{
  "schema": "sma-axis-research-questions-v1",
  "reviewedAt": "2026-11-14",
  "scope": "All 44 registered axes assessed against retained source-specific work, with targeted RNA/regulatory follow-up. This is not 44 AG2 inferences, exhaustive variant coverage or biological validation.",
  "axesWithCurrentAG2Results": [
    "A06",
    "A13",
    "A14",
    "A15",
    "A16",
    "A21",
    "A26",
    "A43",
    "A44"
  ],
  "axes": [
    {
      "axisId": "A01",
      "title": "SARM1 and axonal NADase",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "evidence_gap",
      "existingFinding": "Retained geometry/contact analyses are computational descriptions only. No biological hit; the full tested insert including its 49-aa prefix and physical material remain unbound; SMA-function relevance is unestablished.",
      "counterfinding": "Existing structure/contact mapping is not wholly negative: ligand-contact and common-core analyses were completed for their fixed inputs, but they do not establish activity, assembly, or SMA durability.",
      "question": "For a specifically source-bound human SARM1 transcript/variant, does a public-reference AG2 model predict a reproducible splice or expression consequence at the exact locus? This is only useful after an exact locus/allele or a narrowly defined transcript-regulatory question is pinned; it cannot answer NADase activity or axonal degeneration.",
      "nextEvidence": "Identify an authoritative complete tested-insert/material record; without it no construct-linked model question is executable.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A01&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A02",
      "title": "Mitochondrial oxidative phosphorylation",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "evidence_gap",
      "existingFinding": "AMP/ADP neutral all-atom diagnostics corrected atom-name transfer and preserved heavy coordinates exactly (0.0 Å in-memory change); four references remain computational diagnostics. Separate RNA event context is one GM03813 fibroblast line with shared controls and JC/JCEC not independent contrasts. No flux/function conclusion.",
      "counterfinding": "The source RNA event context provides splice-level information but has one cell line and unresolved sample/producer provenance; it does not measure mitochondrial respiration.",
      "question": "If a specific OXPHOS gene and source-defined transcript event is selected, does AG2 reference sequence support the observed junction topology in the named cell context? This would not establish respiratory-chain flux or explain the current producer/cell-line provenance gap.",
      "nextEvidence": "Obtain the archived launch/script receipt for exactly the two AMPK input constructs;",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A02&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A03",
      "title": "Glycolysis",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "Human motor-neuron PGK1 RNA rows conflict: GSE69175 log2FC +1.25283, q=0.00091257 versus GSE108094 +0.120896, q=0.954189 plus a separate NOTEST row. PXD015115 lists 77 raw files and one inaccessible combine.xlsx; PXD060094 lists 20/20 iHeps and no iMN. No protein contrast or activity result.",
      "counterfinding": "The second RNA source is near-null and the purported iMN proteome is not present in the reviewed PXD060094 inventory; neither establishes PGK1 protein or glycolytic flux.",
      "question": "After retrieving the existing PXD015115 combine.xlsx and sample key, does its explicitly identified human motor-neuron PGK1 protein row agree in direction with either RNA source? AG2 cannot resolve protein abundance or enzyme flux.",
      "nextEvidence": "Retrieve the already identified PXD015115 combine.xlsx plus its sample/reporter/T1 key; if unavailable, record the exact missing file rather than model.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A03&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A04",
      "title": "p38 MAPK14 signaling",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "Pinned native MW150 P11 descriptive arithmetic was independently reproduced and accepted as descriptive only; it does not resolve administered lot, salt/formulation or transfer to SMA.",
      "counterfinding": "The bounded animal-level descriptive contrast exists, but no authenticated administered material or exposure link supports interpreting it as MAPK14 inhibition or broad efficacy.",
      "question": "No AG2 question can answer the present dosing/material gap. Only after exact administered compound identity is recovered could a separate source-bound MAPK14 transcript/variant question be considered; it would not predict inhibition or efficacy.",
      "nextEvidence": "Recover the actual administered material/lot/formulation record and animal-cohort link; this is a source/chemistry question, not AG2.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A04&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A05",
      "title": "NRF2–KEAP1 regulation",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "The deposited P10 whole-liver protein matrix is already checksum-verified and analyzed. FECH/HMBS are higher in the primary SMA subset, while redox markers show mixed directions; SMA-5 remains excluded. The separate accepted heart Nfe2l2 mRNA negative remains unchanged.",
      "counterfinding": "The protein panel is mixed, from whole liver, and is not the separate heart Nfe2l2 mRNA result, a validated pathway response, or independent replication; missing protein rows and sample mapping limit interpretation.",
      "question": "Which authenticated animal/specimen identities link or distinguish the liver and March cross-organ proteomics sources?",
      "nextEvidence": "Bind a real specimen crosswalk or exact deposition accession; no matrix reacquisition or repeated analysis. Reagent tables and file suffixes are not animal identity.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A05&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A06",
      "title": "TP73 and ΔNp73",
      "currentAG2ContextIds": [
        "ag2-tp73-first-junctions"
      ],
      "AG2ResultAvailable": true,
      "questionType": "reference_result_with_open_endpoint_question",
      "existingFinding": "ML006/SMA was incomplete and is excluded from the comparison. Its partial data do not resolve TP73 isoform support. A current-reference AG2 query returns a shared downstream control but neither predeclared first-junction path.",
      "counterfinding": "Most relevant negative/completion bound is that ML002 has no support in the fixed windows; the incomplete ML006 cannot be counted in either direction, and existing windows are not isoform-specific proof. Unreturned model junctions are unscored, not biological absence or an isoform switch.",
      "question": "Can an exact first-exon or transcription-start-site coverage endpoint distinguish the two source-bound TP73 paths when junction-list output does not?",
      "nextEvidence": "Predeclare the first-exon/TSS regions and a suitable output endpoint using the same exact reference identities; retain the difference from frozen low-count source models. No TA-alpha protein or promoter-switching claim.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A06&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A07",
      "title": "Agrin–LRP4–MuSK",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "evidence_gap",
      "existingFinding": "A bounded native source RFD4 feature-processing check passed 13 checks; 384 target atoms were internally conditioned and zero absolutely fixed. No generated binder geometry, model output, or source/resource qualification is established.",
      "counterfinding": "The 384-atom internal conditioning and no absolute restraints do not establish a credible complex or biological interaction; source GSM/library-to-preparation/muscle/animal identity remains open.",
      "question": "No useful AG2 question until the source sample/preparation map is bound; the existing question is whether an input/library belongs to the claimed muscle model, which is provenance, not sequence prediction.",
      "nextEvidence": "Recover the exact GSM/library-to-preparation, muscle pool and animal map; no model call is warranted before that source binding.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A07&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A08",
      "title": "JNK/MAPK10 pathway",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "new_reference_question",
      "existingFinding": "The retained Ottesen event evidence concerns MAPK8 in one GM03813 cell line with shared DMSO controls: HiR1000 ΔPSI −0.159, FDR about 0.0200 (JC) / 0.0182 (JCEC); LoR ΔPSI −0.069, FDR 1.0. This is not a dose response or independent replication.",
      "counterfinding": "The nominally relevant event is MAPK8, not MAPK10; one cell line/shared controls and differing JC/JCEC modes constrain any pathway interpretation.",
      "question": "For the exact source-bound MAPK8 event, does a public-reference AG2 prediction preserve the observed splice junction direction across transcript contexts? It cannot establish MAPK10 involvement, treatment response, kinase activity, or explain JC/JCEC differences.",
      "nextEvidence": "Use the already retained exact MAPK8 event coordinates/reference and ask one public-reference junction-topology question; no drug-effect claim.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A08&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A09",
      "title": "HDAC2 epigenetics",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "Three PBA records remain distinct: sodium 4-PBA 10 µM NIH3T3-SMN2/SmnRNAi nuclear-cell normalized value 0.71 vs vehicle; free-acid 4-PBA PubChem AID1458 engineered HEK293 reporter inactive; sodium PBA 2 mM SMA iPSC motor neurons (Type I 1-38G, Type II 1-51N) about 25% higher full-length SMN mRNA but no SMN protein increase and no reliable PBA-specific survival effect. These do not establish HDAC2-specific response; DOI 10.1016/j.stem.2015.08.003.",
      "counterfinding": "The engineered reporter is inactive and the SMA iPSC study did not show SMN protein or reliable survival increase; broad PBA exposure is not proof of HDAC2 target engagement.",
      "question": "No repeat of the completed source reconciliation. A public-reference HDAC2/SMN2 sequence question would not test PBA response; the discriminating next question requires matched exact reagent and HDAC2 engagement plus protein/function measurement.",
      "nextEvidence": "Require the exact authenticated reagent identity plus matched HDAC2 engagement/protein/function evidence; AG2 is not a substitute.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A09&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A10",
      "title": "Kv2.1 channel clusters",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "Three distinct source UUIDs map to PMID 31851921/title; one retained date matches PubMed and two anomalous dates remain unexplained. The 9/11/10 linked-claim counts are per-row API counts, not independent papers or experiments.",
      "counterfinding": "The date anomalies and UUID multiplicity show bibliographic records cannot be treated as independent evidence; contact geometry is not channel activity.",
      "question": "No AG2 question addresses the open issue. The existing required resolution is whether a named VAP/Kv2.1 construct and runner preserve the exact SEP-tagged construct and compatible physical parameterization; this requires construct/model provenance or cellular measurement.",
      "nextEvidence": "Recover exact deployed runner/parser/version, SEP-containing post-enrichment input, and run-linked output; absent that, retain the source identity gap.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A10&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A11",
      "title": "MCU calcium transport",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "The Taiwanese-SypHy study directly measured stimulus-dependent mitochondrial calcium responses and pyruvate+lactate fuel replacement with sensor/potential controls. It does not identify selective MCU rescue or astrocytic lactate transfer; SypHy cannot fully separate endocytosis from reacidification. Differently normalized calcium values were not combined as a dose interaction.",
      "counterfinding": "The functional calcium/fuel observations are real but do not isolate MCU-specific rescue or demonstrate astrocyte-to-neuron transfer; SypHy endpoint ambiguity remains.",
      "question": "No AG2 model can answer the existing functional distinction. The open item is source provenance of the two MCU–EMRE outputs; sequence prediction would not identify their producing seeds or demonstrate calcium flux.",
      "nextEvidence": "Recover the original manifests for the two specifically named MCU–EMRE outputs; if unavailable, preserve that exact producer-link gap.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A11&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A12",
      "title": "SNPH axonal transport",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "evidence_gap",
      "existingFinding": "Chen and Kang source records remain separate. Chen supports truncated fragment/vector labels and deletion design but not complete sequence/accession/version/species/tag/linker or exact plasmid-source identity. Historical labels do not prove full insert. Functional endpoint review is complete; no qualifying new construct-source record was found.",
      "counterfinding": "The fragment/deletion design is documented, but sequence/construct incompleteness prevents assigning a transcript or full-length sequence model to the tested construct; transport endpoint is separate.",
      "question": "Once a paper-specific full insert/clone sequence is recovered, a public-reference SNPH transcript/context comparison could check sequence identity; it cannot establish transport anchoring or cellular action.",
      "nextEvidence": "Obtain the paper-specific, versioned full insert/plasmid record for the exact construct; only then assess whether reference sequence comparison is meaningful.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A12&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A13",
      "title": "SMN splicing context",
      "currentAG2ContextIds": [
        "ag2-smn2-expression",
        "ag2-smn2-gao-splicing",
        "ag2-mdm4-topology",
        "ag2-smn1-c863"
      ],
      "AG2ResultAvailable": true,
      "questionType": "already_done",
      "existingFinding": "15 Ottesen source runs span five GM03813 treatment groups but one fibroblast line, not 15 donors; one diagnostic site, separate MAPQ/NH marginals, reads not molecules, and no transcript phasing or treatment-effect inference. MS023 continuation adds three libraries and 88,480 source rows/5,168 event-filter contrasts; Full8 LOO strict sign reversal in 451/1,876 events (median absolute index difference 0.00832 for those). Biological independence is unresolved; no confirmed hit.",
      "counterfinding": "The leave-one-out sign reversals show substantial event-level instability, while single-cell-line source design and unbound biological units limit interpretation; no SMN protein/phenotype link is established.",
      "question": "Only if an exact existing SMN1/SMN2 variant or source event remains untested in the AG2 graph, ask whether public-reference prediction distinguishes its splice junctions. Current data instead need animal/litter/pool/culture assignments and RNA-to-protein/phenotype links;",
      "nextEvidence": "Verify exact SMN1/SMN2 context IDs against the already retained AG2 source graph; if represented, mark reused, otherwise first obtain the biological-unit map and RNA-to-protein/phenotype linkage.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A13&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A14",
      "title": "STMN2 and microtubules",
      "currentAG2ContextIds": [
        "ag2-stmn2-cryptic-reference"
      ],
      "AG2ResultAvailable": true,
      "questionType": "reference_result_with_open_cis_source_question",
      "existingFinding": "GSE290979 adds 31 genes, normalization sensitivity and eight markers; STMN2/CHAT is lower in six line comparisons while STMN2/RBFOX3 is mixed. There is no cell-composition correction or MN-specific effect. Sixteen conflicting treatment labels remain blocked; GSE290980 is same study with cell annotation unresolved. AAV9 insert species remains unresolved. The new generic motor-neuron reference output returns both canonical and terminal cryptic STMN2 junctions.",
      "counterfinding": "Normalization/marker choice changes the context and mixed RBFOX3 results counter a simple MN-specific signal; treatment labels cannot support a contrast and AAV material origin is unresolved. This static DNA input cannot model TDP43 depletion or establish cryptic splicing in SMA.",
      "question": "Which exact source-authenticated splice-acceptor or regulatory allele can test the now-addressable cryptic site, with an explicit assay context and interpretable controls?",
      "nextEvidence": "Bind the exact published cis allele/reference base and source assay before another model request; do not invent a mutation or equate raw signals with PSI.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A14&section=sources",
      "interpretationLimit": "ALS/TDP43-loss source context remains separate from SMA overexpression; no trans-state induction or rescue is predicted."
    },
    {
      "axisId": "A15",
      "title": "Non-alpha p38 isoforms",
      "currentAG2ContextIds": [
        "ag2-mapk12-native-paths"
      ],
      "AG2ResultAvailable": true,
      "questionType": "already_done",
      "existingFinding": "MAPK12 p38-gamma reference predictions represent five source-defined junctions. Existing GM03813 RNA outputs and ordered100nt alignment patterns support the nonexclusive exon14-to15-to16 partial chain in all six libraries; no full transcript or treatment response established.",
      "counterfinding": "JC and JCEC use the same libraries and give different qualification; the central SE event has FDR1.0. Generic dermal reference outputs are not treated GM03813. No full four-exon chain, protein or kinase consequence follows.",
      "question": "Which exact long-range RNA or linked-fragment evidence can distinguish complete MAPK12 transcript structures beyond the observed14-to15-to16 partial chain?",
      "nextEvidence": "Reuse the accepted five-edge and partial-pattern results; identify a genuinely informative longer molecule/fragment product before a full-chain claim.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A15&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A16",
      "title": "SMN2 splicing and intervention",
      "currentAG2ContextIds": [
        "ag2-smn2-gao-splicing"
      ],
      "AG2ResultAvailable": true,
      "questionType": "other_method_needed",
      "existingFinding": "One stored SMN-C2/RNA Row13 trajectory (1000 frames; 367 base-near, 0 canonical base-H-bond; first 589 frames only 4 base contacts). Row13/Seq9 vs Row12/Seq6 differ at two bases and begin from different states/candidate sets.",
      "counterfinding": "Single trajectories, correlated frames, fixed +1 microstate, constructed RNA and uncertain force-field terms; no causal sequence selectivity or experimental binding inference.",
      "question": "Can the exact retained Row13/Seq9 versus Row12/Seq6 sequence difference be tested in a matched, prespecified splice-reporter dataset, with matched starting state and construct context?",
      "nextEvidence": "Missing original construct sequence/boundaries plus matched reporter readout for both constructs in the same cell/model context; AG2 cannot interpret ligand/RNA binding trajectories as splicing efficacy.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A16&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A17",
      "title": "Cytoskeletal modifiers",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "deferred",
      "existingFinding": "Accepted structural stoichiometry retained 820 source-bound thresholds, 518 chain-specific pairs, 302 under 4 Å; structures are T2R α/β complexes with rat STMN4/RB3-SLD, not STMN1. Separate Oct 25 SYT2/NCALD RNA/literature context.",
      "counterfinding": "Structural contact counts do not demonstrate human STMN1 binding or SMA contracture mechanism; no complete STMN1 constructs/native inputs.",
      "question": "Can an exact human STMN1 construct and native oligomer/input set be bound before any structural comparison is interpreted?",
      "nextEvidence": "Missing complete human STMN1 construct sequence/isoform and matched native input identity; do not duplicate PLS3 variant modeling assigned elsewhere.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A17&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A18",
      "title": "SMN protein stability",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "evidence_gap",
      "existingFinding": "MIB1 WT vs C1009S HEK293T [35S] pulse-chase: about 4 h vs 2 h, 3 experiments. CHEMBL4068807 maps to Rietz 4c (0.28±0.03 µM; 190±32% SMN-luciferase), not direct protein/artifact-control evidence. HSPA8 peptides/chimeras separately identified.",
      "counterfinding": "Open source-unit and processing gaps remain for Harmine/PIP6A RNA/protein datasets; reporter is indirect and no exact mechanism/isoform prediction follows.",
      "question": "Which GSMs entered the published 11-sample GSE150510 DESeq2 analysis, and what original reference/count recipe generated the mixed gene/transcript-form rows?",
      "nextEvidence": "Missing author inclusion list keyed to GSMs plus original RNA reference/quantifier/aggregation recipe; no AG2 rerun can resolve sample inclusion or count construction.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A18&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A19",
      "title": "INPP5F",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "evidence_gap",
      "existingFinding": "INPP5F loss improves one injury-regeneration context but impairs selected N2A recycling; WT rescue and C458S differ. GSE145146 has n=1 DMSO vs n=3 treated; INPP5F CPM 22.68 vs 22.39/23.69/23.37.",
      "counterfinding": "Small unbalanced RNA libraries cannot support drug-response or mechanistic differential-expression claims; exact historical Hsu construct/insert remains unresolved.",
      "question": "What exact historical Hsu plasmid sequence and expression insert/junctions were used, and do they encode the same INPP5F construct as the current reference?",
      "nextEvidence": "Missing accession-bound historical plasmid or full construct sequence and readable primary Figure 1/source; avoid guessing mutant identity or treating AG2 as construct-sequence validation.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A19&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A20",
      "title": "Bioelectric membrane",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "Kv2.1 model covers 21,870 simulated cells; complete-loss firing rate is 0.308–0.500 of WT while AP half-width is 0.98–1.20. Separate SCS fit uses 3 SMA participants and 7 external controls.",
      "counterfinding": "Model outputs and tiny heterogeneous SCS sample do not establish channel-specific measured human SMA physiology; exact KCNC4 pore structure/construct missing.",
      "question": "Can an authoritative human KCNC4/Q03721 pore-containing structure or construct be bound without substituting KCNC1 7PQT?",
      "nextEvidence": "Missing authoritative exact human KCNC4 pore-containing structure or residue/construct map and assembly; this is a structure identity question, not RNA regulation.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A20&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A21",
      "title": "PERP at the endplate and axon",
      "currentAG2ContextIds": [
        "ag2-perp-arfgef3"
      ],
      "AG2ResultAvailable": true,
      "questionType": "other_method_needed",
      "existingFinding": "GSE2566: n=3 paired rat delayed-peroneal reinnervation samples with opposing Perp probes. GSE252128: 8 SMA-labelled human surgical muscle vs 7 scoliosis controls, PERP TPM means 7.8146 vs 2.1297; all 15 one-sample omissions positive but ranges overlap. P7 mouse array/RNA-seq are same study.",
      "counterfinding": "Different species/tissues and partly repeated cohorts; overlapping values and probe disagreement limit transfer; no direct NMJ localization/binding demonstrated.",
      "question": "Can source-level sample/animal identity and exact PERP probe/feature mapping distinguish independent evidence from reused cohorts and opposing probe behavior?",
      "nextEvidence": "Missing exact original sample crosswalk and probe/feature annotation/source for PERP; AG2 is not a substitute for cohort or localization evidence.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A21&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A22",
      "title": "DOK7–MuSK–Agrin–LRP4 complex",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "Three MuSK-Ig3 BindCraft designs (65/67/91 aa) had 71/102/111 interchain pairs <4 Å in rigid 9NWG projection. Separate RFD4 70-aa B-chain has one Cys and no N-X-S/T sequon; nearest target Cys 16.7589 Å. Boltz2 template-conditioned run had no <4 Å interchain pairs.",
      "counterfinding": "Model/design outputs conflict and rigid projection is not binding validation; Crk/CrkL paralog and construct context remain distinct.",
      "question": "Do accepted explicit-pY contact poses overlap exact experimental Crk/CrkL-SH2 reference contacts for the same phosphosite/construct?",
      "nextEvidence": "Finite source comparison of retained explicit-pY poses against exact experimental Crk/CrkL-SH2 reference contact source; no AG2 call.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A22&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A23",
      "title": "Agrin–LRP4 binding",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "Eight raw Agrin–LRP4 designs plus eight inverse-folded sequence records represent eight designs/16 sequence records, all 80 aa. All backbones overlap eligible AGRN atoms (minimum 0.102–0.469 Å); no pose nominated. Separate context-model attempt SIGBUSed before output.",
      "counterfinding": "Severe overlap prevents nomination; failed model has no result, and structural geometry does not establish binding/stability.",
      "question": "Can the exact source atom/model/chain selection and overlap mask be independently bound for all eight designs before any redesigned pose is considered?",
      "nextEvidence": "Use retained structures/source map for finite source atom-identity and overlap-mask reconciliation; no AG2 call,",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A23&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A24",
      "title": "Myostatin and antibody class",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "evidence_gap",
      "existingFinding": "SAPPHIRE FDA table: age 2–12, apitegromab 10 mg/kg vs placebo n=53/50, adjusted HFMSE difference 2.2 (95% CI 0.49–3.95), nominal p=.0121. Separate from primary 20 mg/kg and pooled-dose contrast.",
      "counterfinding": "Prespecified treatment×SMN-background/age interaction outputs remain absent; one dose subgroup cannot establish mechanism or general efficacy.",
      "question": "What are the original prespecified treatment-by-SMN-background and age interaction estimates for the retained SAPPHIRE endpoints?",
      "nextEvidence": "Missing original prespecified interaction output/table with model specification; AG2 cannot answer clinical subgroup interaction.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A24&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A25",
      "title": "SMN2 splice ternary complex",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "AF3 series 30/30 identity/hash checked; U1-C/RNA ± SMN-C5 PAE medians differ but contact directions vary and severe non-Zn overlaps 7/15 vs 1/15. Source14 fixes second combo library SRR19737679/GSM6253090/SRX15783611/SAMN29180978; lower-skip pattern does not persist; no consistent add effect/interaction.",
      "counterfinding": "Model contact/PAE is not affinity or splice efficacy; combination sample does not reproduce a consistent add effect; risdiplam vs SMN-C5 affinity/activity mapping unresolved.",
      "question": "Can exact original matched RNA-binding affinity and cellular splicing potency measurements be recovered for risdiplam and SMN-C5 under the same RNA/assay conditions?",
      "nextEvidence": "Missing exact primary assay pair with matched construct, condition and numeric affinity/activity endpoint; AG2 is unsuitable for compound affinity or RNA–protein–ligand geometry.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A25&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A26",
      "title": "STMN2 axonal maintenance",
      "currentAG2ContextIds": [
        "ag2-stmn2-cryptic-reference"
      ],
      "AG2ResultAvailable": true,
      "questionType": "reference_result_with_open_cis_source_question",
      "existingFinding": "Pagliari S4D raster means show similar GFAP/IBA1 for SMA+null and SMA+Stmn2, n=3/group. GSE59506 counters uniform axonal mRNA decrease: both Stmn2 probes higher in Smn-shRNA vs WT/empty in soma and axon; one axonal contrast +0.249 and +0.709. The new generic motor-neuron reference output returns both canonical and terminal cryptic STMN2 junctions.",
      "counterfinding": "Pagliari lacks stable animal IDs; raster means small n; probe-level direction is not axonal maintenance function. This static DNA input cannot model TDP43 depletion or establish cryptic splicing in SMA.",
      "question": "Which exact source-authenticated splice-acceptor or regulatory allele can test the now-addressable cryptic site, with an explicit assay context and interpretable controls?",
      "nextEvidence": "Bind the exact published cis allele/reference base and source assay before another model request; do not invent a mutation or equate raw signals with PSI.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A26&section=sources",
      "interpretationLimit": "ALS/TDP43-loss source context remains separate from SMA overexpression; no trans-state induction or rescue is predicted."
    },
    {
      "axisId": "A27",
      "title": "NRF2 and mitochondrial modifiers",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "evidence_gap",
      "existingFinding": "Adami P11 Δ7 SVZ NSCs: nominal 0.5 μM “Cur” changes NRF2 nuclear/cytoplasmic ratio 1.522±.023 to 1.598±.021 (n=4, p=.0464); NQO1 nonsignificant, SMN remains below WT. MTT text says 16% while means imply 21.9%; Ottesen DNM1L context is shared A02/A27/A33, not NRF2 evidence.",
      "counterfinding": "Formulation/lot uncertain; effect is nominal and NRF2 reporter lacks downstream NQO1 significance; DNM1L must not be used as NRF2 evidence.",
      "question": "Can the original Adami supplement and methods resolve compound identity/formulation and reconcile the MTT percent with the reported means?",
      "nextEvidence": "Missing readable original supplement/compound specification and raw MTT values or calculation definition; no AG2 variant prediction warranted.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A27&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A28",
      "title": "Cross-species regeneration",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "evidence_gap",
      "existingFinding": "GSE202429 reconstruction: eight zebrafish features, three deposited libraries, 41,335 barcodes, 24 feature-library rows; PLS3-positive barcode fraction 4.02→6.74→12.15%, ncaldb 4.49→3.46→2.90%. Separate contexts; 1/230 author-labeled mouse MN nuclei detected Perp.",
      "counterfinding": "No author QC/cluster/lineage metadata in retained GEO raw archive; proxy strata are not author cell identities; zebrafish/mouse/human contexts differ.",
      "question": "Can GEO or authors supply GSM+barcode-bound QC/cluster labels and explicit pMN→newborn MN birth/lineage labels for the same cells?",
      "nextEvidence": "Missing barcode-linked author QC/cell-state and birth/lineage metadata; existing threshold sensitivity and marker codetection are complete and do not satisfy original lineage contrast.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A28&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A29",
      "title": "Cardiac and hepatic multisystem effects",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "evidence_gap",
      "existingFinding": "Wu 2025 P4-heart miR-34a-5p qPCR (~4-fold) and stronger FISH; six-run prefix-CPM is directionally similar but not sample-linked. miR-181a-5p lacks quantitative validation.",
      "counterfinding": "qPCR n=10 is not mapped to the six sequencing runs; organ, cohort, and intervention linkage remains open.",
      "question": "Can any retained source manifest bind each P4 heart qPCR sample to the six RNA runs and exact intervention/genotype?",
      "nextEvidence": "Missing input: per-sample crosswalk linking qPCR n=10, six RNA runs, heart tissue, genotype and intervention; without it no AG2 contrast is interpretable.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A29&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A30",
      "title": "SMN restoration plus cytoskeletal rescue",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "Fifteen selected arms across three papers show dose- and assay-specific outcomes; no formal interaction or general synergy is established.",
      "counterfinding": "No matched PLS3-only arm in one mouse comparison; Riessland untreated survival labels conflict; some outcomes are within common-ASO arms.",
      "question": "Do original datasets contain complete matched factorial SMN-treatment × modifier-treatment arms with comparable independent units and endpoints?",
      "nextEvidence": "Missing input: source-bound complete matched arms, animal/sample IDs, dose and endpoint definitions sufficient for a treatment-interaction analysis.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A30&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A31",
      "title": "SMN restoration plus myostatin",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "SAPPHIRE treatment-by-SMN-background/age interaction remains unquantified; a corrected human GM03813C MSTN event query returned zero matching rows in its fixed prefiltered set.",
      "counterfinding": "Zero of 9,778 prefiltered rows is not a global absence; the earlier mouse gene ID was wrong and no interaction estimate exists.",
      "question": "Can exact tested myostatin material and original intervention arms be bound to a muscle endpoint that permits a pre-specified interaction contrast?",
      "nextEvidence": "Missing input: exact myostatin intervention identity plus complete matched SAPPHIRE arm-level outcomes and SMN-background/age labels.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A31&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A32",
      "title": "SMN restoration plus junction rescue",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "Kim 2017 reports selected proximal NMJ/muscle/survival benefits in low-SMN mice with Hb9 chicken Z+Agrin, while motor-neuron/vGlut1 and distal innervation were unchanged and whole-cord SMN was not raised.",
      "counterfinding": "DUET P14 sex-stratified intervals disagree by method; DUET also adds Cas9 and doubles vector genomes, so arms are not isolated single-factor contrasts.",
      "question": "Are source-complete matched intervention arms available to isolate the construct and developmental-stage contribution to NMJ endpoints?",
      "nextEvidence": "Missing input: complete source-linked group assignments and independent-animal endpoint table for comparable construct arms.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A32&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A33",
      "title": "Bioenergetics and mitochondria",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "evidence_gap",
      "existingFinding": "Grandi 2024 muscle data show RNA/protein/mtDNA differences without respirometry or before-after treatment; James2024 redox contrasts change direction by cell-line origin; proteome sensitivity found no corrected hits.",
      "counterfinding": "PBMC mtDNA is a separate cohort; SMN protein did not differ in the measured comparison; MitoSOX subgroup directions oppose and do not prove batch effects.",
      "question": "Can retained sample and assay metadata bind the muscle, PBMC, and cell-line measurements to their actual cohorts, normalization, and intervention status?",
      "nextEvidence": "Missing input: exact sample-to-cohort/assay/normalization crosswalk and any matched respirometry or intervention values; AG2 transcript predictions would not resolve these endpoints.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A33&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A34",
      "title": "Motor-neuron resilience modifiers",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "evidence_gap",
      "existingFinding": "NCALD structural projection is a computational geometry check, not a measured calcium-bound complex; other PERP/FAS4, P4 mouse and CDK4 drug-window evidence remains context-specific and nonvalidating.",
      "counterfinding": "Clathrin sources disagree on calcium direction; only 69 somatomotor nuclei among six human donors; P4 cells are pooled littermates; CDK4 windows are modeled and lack validated complexes/cell assays.",
      "question": "For any proposed NCALD RNA question, is there a source-bound exact allele or transcript interval and a matched human motor-neuron measurement beyond the existing structural and context analyses?",
      "nextEvidence": "Missing input: a specific source-bound NCALD allele/transcript question with exact motor-neuron RNA endpoint; absent that, no new AG2 request is justified.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A34&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A35",
      "title": "Neuromuscular-junction maintenance",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "Corrected Fig. 7D endpoint is proprioceptive VGluT1+ inputs on ChAT+ L2 motor-neuron somata at P11, not motor-neuron counts; the delayed SMN-C3/MW150 combination did not significantly increase that endpoint.",
      "counterfinding": "Direction-only +1.297619 normalized units and 25/25 leave-one-out results are descriptive; survival RMST concerns a different comparison; Munc13 data lack independent replicate pairing.",
      "question": "Can source records link the Munc13 single-cell values to independent biological replicates and paired controls for a valid contrast?",
      "nextEvidence": "Missing input: original Munc13 sample-to-replicate/control mapping; AG2 sequence scoring cannot substitute for NMJ endpoint evidence.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A35&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A36",
      "title": "Multisystem metabolism",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "evidence_gap",
      "existingFinding": "SLC6A6 muscle RNA contrasts are source-specific; post-hoc human/mouse values and treatment contrast do not supply paired taurine measurements. PERP-CSAD single-library relation is descriptive; LRRC58/CDO1 synthesis differs from SLC6A6 transport.",
      "counterfinding": "OMIX006777 is not released; the required same-person muscle RNA/taurine and side/aliquot mapping is unavailable; PXD060060 did not resolve treatment reference arm.",
      "question": "Does a retained accession or source table bind SLC6A6 muscle RNA and taurine concentration in the same person and aliquot, with treatment/genotype recorded?",
      "nextEvidence": "Missing input: released source data or exact same-person sample/side/aliquot crosswalk with taurine values; do not run an AG2 reference prediction as a proxy for this paired test.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A36&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A37",
      "title": "Axonal transport and proteostasis",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "Existing P7 mouse triceps matrix adds Dnajc5 values with nonsignificant contrasts; treatment interaction is near zero, and HSPA8 control studies have unresolved construct identity.",
      "counterfinding": "The RNA result is small and statistically unresolved, not an independent cohort; DnaJ chimera/preprint identities and HSPA8/NEF construct/run pairing remain unbound.",
      "question": "Can the exact published and tested HSPA8/NEF constructs, chimera junctions, tags, and raw run/well pairing be recovered to resolve the control identity before any calibrated comparison?",
      "nextEvidence": "Missing input: exact chimera junctions and construct/tag sequences plus source-bound raw run/well pairing; no new AG2 run needed.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A37&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A38",
      "title": "Neuroinflammation and glia",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "GSE320428 arrays and sample labels are bound; PERP/p53 association direction is robust to fixed omissions, while PERP/microglia association changes sign across omissions.",
      "counterfinding": "Biological replicate-to-animal/pool mapping is missing; no new p/q values or CIs; the estimand and error model are not specified.",
      "question": "What estimand and covariance/error model should govern the existing PERP/p53 and PERP/microglia contrasts, given unresolved replicate grouping?",
      "nextEvidence": "Next step: specify the estimand and error model from the documented biological sample structure, using the pinned source review; only then decide whether existing data support additional inference.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A38&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A39",
      "title": "SMN2 base-editing reference",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "D10/P8 source Oligo overlaps one possible 20-nt window in reverse-complement orientation once in SMN2; none in SMN1. Separately, none of 19 saved local guide strings matches four Oligo windows.",
      "counterfinding": "The possible spacer-window hit is only sequence identity; authentic spacer, guide/PAM, construct and editing function remain unverified. Two searches used distinct sequence sets and are not contradictory.",
      "question": "Can the authentic D10/P8 spacer and complete guide/PAM/construct sequence be source-bound, then compared to the single SMN2 genomic match?",
      "nextEvidence": "Missing input: original full spacer/PAM and construct sequence with authenticated orientation; AG2 is not an editing-efficiency assay.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A39&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A40",
      "title": "Expression-signature reversal",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "Mapping audit preserves 112,180 RNA/splice rows and 61,166 ambiguous B candidates; GSE290980 has 8 libraries/39,266 barcodes, while the GSE108094 panel has no PERP event and one TP73 SMA value.",
      "counterfinding": "Possible coordinate matches are not confirmed gene identities; two libraries per cell line are not independent donors; historical regulon code mishandled zero/NaN/Inf and the offline fix is not deployed.",
      "question": "Which documented method version and sign convention produced the historical regulon result, and which source rows were affected?",
      "nextEvidence": "Missing input: immutable producer/helper source and execution logs for the regulated output; do not use AG2 to validate ambiguous row-to-gene mapping.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A40&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A41",
      "title": "mTOR–DEPTOR energy sensing",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "No qualifying primary source establishes direct WT p62-PB1/SMN binding or SMA muscle p-4E-BP1 reduction; 90-nM structure contains mutant SQSTM1 PB1, not WT or SMN.",
      "counterfinding": "Tagged-cell co-recovery and endogenous mouse-motor-neuron co-IP are distinct from purified direct binding; exact gift-plasmid sequence/tags are unavailable; proteome sensitivity had no corrected hits.",
      "question": "Can exact WT p62/PB1/SMN constructs and a direct binding assay be source-bound, or a qualifying primary p-4E-BP1 SMA skeletal-muscle measurement be identified?",
      "nextEvidence": "Missing input: complete plasmid/construct/tag sequences and qualified direct assay, or a source-bound relevant SMA muscle phospho-measurement; AG2 cannot answer protein binding.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A41&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A42",
      "title": "GSK3B and SMN increase",
      "currentAG2ContextIds": [],
      "AG2ResultAvailable": false,
      "questionType": "other_method_needed",
      "existingFinding": "The 400-molecule panel matches a dated Enamine kinase set, but selection-pool definition/order remain unknown. GSK3B biochemical, HEK293 reporter, fibroblast and motor-neuron reports are not interchangeable.",
      "counterfinding": "Makhortova fibroblast ligand labels and PDGF result conflict with separate mouse ESC-derived MN report; tested isoform/preparation/dose are not known to match; Ohuchi uses one patient and three clones, not three people.",
      "question": "Can the original 48,915-member selection pool and selection script/order be recovered, and can exact tested PDGF preparation/dose be tied across the source assays?",
      "nextEvidence": "Missing input: original pool-selection provenance plus exact ligand/isoform/dose and assay arm crosswalk; do not treat a GSK3B score as SMN stabilization.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A42&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A43",
      "title": "SMN2 cis-regulatory expression",
      "currentAG2ContextIds": [
        "ag2-smn2-expression",
        "ag2-smn2-gene-first",
        "ag2-smn2-regulatory-sources"
      ],
      "AG2ResultAvailable": true,
      "questionType": "already_done",
      "existingFinding": "Prior source-bound AG2 SMN2 gene-first, variant/splice and regulatory-source contexts are already integrated in the 11-context Explorer; six donor ATAC comparison has no selected peaks and no SMA donors.",
      "counterfinding": "Historical minigene T−255C/C−255T is not physically bound to rs1317747440/NM_017411.4:c.835−260C>T; no supplement link in checked metadata does not prove none exists; transgene context limits locus-specific interpretation.",
      "question": "Can an original supplement, accession, or complete minigene sequence bind the historical variant to an exact genomic allele/transcript, without repeating existing AG2 contexts?",
      "nextEvidence": "Missing input: authentic complete minigene sequence or source supplement/accession establishing physical variant identity; no new AG2 call until this identity is resolved.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A43&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    },
    {
      "axisId": "A44",
      "title": "Modifier cis-regulatory dosage",
      "currentAG2ContextIds": [
        "ag2-pls3-rs73226811",
        "ag2-pls3-gene-first",
        "ag2-hspa8-mouse-cis",
        "ag2-pls3-blood-c367"
      ],
      "AG2ResultAvailable": true,
      "questionType": "already_done",
      "existingFinding": "Prior source-bound AG2 contexts for PLS3 allele/splicing/reference questions are already integrated; NCALD source libraries are same-donor and not genotype-linked, and GSE290441 lacks its FLAIR annotation model.",
      "counterfinding": "BL35 terminal signature appears only in the defining read; discordant-sibling source has no accessible RNA accession or modifier genotype mapping; PLS3 c.367+182C>T remains separate and identity-unresolved.",
      "question": "Can the original GSE290441 FLAIR GTF/BED/model or an independent genotype-bound human motor-neuron RNA source be obtained for the existing NCALD/PLS3 question?",
      "nextEvidence": "Missing input: GSE290441 FLAIR GTF/BED/model or independent source accession binding genotype, transcript, and motor-neuron RNA; no duplicate AG2 PLS3 call.",
      "sourceArchiveUrl": "https://sma-research.info/pathway/?axis=A44&section=sources",
      "interpretationLimit": "This is a source-based research question, not an experimental result or a claim of model efficacy."
    }
  ]
}