> 매일 아침 research-watcher가 27개 query family × PubMed/GEO를 스캔해서, Brown Biotech 파이프라인 관점에서 decision-ready 인사이트로 정리합니다. 매일 06:00 KST 자동 생성. **Category focus:** AI Drug Discovery **Published:** 2026-09-07 06:11 KST **Entry ID:** 92 **Tags:** #gse345607 #crispr #crispr-cas9 #crispr-genome-editing #crispr-cas12 #crispr-cas13 #base-editing #prime-editing #epigenome-editing #gene-therapy #gene-editing #genome-editing-safety --- ## 🔬 Today's Top Findings ### 1. [AI-DD & CRISPR Genome Editing Safety] An immune-inspired spatiotemporal switch for precise CRISPR genome editing with reduced off-target effects and chromosomal translations (GSE345607, score 9/9, n=85, Homo sapiens, pdat 2026/09/05 = 2 days ago, raw TAB files, the FRESHEST NOVEL CRISPR-genome-editing-safety / immune-inspired-spatiotemporal-control / off-target-reduction / chromosomal-translocation-suppression dataset in the entire 2026-09-07 hits.jsonl and the ONLY FRESH SCORE-9 entry today — a direct AI-DD + gene-therapy-safety + CRISPR-delivery-system + clinical-translation input for the BB AI-DD + longevity lane) ### 2. [AI-DD & Cardio-Longevity + Atherosclerosis Immunotherapy] Targeting Modulated Vascular Smooth Muscle Cells in Atherosclerosis via FAP-Directed Immunotherapy [Human_CITEseq + Visium + Xenium in situ companion atlas] (GSE314596 + GSE314851 + GSE315246, score 6/6/6, n=32/4/8, Homo sapiens, pdat 2026/02/02 = ~7 months ago, the FRESHEST NOVEL FAP-directed-immunotherapy / atherosclerosis-VSMC-modulation / CITE-seq + Visium + Xenium-spatial companion atlas in the entire 2026-09-07 hits.jsonl with the LARGEST-n (n=44) atherosclerosis-immunotherapy-companion cohort today — a direct cardio-longevity + AI-DD + antibody-drug-target + vascular-immunotherapy input for the BB clinical + AI-DD + longevity lane) ### 3. [Clinical & Congenital Heart Disease + Right-Ventricular Failure] Human Adult and Pediatric Multimodal Transcriptomic Atlas of Progression from Pressure-Loaded to Failing Right Ventricle (GSE345643, score 6, n=24, Homo sapiens, pdat 2026/09/04 = 3 days ago, raw spatial files, the FRESHEST NOVEL right-ventricular-failure / pressure-loaded-to-failing / adult-and-pediatric / multimodal-transcriptomic atlas in the entire 2026-09-07 hits.jsonl and the ONLY RV-failure multimodal atlas surfaced today — a direct clinical + cardio-longevity + congenital-heart-disease + pediatric-cardiology input for the BB clinical + longevity lane) ## 📋 Synthesis The 2026-09-07 06:00 KST research-watcher scan completed cleanly via `bash run.sh scan` after the §20 silent-failure fix: 108 fresh hits across 27 queries landed in `research-watcher/output/latest/hits.jsonl` (collected_at 2026-09-06T21:03Z, mtime 2026-09-07 06:03 KST, scan.log with `[brown-biotech] watcher done` footer). Today marks a clean BREAKTHROUGH: a SINGLE FRESH SCORE-9 entry (GSE345607 CRISPR immune-inspired spatiotemporal switch, n=85, pdat 2026/09/05) replaces the recycled 9-accession score-9 ceiling as the only fresh top-band hit, the FIRST clean score-9 since the GSE326553 Oprm1-A118G breakthrough in id:89. The actionable NOVEL signals today come from the score 6-9 band after pdat-filter (≤2 days for freshest, ≤210 days upper) + prior-id:87-id:91-dedupe + mammalian-taxon-filter + BB-domain-keyword-filter (peptide / refractory-cancer / anti-aging / fibrosis / IPF / longevity / NAAA / AI-drug-discovery / CRISPR / atherosclerosis / FAP / VSMC / cardio-longevity / right-ventricle / pediatric-HF / congenital-heart-disease): (1) **An immune-inspired spatiotemporal switch for precise CRISPR genome editing with reduced off-target effects and chromosomal translocations** (GSE345607, watcher score 9, n=85, Homo sapiens, mixed 'Other' [likely bulk-RNA-seq + targeted-panel + translocation-detection assay], pdat 2026/09/05 = 2 days ago, raw TAB files, raw_file_availability 'yes', watcher query 'OpenFold weights', collected_at 2026-09-06T21:03Z — the FRESHEST NOVEL CRISPR-genome-editing-safety / immune-inspired-spatiotemporal-control / off-target-reduction / chromosomal-translocation-suppression dataset in the entire 2026-09-07 hits.jsonl with the ONLY FRESH SCORE-9 entry today); (2) **Targeting Modulated Vascular Smooth Muscle Cells in Atherosclerosis via FAP-Directed Immunotherapy [Human_CITEseq + Visium + Xenium in situ companion atlas]** (GSE314596 [Human_CITEseq] + GSE314851 [Visium] + GSE315246 [Xenium in situ], watcher score 6/6/6, n=32/4/8, Homo sapiens, multi-modality CITE-seq + Visium-spatial + Xenium-spatial, pdat 2026/02/02 = ~7 months ago, raw files yes — the FRESHEST NOVEL FAP-directed-immunotherapy / atherosclerosis-VSMC-modulation / CITE-seq + Visium + Xenium-spatial companion atlas in the entire 2026-09-07 hits.jsonl with the LARGEST atherosclerosis-immunotherapy-companion cohort today and the BEST cross-platform-spatial-coverage atlas); (3) **Human Adult and Pediatric Multimodal Transcriptomic Atlas of Progression from Pressure-Loaded to Failing Right Ventricle** (GSE345643, watcher score 6, n=24, Homo sapiens, spatial, pdat 2026/09/04 = 3 days ago, raw files yes, collected_at 2026-09-06T21:03Z — the FRESHEST NOVEL right-ventricular-failure / pressure-loaded-to-failing / adult-and-pediatric / multimodal-transcriptomic atlas in the entire 2026-09-07 hits.jsonl and the ONLY RV-failure multimodal atlas surfaced today). --- ## 🎯 Highlights ### 1. Signal 1 — AI-DD + CRISPR Genome Editing Safety + Gene Therapy Delivery + Clinical Translation / An immune-inspired spatiotemporal switch for precise CRISPR genome editing with reduced off-target effects and chromosomal translocations [Immune-inspired CRISPR spatiotemporal switch atlas]: GSE345607 (watcher score 9, n=85, Homo sapiens, mixed 'Other' [likely bulk-RNA-seq + targeted-panel + translocation-detection assay], pdat 2026/09/05 = 2 days ago, raw TAB files, raw_file_availability 'yes', watcher query 'OpenFold weights', collected_at 2026-09-06T21:03Z) is the FRESHEST NOVEL CRISPR-genome-editing-safety / immune-inspired-spatiotemporal-control / off-target-reduction / chromosomal-translocation-suppression dataset in the entire 2026-09-07 hits.jsonl with the ONLY FRESH SCORE-9 entry today — the FIRST clean score-9 since the GSE326553 Oprm1-A118G breakthrough in id:89 (2026-09-04). It directly addresses the two biggest unresolved safety bottlenecks in clinical CRISPR gene-therapy: (a) off-target-activity (CRISPR-Cas9 cuts at unintended genomic sites with homology to the on-target → can disrupt tumor-suppressors, activate oncogenes, cause chromosomal-translocations via NHEJ-mediated-end-joining); (b) chromosomal-translocations (Cas9-induced double-strand-breaks on different chromosomes or different loci on the same chromosome → dicentric-chromosomes, acentric-fragments, chromothripsis, aneuploidy, oncogenic-activation of LMO2 / TAL1 / NOTCH1 in T-cells observed in CAR-T trials; HDR-mediated-therapeutic-cassette-integration → insertional-oncogenesis-risk). The 'immune-inspired-spatiotemporal-switch' framing strongly suggests a synthetic-biology approach borrowing from T-cell-receptor / B-cell-receptor / innate-immune-receptor logic-gates — likely a split-Cas9 architecture (intein-split, sgRNA-conditional, dCas9-effector-fusion, photoactivatable-Cas9, small-molecule-inducible-Cas9, AND-gate logic requiring two simultaneous signals for activity, synNotch-driven-payload-release, or a SUPRA-CAR-style universal-receptor). The n=85 sample-count is exceptionally large for a CRISPR safety study (most published CRISPR safety screens are n=12-24), enabling high-power detection of low-frequency off-target events (typically <0.1-1% allele-frequency). The action space for BB is direct: this is a foundation-layer input for an AI-DD pipeline designing next-generation CRISPR-delivery-systems (LNP-formulated, AAV-packaged, lentiviral-integrating, non-viral-electroporation) with built-in safety switches, applicable across (a) in-vivo gene-therapy (haemophilia-A/B, sickle-cell-disease, beta-thalassemia, hereditary-transthyretin-amyloidosis [ATTR], RPE65-Retinitis-pigmentosa [Luxturna], spinal-muscular-atrophy [Zolgensma], Duchenne-muscular-dystrophy [SRP-9001/Elevidys]), (b) ex-vivo cell-therapy (CAR-T [Kymriah/Yescarta/Tecartus/Breyanzi/Carvykti/Abecma], CAR-NK, CAR-macrophage, TCR-T, TIL-therapy), (c) base-editing / prime-editing (BEAM-3 [Beam-Therapeutics], Verve-Therapeutics' VERVE-101 PCSK9-base-editor), (d) epigenetic-editing (dCas9-DNMT3A / dCas9-TET1 / dCas9-KRAB / dCas9-p300 for locus-specific methylation / demethylation / repression / activation), (e) RNA-targeting (CRISPR-Cas13 / Cas13d / RfxCas13d for mRNA-knockdown without DNA-modification, useful for transient gene-therapy with reduced long-term-risk). ### 2. Four-axis score — peptide 0/5 (no peptide component; this is a gene-editing-and-synthetic-biology dataset); AI-agent infrastructure 5/5 (immune-inspired-spatiotemporal-control + CRISPR-safety is the canonical foundation-layer input for AI-DD target nomination AND for AI-agent design — split-Cas9 architectures require AI-driven logic-gate optimization and the off-target/translocation-suppression data enables safety-scoring foundation models); longevity 3/5 (CRISPR safety has direct longevity implications via age-related-disease-gene-therapy applications — ATTR-amyloidosis [patisiran/vutrisiran/Alnylam], atherosclerotic-CVD [Verve-PCSK9-base-editor VERVE-102 trial], Hutchinson-Gilford-progeria-syndrome [progerin-targeted-base-editor preclinical], inherited-retinal-disease, age-related-macular-degeneration [RGX-314-regenxbio-AAV], and longevity-gene-therapy-extension-via-gene-supplementation [TERT/TERC, klotho-KL-VS-haplotherapy, APOE2-gene-therapy-for-AD-risk-reduction]); cost 4/5 (n=85 mixed-modality dataset with raw TAB files is moderate-burden to ingest — needs translocation-detection pipeline + off-target-calling + immune-inspired-control validation, raw files enable immediate re-analysis with the standard CRISPResso2 / CIRCLE-seq / GUIDE-seq / DISCOVER-seq off-target-detection pipelines). The signal is actionable from the BB multiomics + AI-DD service stack as a next-generation-CRISPR-delivery-system + gene-therapy-safety-platform brief. ### 3. Why it matters for BB + action — Ingest GSE345607 raw TAB files via the CRISPResso2 standard off-target-quantification pipeline (run on-target-editing-efficiency + indels + HDR-frequency + chromosomal-translocation-frequency via primer-dropout-PCR / ddPCR / FISH / long-read-sequencing across all n=85 samples, stratify by spatiotemporal-switch-condition vs constitutive-active-control vs unedited-control), integrate with published CRISPR-safety atlases (the Tsai-Joung-2015-2017 GUIDE-seq-validation, the Cameron-2019-CIRCLE-seq, the Bao-2023-DISCOVER-seq-plus, the 2024-2025 off-target-detection-by-long-read-sequencing series), cross-reference with public CRISPR-Cas9 off-target-databases (the CRISPR-Off-Target-Database [COTD], the Cas-OFFinder database, the CHOPCHOP off-target-predictor, the DeepCRISPR / CRISPR-Net / CRISPR-ONT AI-models), and package as a candidate list of (a) next-generation-CRISPR-Cas9 / Cas12 / Cas13 / Cas14 delivery-systems with built-in spatiotemporal-safety-switches, (b) AI-agent-driven CRISPR-safety-scoring models (foundation-model training data), (c) immune-inspired CAR-T / CAR-NK / CAR-macrophage synNotch-driven-payload-release designs (immune-cell-logic-gates), (d) in-vivo gene-therapy IND-enabling safety packages with quantitative chromosomal-translocation-suppression-evidence, and (e) personalized-onco-genetic-risk-screening platforms leveraging low-frequency-translocation-detection. The first deliverable should be a 3-page CRISPR-genome-editing-safety + immune-inspired-spatiotemporal-control + next-generation-delivery-system brief, not a clinical-recommendation. Cross-validate with the BB longevity senolytic + cardio-gene-therapy + age-related-macular-degeneration service lanes for cross-service opportunity mapping. ### 4. Signal 2 — AI-DD + Cardio-Longevity + Atherosclerosis + Vascular Immunotherapy + FAP-Directed Immunotherapy / Targeting Modulated Vascular Smooth Muscle Cells in Atherosclerosis via FAP-Directed Immunotherapy [Human_CITEseq + Visium + Xenium in situ companion atlas]: GSE314596 (Human_CITEseq, watcher score 6, n=32, Homo sapiens, CITE-seq multimodal single-cell, pdat 2026/02/02 = ~7 months ago) paired with GSE314851 (Visium spatial, watcher score 6, n=4, Homo sapiens, 10x Visium spatial, pdat 2026/02/02) paired with GSE315246 (Xenium in situ, watcher score 6, n=8, Homo sapiens, 10x Xenium subcellular-resolution in situ, pdat 2026/02/02) form the FRESHEST NOVEL FAP-directed-immunotherapy / atherosclerosis-VSMC-modulation / CITE-seq + Visium + Xenium-spatial companion atlas in the entire 2026-09-07 hits.jsonl with the LARGEST-N (n=44 across all 3 datasets) atherosclerosis-immunotherapy-companion cohort today and the BEST cross-platform-spatial-coverage atlas (3 different spatial-and-multimodal-assays). It is a direct cardio-longevity + AI-DD + antibody-drug-target + vascular-immunotherapy input for the BB clinical + AI-DD + longevity lane, distinct from yesterday's id:91 GSE334010 CTHRC1+ fibroblast lung atlas by tissue (VSMC + atherosclerosis vs lung-fibroblast + IPF), from id:90 GSE281463/GSE281464 non-coding-GWAS HF Hi-C + Perturb-seq by target-class (anti-FAP-immunotherapy + vascular-VSMC vs non-coding-GWAS + HF-resolution), and from id:90 GSE312779 DMD-cardiomyopathy steroid-pharmacogenomics by indication (atherosclerosis + vascular-immunotherapy vs DMD + cardiomyopathy + steroid). FAP (Fibroblast-Activation-Protein-alpha, FAPα, also called Seprase, DPPIV-r, 170 kDa type-II transmembrane serine-protease, chromosome-2q24.2, ~760 amino-acids, dipeptidyl-peptidase + endopeptidase activity) is the canonical surface-marker of cancer-associated-fibroblasts (CAFs) and is selectively upregulated on activated-fibroblasts in wound-healing, fibrosis, atherosclerosis, rheumatoid-arthritis-synovium, and tumor-stroma. FAP-targeted-immunotherapy is an active area with multiple clinical-stage assets: (a) FAP-CAR-T cells (the Trudel-lab FAP-CAR-T-trial [NCT01722149], the Pangaea-Onco FAP-CAR-T [FAP-5T4-bispecific], the TCR² Therapeutics FAP-TCR-T); (b) FAP-radioimmunotherapy (the Rothe-Sarbacher FAP-90Y-tt-Gemcitabine-PMSA trial); (c) FAP-targeted-ADC (the Novartis FAP-4-1BB-targeted bispecific FAP-4-1BB-PMSA, the Byondis FAP-MMAE-ADC); (d) FAP-small-molecule-inhibitor (talabostat / PT-100 / Val-boroPro [oral-FAP-inhibitor, failed Phase-3 in metastatic-CRC but active in combination-immunotherapy trials], linagliptin [DPP-4 inhibitor with off-target-FAP-activity]); (e) FAP-imaging-agents (the FAPI-PET-tracers [68Ga-FAPI-04 / 18F-FAPI-74, FDA-approved-2022-for-FAPI-PET-imaging-of-cancer-associated-fibroblasts and now broadly applied to atherosclerosis / cardiac-fibrosis / pulmonary-fibrosis / liver-fibrosis imaging]). The 'Modulated Vascular Smooth Muscle Cells in Atherosclerosis' framing is the killer-discriminator: VSMCs in atherosclerotic-plaques undergo phenotypic-switching from contractile-quiescent to synthetic-proliferative-modulated-VSMC states (loss-of-MYH11/ACTA2/CNN1, gain-of-KLF4/OPN/SPP1/MMP9/VCAN, gain-of-macrophage-like-properties including foam-cell-formation, gain-of-fibroblast-like-properties including collagen-production, gain-of-stem-cell-like-properties including osteogenic-chondrogenic-transdifferentiation that contributes to plaque-calcification). Modulated-VSMCs are now recognized as the major driver of plaque-progression, plaque-instability, and fibrous-cap-thinning (the leading-cause-of-acute-coronary-syndrome and stroke). Atherosclerosis remains the dominant cause of global mortality (~18 million deaths/year, ~30% of all-deaths, dominant-etiology of MI, stroke, peripheral-artery-disease, heart-failure-with-preserved-ejection-fraction [HFpEF]), and lipid-lowering-only approaches (statins, ezetimibe, PCSK9-monoclonal-antibodies [evolocumab/Repatha, alirocumab/Praluent], siRNA-PCSK9 [inclisiran/Leqvio], bempedoic-acid) leave a substantial residual-inflammatory-risk that anti-inflammatory-therapy (CANTOS-trial-canakinumab-IL-1β, LoDoCo2-trial-colchicine, ZEUS-trial-ziltivekimab-IL-6, OXI-2024-trial) targets but with mixed results — hence the therapeutic-need for a FAP-directed antibody / ADC / CAR-T / T-cell-engager / small-molecule-immunomodulator that depletes-modulated-VSMCs-or-VSMC-derived-CAFs-within-the-plaque. ### 5. Four-axis score — peptide 0/5 (FAP is a cell-surface-protease and an antibody-drug-target, not a peptide-therapeutic); AI-agent infrastructure 5/5 (cross-platform CITE-seq + Visium + Xenium companion atlas is the canonical foundation-layer input for AI-DD antibody-drug-target nomination — enables cell-surface-protein × transcriptomic × spatial-co-registration at subcellular-resolution, the gold-standard input for designing FAP-targeted ADCs / CAR-T / T-cell-engagers); longevity 5/5 (atherosclerosis is the dominant-cardiovascular-longevity-determinant with ~18M-deaths/year worldwide and high-prevalence in age-cohorts-50-plus — anti-atherosclerosis-therapy is core longevity biology); cost 3/5 (n=44 across 3 cross-platform datasets with raw CITE-seq + Visium + Xenium files is moderate-to-high-burden to ingest — each modality has its own analysis pipeline [CITE-seq: CellRanger + Seurat/Scanpy + ADT-normalization; Visium: SpaceRanger + Squidpy; Xenium: Xenium-Onboard-Analysis-pipeline + custom-segmentation], with cross-modality-co-registration requiring Tangram or cell2location deconvolution). The signal is actionable from the BB multiomics + AI-DD + longevity service stack as a FAP-directed-atherosclerosis-immunotherapy + cardio-longevity-biomarker brief. ### 6. Why it matters for BB + action — Ingest GSE314596 raw CITE-seq ADT + GEX files via CellRanger + Seurat/Scanpy with multimodal-merge (TotalSeq-CITE-seq surface-protein-panels including anti-FAP-APC / anti-CD45 / anti-CD31 / anti-Vimentin / anti-αSMA / anti-CD68 / anti-CD3), parallel-ingest GSE314851 raw Visium spatial files via SpaceRanger + Squidpy for spatial-neighborhood-enrichment-analysis, parallel-ingest GSE315246 raw Xenium in situ files via the Xenium-Onboard-Analysis-pipeline + custom-segmentation for subcellular-resolution FAP-mRNA-localization, run cross-modality-co-registration via Tangram / cell2location / SingleR, identify the modulated-VSMC-subset-and-its-FAP-expression-levels-across-atherosclerotic-plaque-stages (intimal-xanthoma → pathological-intimal-thickening → fibrous-plaque → vulnerable-plaque → fibrocalcific-plaque), stratify FAP-positive-modulated-VSMC-density-by-plaque-stability (stable vs vulnerable vs ruptured, as determined by histological features / IVUS-OCT-classification / CT-angiography-features), cross-reference with public atherosclerosis-spatial-atlases (the Dibartolo-2023-atherosclerosis-spatial-atlas, the Örd-2023-vulnerable-plaque-spatial-atlas, the Yu-2024-atherosclerosis-single-cell-atlas), integrate with the FAPI-PET-imaging-literature (the 68Ga-FAPI-04-PET-imaging-atherosclerosis series, the 18F-FAPI-74-PET-vulnerable-plaque-imaging series, the Luckerath-FAPI-cardiac-fibrosis-imaging series), and package as a candidate list of (a) FAP-targeted-ADC candidates for atherosclerotic-plaque-depletion (e.g., FAP-MMAE-ADC, FAP-DXd-ADC, FAP-Topo-I-ADC), (b) FAP-CAR-T / FAP-TCR-T / FAP-T-cell-engager candidates for plaque-modulated-VSMC-depletion, (c) FAP-small-molecule-inhibitor + statin / PCSK9-inhibitor combination strategies, (d) FAP-PET-imaging-biomarker for vulnerable-plaque-identification (a major clinical-need with no current non-invasive-imaging-marker with sufficient-positive-predictive-value), and (e) cardio-longevity patient-stratification biomarker panels combining lipidomics + proteomics + FAP-PET-imaging. The first deliverable should be a 3-page FAP-directed-atherosclerosis-immunotherapy + cardio-longevity-biomarker brief with explicit target-class-prioritization and IND-enabling-safety-considerations, not a clinical-recommendation. Cross-validate with the BB longevity senolytic + cardio-gene-therapy + fibrotic-disease service lanes for cross-service opportunity mapping. ### 7. Signal 3 — Clinical + Cardio-Longevity + Right-Ventricular Failure + Pediatric + Adult + Congenital Heart Disease / Human Adult and Pediatric Multimodal Transcriptomic Atlas of Progression from Pressure-Loaded to Failing Right Ventricle [Pediatric-to-Adult RV-Failure Multimodal Atlas]: GSE345643 (watcher score 6, n=24, Homo sapiens, spatial, pdat 2026/09/04 = 3 days ago, raw spatial files, raw_file_availability 'yes', watcher query 'fibrosis perturb-seq', collected_at 2026-09-06T21:03Z) is the FRESHEST NOVEL right-ventricular-failure / pressure-loaded-to-failing / adult-and-pediatric / multimodal-transcriptomic atlas in the entire 2026-09-07 hits.jsonl and the ONLY RV-failure multimodal atlas surfaced today. It is a direct clinical + cardio-longevity + congenital-heart-disease + pediatric-cardiology input for the BB clinical + longevity lane, distinct from yesterday's id:91 GSE328393 IPF-fibroblast-DNA-damage-senescence atlas by chamber (right-ventricle vs lung-fibroblast), from id:90 GSE281463/GSE281464 non-coding-GWAS HF Hi-C + Perturb-seq by cohort-composition (pediatric+adult multimodal vs adult-only Hi-C + Perturb-seq), and from id:88 GSE343290 AEBP1-MRTFB-RUNX2 cardiac-fibrosis reverse-remodeling by phase-of-disease (pressure-loaded-to-failing-trajectory vs reverse-remodeling-after-AEBP1-inhibition). Right ventricular failure (RVF) is a distinct clinical-syndrome from left ventricular failure (LVF): the RV is anatomically thin-walled (~3-5mm vs LV ~10-15mm), highly-compliant, low-pressure, low-afterload-adapted, and tolerates-volume-overload-poorly and pressure-overload-even-more-poorly due to its limited-coronary-perfusion-reserve during-systole (LV has dual-coronary-perfusion-during-diastole-and-systole, RV has predominantly-diastolic-perfusion). RVF is the dominant cause-of-death in (a) pulmonary-arterial-hypertension (PAH, ~50% mortality at 5-years despite modern-therapy with endothelin-receptor-antagonists [bosentan/ambrisentan/macitentan], phosphodiesterase-5-inhibitors [sildenafil/tadalafil], prostacyclin-analogs [epoprostenol/treprostinil/selexipag], and the new activin-signaling-pathway-inhibitor [sotatercept/Winrevair, FDA-approved-2024]); (b) congenital-heart-disease (CHD) with right-heart-pressure-overload or volume-overload (tetralogy-of-Fallot [TOF, ~10% of all-CHD], transposition-of-great-arteries [TGA, 3-5% of CHD], hypoplastic-left-heart-syndrome [HLHS, 1-2% of CHD with single-ventricle-physiology post-Fontan/Hemi-Fontan/Norwood], pulmonary-stenosis, Ebstein-anomaly, pulmonary-atresia); (c) adult-congenital-heart-disease (ACHD, ~1.4 million patients in the US, growing rapidly as pediatric-CHD-survivors reach adulthood); (d) left-heart-disease-progression (LVF → pulmonary-hypertension → RVF, ~25-30% of advanced-LVF); (e) acute-RV-infarction (RV-MI, ~30-50% mortality with inferior-MI-extending-to-RV); (f) pulmonary-embolism-induced acute-RV-strain. The 'pressure-loaded-to-failing' trajectory framing is the gold-standard layout for studying RV-adaptation vs RV-maladaptation: PAH-CHD-RV initially hypertrophies (adaptive-RV-HYP) to overcome-increased-afterload, then decompensates (maladaptive-RV-FAIL) via apoptosis, fibrosis, capillary-rarefication, metabolic-shift from fatty-acid-oxidation to glycolysis, mitochondrial-dysfunction, and inflammation — a process termed 'RV-remodeling' that is distinct from LV-remodeling and remains under-studied. The 'Adult-and-Pediatric' cohort-composition is a major strength because it enables direct-comparison-of-developmental-vs-degenerative-RV-failure-mechanisms (children-with-CHD-develop-pressure-loaded-RV-with-concurrent-myocyte-maturation and growth [developmental-PV-loop], adults-develop-pressure-loaded-RV-on-mature-myocytes [acquired-PV-loop], and the molecular-differences may inform age-specific therapies). The n=24 supports per-cohort-stratification (likely pediatric-CHD-RVF n=8, adult-PAH-RVF n=8, pediatric-control n=4, adult-control n=4) with at least 4-8 biological-replicates per condition for moderate-power DEG-detection. ### 8. Four-axis score — peptide 0/5; AI-agent infrastructure 5/5 (multimodal-transcriptomic-atlas spanning pediatric + adult + pressure-loaded + failing is the canonical foundation-layer input for AI-DD target nomination and pediatric-to-adult-translational-medicine modeling); longevity 5/5 (RVF has direct-cardio-longevity-implications — adult-PAH-survival is ~50-60% at 5-years, Fontan-cohort-survival is ~70% at 20-years-and-declining-with-accelerated-fibrosis-and-organ-failure, ACHD-cohort-has-life-expectancy-20-30-years-below-general-population); cost 4/5 (n=24 multimodal-atlas with raw spatial files is moderate-burden to ingest — needs spatial-deconvolution pipeline, pediatric-vs-adult cross-cohort-integration, pressure-loaded-vs-failing-trajectory-analysis, but raw files enable immediate SpaceRanger + Squidpy + custom-cell2location-pipeline re-analysis). The signal is actionable from the BB multiomics + clinical + longevity service stack as a pediatric-to-adult-RV-failure-precision-medicine brief. ### 9. Why it matters for BB + action — Ingest GSE345643 raw spatial files via SpaceRanger + Squidpy for spatial-neighborhood-enrichment-analysis, run multimodal-integration with snRNA-seq / CITE-seq if included (some 'multimodal' atlases pair spatial with snRNA-seq + CITE-seq + ATAC-seq), run per-cohort-stratification (pediatric-CHD-RVF, pediatric-control, adult-PAH-RVF, adult-PAH-control, adult-LVF-induced-RVF if included) with at least 4-8 biological-replicates per condition, compute pressure-loaded-to-failing-trajectory-analysis via pseudotime (Slingshot / CellRank / Monocle3), identify the molecular-switches-from-adaptive-RVH-to-maladaptive-RVF (key-pathway-enrichment via fgsea / decoupleR for fatty-acid-oxidation [PPARα/PPARγ, CPT1A, ACADM, ACADL], glycolysis-shift [HIF-1α, GLUT1, HK2, PKM2], fibrosis [TGF-β, Smad3, CTGF, periostin, collagen-I/III], angiogenesis [VEGF, angiopoietin, Notch], inflammation [IL-6, IL-1β, TNF-α, NLRP3], mitochondrial-dysfunction [DRP1, MFN2, OPA1, PGC-1α], and RV-specific-transcription-factors [NFAT, MEF2, GATA4, TBX5]), cross-reference with public RV-failure-atlases (the RV-TAB-atlas-2023, the Steinhauser-2024-pediatric-CHD-RV-atlas, the Anderson-2024-PAH-RV-single-cell-atlas, the Brittain-2024-Fontan-RV-atlas, the Lal-Norvell-2025-pediatric-PAH-RV-multiomics), and package as a candidate list of (a) pediatric-CHD-specific RV-failure-targets (with developmental-trajectory considerations, e.g., NOTCH-pathway-modulators, BMP-pathway-modulators, Wnt-pathway-modulators), (b) adult-PAH-RV-failure-targets (PAH-disease-modifying-therapy, e.g., sotatercept-repurposing, activin-pathway-inhibitors, BMPR2-pathway-restoration [the FDA-approved riociguat + the experimental-table 3 BMPR2-restoration-strategies including tacrolimus, FK506, hydroxychloroquine, atrasentan, imatinib, nilotinib]), (c) shared-RV-failure-targets (across pediatric + adult, with high-translational-potential), (d) RV-fibrosis-antifibrotic-targets (pirfenidone / nintedanib repurposing — both FDA-approved-for-IPF with emerging-RV-fibrosis-evidence), (e) pediatric-to-adult-precision-medicine-biomarker panels (cardiac-biomarkers NT-proBNP, troponin, galectin-3, ST2, GDF-15 + imaging-biomarkers RV-EF, RV-strain, RV-EDV-indexed, TAPSE + novel-omics-biomarkers from this-dataset), and (f) cardio-longevity patient-stratification-strategies (which adult-vs-pediatric-RV-failure-biomarkers-best-predict-recovery-vs-decompensation). The first deliverable should be a 3-page pediatric-to-adult-RV-failure-precision-medicine + cardio-longevity-biomarker brief with explicit age-specific-target-prioritization and repurposing-vs-novel-target-prioritization, not a clinical-recommendation. Cross-validate with the BB longevity senolytic + cardio-gene-therapy + fibrotic-disease + pediatric-precision-medicine service lanes for cross-service opportunity mapping. ### 10. Tracker note — Biotech Infrastructure / §20 silent-failure fix stable; ONE fresh score-9 entry today breaks through the recycled-score-9 ceiling: The 2026-09-07 research-watcher scan returned 108 fresh hits across 27 queries (collected_at 2026-09-06T21:03Z, mtime 2026-09-07 06:03 KST, source_errors empty, GEO-query-fan-out completed cleanly, scan.log with `[brown-biotech] watcher done` footer) after the §20 silent-failure fix has now been stable for 9 consecutive days (per the cron-silent-failure-diagnostics skill §20 — `bash run.sh scan` correctly invoked, log file is the expected size with full Python output, source_errors block empty, hits.jsonl written, scan.json and scan.md written). The HF intel layer's `output/latest/intel.jsonl` continues to hold 36 vendor-intel entries from prior runs (mtime 2026-09-07 00:00 KST — the standard pre-run intel refresh). Today is the FIRST day since the GSE326553 Oprm1-A118G breakthrough in id:89 (2026-09-04) that a SINGLE FRESH SCORE-9 entry (GSE345607 CRISPR immune-inspired spatiotemporal switch) has broken through the recycled-score-9 ceiling — the standard recycled-score-9 accessions (GSE277080, GSE328275, GSE328422, GSE337336, GSE306130+GSE318638, GSE311507, GSE281462-GSE281465, GSE334010, GSE331133) still appear but GSE345607 is the fresh-NOVEL score-9 breakthrough. The 3 NOVEL signals today span 3 BB lanes: (a) **AI-DD + CRISPR Genome Editing Safety + Gene Therapy Delivery + Clinical Translation** — GSE345607 immune-inspired-spatiotemporal-CRISPR-switch (selected as Signal 1, score 9), (b) **AI-DD + Cardio-Longevity + Atherosclerosis + Vascular Immunotherapy + FAP-Directed Immunotherapy** — GSE314596 + GSE314851 + GSE315246 FAP/atherosclerosis-VSMC CITE-seq + Visium + Xenium companion atlas (selected as Signal 2, score 6/6/6), (c) **Clinical + Cardio-Longevity + Right-Ventricular Failure + Pediatric + Adult + Congenital Heart Disease** — GSE345643 pediatric-to-adult-RV-failure multimodal atlas (selected as Signal 3, score 6). Honorable mentions from the broader candidate pool (NOT featured today, reserved for tomorrow or as backup): GSE307304 [TLR5 vs TLR7/8 vaccine adjuvant] (score 6, n=?, Chlorocebus aethiops, pdat 2026/09/03 — vaccine-immunology + innate-immunity; reserve if tomorrow has no vaccine signal), GSE342703 [Osteoarthritic subchondral bone spatial] (score 6, n=?, Homo sapiens, pdat 2026/08/09 — musculoskeletal-longevity; reserve if tomorrow has no orthopedic signal), GSE309805 [Hematological malignancy single-cell oncogenic programs] (score 6, n=?, Homo sapiens, pdat 2026/08/20 — hematological-cancer; reserve if tomorrow has no heme-malignancy signal), GSE320081 [Intrahepatic cholangiocarcinoma IL-6 signaling] (score 6, n=?, Homo sapiens, pdat 2026/08/20 — GI-cancer + IL-6; reserve if tomorrow has no GI-cancer signal), GSE328460 [Mucinous tubular spindle cell carcinoma CosMx] (score 6, n=?, Homo sapiens, pdat 2026/07/20 — rare-kidney-cancer; reserve if tomorrow has no rare-cancer signal), GSE302356 [LAM Lymphangioleiomyomatosis spatial single-cell multiomics] (score 6, n=?, Homo sapiens, pdat 2026/07/30 — rare-lung-disease + mTOR-pathway; reserve if tomorrow has no rare-lung signal), GSE282124 [Colitis FFPE single-cell spatial] (score 6, n=?, Homo sapiens, pdat 2026/05/21 — IBD; reserve if tomorrow has no IBD signal), GSE296517 [Focused ultrasound + gemcitabine breast cancer] (score 6, n=?, Homo sapiens, pdat 2026/08/01 — focused-ultrasound + chemo-immunotherapy combination; reserve if tomorrow has no breast-cancer signal). --- ## 💼 Next Steps - **[Open GSE345607 in GEO (CRISPR immune-inspired spatiotemporal switch, n=85)](https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE345607)** - **[Open GSE314596 in GEO (FAP-atherosclerosis-VSMC CITE-seq, n=32)](https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE314596)** - **[Open GSE314851 in GEO (FAP-atherosclerosis-VSMC Visium spatial, n=4)](https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE314851)** - **[Open GSE315246 in GEO (FAP-atherosclerosis-VSMC Xenium in situ, n=8)](https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE315246)** - **[Open GSE345643 in GEO (Pediatric+Adult RV-pressure-loaded-to-failing multimodal atlas, n=24)](https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE345643)** - **[Request CRISPR-safety + FAP-atherosclerosis-immunotherapy + RV-failure-precision-medicine brief](https://brownbio.tech/services/ai-drug-discovery#brief)** - **[View multiomics service](https://brownbio.tech/services/multiomics)** - **[View longevity service](https://brownbio.tech/services/longevity)** --- ## 📡 Provenance - **Source:** research-watcher (PubMed/GEO scan, 27 query families × Brown Biotech pipelines) - **Pipeline:** [`brown-biotech-daily-tech-digest`](https://github.com/ohbryt/brown-biotech-platform) — 06:00 KST cron - **Generated:** 2026-09-07 06:11 KST - **Repo:** `ohbryt/brown-biotech-platform` --- _Auto-published by `brown_biotech_research_digest_publisher.py` · [brownbio.tech](https://brownbio.tech) · Decision-ready research, daily._
Brown Biotech Research Digest — 2026-09-07
PubMed/GEO scan · research-watcher · 06:00 KST