD163"], (0.03, 0.08), ["quiescent", "inflammatory"]),
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| | ],
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| | "skin": [
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| | CellTypeTemplate("keratinocyte", ["KRT14", "KRT5", "KRT1"], (0.40, 0.55), ["basal", "differentiated"]),
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| | CellTypeTemplate("melanocyte", ["MLANA", "PMEL", "TYR"], (0.05, 0.10), ["normal", "activated"]),
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| | CellTypeTemplate("fibroblast", ["COL1A1", "COL3A1", "DCN"], (0.10, 0.20), ["quiescent", "activated"]),
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| | CellTypeTemplate("T_cell", ["CD3D", "CD3E", "IL7R"], (0.08, 0.15), ["quiescent", "activated"]),
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| | CellTypeTemplate("macrophage", ["CD68", "CD163", "CSF1R"], (0.05, 0.10), ["quiescent", "inflammatory"]),
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| | CellTypeTemplate("endothelial", ["PECAM1", "VWF"], (0.05, 0.10), ["quiescent"]),
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| | ],
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| | "breast": [
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| | CellTypeTemplate("luminal_epithelial", ["KRT8", "KRT18", "EPCAM"], (0.25, 0.40), ["normal", "stressed"]),
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| | CellTypeTemplate("basal_epithelial", ["KRT14", "KRT5", "TP63"], (0.10, 0.20), ["normal"]),
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| | CellTypeTemplate("fibroblast", ["COL1A1", "COL3A1", "FAP"], (0.10, 0.20), ["quiescent", "activated"], True, (1.2, 1.8)),
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| | CellTypeTemplate("T_cell", ["CD3D", "CD3E", "CD8A"], (0.08, 0.15), ["quiescent", "activated", "exhausted"]),
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| | CellTypeTemplate("macrophage", ["CD68", "CD163", "CSF1R"], (0.05, 0.12), ["quiescent", "inflammatory"], True, (1.3, 2.0)),
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| | CellTypeTemplate("endothelial", ["PECAM1", "VWF", "CDH5"], (0.05, 0.10), ["quiescent"]),
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| | ],
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| | "synovium": [
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| | CellTypeTemplate("fibroblast", ["COL1A1", "FAP", "THY1"], (0.20, 0.30), ["quiescent", "activated"], True, (1.2, 1.8)),
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| | CellTypeTemplate("CD4_T_cell", ["CD3D", "CD4", "IL7R"], (0.12, 0.22), ["quiescent", "activated"]),
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| | CellTypeTemplate("CD8_T_cell", ["CD3D", "CD8A", "GZMB"], (0.08, 0.15), ["quiescent", "activated"]),
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| | CellTypeTemplate("macrophage", ["CD68", "CD163", "MARCO"], (0.10, 0.18), ["quiescent", "inflammatory"], True, (1.3, 2.0)),
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| | CellTypeTemplate("B_cell", ["CD19", "MS4A1", "CD79A"], (0.05, 0.12), ["quiescent"]),
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| | CellTypeTemplate("endothelial", ["PECAM1", "VWF"], (0.05, 0.10), ["quiescent"]),
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| | CellTypeTemplate("mast_cell", ["KIT", "TPSAB1", "CPA3"], (0.03, 0.08), ["quiescent"]),
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| | ],
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| | "aorta": [
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| | CellTypeTemplate("smooth_muscle", ["ACTA2", "MYH11", "TAGLN"], (0.30, 0.45), ["contractile", "synthetic"], True, (0.6, 0.9)),
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| | CellTypeTemplate("endothelial", ["PECAM1", "VWF", "CDH5"], (0.15, 0.25), ["quiescent", "activated"]),
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| | CellTypeTemplate("macrophage", ["CD68", "CD163", "TREM2"], (0.08, 0.15), ["quiescent", "inflammatory"], True, (1.5, 2.5)),
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| | CellTypeTemplate("fibroblast", ["COL1A1", "LUM", "DCN"], (0.08, 0.15), ["quiescent", "activated"]),
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| | CellTypeTemplate("T_cell", ["CD3D", "CD3E", "IL7R"], (0.05, 0.12), ["quiescent", "activated"]),
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| | CellTypeTemplate("dendritic_cell", ["FCER1A", "CD1C", "CLEC10A"], (0.03, 0.08), ["quiescent"]),
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| | ],
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| | "blood": [
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| | CellTypeTemplate("CD4_T_cell", ["CD3D", "CD4", "IL7R"], (0.15, 0.25), ["quiescent", "activated"]),
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| | CellTypeTemplate("CD8_T_cell", ["CD3D", "CD8A", "GZMB"], (0.10, 0.18), ["quiescent", "activated"]),
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| | CellTypeTemplate("B_cell", ["CD19", "MS4A1", "CD79A"], (0.08, 0.15), ["quiescent"]),
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| | CellTypeTemplate("NK_cell", ["NKG7", "GNLY", "KLRD1"], (0.05, 0.12), ["quiescent", "activated"]),
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| | CellTypeTemplate("monocyte", ["CD14", "CSF1R", "FCGR3A"], (0.15, 0.25), ["classical", "non_classical"]),
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| | CellTypeTemplate("neutrophil", ["ELANE", "MPO", "CTSG"], (0.10, 0.20), ["mature"]),
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| | CellTypeTemplate("platelet", ["ITGA2B", "GP1BA", "PF4"], (0.03, 0.08), ["normal"]),
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| | ],
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| | "spleen": [
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| | CellTypeTemplate("B_cell", ["CD19", "MS4A1", "CD79A"], (0.20, 0.35), ["quiescent", "activated"]),
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| | CellTypeTemplate("T_cell", ["CD3D", "CD3E", "IL7R"], (0.15, 0.25), ["quiescent", "activated"]),
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| | CellTypeTemplate("macrophage", ["CD68", "CD163", "CSF1R"], (0.10, 0.18), ["quiescent", "inflammatory"]),
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| | CellTypeTemplate("dendritic_cell", ["FCER1A", "CD1C", "CLEC10A"], (0.05, 0.10), ["quiescent"]),
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| | CellTypeTemplate("NK_cell", ["NKG7", "GNLY", "KLRD1"], (0.05, 0.12), ["quiescent"]),
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| | CellTypeTemplate("endothelial", ["PECAM1", "STAB2"], (0.05, 0.10), ["quiescent"]),
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| | ],
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| | "thymus": [
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| | CellTypeTemplate("double_negative_T", ["CD3D", "PTCRA"], (0.10, 0.18), ["progenitor"]),
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| | CellTypeTemplate("double_positive_T", ["CD3D", "CD4", "CD8A"], (0.30, 0.45), ["progenitor"]),
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| | CellTypeTemplate("CD4_SP", ["CD3D", "CD4", "IL7R"], (0.10, 0.18), ["mature"]),
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| | CellTypeTemplate("CD8_SP", ["CD3D", "CD8A", "CD8B"], (0.08, 0.15), ["mature"]),
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| | CellTypeTemplate("thymic_epithelial", ["FOXN1", "KRT5", "KRT8"], (0.05, 0.12), ["cortical", "medullary"]),
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| | CellTypeTemplate("dendritic_cell", ["FCER1A", "CD1C"], (0.03, 0.08), ["quiescent"]),
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| | CellTypeTemplate("macrophage", ["CD68", "CD163"], (0.03, 0.08), ["quiescent"]),
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| | ],
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| | }
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| |
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| |
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| |
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| |
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| |
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| | @dataclass
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| | class DiseaseProfile:
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| | name: str
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| | display_name: str
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| | tissue: str
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| | condition_name: str
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| | de_genes: Dict[str, Tuple[float, float]]
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| | pathways: Dict[str, Tuple[float, float]]
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| | markers: List[str]
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| | mechanism_templates: List[str]
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| | responding_cell_types: List[str] = field(default_factory=list)
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| | hidden_failure_templates: List[str] = field(default_factory=list)
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| |
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| |
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| | DISEASE_PROFILES: Dict[str, DiseaseProfile] = {
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| | "dilated_cardiomyopathy": DiseaseProfile(
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| | name="dilated_cardiomyopathy",
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| | display_name="dilated cardiomyopathy",
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| | tissue="heart",
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| | condition_name="dilated_cardiomyopathy",
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| | de_genes={
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| | "NPPA": (1.8, 3.5), "NPPB": (2.0, 4.0), "MYH7": (1.0, 2.5),
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| | "COL1A1": (1.0, 2.2), "COL3A1": (0.8, 1.8), "POSTN": (1.5, 3.0),
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| | "CCL2": (0.8, 1.8), "IL6": (0.5, 1.5), "TGFB1": (0.7, 1.6),
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| | "ANKRD1": (1.5, 3.0), "XIRP2": (-2.0, -0.8), "MYL2": (-1.5, -0.5),
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| | },
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| | pathways={
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| | "cardiac_muscle_contraction": (0.3, 0.6),
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| | "extracellular_matrix_organisation": (0.7, 0.95),
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| | "inflammatory_response": (0.5, 0.8),
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| | "TGF_beta_signalling": (0.6, 0.85),
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| | "apoptosis": (0.4, 0.65),
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| | },
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| | markers=["NPPA", "NPPB", "POSTN", "COL1A1"],
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| | mechanism_templates=[
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| | "TGF-beta-driven fibrosis",
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| | "inflammatory macrophage infiltration",
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| | ],
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| | responding_cell_types=["cardiac_fibroblast", "macrophage"],
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| | ),
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| | "IPF": DiseaseProfile(
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| | name="IPF",
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| | display_name="idiopathic pulmonary fibrosis",
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| | tissue="lung",
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| | condition_name="IPF",
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| | de_genes={
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| | "SPP1": (2.0, 4.0), "MERTK": (0.8, 2.0), "MMP9": (1.0, 2.5),
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| | "TREM2": (0.8, 2.0), "COL1A1": (1.5, 3.0), "COL3A1": (1.2, 2.5),
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| | "POSTN": (1.5, 3.5), "SFTPC": (-2.0, -0.8), "AGER": (-2.5, -1.0),
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| | },
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| | pathways={
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| | "extracellular_matrix_organisation": (0.75, 0.95),
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| | "integrin_signalling": (0.6, 0.85),
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| | "macrophage_activation": (0.65, 0.9),
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| | "Wnt_signalling": (0.4, 0.7),
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| | },
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| | markers=["SPP1", "MERTK", "POSTN", "MMP9"],
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| | mechanism_templates=[
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| | "SPP1+ macrophage-driven fibroblast activation",
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| | "integrin-mediated SPP1 signalling in fibrosis",
|
| | ],
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| | responding_cell_types=["fibroblast", "alveolar_macrophage"],
|
| | ),
|
| | "Alzheimer": DiseaseProfile(
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| | name="Alzheimer",
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| | display_name="Alzheimer's disease",
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| | tissue="brain",
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| | condition_name="Alzheimer",
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| | de_genes={
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| | "TREM2": (1.0, 2.5), "APOE": (1.2, 2.8), "CLU": (0.8, 2.0),
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| | "C1QA": (1.0, 2.2), "C1QB": (0.9, 2.0), "GFAP": (1.5, 3.0),
|
| | "AQP4": (0.6, 1.5), "SLC17A7": (-1.5, -0.5), "NRGN": (-2.0, -0.8),
|
| | "SNAP25": (-1.2, -0.4),
|
| | },
|
| | pathways={
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| | "complement_cascade": (0.7, 0.9),
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| | "neuroinflammation": (0.65, 0.85),
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| | "amyloid_processing": (0.6, 0.8),
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| | "synaptic_signalling": (0.3, 0.5),
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| | "lipid_metabolism": (0.5, 0.7),
|
| | },
|
| | markers=["TREM2", "APOE", "GFAP", "C1QA"],
|
| | mechanism_templates=[
|
| | "TREM2-mediated microglial activation in amyloid clearance",
|
| | "complement-driven synaptic pruning",
|
| | "reactive astrogliosis amplifying neuroinflammation",
|
| | ],
|
| | responding_cell_types=["microglia", "astrocyte"],
|
| | ),
|
| | "colorectal_cancer": DiseaseProfile(
|
| | name="colorectal_cancer",
|
| | display_name="colorectal cancer",
|
| | tissue="colon",
|
| | condition_name="colorectal_cancer",
|
| | de_genes={
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| | "MYC": (1.5, 3.0), "KRAS": (0.8, 1.8), "TP53": (-1.5, -0.5),
|
| | "APC": (-1.8, -0.8), "CDH1": (-1.2, -0.4), "VIM": (1.0, 2.5),
|
| | "MKI67": (1.5, 3.0), "CD44": (1.0, 2.2), "LGR5": (0.8, 2.0),
|
| | },
|
| | pathways={
|
| | "Wnt_signalling": (0.75, 0.95),
|
| | "cell_cycle": (0.7, 0.9),
|
| | "EMT": (0.6, 0.85),
|
| | "p53_signalling": (0.3, 0.5),
|
| | "MAPK_signalling": (0.55, 0.75),
|
| | },
|
| | markers=["MYC", "CD44", "VIM", "MKI67"],
|
| | mechanism_templates=[
|
| | "Wnt/beta-catenin-driven tumour stem cell expansion",
|
| | "epithelial-mesenchymal transition promoting invasion",
|
| | ],
|
| | responding_cell_types=["stem_cell", "macrophage", "fibroblast"],
|
| | ),
|
| | "type2_diabetes": DiseaseProfile(
|
| | name="type2_diabetes",
|
| | display_name="type 2 diabetes",
|
| | tissue="pancreas",
|
| | condition_name="type2_diabetes",
|
| | de_genes={
|
| | "INS": (-2.0, -0.8), "MAFA": (-1.5, -0.5), "PDX1": (-1.2, -0.4),
|
| | "UCN3": (-1.8, -0.6), "GCG": (0.8, 2.0), "ARX": (0.5, 1.5),
|
| | "IAPP": (0.6, 1.8), "TXNIP": (1.0, 2.5), "DDIT3": (0.8, 2.0),
|
| | },
|
| | pathways={
|
| | "insulin_signalling": (0.3, 0.5),
|
| | "ER_stress_response": (0.7, 0.9),
|
| | "oxidative_stress": (0.6, 0.8),
|
| | "glucagon_signalling": (0.6, 0.8),
|
| | "apoptosis": (0.5, 0.7),
|
| | },
|
| | markers=["INS", "TXNIP", "IAPP", "DDIT3"],
|
| | mechanism_templates=[
|
| | "ER stress-induced beta cell apoptosis",
|
| | "glucotoxicity-driven beta cell dedifferentiation",
|
| | ],
|
| | responding_cell_types=["beta_cell", "stellate"],
|
| | ),
|
| | "AML": DiseaseProfile(
|
| | name="AML",
|
| | display_name="acute myeloid leukemia",
|
| | tissue="bone_marrow",
|
| | condition_name="AML",
|
| | de_genes={
|
| | "FLT3": (1.5, 3.0), "NPM1": (0.8, 2.0), "IDH2": (0.6, 1.5),
|
| | "RUNX1": (-1.5, -0.5), "CEBPA": (-1.2, -0.4), "KIT": (1.0, 2.5),
|
| | "WT1": (1.2, 2.8), "MYC": (0.8, 2.0),
|
| | },
|
| | pathways={
|
| | "hematopoietic_cell_lineage": (0.3, 0.5),
|
| | "MAPK_signalling": (0.7, 0.9),
|
| | "PI3K_AKT_signalling": (0.65, 0.85),
|
| | "cell_cycle": (0.7, 0.9),
|
| | "apoptosis": (0.3, 0.5),
|
| | },
|
| | markers=["FLT3", "NPM1", "WT1", "KIT"],
|
| | mechanism_templates=[
|
| | "FLT3-ITD-driven proliferative advantage",
|
| | "myeloid differentiation block via RUNX1 loss",
|
| | ],
|
| | responding_cell_types=["HSC", "GMP"],
|
| | ),
|
| | "rheumatoid_arthritis": DiseaseProfile(
|
| | name="rheumatoid_arthritis",
|
| | display_name="rheumatoid arthritis",
|
| | tissue="synovium",
|
| | condition_name="rheumatoid_arthritis",
|
| | de_genes={
|
| | "IFNG": (1.0, 2.5), "TBX21": (0.8, 1.8), "IL17A": (1.0, 2.2),
|
| | "RORC": (0.6, 1.5), "TNF": (1.2, 2.5), "IL6": (1.0, 2.2),
|
| | "MMP3": (1.5, 3.0), "MMP1": (1.2, 2.5), "CXCL13": (1.0, 2.5),
|
| | },
|
| | pathways={
|
| | "JAK_STAT_signalling": (0.7, 0.9),
|
| | "TNF_signalling": (0.7, 0.9),
|
| | "Th17_differentiation": (0.6, 0.8),
|
| | "NF_kB_signalling": (0.65, 0.85),
|
| | "matrix_metalloproteinase_activity": (0.7, 0.9),
|
| | },
|
| | markers=["TNF", "IL6", "MMP3", "CXCL13"],
|
| | mechanism_templates=[
|
| | "TNF/NF-kB-driven synovial inflammation",
|
| | "Th17-mediated cartilage destruction via MMPs",
|
| | ],
|
| | responding_cell_types=["fibroblast", "macrophage", "CD4_T_cell"],
|
| | ),
|
| | "hepatocellular_carcinoma": DiseaseProfile(
|
| | name="hepatocellular_carcinoma",
|
| | display_name="hepatocellular carcinoma",
|
| | tissue="liver",
|
| | condition_name="HCC",
|
| | de_genes={
|
| | "GPC3": (2.0, 4.0), "AFP": (1.5, 3.5), "EPCAM": (1.0, 2.5),
|
| | "MYC": (1.0, 2.5), "VEGFA": (1.2, 2.8), "MKI67": (1.5, 3.0),
|
| | "ALB": (-2.0, -0.8), "CYP3A4": (-1.8, -0.6), "APOB": (-1.5, -0.5),
|
| | },
|
| | pathways={
|
| | "Wnt_signalling": (0.7, 0.9),
|
| | "cell_cycle": (0.75, 0.95),
|
| | "angiogenesis": (0.6, 0.8),
|
| | "PI3K_AKT_signalling": (0.65, 0.85),
|
| | "p53_signalling": (0.3, 0.5),
|
| | },
|
| | markers=["GPC3", "AFP", "VEGFA", "MKI67"],
|
| | mechanism_templates=[
|
| | "Wnt/beta-catenin-driven hepatocyte dedifferentiation",
|
| | "VEGF-mediated tumour angiogenesis",
|
| | ],
|
| | responding_cell_types=["kupffer_cell", "stellate_cell"],
|
| | hidden_failure_templates=[
|
| | "Tumour heterogeneity may confound DE in mixed biopsies",
|
| | ],
|
| | ),
|
| | "atherosclerosis": DiseaseProfile(
|
| | name="atherosclerosis",
|
| | display_name="atherosclerosis",
|
| | tissue="aorta",
|
| | condition_name="atherosclerosis",
|
| | de_genes={
|
| | "TREM2": (1.5, 3.0), "CD9": (1.0, 2.2), "LGALS3": (1.2, 2.5),
|
| | "APOE": (0.8, 2.0), "MMP9": (1.0, 2.5), "IL1B": (0.8, 2.0),
|
| | "ACTA2": (-1.5, -0.5), "MYH11": (-2.0, -0.8), "CNN1": (-1.5, -0.5),
|
| | },
|
| | pathways={
|
| | "lipid_metabolism": (0.7, 0.9),
|
| | "inflammatory_response": (0.65, 0.85),
|
| | "foam_cell_formation": (0.7, 0.9),
|
| | "smooth_muscle_contraction": (0.3, 0.5),
|
| | "complement_cascade": (0.5, 0.7),
|
| | },
|
| | markers=["TREM2", "LGALS3", "MMP9", "CD9"],
|
| | mechanism_templates=[
|
| | "TREM2+ macrophage-driven foam cell formation",
|
| | "smooth muscle cell phenotypic switching in plaque",
|
| | ],
|
| | responding_cell_types=["macrophage", "smooth_muscle"],
|
| | ),
|
| | "breast_cancer": DiseaseProfile(
|
| | name="breast_cancer",
|
| | display_name="breast cancer",
|
| | tissue="breast",
|
| | condition_name="breast_cancer",
|
| | de_genes={
|
| | "ERBB2": (1.5, 3.5), "ESR1": (-1.5, 1.5), "MKI67": (1.5, 3.0),
|
| | "MYC": (1.0, 2.5), "CDH1": (-1.5, -0.3), "VIM": (0.8, 2.2),
|
| | "CD274": (0.8, 2.0), "FOXP3": (0.6, 1.5), "GZMB": (0.8, 2.0),
|
| | },
|
| | pathways={
|
| | "cell_cycle": (0.7, 0.9),
|
| | "PI3K_AKT_signalling": (0.65, 0.85),
|
| | "EMT": (0.55, 0.8),
|
| | "immune_checkpoint": (0.5, 0.75),
|
| | "estrogen_signalling": (0.3, 0.7),
|
| | },
|
| | markers=["ERBB2", "MKI67", "CD274", "VIM"],
|
| | mechanism_templates=[
|
| | "ERBB2-driven proliferative signalling",
|
| | "immune evasion via PD-L1 upregulation",
|
| | ],
|
| | responding_cell_types=["macrophage", "T_cell", "fibroblast"],
|
| | ),
|
| | "multiple_sclerosis": DiseaseProfile(
|
| | name="multiple_sclerosis",
|
| | display_name="multiple sclerosis",
|
| | tissue="brain",
|
| | condition_name="multiple_sclerosis",
|
| | de_genes={
|
| | "CD68": (1.0, 2.5), "CXCL10": (1.2, 2.8), "STAT1": (0.8, 2.0),
|
| | "IRF1": (0.8, 1.8), "MBP": (-2.0, -0.8), "PLP1": (-1.8, -0.6),
|
| | "MOG": (-1.5, -0.5), "GFAP": (1.0, 2.5), "C3": (0.8, 2.0),
|
| | },
|
| | pathways={
|
| | "interferon_signalling": (0.7, 0.9),
|
| | "neuroinflammation": (0.7, 0.9),
|
| | "complement_cascade": (0.6, 0.8),
|
| | "myelination": (0.2, 0.4),
|
| | "T_cell_activation": (0.6, 0.8),
|
| | },
|
| | markers=["CXCL10", "STAT1", "GFAP", "C3"],
|
| | mechanism_templates=[
|
| | "interferon-driven microglial activation in demyelination",
|
| | "complement-mediated oligodendrocyte damage",
|
| | ],
|
| | responding_cell_types=["microglia", "astrocyte"],
|
| | ),
|
| | "diabetic_nephropathy": DiseaseProfile(
|
| | name="diabetic_nephropathy",
|
| | display_name="diabetic nephropathy",
|
| | tissue="kidney",
|
| | condition_name="diabetic_nephropathy",
|
| | de_genes={
|
| | "HAVCR1": (1.5, 3.0), "LCN2": (1.2, 2.8), "COL4A1": (1.0, 2.5),
|
| | "VEGFA": (0.8, 2.0), "NPHS1": (-1.8, -0.6), "NPHS2": (-1.5, -0.5),
|
| | "WT1": (-1.2, -0.4), "TGFB1": (1.0, 2.2), "FN1": (1.2, 2.5),
|
| | },
|
| | pathways={
|
| | "TGF_beta_signalling": (0.7, 0.9),
|
| | "extracellular_matrix_organisation": (0.7, 0.9),
|
| | "oxidative_stress": (0.6, 0.8),
|
| | "VEGF_signalling": (0.5, 0.7),
|
| | "apoptosis": (0.5, 0.7),
|
| | },
|
| | markers=["HAVCR1", "LCN2", "TGFB1", "FN1"],
|
| | mechanism_templates=[
|
| | "TGF-beta-driven glomerular fibrosis",
|
| | "podocyte loss via oxidative stress",
|
| | ],
|
| | responding_cell_types=["fibroblast", "macrophage"],
|
| | ),
|
| | "melanoma": DiseaseProfile(
|
| | name="melanoma",
|
| | display_name="melanoma",
|
| | tissue="skin",
|
| | condition_name="melanoma",
|
| | de_genes={
|
| | "MLANA": (1.5, 3.0), "PMEL": (1.2, 2.5), "SOX10": (1.0, 2.2),
|
| | "MKI67": (1.5, 3.0), "CD274": (0.8, 2.0), "PDCD1": (0.8, 2.0),
|
| | "GZMB": (0.8, 2.0), "HAVCR2": (0.6, 1.5), "LAG3": (0.6, 1.5),
|
| | },
|
| | pathways={
|
| | "MAPK_signalling": (0.7, 0.9),
|
| | "immune_checkpoint": (0.6, 0.85),
|
| | "cell_cycle": (0.7, 0.9),
|
| | "melanogenesis": (0.5, 0.7),
|
| | "T_cell_exhaustion": (0.55, 0.8),
|
| | },
|
| | markers=["MLANA", "CD274", "GZMB", "MKI67"],
|
| | mechanism_templates=[
|
| | "MAPK-driven melanocyte proliferation",
|
| | "T cell exhaustion via immune checkpoint upregulation",
|
| | ],
|
| | responding_cell_types=["T_cell", "macrophage"],
|
| | ),
|
| | }
|
| |
|
| |
|
| |
|
| |
|
| | PATHWAY_LIBRARY: Dict[str, List[str]] = {
|
| | "TGF_beta_signalling": ["TGFB1", "TGFB2", "SMAD2", "SMAD3", "SMAD4", "ACVR1"],
|
| | "Wnt_signalling": ["WNT3A", "CTNNB1", "APC", "AXIN2", "LGR5", "TCF7L2"],
|
| | "MAPK_signalling": ["KRAS", "BRAF", "MAP2K1", "MAPK1", "MAPK3", "FOS", "JUN"],
|
| | "JAK_STAT_signalling": ["JAK1", "JAK2", "STAT1", "STAT3", "STAT5A", "SOCS1", "SOCS3"],
|
| | "PI3K_AKT_signalling": ["PIK3CA", "AKT1", "MTOR", "PTEN", "TSC2"],
|
| | "NF_kB_signalling": ["NFKB1", "RELA", "IKBKB", "TNF", "IL1B"],
|
| | "cell_cycle": ["CDK4", "CDK6", "CCND1", "CCNE1", "RB1", "E2F1", "MKI67"],
|
| | "apoptosis": ["BCL2", "BAX", "BAK1", "CASP3", "CASP9", "TP53", "BID"],
|
| | "inflammatory_response": ["TNF", "IL6", "IL1B", "CCL2", "CXCL8", "NFKB1"],
|
| | "extracellular_matrix_organisation": ["COL1A1", "COL3A1", "FN1", "POSTN", "MMP2", "MMP9", "TIMP1"],
|
| | "complement_cascade": ["C1QA", "C1QB", "C3", "C4A", "C5", "CFB"],
|
| | "neuroinflammation": ["TREM2", "CX3CR1", "P2RY12", "IL1B", "TNF", "C1QA"],
|
| | "synaptic_signalling": ["SLC17A7", "GRIA1", "GRIN1", "DLG4", "SNAP25", "SYP"],
|
| | "hematopoietic_cell_lineage": ["CD34", "KIT", "FLT3", "GATA1", "CEBPA", "SPI1"],
|
| | "insulin_signalling": ["INS", "INSR", "IRS1", "PIK3CA", "AKT1", "SLC2A4"],
|
| | "ER_stress_response": ["DDIT3", "ATF4", "XBP1", "HSPA5", "EIF2AK3"],
|
| | "oxidative_stress": ["SOD1", "SOD2", "CAT", "GPX1", "NFE2L2", "HMOX1"],
|
| | "angiogenesis": ["VEGFA", "VEGFB", "KDR", "FLT1", "ANGPT1", "ANGPT2"],
|
| | "EMT": ["CDH1", "CDH2", "VIM", "SNAI1", "SNAI2", "TWIST1", "ZEB1"],
|
| | "immune_checkpoint": ["CD274", "PDCD1", "CTLA4", "HAVCR2", "LAG3", "TIGIT"],
|
| | "T_cell_activation": ["CD3D", "CD28", "LCK", "ZAP70", "IL2", "IFNG"],
|
| | "T_cell_exhaustion": ["PDCD1", "HAVCR2", "LAG3", "TIGIT", "TOX", "ENTPD1"],
|
| | "TNF_signalling": ["TNF", "TNFRSF1A", "TRADD", "RIPK1", "NFKB1", "CASP8"],
|
| | "Th17_differentiation": ["IL17A", "IL17F", "RORC", "IL23R", "CCR6", "STAT3"],
|
| | "interferon_signalling": ["IFNG", "IFNB1", "STAT1", "IRF1", "IRF7", "MX1", "OAS1"],
|
| | "lipid_metabolism": ["APOE", "APOB", "LDLR", "HMGCR", "ABCA1", "PPARG"],
|
| | "myelination": ["MBP", "PLP1", "MOG", "MAG", "OLIG2", "SOX10"],
|
| | "foam_cell_formation": ["CD36", "MSR1", "ABCA1", "APOE", "LGALS3", "TREM2"],
|
| | "smooth_muscle_contraction": ["ACTA2", "MYH11", "TAGLN", "CNN1", "MYLK"],
|
| | "glucagon_signalling": ["GCG", "GCGR", "CREB1", "PCK1", "G6PC"],
|
| | "matrix_metalloproteinase_activity": ["MMP1", "MMP2", "MMP3", "MMP9", "TIMP1", "TIMP2"],
|
| | "estrogen_signalling": ["ESR1", "ESR2", "PGR", "GREB1", "TFF1"],
|
| | "melanogenesis": ["MITF", "TYR", "TYRP1", "DCT", "MLANA", "PMEL"],
|
| | "VEGF_signalling": ["VEGFA", "VEGFB", "KDR", "FLT1", "NRP1"],
|
| | }
|
| |
|
| |
|
| |
|
| |
|
| | REGULATORY_TEMPLATES: Dict[str, Dict[str, List[str]]] = {
|
| | "erythroid": {
|
| | "GATA1": ["KLF1", "HBB", "HBA1", "GYPA", "ALAS2"],
|
| | "KLF1": ["HBB", "HBA1", "SLC4A1"],
|
| | },
|
| | "myeloid": {
|
| | "CEBPA": ["CSF3R", "ELANE", "MPO", "CTSG"],
|
| | "SPI1": ["CSF1R", "CD14", "FCGR3A", "CD68"],
|
| | },
|
| | "lymphoid": {
|
| | "TCF7": ["CD3D", "CD3E", "IL7R", "LEF1"],
|
| | "PAX5": ["CD19", "MS4A1", "CD79A"],
|
| | },
|
| | "fibrotic": {
|
| | "SMAD3": ["COL1A1", "COL3A1", "FN1", "POSTN"],
|
| | "TGFB1": ["ACTA2", "COL1A1", "CTGF"],
|
| | },
|
| | "inflammatory": {
|
| | "NFKB1": ["TNF", "IL6", "IL1B", "CCL2", "CXCL8"],
|
| | "STAT1": ["IRF1", "CXCL10", "MX1", "OAS1"],
|
| | },
|
| | "stem_cell": {
|
| | "RUNX1": ["CD34", "KIT", "FLT3"],
|
| | "MYC": ["CDK4", "CCND1", "E2F1"],
|
| | },
|
| | "neuronal": {
|
| | "NEUROD1": ["SLC17A7", "NRGN", "SNAP25"],
|
| | "DLX1": ["GAD1", "GAD2", "SLC32A1"],
|
| | },
|
| | }
|
| |
|
| |
|
| |
|
| |
|
| | @dataclass
|
| | class PerturbationTemplate:
|
| | name: str
|
| | target_pathway: str
|
| | gene_effects: Dict[str, float]
|
| | description: str
|
| |
|
| |
|
| | PERTURBATION_TEMPLATES: Dict[str, PerturbationTemplate] = {
|
| | "JAK_inhibitor": PerturbationTemplate(
|
| | name="JAK_inhibitor",
|
| | target_pathway="JAK_STAT_signalling",
|
| | gene_effects={"STAT1": -0.8, "STAT3": -0.7, "IFNG": -1.5, "IL17A": -1.3, "SOCS1": 1.2},
|
| | description="JAK inhibitor treatment",
|
| | ),
|
| | "anti_TNF": PerturbationTemplate(
|
| | name="anti_TNF",
|
| | target_pathway="TNF_signalling",
|
| | gene_effects={"TNF": -1.5, "IL6": -1.0, "IL1B": -0.8, "MMP3": -1.2, "SOCS3": 0.8},
|
| | description="anti-TNF biologic therapy",
|
| | ),
|
| | "PD1_blockade": PerturbationTemplate(
|
| | name="PD1_blockade",
|
| | target_pathway="immune_checkpoint",
|
| | gene_effects={"PDCD1": -1.0, "GZMB": 1.5, "IFNG": 1.2, "PRF1": 1.0, "TNF": 0.8},
|
| | description="anti-PD-1 immune checkpoint blockade",
|
| | ),
|
| | "BRAF_inhibitor": PerturbationTemplate(
|
| | name="BRAF_inhibitor",
|
| | target_pathway="MAPK_signalling",
|
| | gene_effects={"BRAF": -0.5, "MAPK1": -1.0, "MKI67": -1.5, "CCND1": -1.2, "FOS": -0.8},
|
| | description="BRAF inhibitor treatment",
|
| | ),
|
| | "TGFb_inhibitor": PerturbationTemplate(
|
| | name="TGFb_inhibitor",
|
| | target_pathway="TGF_beta_signalling",
|
| | gene_effects={"TGFB1": -0.8, "COL1A1": -1.2, "COL3A1": -1.0, "POSTN": -1.5, "ACTA2": -0.8},
|
| | description="TGF-beta pathway inhibitor",
|
| | ),
|
| | "mTOR_inhibitor": PerturbationTemplate(
|
| | name="mTOR_inhibitor",
|
| | target_pathway="PI3K_AKT_signalling",
|
| | gene_effects={"MTOR": -0.8, "AKT1": -0.6, "MKI67": -1.2, "CCND1": -1.0, "HIF1A": -0.7},
|
| | description="mTOR inhibitor treatment",
|
| | ),
|
| | "CRISPR_TP53_KO": PerturbationTemplate(
|
| | name="CRISPR_TP53_KO",
|
| | target_pathway="p53_signalling",
|
| | gene_effects={"TP53": -2.0, "BAX": -1.0, "CDKN1A": -1.5, "MDM2": -0.8, "MKI67": 1.0},
|
| | description="CRISPR knockout of TP53",
|
| | ),
|
| | }
|
| |
|
| |
|
| |
|
| |
|
| | @dataclass
|
| | class TrajectoryTemplate:
|
| | """Template for a developmental trajectory through cell populations."""
|
| | root_population: str
|
| | branches: List[List[str]]
|
| | n_lineages: int
|
| | tissue: str
|
| |
|
| |
|
| | TRAJECTORY_TEMPLATES: List[TrajectoryTemplate] = [
|
| | TrajectoryTemplate(
|
| | root_population="HSC",
|
| | branches=[
|
| | ["HSC", "CMP", "GMP", "neutrophil"],
|
| | ["HSC", "CMP", "GMP", "monocyte"],
|
| | ["HSC", "MEP", "erythrocyte"],
|
| | ["HSC", "MEP", "megakaryocyte"],
|
| | ],
|
| | n_lineages=3,
|
| | tissue="bone_marrow",
|
| | ),
|
| | TrajectoryTemplate(
|
| | root_population="double_negative_T",
|
| | branches=[
|
| | ["double_negative_T", "double_positive_T", "CD4_SP"],
|
| | ["double_negative_T", "double_positive_T", "CD8_SP"],
|
| | ],
|
| | n_lineages=2,
|
| | tissue="thymus",
|
| | ),
|
| | TrajectoryTemplate(
|
| | root_population="stem_cell",
|
| | branches=[
|
| | ["stem_cell", "colonocyte"],
|
| | ["stem_cell", "goblet_cell"],
|
| | ],
|
| | n_lineages=2,
|
| | tissue="colon",
|
| | ),
|
| | TrajectoryTemplate(
|
| | root_population="OPC",
|
| | branches=[
|
| | ["OPC", "oligodendrocyte"],
|
| | ],
|
| | n_lineages=1,
|
| | tissue="brain",
|
| | ),
|
| | ]
|
| |
|
| |
|
| |
|
| |
|
| | HIDDEN_FAILURE_TEMPLATES: List[str] = [
|
| | "High ambient RNA may confound DE in low-abundance transcripts",
|
| | "Strong batch effects between conditions may inflate false positives",
|
| | "Low cell viability in disease samples reduces statistical power",
|
| | "Doublet contamination in dense populations obscures rare cell types",
|
| | "Sample degradation during processing introduces 3' bias artefacts",
|
| | "Dissociation-induced gene expression changes confound stress signatures",
|
| | "Unbalanced sample sizes between conditions reduce DE sensitivity",
|
| | ]
|
| |
|
