A genome-scale CRISPRi Perturb-seq re-analysis in primary human CD4+ T cells — hunting knockdowns that suppress the Th2 (allergy) program without flipping cells toward Th1, stress-testing that claim to destruction, then asking whether a different, degrader-relevant phenotype is the more useful question.
The full self-contained story: the 2D arm plane, scored shortlist, mechanism dossiers, independent review, and the hardened re-analysis — all readable in-page.
Open the dashboard →Click through every underlying file — figures, tables, parquet data, dossiers, and the analysis notebooks — with relative links.
Browse the files →A from-scratch replication — streaming pipeline, its own QC catch, independent verification — that reaches the same negative result, plus a biology primer and the full reasoning as an interactive page.
Open the primer →A degrader-relevant reframe: score every perturbation for STAT6/GATA3 collapse phenocopy (a positive anchor that calibrates where the selectivity residual gave FDR ≈ 1), then weight by chemical tractability, AD genetics, and AD patient skin. Nominates off-axis nodes — ITK & INPP5D/SHIP1 — conditioned on the same negative.
Open the deck →The reusable collapse scorer, the 63-node ranked map, the patient-anchoring layer, and a report — three-notebook reproducible pipeline.
Read the project on GitHub →dashboard.html — interactive, self-contained report (every figure & document embedded)outputs/synthesis.md — plain-language synthesis (with the hardened-result reversal up top)outputs/review_report.md — independent review: data/QC audit, 6-agent literature + methods audit, hardened re-analysisoutputs/mechanism_dossiers/ — per-candidate agentic dossiers (investigate → adversarial verify)notebooks/01–10 — the reproducible pipeline (streams a 16.8 GB matrix without downloading it)th2-druggable-network/deck.html — self-contained deck: a druggable intracellular type-2 network beyond STAT6th2-druggable-network/notebooks/01–03 — byte-range streaming → STAT6/GATA3 collapse scorer → composite network assemblyoutputs/th2_collapse_scorer.py — reusable, documented scorer; anchors self-recover (GATA3 #1, permutation p < 0.001, known-reg 87th pctile)ITK, INPP5D/SHIP1 (existing chemical matter + AD genetics), KDM8, UBA5, DOHH (enzyme handles up in AD skin)outputs/druggable_type2_network.csv — ranked map (tractability + GWAS + patient); outputs/AD_patient_validation.csv — GSE147424 anchoring; outputs/next_degrader_report.md