DQIS — Register of Scientific Objections v31

Supplementary document to the DQIS Consolidated Framework v30. 0 (Zenodo DOI: 10. 5281/zenodo. 19855263). Register of scientific objections identified during preparation for academic validation of the DQIS framework — Distributed Quorum-Based Independent Immune Surveillance. 34 objections addressed across mathematical, biological, engineering, clinical, empirical, and structural categories. Status distribution (v30. 0, May 2026). 12 RESOLVED · 2 LOW · 14 MEDIUM open · 4 HIGH open (O7, O8, O14, O27). O33 RESOLVED via Design B. O34 MEDIUM OPEN (Channel Paradox — primary resolution via Adaptive k=1/N + GateG). O28 maintained MEDIUM-HIGH. O1 — pᵢ empirical grounding: T-γ* and T-δ on target; T-β pᵢ=0. 004 median (AND-gate, Monte Carlo) ; T-α v3. 0 pᵢ=0. 0003–0. 002. MEDIUM. O2 — Channel independence: empirically validated GSE72056; inter-M/E LTD≈0; θ=0. 17 canonical; balanced quorum eliminates mTOR hub. MEDIUM. O3 — Population-level selective pressure: O3-A mitigated by Pattern Drift Sensor; O3-B open as infrastructure requirement. MEDIUM. O4 — T-ε reachability pᵢ=0. 01: histotype-dependent; on target for HER2+/EGFR-amplified. MEDIUM. O5 — DQIS-J paediatric procedures: RESOLVED — single-dose architecture; self-sustaining threshold effect. LOW. O6 — T-γ* temporal criterion: RESOLVED — NFAT-like integrator; 3–4 brief contacts to threshold. O7 — CHIP clonal drift: OPEN HIGH — pre-infusion conditioning + cfDNA barcoding + selective iC9 reset managed; organoid long-term validation required. O8 — Epigenetic transgene silencing: OPEN HIGH — SFFV+AAVS1+computationally optimal insulator; T-cell organoid validation required before Phase I. O9 — Pquorum in TME: RESOLVED — transit model; Pquorum ≥99. 93% all tumour phases; detection threshold N~3×10³ cells. O10 — Bulk vs single-cell correlations: RESOLVED — ρₛc ≤ ρbulk for inter-group pairs; θ=0. 17 upper bound; k=3 Monte Carlo correct reference. O11 — Ci-VSP immunogenicity: managed Phase 0 — H→Q mutation recommended before Phase I. MEDIUM. O12 — CDIC dormant cells: managed — T-δ and T-ε cover structurally; pregnancy contraindication. MEDIUM. O13 — HLA silencing and NK missing self: RESOLVED — HLA-E in construct; pool 6. 7× above threshold. LOW. O14 — Penn Medicine data transferability to children: OPEN HIGH — Nₛs 5–9× above threshold computationally; preclinical mouse model required before Phase I. O15 — Brain reporter gap: RESOLVED — Sₜm + hepatic S₂ cascade; blue urine 11–24h from brain. O16 — T-α self-activation: RESOLVED MATHEMATICALLY — triple-AND-gate v3. 0; pᵢ=0. 0003–0. 002. O17 — Tonic signalling exhaustion: RESOLVED MATHEMATICALLY — PAA ε (10y) =0. 921; doxycycline+tet-on analytically proven. O18 — θ cold tumours: RESOLVED WITH DATA — GBM θ=0. 199 (reclassified hot) ; PDAC θ=1. 214 (confirmed cold, IPS module resolves). O19 — Magenta Therapeutics closure: RESOLVED — replaced with Jasper Therapeutics (briquilimab). O20 — Data access bottleneck: RESOLVED — datasets downloaded and analysed May 2026. O21 — Normal pancreas intrinsically cold: RESOLVED — biological explanation; IPS discriminates where θ cannot. O22 — IPS module PDAC detection: RESOLVED — 15. 5× penetrance signal; P (false alarm) =0. 0003. O23 — Bone marrow self-attack (HSC/h-MSC overlap): RESOLVED — TASE dual-mode CXCL12-responsive synNotch (Mode A peripheral / Mode B bone marrow with stemness exclusion). O24 — Piezo1 Goldilocks chronic exhaustion: OPEN MEDIUM — 5 mitigation pathways; primary track forced turnover (degron tag) 70–80% success. O25 — NKG2D-CAR documented in vivo toxicity: OPEN MEDIUM — primary track AND-gate + SASP discriminator; toxicity 0. 10): OPEN HIGH — GateG (Ki-67, Phase 2+) primary resolution; Sequential Verification (Phase 0/1) interim resolution. STRATEGIC: GateG resolution unlocks Adaptive Quorum k=1/N for ~70+ tumour types, upgrading coverage from ~68% to ~91% Class A/A-B/B. O30 — T-ε ex vivo fratricide: RESOLVED BY ARCHITECTURE — separate GMP sub-pool expansion. LOW. O31 — DMI flag degradation in desmoplastic TME: OPEN MEDIUM — PDAC tₕalf 8h vs 36h physiological; poly-cationic 4xKKKK extension restores Pquorum. O32 — Sequential Verification ordered quorum: MEDIUM (resolved protocol level Phase 0/1) — T-γ* as conditional investigative trigger; CCL22-mut recruits T-δ within 90 min; P (FP melanocytes) reduced 3. 3×. O33 — Inter-group correlation T-α/T-δ ACLY causal link: RESOLVED via Design B — θME was incorrectly stated as 0. 05–0. 15; correct value 0. 40–0. 50 via ACLY→acetyl-CoA→HAT (Shi et al. 2019, TCGA n=5, 726). T-δ v2. 0 CIN sensor (cGAS-STING) achieves θME ~0. 10. O34 — Channel Paradox: adding channels with current design reduces security below Phase 0: MEDIUM OPEN — with θME=0. 40 + T-α/T-β τ=0. 31 (mTOR hub), DQIS-5 k=3 gives ~24× vs Phase 0 ~30–75×. Primary resolution: Adaptive Quorum k=1/N + GateG (Phase 2+, ~1, 286–1, 800×). Standard resolution: Design B k=2 (~774×, O29 required). Long-term resolution: Opt-B T-TRT replacing T-β (~7, 500×, Phase 3+). O35 — T-δ v2. 0 extracellular detection mechanism: MEDIUM OPEN — cGAS-STING is intracellular; two literature-validated detection paths documented: (1) STING ectodomain receptor for extracellular cGAMP exported via LRRC8A: C/VRAC (Lahey et al. 2020; Wang et al. J Immunol 2024) ; (2) MICA/MICB via ATM/ATR DDR pathway (MedComm 2024). Key experiment: extracellular cGAMP in CIN model, EUR 20–40k, 8–12 weeks. Read alongside Consolidated v31 and Addendum I v16. Not a peer-reviewed publication. Prior art deposit — CC BY 4. 0. Contact: dqis. research@proton. meRelated documents: - DQIS Consolidated Framework (main document): https: //zenodo. org/records/19877553 - Addendum I — Temporal Stratification of Tail Dependence Risk: https: //zenodo. org/records/19877810