h02 log

2026-04-23

AAV-LNP stack model confirms Piezo S-tier independent of AAV path → STRC AAV-LNP Stack PKPD
Parameter provenance audit complete: 3 phantom cites caught (K_D A666-prestin = 10 nM; ETA_POLY = 0.7; d31 Phase1/Phase2 inconsistency). 9 additional ⚠ constants. New topic files: piezoelectric-materials, tectorial-membrane. Full audit at /tmp/strc-lit-params-h02.md. New finding: TM stiffness (24–210 kPa) vs. PVDF-TrFE (3 GPa) mismatch not currently modeled — potential hypothesis-level mechanical flaw.
Post-audit fix applied: scripts pinned phantoms (A666, ETA_POLY, SELECT_S), d31 reconciled to −12 pC/N (was silent 2× split). Phase 1 baseline no longer passes 60 dB. TM mismatch 10⁵× flagged in output JSON. Tier S → B. Mech 3→2, Deliv 2→1. → STRC h02 Parameter Provenance Audit 2026-04-23

Phases 1-3 complete; delivery model 92% audiogram coverage → STRC Piezo Delivery Feasibility OHC Targeting
Initial assignment: S-tier, Mech 3, Deliv 2, Misha 5 → STRC Hypothesis Ranking

#9 Hydrogel: A held, Mech 4 held, Deliv 3 held. Phase 4i Kd × Kd 5×5 sensitivity sweep on therapeutic window: f ≥ 0.3 reachable on 80% of plausible grid (PASS 56% single-dose ≤ 5 mg + MARGINAL 24% at 5-20 mg); FAIL 20% only at WH2 Kd ≥ 1 mM (Tβ4 analog floor) where G-actin toxicity ceiling hits before f=0.3 achievable. Strategic reorder: WH2×F-actin Kd dominates, TMEM145 Kd secondary. Phase 2c WH2 bundling (HEK293 GFP-actin confocal) now wet-lab gate #1; TMEM145 SPR/BLI → #2 (ipSAE already places in operable band). Verdict A_hold_multi_dose_ok — S promotion still requires WH2 Kd narrowing. → STRC h09 Phase 4i Kd Sensitivity Sweep 2026-04-23
#2 Piezo post-audit fix: S → B. Mech 3→2, Deliv 2→1. d31 reconciled to −12 pC/N (was silent 2× split); A666 ligand phantom (no Zou 2015); ETA_POLY, SELECT_S phantom; TM stiffness mismatch 10⁵× flagged in output. Phase 1 baseline no longer passes 60 dB post-reconcile. → STRC h02 Parameter Provenance Audit 2026-04-23

Note created. Initial assignment 24 hypotheses. S: {#1 Pharmacochaperone, #2 Piezo, #3 Mini-STRC, #4 Strategy B}. Killed: {OTOA chimera, ZP prion, protein replacement}. Paused: {Sonogenetics, Recombinases}.