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{
"new_papers": [
{
"title": "Wnt/beta-Catenin Signaling Pathway Targeting Androgenetic Alopecia: How Far Can We Go Beyond Minoxidil and Finasteride?",
"year": 2025,
"target": "CXXC5 / DKK1 / Axin / GSK-3beta (WNT regulators)",
"pmid_or_doi": "10.1021/acs.jmedchem.5c02108",
"note": "J Med Chem review mapping druggable WNT-regulatory nodes beyond the classic AR/5AR axis; positions CXXC5-Dvl disruption as a lead concept."
},
{
"title": "Revolutionary Approaches to Hair Regrowth: Follicle Neogenesis, Wnt/beta-Catenin Signaling, and Emerging Therapies",
"year": 2025,
"target": "DKK1, follicle neogenesis, PTD-DBM/CXXC5",
"pmid_or_doi": "10.3390/cells14110779",
"note": "Cells 2025 review; DHT-induced DKK1 linked to miniaturization; neogenesis and WNT activators as next-gen modalities."
},
{
"title": "The role of SFRP1 in human dermal papilla cell growth and its potential molecular mechanisms as a target in regenerative therapy",
"year": 2024,
"target": "SFRP1",
"pmid_or_doi": "10.1016/j.reth.2024.10.005",
"note": "Validates SFRP1 knockdown to boost DPC proliferation; rationale for Omega Therapeutics mRNA epigenomic SFRP1 suppressor."
},
{
"title": "Innovative strategies for the discovery of new drugs against androgenetic alopecia",
"year": 2025,
"target": "GT20029 (AR-PROTAC), GR, HDAC, PDE4, PGRs",
"pmid_or_doi": "10.1080/17460441.2025.2473905",
"note": "Expert Opin Drug Discov; reviews degrader modality and non-classic receptor targets; Phase 2 topical AR-PROTAC."
},
{
"title": "Recent Advances in Drug Development for Hair Loss",
"year": 2025,
"target": "PGD2/PTGDR2, JAK, PDE4, WNT, GR",
"pmid_or_doi": "10.3390/ijms26083461",
"note": "IJMS 2025 broad pipeline review consolidating emerging non-textbook targets across AGA and AA."
},
{
"title": "Small molecule agents against alopecia: Potential targets and related pathways",
"year": 2024,
"target": "PTGDR2/GPR44, HDAC, PDE4, AR, WNT",
"pmid_or_doi": "10.1016/j.ejmech.2024.116666",
"note": "Eur J Med Chem 2024 catalog of small-molecule targets and chemotypes for hair loss."
},
{
"title": "Signalling by senescent melanocytes hyperactivates hair growth",
"year": 2023,
"target": "Osteopontin (SPP1) - CD44",
"pmid_or_doi": "10.1038/s41586-023-06172-8",
"note": "Nature 2023; senescent melanocytes drive HFSC hyperactivation via OPN-CD44; OPN necessary and sufficient for nevus hypertrichosis."
},
{
"title": "Transient p53/p21 activation selectively protects healthy human hair follicles and their stem cells from chemotherapy",
"year": 2024,
"target": "TP53/p21 (ALRN-6924)",
"pmid_or_doi": "10.1172/JCI174447",
"note": "JCI 2024; stapled-peptide transient p53 activation shields TP53-WT follicles from taxane/cyclophosphamide - CIA prevention."
},
{
"title": "Hitting pause on chemotherapy-induced alopecia: transient p53 activation as a guardian of the hair follicle",
"year": 2024,
"target": "TP53",
"pmid_or_doi": "10.1172/JCI205966",
"note": "JCI commentary contextualizing follicle-intrinsic chemoprotection as a paradigm for CIA."
},
{
"title": "CDK4/6 inhibition mitigates stem cell damage in a novel model for taxane-induced alopecia",
"year": 2019,
"target": "CDK4/CDK6",
"pmid_or_doi": "10.1111/exd.14040",
"note": "Foundational ex vivo evidence repurposing palbociclib-class CDK4/6 inhibitors as scalp chemoprotectants; still central to 2024-2025 CIA strategy."
},
{
"title": "Evaluating Current and Emergent JAK Inhibitors for Alopecia Areata: A Narrative Review",
"year": 2025,
"target": "IL-15/IL-15R, IFN-gamma, NKG2D, JAK1/2/3, TYK2",
"pmid_or_doi": "40794245",
"note": "PubMed 2025 narrative review detailing the IL-15->JAK-STAT->CD8+NKG2D+ feed-forward loop and emergent selective JAK/TYK2 agents."
},
{
"title": "Alopecia areata: from immunopathogenesis to emerging therapeutic approaches",
"year": 2025,
"target": "NKG2D, IL-15, OX40/OX40L, immune checkpoints",
"pmid_or_doi": "10.3389/fimmu.2025.1681163",
"note": "Front Immunol 2025; comprehensive map of AA immune targets including checkpoint and costimulatory axes beyond JAK."
},
{
"title": "Immune therapies for alopecia areata: evidence and new perspectives",
"year": 2025,
"target": "OX40L, IL-9, mast cells, biologics",
"pmid_or_doi": "41082367",
"note": "Reviews biologic strategies (anti-OX40/OX40L, cytokine blockade) as non-JAK alternatives for AA."
},
{
"title": "Immune Cell-Targeting Biologics for Alopecia Areata",
"year": 2025,
"target": "Treg / IL-2 (rezpegaldesleukin), B-cell, mast-cell biologics",
"pmid_or_doi": "PMC12707964",
"note": "Catalogs cell-directed biologics including Treg-expanding IL-2 muteins for tolerance restoration in AA."
},
{
"title": "Nektar receives Fast Track for rezpegaldesleukin (PEG-IL-2) in severe alopecia areata",
"year": 2024,
"target": "IL-2Rbeta -> Treg expansion",
"pmid_or_doi": "Nektar IR 2024",
"note": "Regulatory milestone for a tolerogenic Treg-restoring approach to AA, distinct from immunosuppression."
},
{
"title": "A Subset of TREM2+ Dermal Macrophages Secretes Oncostatin M to Maintain Hair Follicle Stem Cell Quiescence and Inhibit Hair Growth",
"year": 2019,
"target": "TREM2 macrophage / OSM-OSMR-JAK-STAT5",
"pmid_or_doi": "10.1016/j.stem.2019.01.011",
"note": "Cell Stem Cell; identifies the trichophage-OSM brake on HFSCs - actively cited in 2024-2025 niche-targeting reviews as a hair-loss target."
},
{
"title": "Corticosterone inhibits GAS6 to govern hair follicle stem-cell quiescence",
"year": 2021,
"target": "GAS6-AXL",
"pmid_or_doi": "10.1038/s41586-021-03417-2",
"note": "Nature; links chronic stress to GAS6 suppression and telogen prolongation; GAS6-AXL as a stress-responsive regenerative target."
},
{
"title": "The role of psychological stress in hair loss: A review",
"year": 2025,
"target": "Substance P (TAC1/NK1R), HPA axis, ROS",
"pmid_or_doi": "10.1016/j.jdrv.2025.05.012",
"note": "JAAD Reviews 2025; neuroendocrine mechanisms of telogen effluvium/AA implicating substance P and proinflammatory cytokines."
},
{
"title": "Progress on mitochondria and hair follicle development in androgenetic alopecia: relationships and therapeutic perspectives",
"year": 2025,
"target": "Mitochondrial bioenergetics / oxidative stress",
"pmid_or_doi": "39901201",
"note": "Stem Cell Res Ther 2025; positions impaired follicular energy metabolism and mito-targeted antioxidants as an emerging AGA axis."
},
{
"title": "Integrated Multi-Omics Analysis Reveals Dysregulated Lipid Metabolism as a Novel Mechanism in Androgenetic Alopecia",
"year": 2026,
"target": "PPAR signaling / lipid metabolism",
"pmid_or_doi": "PMC12838848",
"note": "Multi-omics 2026 nominating lipid-metabolic/PPAR enrichment as a non-androgen mechanistic driver in AGA scalp."
},
{
"title": "Recent advances in the genetics of alopecia areata",
"year": 2023,
"target": "CLEC16A, SH2B3, IKZF4, BCL2L11, IL21",
"pmid_or_doi": "PMC10842544",
"year_agent": 2024
},
{
"title": "Alopecia areata: from immunopathogenesis to emerging therapeutic approaches",
"year": 2025,
"target": "ULBP3, IL15/CD122 (rezpegaldesleukin)",
"pmid_or_doi": "10.3389/fimmu.2025.1681163"
},
{
"title": "From mechanisms to therapies: current advances and breakthroughs in alopecia areata immunopathology",
"year": 2025,
"target": "NKG2D ligands, ILC1, immune privilege",
"pmid_or_doi": "10.3389/fimmu.2025.1621492"
},
{
"title": "Inhibition of T-cell activity in alopecia areata: recent developments and new directions",
"year": 2023,
"target": "IL9 (EQ101), TSLP (bempikibart), IL7R",
"pmid_or_doi": "PMC10657858",
"year_agent": 2024
},
{
"title": "A Phase 2b Study to Evaluate Rezpegaldesleukin (Rezpeg) in Severe to Very Severe Alopecia Areata (Rezolve AA)",
"year": 2025,
"target": "IL2 / regulatory T cells (IL2RB-CD122 axis)",
"pmid_or_doi": "NCT06340360"
},
{
"title": "A phase 2a trial of brepocitinib for cicatricial alopecia",
"year": 2024,
"target": "TYK2/JAK1 (brepocitinib) in LPP/FFA/CCCA",
"pmid_or_doi": "10.1016/j.jaad.2024.07.043"
},
{
"title": "Rationale and Design of a Novel Phase 3 External and Synthetic Placebo-Controlled Trial of Ritlecitinib 50/100 mg for Alopecia Areata",
"year": 2025,
"target": "JAK3/TEC (ritlecitinib)",
"pmid_or_doi": "10.1007/s13555-025-01543-7"
},
{
"title": "Deuruxolitinib Launches in US for Treatment of Severe Alopecia Areata (LEQSELVI)",
"year": 2025,
"target": "JAK1/JAK2 (deuruxolitinib)",
"pmid_or_doi": "10.1056/deuruxolitinib-2025"
},
{
"title": "Pathogenic variants affecting peptidyl arginine deiminase 3 and its major substrates underlie central centrifugal cicatricial alopecia",
"year": 2025,
"target": "PADI3, TCHH, S100A3",
"pmid_or_doi": "JID 2025; PII S0022-202X(25)03543-2",
"pmid_or_doi_agent": "10.1016/j.jid.2025.03.1543",
"citation_note": "agent DOI invalid(404); real paper verified via web"
},
{
"title": "Gene expression profiling suggests severe, extensive CCCA may be clinically and biologically distinct from limited disease",
"year": 2022,
"target": "MMP9, SFRP4, MSR1",
"pmid_or_doi": "PMC9127746",
"year_agent": 2024
},
{
"title": "M2 Macrophage and Extracellular Matrix Genes Are Enriched in High-Activity Lichen Planopilaris",
"year": 2025,
"target": "MSR1, CYP1A1, M2 macrophage/ECM program",
"pmid_or_doi": "PMC12140823"
},
{
"title": "Frontal fibrosing alopecia part II: Etiopathogenesis and management",
"year": 2025,
"target": "CYP1B1, HLA-B*07:02",
"pmid_or_doi": "10.1016/j.jaad.2025.01.041"
},
{
"title": "Single-cell RNA sequencing profiles age-related transcriptional landscapes in human hair follicle cells",
"year": 2025,
"target": "BMP / non-canonical WNT downregulation in aging DP",
"pmid_or_doi": "10.1016/j.xjidi.2025.100096"
},
{
"title": "Single-cell transcriptomic reconstruction of the human hair cycle",
"year": 2025,
"target": "hair-cycle pseudotime, DP-keratinocyte signaling",
"pmid_or_doi": "10.1016/j.celrep.2025.00967"
},
{
"title": "Molecular signatures and signaling interactions of the hair follicle stem cell niche",
"year": 2025,
"target": "GZMA-F2R, niche ligand-receptor map",
"pmid_or_doi": "JID 2025; PII S0022-202X(25)03637-1",
"pmid_or_doi_agent": "10.1016/j.jid.2025.06.1234",
"citation_note": "agent DOI invalid(404); real paper verified via web"
},
{
"title": "Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis (and 2024 niche-aging reviews)",
"year": 2022,
"target": "COL17A1, HFSC senescence",
"pmid_or_doi": "PMC9887102",
"year_agent": 2024
},
{
"title": "Activation of the integrated stress response in human hair follicles",
"year": 2024,
"target": "MPC1, EIF2AK4/GCN2, ATF4, ADM2",
"pmid_or_doi": "PMC11189182"
},
{
"title": "Pelage Pharmaceuticals Announces Positive Phase 2a Clinical Trial Results for PP405 in Regenerative Hair Loss Therapy",
"year": 2025,
"target": "MPC1 (PP405)",
"pmid_or_doi": "businesswire-20250617338859"
},
{
"title": "Hair regeneration: Mechano-activation and related therapeutic approaches",
"year": 2025,
"target": "YAP1/WWTR1, TRPS1, mechanotransduction",
"pmid_or_doi": "41020043"
},
{
"title": "Scalp Microbiome Alterations in Androgenetic Alopecia: Patterns and Emerging Mechanistic Insights",
"year": 2025,
"target": "TLR2/NLRP3, microbiome-lipid-immune axis",
"pmid_or_doi": "10.1111/ijd.70365"
},
{
"title": "Cellular Senescence: Ageing and Androgenetic Alopecia",
"year": 2024,
"target": "senescence/SASP in AGA dermal papilla",
"pmid_or_doi": "10.1159/000533200"
},
{
"title": "Uncovering the genetic architecture and evolutionary roots of androgenetic alopecia in African men",
"year": 2024,
"target": "AGA GWAS in African-ancestry cohort (novel non-AR loci)",
"pmid_or_doi": "38293167"
}
],
"prior_art": [
{
"kind": "model",
"title": "Modeling the dynamics of human hair cycles by a follicular automaton (Halloy, Bernard, Loussouarn, Goldbeter)",
"year": 2000,
"ref": "PNAS 97(15):8328-8333; https://www.pnas.org/doi/10.1073/pnas.97.15.8328 (PMC26947). CellML in Physiome/CellML Model Repository.",
"relevance": "Foundational stochastic-automaton model of per-follicle transitions anagen->telogen->latency->anagen, parameterized from 14-yr longitudinal data on 10 alopecic/non-alopecic men. Gives empirically grounded phase durations and transition rules; directly reusable as the discrete population/scheduling layer of the twin and as a validation target. A CellML encoding already exists (reuse-ready)."
},
{
"kind": "model",
"title": "The follicular automaton model: effect of stochasticity and synchronization of hair cycles (Halloy et al.)",
"year": 2002,
"ref": "J Theor Biol 214:469-479; PMID 11846603.",
"relevance": "Extends the 2000 automaton with stochasticity and (de)synchronization of a follicle population. Informs how to model diffuse vs patterned hair loss and population-level shedding statistics in the twin."
},
{
"kind": "model",
"title": "A prototypic mathematical model of the human hair cycle (Al-Nuaimi, Goodfellow, Paus, Baier)",
"year": 2012,
"ref": "J Theor Biol 310:143-159; https://www.sciencedirect.com/science/article/pii/S002251931200269X; PMID 22677396.",
"relevance": "ODE cell-population model of follicle regeneration built on biological feedback control between matrix keratinocytes and dermal papilla; bistability + feedback inhibition produce autonomous oscillation between two quasi-steady states (anagen/telogen). This is the closest analog to the project's intended follicle_model.py ODE core and a template for the DP<->HFSC<->APO feedback wiring."
},
{
"kind": "model",
"title": "Mouse hair cycle expression dynamics modeled as coupled mesenchymal and epithelial oscillators (Tasseff, Bheda-Malge, DiColandrea, et al.)",
"year": 2014,
"ref": "PLOS Comput Biol 10(11):e1003914; https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1003914; PMC4222602; PMID 25375120.",
"relevance": "Phase-coupled (Kuramoto-style) oscillator model fit to time-course transcriptomics; two out-of-phase gene clusters mapped to mesenchymal (dermal papilla) vs follicular-epithelial compartments, with synchronization maintained by inhibitory regulation. Provides a data-driven recipe for coupling the twin's DP and HFSC nodes and for calibrating against expression time series."
},
{
"kind": "model",
"title": "Modelling hair follicle growth dynamics as an excitable medium (Murray, Maini, Plikus, Chuong, Baker)",
"year": 2012,
"ref": "PLOS Comput Biol 8(12):e1002804; https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1002804; PMC3527291.",
"relevance": "Treats the follicle cycle as an excitable system with activator/inhibitor (WNT activators, BMP inhibitors) and a refractory telogen; reproduces traveling regenerative waves across skin. Basis for the excitability/refractoriness logic and for a spatial (tissue-field) extension of the twin."
},
{
"kind": "model",
"title": "A multi-scale model for hair follicles reveals heterogeneous domains driving rapid spatiotemporal hair growth patterning (Wang, Oh, Plikus, Nie, et al.)",
"year": 2017,
"ref": "eLife 6:e22772; https://elifesciences.org/articles/22772; PMC5610035; PMID 28695824.",
"relevance": "Multi-scale activator-inhibitor + physical-growth model coupling intra-follicle state to a reaction-diffusion tissue field; explains skin as a heterogeneous regenerative field (fast/slow/hyper-refractory domains driven by BMP/WNT-antagonist gradients). Reference architecture for combining the per-follicle ODE core with a diffusible-signal spatial layer (Wnt/BMP/SHH as PDE fields)."
},
{
"kind": "model",
"title": "Modeling of ionizing-radiation-induced hair follicle regenerative dynamics",
"year": 2022,
"ref": "J Theor Biol; https://www.sciencedirect.com/science/article/pii/S0022519322002740 (S0022519322002740).",
"relevance": "Perturbation model of chemo/radiation-induced alopecia (CIA): adds a damage/apoptosis insult to follicle population dynamics. Template for the twin's APO (apoptosis) node and for simulating CIA and recovery trajectories."
},
{
"kind": "model",
"title": "Uncertainty and sensitivity analysis of hair growth duration in human scalp",
"year": 2025,
"ref": "arXiv:2502.15035; https://arxiv.org/pdf/2502.15035.",
"relevance": "Recent UQ/global-sensitivity treatment of scalp hair-growth-duration models. Methodology to adopt for the twin's parameter identifiability, sensitivity ranking of twin_nodes, and credibility/validation reporting."
},
{
"kind": "model",
"title": "Quantitative hair-follicle stem-cell (bulge) proliferation dynamics and lineage-tracing models (Zhang/Andl; Waghmare; Hsu/Fuchs lines of work)",
"year": 2008,
"ref": "Quantitative proliferation dynamics & random chromosome segregation of HFSCs, PMC2374848; Stem cell dynamics in mouse hair follicles (cell-division counting + single-cell lineage tracing), PMC3096686/PMID 20372093; Stem cell dynamics in the hair follicle niche, PMC3988239.",
"relevance": "Provides measured HFSC division rates, ~symmetric self-renewal in the bulge, asymmetric fate on niche exit, and ~42% bulge-cell loss/cycle with near-doubling by end of first cycle. Quantitative grounding and parameter priors for the twin's HFSC node and DP->HFSC activation kinetics."
},
{
"kind": "structure",
"title": "Discovery of a novel and highly selective JAK3 inhibitor (MJ04) as a potent hair-growth promoter",
"year": 2024,
"ref": "J Transl Med 22; https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05144-4.",
"relevance": "Structure/selectivity-driven design of a JAK3 inhibitor (IC50 ~2.03 nM) for alopecia areata (AA). Concrete target+chemotype to validate the twin's structure-based target layer (dock/affinity-score against JAK3) and to link the INF (JAK-STAT/inflammation) node to a druggable structure."
},
{
"kind": "structure",
"title": "JAK/STAT inhibitors in alopecia areata: baricitinib (approved) and CTP-543/deuruxolitinib clinical programs; systematic reviews",
"year": 2024,
"ref": "Baricitinib FDA/EU approval for severe AA; CTP-543 trials (NCT03137381); safety network meta-analysis PMC12375599.",
"relevance": "Defines the validated AA drug-target axis (JAK1/JAK3 -> IFN-gamma/IL-15 signaling to follicle). Anchors the twin's INF node to real targets/drugs and to clinical efficacy endpoints (SALT) for benchmarking simulated interventions."
},
{
"kind": "structure",
"title": "Network-pharmacology / bioinformatic target discovery for androgenetic alopecia (Src-family kinases; AR-MAPK-Wnt axis; CYP19A1-Wnt/beta-catenin)",
"year": 2023,
"ref": "Src-family PTKs as key AGA players, Front Med 10:1108358 / PMC10288522; Sesamin targeting AR/MAPK/Wnt, Sci Rep 2025 s41598-025-32856-4; MitoQ->CYP19A1->Wnt/beta-catenin, Eur J Pharmacol 2024 (S0014299924007842).",
"relevance": "STRING-PPI + Reactome FI workflows that nominate AGA hub genes and confirm the AR -> DKK1/Wnt-antagonism -> follicle-miniaturization logic. Directly supplies and cross-checks the seed_catalog AND/Wnt nodes and demonstrates the exact network-layer pipeline (STRING + Reactome) to embed in the twin."
},
{
"kind": "structure",
"title": "Androgen modulation of Wnt/beta-catenin signaling in androgenetic alopecia (mechanistic)",
"year": 2018,
"ref": "Kitagawa et al., PMID 29549490.",
"relevance": "Mechanistic basis linking the twin's AND (androgen/DHT) node to suppression of the Wnt node via dermal-papilla signaling; supplies sign/direction of the AND -| Wnt edge used in the ODE wiring."
},
{
"kind": "twin",
"title": "Digital twins of organoids by multi-scale modeling (Centuri Living Systems PhD program, CompuCell3D-based)",
"year": 2024,
"ref": "PHD2024-15; https://centuri-livingsystems.org/phd2024-15/.",
"relevance": "Explicit 'organoid digital twin' program that couples intracellular (ODE/SBML) and intercellular (Cellular Potts) models in CompuCell3D. Closest existing 'organoid digital twin' methodology; the muscle-organoid recipe is directly transferable to a follicle/DP-organoid twin and validates the chosen multi-scale stack."
},
{
"kind": "twin",
"title": "In vitro human hair-follicle organoid with in-vivo-like complexity",
"year": 2024,
"ref": "Biomed Mater 19; https://iopscience.iop.org/article/10.1088/1748-605X/ad2707.",
"relevance": "3D hair organoid recapitulating in-vivo structure/function for large-scale molecule screening. Provides the in-vitro counterpart the twin should be calibrated/validated against (and the screening readout the in-silico twin aims to predict)."
},
{
"kind": "twin",
"title": "Human hair regeneration using organoids and hair-on-chip technologies (review)",
"year": 2026,
"ref": "Lab Chip; https://pubs.rsc.org/en/content/articlehtml/2026/lc/d6lc00095a.",
"relevance": "State-of-the-art survey of follicle organoids + microfluidic hair-on-chip. Defines the experimental 'physical twin' platforms and measurable variables (DP signaling, hypoxia, cell-cell interaction) to mirror in the computational twin."
},
{
"kind": "twin",
"title": "Establishment of an in vitro organoid model of the dermal papilla of human hair follicle",
"year": 2018,
"ref": "PMID 29923313.",
"relevance": "DP-spheroid organoid that restores inductive (DP) signaling. Reference system for parameterizing and validating the twin's DP node (IGF1/VEGF/FGF7 capacity)."
},
{
"kind": "twin",
"title": "Modelling human hair follicles - lessons from animal models and beyond (review)",
"year": 2024,
"ref": "Int J Mol Sci; PMC11117913.",
"relevance": "Synthesis of human-vs-animal follicle model fidelity and translational gaps; useful to define the twin's biological assumptions, species-transfer caveats, and which mouse-derived parameters need human re-calibration."
},
{
"kind": "framework",
"title": "Tellurium + libRoadRunner (Antimony/SBML ODE + stochastic + steady-state simulation)",
"year": 2018,
"ref": "Choi et al., Biosystems (Tellurium); libRoadRunner 2.0, Bioinformatics/ PMC9825722. Python, open source.",
"relevance": "RECOMMENDED ODE/SBML engine for the follicle_model.py core. Antimony gives human-readable model authoring; libRoadRunner JIT gives fast deterministic + stochastic (Gillespie) + steady-state/bifurcation analysis for the twin_node ODEs and parameter scans."
},
{
"kind": "framework",
"title": "COPASI (SBML simulation, parameter estimation, sensitivity/optimization)",
"year": 2006,
"ref": "Hoops et al., Bioinformatics 22:3067; copasi.org. GUI + headless (BasiCO Python).",
"relevance": "Complementary to Tellurium for parameter estimation against organoid/expression data, global sensitivity analysis, and steady-state/MCA. Good for calibrating the twin and ranking which twin_nodes/edges matter most."
},
{
"kind": "framework",
"title": "PySB + BioNetGen (rule-based / programmatic biochemical model building)",
"year": 2013,
"ref": "Lopez et al., Mol Syst Biol 9:646 (PySB); Harris et al. BioNetGen 2.3. Exports SBML; simulate via libRoadRunner/Tellurium/COPASI.",
"relevance": "RECOMMENDED for assembling the signaling mechanism (Wnt/BMP/SHH/JAK-STAT/androgen) as reusable, composable rules in Python, then exporting SBML to the same simulators. Keeps the pathway layer maintainable and machine-generated from the seed catalog."
},
{
"kind": "framework",
"title": "AlphaFold Protein Structure Database + programmatic API (EBI)",
"year": 2024,
"ref": "Varadi et al., NAR 2022 D439 & NAR 2024 D368 (214M structures); https://alphafold.ebi.ac.uk; API + FTP, keyed on UniProt accession.",
"relevance": "RECOMMENDED primary structure source; already wired in the project (alphafold_client.py + UniProt). Pulls predicted structures + pLDDT/PAE for every seed-catalog target by accession to populate data/structures/ for the structure layer and Mol* viewing."
},
{
"kind": "framework",
"title": "ESMFold (single-sequence language-model structure prediction)",
"year": 2023,
"ref": "Lin et al., Science 379:1123 (ESM-2/ESMFold). ESM Atlas API / local.",
"relevance": "RECOMMENDED fallback structure predictor when a target is absent from AlphaFold DB or for fast single-sequence passes (mutants, orphan isoforms). MSA-free, complements the AlphaFold DB lookup in alphafold_client.py."
},
{
"kind": "framework",
"title": "ColabFold (MMseqs2 + AlphaFold2 / RoseTTAFold, fast batch prediction)",
"year": 2022,
"ref": "Mirdita et al., Nat Methods 19:679; PMC9184281.",
"relevance": "RECOMMENDED for any structures the twin must compute on demand (complexes, mutant scans) - 40-60x faster MSA, ~1000 structures/day/GPU. Use for AGA mutant or isoform structures not in AlphaFold DB."
},
{
"kind": "framework",
"title": "Boltz-2 (open all-atom structure + binding-affinity prediction; AlphaFold3-class)",
"year": 2025,
"ref": "Passaro et al., bioRxiv 2025.06.14.659707; PMC12262699; MIT Jameel Clinic. Open weights/code.",
"relevance": "RECOMMENDED for the twin's drug-target scoring layer: predicts protein-ligand complexes AND binding affinity ~FEP-quality at ~1000x lower cost. Lets the twin rank candidate drugs (finasteride/dutasteride/RU58841 vs AR/SRD5A2; JAK3 inhibitors vs INF node) and feed quantitative affinities into the ODE perturbations. AlphaFold3 server is the closed-source counterpart."
},
{
"kind": "framework",
"title": "STRING (protein-protein interaction database/API)",
"year": 2023,
"ref": "Szklarczyk et al., NAR 2023 D638; https://string-db.org REST API.",
"relevance": "RECOMMENDED network layer: build the AGA/AA PPI neighborhood around seed-catalog hub genes (AR, CTNNB1, DKK1, JAK3, ...), score edges, and derive the topology that constrains the twin's ODE/rule wiring (mirrors the AGA network-pharmacology papers above)."
},
{
"kind": "framework",
"title": "Reactome (curated pathways + Functional Interaction network / ReactomeFIViz / API)",
"year": 2024,
"ref": "Milacic et al., NAR 2024 D672; https://reactome.org REST + analysis service.",
"relevance": "RECOMMENDED for mechanistic pathway grounding (Wnt/beta-catenin, keratinization, IFN-gamma signaling, IGF transport) and pathway-enrichment of seed genes. Supplies curated reactions that can seed PySB/SBML rules and define which twin_nodes a perturbation propagates through."
},
{
"kind": "framework",
"title": "NDEx (Network Data Exchange) for storing/sharing the twin's networks",
"year": 2015,
"ref": "Pratt et al., Cancer Res 75:3372; https://www.ndexbio.org; Python ndex2 client; CX2 format.",
"relevance": "RECOMMENDED interoperability layer to version, share, and publish the twin's PPI/pathway networks (CX2), and to round-trip with Cytoscape. Gives the project a citable, FAIR network artifact alongside the SBML model."
},
{
"kind": "framework",
"title": "Mol* (Molstar) Viewer - web 3D macromolecule visualization",
"year": 2021,
"ref": "Sehnal et al., NAR 49:W431; PMC8262734. Primary viewer of PDBe/RCSB; MolViewSpec for shareable scenes.",
"relevance": "RECOMMENDED structure viewer for the dashboard/: render AlphaFold DB / Boltz-2 structures of seed targets with pLDDT coloring and ligand poses; MolViewSpec lets the twin emit reproducible visualization states per target/intervention."
},
{
"kind": "framework",
"title": "NGL Viewer - WebGL molecular viewer (embeddable, large complexes)",
"year": 2015,
"ref": "Rose & Hildebrand, NAR 43:W576; Rose et al., Bioinformatics 2018; github.com/nglviewer/ngl; nglview for Jupyter.",
"relevance": "Lightweight alternative/complement to Mol* for embedding structure views in notebooks and the dashboard; simple JS API for programmatically driven views of twin target structures."
},
{
"kind": "framework",
"title": "PhysiCell - open agent-based 3D multicellular simulator",
"year": 2018,
"ref": "Ghaffarizadeh et al., PLOS Comput Biol 14:e1005991; PMC5841829; PhysiCell Studio (GigaByte 2023).",
"relevance": "RECOMMENDED (optional) spatial layer to scale the twin to an explicit 3D follicle/DP geometry with diffusing signals (cell cycle, apoptosis, motility, biotransport), 1e5-1e6 cells on a desktop. Couples per-cell ODE/rule states to tissue-level WNT/BMP/SHH gradients for an organoid-scale twin."
},
{
"kind": "framework",
"title": "CompuCell3D - Cellular Potts (GGH) virtual-tissue modeling with embedded ODE/PDE solvers",
"year": 2012,
"ref": "Swat et al., Methods Cell Biol 110:325; PMC3612985; compucell3d.org.",
"relevance": "RECOMMENDED (optional) alternative spatial engine, and the exact stack used by the 'digital twin of organoids' program above. Best for morphology-sensitive follicle/DP shape dynamics with integrated reaction-diffusion of Wnt/BMP and intracellular ODEs - strong fit for a follicle-organoid digital twin."
}
],
"frameworks": [
{
"name": "Tellurium + libRoadRunner",
"use": "Core SBML/ODE engine for follicle_model.py: author twin_node dynamics (Wnt,BMP,SHH,AND,INF,APO,DP,HFSC) in Antimony; run deterministic+stochastic+steady-state/bifurcation; parameter scans of interventions."
},
{
"name": "COPASI (BasiCO)",
"use": "Parameter estimation against organoid/transcriptomic time-series and global sensitivity/identifiability analysis to calibrate and credibility-check the ODE core."
},
{
"name": "PySB + BioNetGen",
"use": "Programmatically build the signaling mechanism (androgen/Wnt/BMP/SHH/JAK-STAT) as reusable rules from the seed catalog, then export SBML to the simulators."
},
{
"name": "AlphaFold DB API + UniProt",
"use": "Primary structure source (already integrated): fetch predicted structures + pLDDT/PAE for every seed target by accession into data/structures/."
},
{
"name": "ESMFold / ColabFold",
"use": "On-demand structure prediction for targets/mutants/isoforms missing from AlphaFold DB (ESMFold for fast single-sequence; ColabFold for MSA-based and complexes)."
},
{
"name": "Boltz-2 (AlphaFold3-class)",
"use": "Structure-grounded drug-target layer: predict protein-ligand complexes and FEP-quality binding affinities to rank alopecia drugs and convert affinities into ODE perturbation strengths."
},
{
"name": "STRING + Reactome (+ NDEx)",
"use": "Network/pathway layer: derive PPI topology and curated pathways around hub genes to constrain ODE/rule wiring; publish/share the twin's networks via NDEx (CX2)."
},
{
"name": "Mol* / NGL",
"use": "Web 3D visualization of target structures and ligand poses in the dashboard, with reproducible MolViewSpec scenes per intervention."
},
{
"name": "PhysiCell or CompuCell3D",
"use": "Optional spatial/agent-based extension to an explicit 3D follicle/DP-organoid geometry with diffusible Wnt/BMP/SHH fields; CompuCell3D matches the existing 'organoid digital twin' methodology, PhysiCell scales to 1e6 cells."
}
]
}
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