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"validReplicates": 10000, "degenerate": true }, "left_accuracy": { "lo": 0.464, "hi": 0.584, "validReplicates": 10000, "degenerate": false }, "right_accuracy": { "lo": 0.464, "hi": 0.584, "validReplicates": 10000, "degenerate": false }, "difference_accuracy": { "lo": 0, "hi": 0, "validReplicates": 10000, "degenerate": true }, "left_balancedAccuracy": { "lo": 0.42311632416279316, "hi": 0.5910502955825536, "validReplicates": 10000, "degenerate": false }, "right_balancedAccuracy": { "lo": 0.42311632416279316, "hi": 0.5910502955825536, "validReplicates": 10000, "degenerate": false }, "difference_balancedAccuracy": { "lo": 0, "hi": 0, "validReplicates": 10000, "degenerate": true } } } } ], "combined": { "models": [ "claude-sonnet-5-5", "gpt-6-astra", "gemini-4-argon-high" ], "hypotheses": 245, "questions": 49, "rules": [ { "minVotes": 1, "strict": { "hypotheses": 245, "questions": 49, "selected": 97, "matches": 4, "known": 4, "missed": 0, "counts": { "yes_true": 4, "yes_false": 93, 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"yes_false": 14, "no_true": 23, "no_false": 195 }, "rates": { "ppv": 0.48148148148148145, "npv": 0.8944954128440367, "sens": 0.3611111111111111, "spec": 0.9330143540669856, "youden": 0.2941254651780967, "accuracy": 0.8489795918367347, "balancedAccuracy": 0.6470627325890483 } } } ] }, "promptExample": { "system": "Return a JSON object.", "user": "For each hypothesis below, will it be confirmed experimentally?\n\nBACKGROUND\nIntestinal stem-cell function and regenerative capacity decline with age, compromising maintenance and repair of the intestinal epithelium. Both cell-intrinsic changes and signals from the aged systemic environment may contribute to this decline. Chronic inflammation and altered cellular metabolism are common features of ageing, but how circulating conditions are translated into functional defects in intestinal regeneration was unresolved. It was also unclear whether manipulating systemic or metabolic processes could preserve or restore aged stem-cell activity.\n\nRESEARCH QUESTION\nHow does the aged systemic environment causally impair intestinal stem-cell metabolism and regenerative function?\n\nHYPOTHESES\n[H1] Elevated circulating kynurenine in aged animals persistently activates aryl hydrocarbon receptor signaling in intestinal stem cells, reducing their capacity to use fatty acids for regeneration. Mechanism: Sustained kynurenine–aryl hydrocarbon receptor signaling represses the PPAR-regulated fatty-acid oxidation program, limiting mitochondrial substrate flexibility during regenerative proliferation. Prediction: Kynurenine at concentrations measured in aged plasma reproduces reduced fatty-acid oxidation and regenerative output; stem-cell aryl hydrocarbon receptor deletion prevents both effects despite equivalent kynurenine exposure.\n\n[H2] An age-associated increase in circulating saturated fatty acids impairs intestinal stem cells through ceramide accumulation rather than through inflammatory cytokines alone. Mechanism: Excess saturated fatty acids drive de novo ceramide synthesis in stem cells, disrupting mitochondrial membrane function and increasing reactive oxygen species sufficiently to impair self-renewal. Prediction: The lipid fraction of aged serum reproduces the metabolic and regenerative defects, whereas lipid depletion removes them; inhibiting stem-cell ceramide synthesis rescues function even when aged-serum cytokines remain present.\n\n[H3] The aged systemic environment impairs intestinal stem-cell metabolism primarily by disrupting metabolic support from Paneth cells. Stem-cell defects therefore arise secondarily from an altered local niche. Mechanism: Circulating inflammatory factors suppress Paneth-cell glycolysis and lactate export, reducing the supply of lactate available for oxidation by neighboring intestinal stem cells. Prediction: Paneth cells exposed to aged serum impair otherwise untreated young stem cells after serum washout, with reduced transfer of isotope-labeled lactate into stem-cell mitochondrial metabolites; restoring Paneth-cell lactate export rescues regeneration.\n\n[H4] Elevated circulating TNF in aged animals impairs intestinal regeneration by suppressing mitochondrial pyruvate oxidation in intestinal stem cells. This metabolic restriction directly limits their expansion after injury. Mechanism: TNF activates stem-cell TNFR1–NF-κB signaling, increasing pyruvate dehydrogenase kinase activity and inhibitory phosphorylation of pyruvate dehydrogenase, thereby reducing glucose-derived carbon entry into the tricarboxylic acid cycle. Prediction: Aged serum reduces glucose-derived mitochondrial carbon flux and organoid formation; stem-cell-specific TNFR1 deletion or blockade of pyruvate dehydrogenase inhibition restores both despite continued exposure to aged serum.\n\n[H5] Chronic exposure to circulating interferons in old age depletes intestinal stem-cell NAD+ and thereby compromises mitochondrial function and regeneration. Mechanism: Sustained interferon signaling induces oxidative DNA damage and PARP-dependent NAD+ consumption, reducing NAD+-dependent mitochondrial enzyme activity and respiratory capacity. Prediction: Aged serum increases stem-cell PARylation before NAD+ and respiration decline; interferon-receptor deletion or selective suppression of PARP activity prevents these changes and restores regeneration without correcting circulating lipid or nutrient levels.\n\nReturn a JSON object with a \"forecasts\" array. For each hypothesis include its \"id\" and a boolean \"confirmed\"." }, "interpretation": "Direct yes/no forecasts of experimental confirmation, evaluated retrospectively against saved article correspondence. This does not establish biological falsehood for unmatched hypotheses, prospective experimental calibration, a causal effect of removing criteria, or learning of model parameters. The old advice question and the old probability >= .5 are separate comparators; both use exact common identities. No multiplicity-adjusted superiority claim.", "design": { "protocol": "direct-confirmation-v1", "createdAt": "2026-10-22T19:55:28.638889+00:00", "models": [ "claude-sonnet-5-5", "gpt-6-astra", "gemini-4-argon-high", "grok-4.5" ], "questions": 50, "hypotheses": 250, "inputSha256": "42f5a42e0d31a3e92177e9e45f314a64765e4309a3ea131e5b1b30b4361e3f68", "previousInputSha256": "f1f53a813f414f6a2c30e6b75eaa96e770cf703ad93e32204b69bee8ee561039", "taskSourceSha256": "068c3136304a39fb31e7a68aa933ce5b4949a46d7f23d5b32fc67c53a688e8f0", "system": "Return a JSON object.", "question": "For each hypothesis below, will it be confirmed experimentally?", "context": "Same full background, research question and five anonymous full hypotheses as previous experimental-support-v1 run", "output": "One id and confirmed boolean per hypothesis; no scientific rubric, requested justification or probability", "policy": "Use each saved confirmed boolean exactly as issued; no forced positive count", 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"381268acc642782b40a51e66ab0eebee35db66c813c65a81695b65df000edd48", "runs/grok-4.5/R42601407.invalid.json": "94678baea30dc7084146c7d6ade03a5c7890d5fa2616f1ed1ca54a7adee1d73d", "runs/grok-4.5/R42605193.attempt-1.json": "c8c206e274f98e26d23b9d5587e0bed8617f8e6b9454b78be7c65c0eb77c7f1c", "runs/grok-4.5/R42605193.attempt-2.json": "c39dc5669e43ddbad553537a2b392b40f7ff3fb299b60373645d6a0ebe5f9666", "runs/grok-4.5/R42605193.invalid.json": "0462570653be0635170d2001f5aa7692d3fd8da51a3337e4ee8f516090c2ada0", "runs/grok-4.5/pilot-format-failure.json": "dc244168eeefdd3d963593893b076917a4e47298e812bbdcd0effc7c1343c280", "previous/grok-4.5.json": "5625fd8a3935d5ed2bf5b9f7cdf57ccc8e9a4a8a95d816e5b27836650f518d89" }, "callCountMeaning": "calls counts audited logical application completions. The fixed two-response budget applies at this boundary. Internal client retries may occur within a logical completion; sanitized attempt histories and their separate counts are retained, without private service addresses.", "transportNote": "The benchmark messages contain no scientific rubric. Existing provider CLI wrappers retain their standard no-tools and final-answer/JSON instructions, unchanged from the preceding run. Transport source hashes, technical instruction text and actual audited no-tool receipts are included; private provider-wrapper code remains outside the public archive. The displayed request shows benchmark messages, not an assertion that provider/platform base instructions are absent.", "reproduction": "Reconstruct saved replies, audit receipts and matched identities; jointly resample original questions 10000 times. Recorded coin remains unchanged." }