{
  "study_series_id": "STUDY-SERIES-SARCOMERIC-MEGAPROTEINS-TITIN-OBSCURIN-034",
  "validation_set_id": "VAL-SET-034-SARCOMERIC-MEGAPROTEINS-TITIN-OBSCURIN-28COHORT",
  "title": "Anchor-Segmented Sub-Domain Partitioning of 35,000-Residue Titin, Obscurin, and Nebulin Megaproteins Resolves Bilaterian Sarcomere Evolution and Cardiomyopathy Truncation Hotspots",
  "created_at": "2026-11-04T03:50:00Z",
  "prior_beakers": 5,
  "posterior_beakers": 5,
  "computational_scaling_benchmark": {
    "single_locus_max_cds_bp": 107976,
    "single_locus_max_aa": 35991,
    "single_locus_exons": 363,
    "tandem_ig_fn3_domains_per_chain": 244,
    "standard_gotoh_dp_cells_per_pair": 1295352081,
    "unsegmented_mafft_wall_time_sec": 1482.4,
    "runie_anchor_segmented_wall_time_sec": 46.6,
    "speedup_factor": 31.8,
    "register_shift_errors_eliminated_pct": 100.0
  },
  "tier_1_exploratory_telemetry": {
    "stage": "Tier 1: Exploratory",
    "cohorts_evaluated": 12,
    "taxa_evaluated": 28,
    "total_sequence_span_mb": 1.42,
    "posterior_z_score": 4.46,
    "beakers_earned": 4,
    "key_findings": [
      "Standard whole-protein aligners take >24 minutes across 35,991-aa Titin chains and suffer from 244-domain Ig/FN3 tandem register shifts plus PEVK (2,174-aa Pro-Glu-Val-Lys) low-complexity compositional drift (RCFV = 0.176).",
      "9-mer anchor-segmented Gotoh + Plan-7 HMM domain indexing achieves a 31.8x speedup (46.6 s vs. 1,482.4 s) and isolates the Z-disc Z1-Z2 Telethonin clasp (PDB:2F8V), I-band I27 force sensor (PDB:1TIT), and M-band Titin Kinase + autoregulatory tail (PDB:1TKI)."
    ]
  },
  "tier_2_blind_validation_telemetry": {
    "stage": "Tier 2: Validation (Dual-Pass Blinded SHA-256 Extrapolation -> Unblinding Audit)",
    "cohorts_evaluated": 28,
    "dev_cohorts": 14,
    "reserve_cohorts": 14,
    "total_sequence_span_mb": 3.48,
    "clean_cohorts_recovered": "24/24 (100.0% biotype, exon-phase & clade concordance)",
    "mean_clean_d_ctx_sd": 0.034,
    "reserve_split_z_score": 5.28,
    "posterior_z_score": 5.36,
    "beakers_earned": 5,
    "anomalies_isolated": [
      {
        "token": "BLIND-TITIN-05",
        "split": "DEV-03",
        "repository_label": "Drosophila melanogaster Sallimus/Projectin Divergent Non-Orthologous Sarcomere Repeat",
        "pass1_blinded_extrapolation": "Orthologous Ecdysozoan Titin Core + 1,850-aa PEVK-Like Pro/Glu/Lys Elastic Spring Drift (Error Type A: RCFV = 0.176; Core PDB:1TKI TM = 0.928)",
        "d_ctx_sd": 5.74,
        "error_class": "Error Type A (Intrinsic Disordered PEVK Spring Drift & Tandem Ig/FN3 Register Shift)"
      },
      {
        "token": "BLIND-TITIN-12",
        "split": "DEV-09",
        "repository_label": "Danio rerio Full-Length Titin M-Band Kinase & C-Terminal Cap",
        "pass1_blinded_extrapolation": "Cropped Draft Model Missing 42-aa Autoregulatory C-Terminal Alpha-R1/R2 Tail & NBR1/p62 Mechanosensor Clasp (Error Type B: |J_ij| Dropped 1.762 -> 0.174)",
        "d_ctx_sd": 5.46,
        "error_class": "Error Type B (Clipped Mechanosensory Autoregulatory Tail SLiM)"
      },
      {
        "token": "BLIND-TITIN-19",
        "split": "RES-06",
        "repository_label": "Homo sapiens TTN Pathogenic Dilated Cardiomyopathy (DCM) Nonsense Variant Contig",
        "pass1_blinded_extrapolation": "Benign Low-PSI Foetal-Only I-Band Exon 112 Truncation (PSI = 0.08 in Adult LV) vs. Constitutive A-Band Super-Repeat Exon 326 DCM Hotspot (PSI = 1.00)",
        "d_ctx_sd": 5.92,
        "error_class": "Clinical Splice-Isoform Misclassification (Low-PSI I-Band Benign vs. High-PSI A-Band Pathogenic TTNtv)"
      },
      {
        "token": "BLIND-TITIN-26",
        "split": "RES-13",
        "repository_label": "Callorhinchus milii Obscurin Giant Sarcomeric RhoGEF Assembly",
        "pass1_blinded_extrapolation": "Chimeric Assembly Collapse Fusing 11 Tandem Ig Repeats of Obscurin with Nebulin 35-aa SDXXYK Actin-Binding Super-Repeats",
        "d_ctx_sd": 6.18,
        "error_class": "Short-Read Repeat Collapse Chimera (Tandem Ig/Nebulin Misassembly)"
      }
    ]
  },
  "tier_3_scientific_synthesis_telemetry": {
    "stage": "Tier 3: Scientific Synthesis",
    "discovery_number": 101,
    "discovery_slug": "titin-obscurin-sarcomere-megaproteins",
    "taxa_evaluated": 72,
    "cohorts_evaluated": 36,
    "total_sequence_span_mb": 6.84,
    "cumulative_protein_families": 22,
    "cumulative_taxa": 460,
    "cumulative_span_mb": 20.70,
    "hypotheses": [
      {
        "id": "H1",
        "name": "M-Band Titin/Projectin/UNC-89 Kinase Core & Mechanosensory Autoregulatory Tail SLiM (PDB: 1TKI)",
        "rcfv_unpartitioned": 0.176,
        "rcfv_partitioned": 0.021,
        "rcfv_reduction_pct": 88.1,
        "core_dnds": 0.029,
        "potts_j_ij": 1.762,
        "tm_score": 0.936,
        "ufboot_pct": 99.8,
        "z_score": 5.64,
        "beakers": 5
      },
      {
        "id": "H2",
        "name": "Z-Disc Titin Z1-Z2 Telethonin Beta-Sheet Clasp & I-Band I27 Force-Clamp vs. PEVK Spring (PDB: 2F8V, 1TIT)",
        "rcfv_unpartitioned": 0.169,
        "rcfv_partitioned": 0.020,
        "rcfv_reduction_pct": 88.2,
        "core_dnds": 0.033,
        "potts_j_ij": 1.718,
        "tm_score": 0.928,
        "ufboot_pct": 99.7,
        "z_score": 5.48,
        "beakers": 5
      },
      {
        "id": "H3",
        "name": "Obscurin/UNC-89 DH-PH RhoGEF Signalling & Nebulin SDXXYK Actin-Ruler Architecture",
        "rcfv_unpartitioned": 0.162,
        "rcfv_partitioned": 0.021,
        "rcfv_reduction_pct": 87.0,
        "core_dnds": 0.036,
        "potts_j_ij": 1.694,
        "tm_score": 0.922,
        "ufboot_pct": 99.5,
        "z_score": 5.38,
        "beakers": 5
      },
      {
        "id": "H4",
        "name": "Falsification Control on Unsegmented PEVK Repeats & Unphased Tandem Ig/FN3 Arrays",
        "rcfv_unpartitioned": 0.182,
        "rcfv_partitioned": 0.182,
        "rcfv_reduction_pct": 0.0,
        "core_dnds": 0.842,
        "potts_j_ij": 0.158,
        "tm_score": 0.0,
        "ufboot_pct": 31.8,
        "z_score": 0.96,
        "beakers": 1
      }
    ],
    "runie_models": [
      {
        "rank": "1st (Best)",
        "architecture": "Super-BLAST -> Minimizer Exon-Phase Synteny -> 9-mer Anchor Gotoh + Plan-7 HMM (Kinase/Z1-Z2/I27 + Autoregulatory SLiM vs. PEVK/Tandem-Repeat Split) -> 2D Dayhoff-6 -> 4-Stage BIONJ+NNI ML -> Potts Co-Evolution & Splicing PSI -> 3D Kabsch TM (PDB*:1TIT/1TKI/2F8V)",
        "marginal_ln_l": -418210.4,
        "delta_ln_l": 0.0,
        "rcfv": 0.021,
        "posterior_z": "+5.64 SD (Pos) / +4.92 SD (All)"
      },
      {
        "rank": "2nd (Nearest)",
        "architecture": "Super-BLAST -> 9-mer Anchor Gotoh + Plan-7 HMM (Kinase/Z1-Z2/I27 + Autoregulatory SLiM vs. PEVK/Tandem-Repeat Split) -> 2D Dayhoff-6 -> 4-Stage BIONJ+NNI ML -> Potts Co-Evolution (No 3D PDB* Superposition or PSI Filter)",
        "marginal_ln_l": -418284.6,
        "delta_ln_l": -74.2,
        "rcfv": 0.024,
        "posterior_z": "+4.74 SD"
      },
      {
        "rank": "3rd (Medium)",
        "architecture": "Super-BLAST -> Gotoh 3-State MSA -> IQ-TREE 2* Standard LG+G4 ML* (Pfam*-Clipped Kinase/Ig Core Only, Error Type B: Alpha-R1/R2 Mechanosensor Tail & Telethonin Clasp Clipped)",
        "marginal_ln_l": -418452.9,
        "delta_ln_l": -242.5,
        "rcfv": 0.054,
        "posterior_z": "+3.48 SD"
      },
      {
        "rank": "4th (Rejected)",
        "architecture": "MAFFT* Unsegmented Whole-Megaprotein Concatenation (35,991-aa TTN Includes 2,174-aa PEVK Spring & Unphased 244x Ig/FN3 Tandem Repeats) -> IQ-TREE 2* WAG+G4 ML* (Error Type A Register Collapse)",
        "marginal_ln_l": -418624.8,
        "delta_ln_l": -414.4,
        "rcfv": 0.176,
        "posterior_z": "+0.96 SD (0/5 Collapse)"
      }
    ]
  }
}