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Procedural Refinement by LLM-driven Algorithmic Debugging for ARC-AGI-2

arXiv:2603.20334v4 Announce Type: replace-cross Abstract: In high-complexity abstract reasoning, a system must infer a latent rule from a few examples or structured observations and apply it to unseen instances. LLMs can express such rules as programs, but ordinary conversation-based refinement is largely outcome-level: it observes that an answer or output is wrong without formally re-checking which abstraction, relation, or transformation justified that outcome. We propose \emph{Abduction-Based Procedural Refinement} (ABPR), a neuro-symbolic refinement approach that couples an LLM with a Prolog meta-interpreter. ABPR treats each candidate program as an executable declarative hypothesis of the latent rule and reifies its SLD goal--subgoal resolution into compact proof-tree-style derivations, following Shapiro's algorithmic program debugging (APD). In this view, refinement is not merely code-level debugging, but semantic re-checking of the model's hypothesised rule. We evaluate ABPR primarily on ARC-AGI-2, a challenging few-shot abstract rule induction benchmark over grid transformations. ABPR with Gemini-3-Flash achieves 56.67\% Pass@2, while GPT-5.5 xHigh with ABPR reaches 98.33\% Pass@2 on the public evaluation set. Supplementary experiments on fill-in-the-blank I-RAVEN-X and A-I-RAVEN adaptations provide evidence that the same trace-guided framework extends beyond ARC-specific grid tasks to RAVEN-style relational and analogical abstraction. Repeated-run and sensitivity analyses show that parallel trace-guided search reduces stochastic variance as search breadth and total search depth increase.
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Integrated analysis of network pharmacology and multi-omics reveals the mechanisms of Zuogui Jiangtang Qinggan formula ameliorates MASLD via fatty acid metabolic reprogramming

Phytomedicine. 2026 Mar 30;155:158128. doi: 10.1016/j.phymed.2026.158128. Online ahead of print.

ABSTRACT

BACKGROUND: The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise, and its pathogenesis is complex, creating an urgent need to discover novel and effective therapeutic strategies. The Zuogui Jiangtang Qinggan formula (ZGJTQGF), an approved in-hospital preparation, has demonstrated significant clinical efficacy in treating diabetes over several decades. However, the mechanisms underlying its potential therapeutic effects on MASLD remain unclear PURPOSE: This study systematically investigates the therapeutic effects and molecular mechanisms of ZGJTQGF on MASLD through the integration of network pharmacology and multi-omics strategies.

METHODS: The model of MASLD was successfully induced in db/db mice by a high-fat diet (HFD), which displayed characteristic dyslipidaemia. Serum biomarkers, histology, and hepatic multi-omics analyses were employed to assess metabolic status, steatosis, targets, and pathways. Ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), molecular docking analysis and in vitro verification were applied to explore the active ingredients of ZGJTQGF.

RESULTS: ZGJTQGF significantly reduced dyslipidemia in HFD-fed mice, inhibited pro-inflammatory cytokines, and restored glucose metabolic balance by lowering levels of glucose, insulin, OGTT, and HOMA-IR. Histopathology showed reduced lipid deposition and hepatocyte damage. Comprehensive multi-omics analysis suggested that regulating the AMPK/PGC-1Ξ±/PPARΞ± and FXR-BSEP signaling pathways could be potential targets for ZGJTQGF in reprogramming glucose and lipid metabolism in MASLD treatment. Blood component analysis identified 52 ZGJTQGF-derived compounds. In molecular docking experiments, Wogonin, Naringenin, Quercetin, Tanshinone IIA and Berberine showed high-affinity binding to core targets in AMPK, PPARΞ±, PGC-1Ξ±, FXR and FAS. Mechanistically, ZGJTQGF activated AMPK/PPARΞ± /PGC-1Ξ± and FXR-BSEP signaling pathway, promotes fatty acid Ξ² oxidation and enhances energy consumption in AML-2 and 3T3-L1 cells, downregulates SREBP-1-dependent adipogenesis (reduces ACC1 and FAS expression), alleviates MASLD driven reprogramming of glucose and lipid metabolism, and regulates lipid metabolism and fatty acid synthesis.

CONCLUSIONS: ZGJTQGF activates the AMPK/PPARΞ± /PGC-1Ξ± pathway and inhibits abnormal lipid accumulation in diabetic fatty liver by promoting fatty acid Ξ²-oxidation, energy consumption, and bile acid metabolism. These findings provide new insights into the mechanism of ZGJTQGF in the treatment of diabetic fatty liver disease.

PMID:41962267 | DOI:10.1016/j.phymed.2026.158128

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Integrated analysis of network pharmacology and multi-omics reveals the mechanisms of Zuogui Jiangtang Qinggan formula ameliorates MASLD via fatty acid metabolic reprogramming

Phytomedicine. 2026 Mar 30;155:158128. doi: 10.1016/j.phymed.2026.158128. Online ahead of print.

ABSTRACT

BACKGROUND: The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise, and its pathogenesis is complex, creating an urgent need to discover novel and effective therapeutic strategies. The Zuogui Jiangtang Qinggan formula (ZGJTQGF), an approved in-hospital preparation, has demonstrated significant clinical efficacy in treating diabetes over several decades. However, the mechanisms underlying its potential therapeutic effects on MASLD remain unclear PURPOSE: This study systematically investigates the therapeutic effects and molecular mechanisms of ZGJTQGF on MASLD through the integration of network pharmacology and multi-omics strategies.

METHODS: The model of MASLD was successfully induced in db/db mice by a high-fat diet (HFD), which displayed characteristic dyslipidaemia. Serum biomarkers, histology, and hepatic multi-omics analyses were employed to assess metabolic status, steatosis, targets, and pathways. Ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), molecular docking analysis and in vitro verification were applied to explore the active ingredients of ZGJTQGF.

RESULTS: ZGJTQGF significantly reduced dyslipidemia in HFD-fed mice, inhibited pro-inflammatory cytokines, and restored glucose metabolic balance by lowering levels of glucose, insulin, OGTT, and HOMA-IR. Histopathology showed reduced lipid deposition and hepatocyte damage. Comprehensive multi-omics analysis suggested that regulating the AMPK/PGC-1Ξ±/PPARΞ± and FXR-BSEP signaling pathways could be potential targets for ZGJTQGF in reprogramming glucose and lipid metabolism in MASLD treatment. Blood component analysis identified 52 ZGJTQGF-derived compounds. In molecular docking experiments, Wogonin, Naringenin, Quercetin, Tanshinone IIA and Berberine showed high-affinity binding to core targets in AMPK, PPARΞ±, PGC-1Ξ±, FXR and FAS. Mechanistically, ZGJTQGF activated AMPK/PPARΞ± /PGC-1Ξ± and FXR-BSEP signaling pathway, promotes fatty acid Ξ² oxidation and enhances energy consumption in AML-2 and 3T3-L1 cells, downregulates SREBP-1-dependent adipogenesis (reduces ACC1 and FAS expression), alleviates MASLD driven reprogramming of glucose and lipid metabolism, and regulates lipid metabolism and fatty acid synthesis.

CONCLUSIONS: ZGJTQGF activates the AMPK/PPARΞ± /PGC-1Ξ± pathway and inhibits abnormal lipid accumulation in diabetic fatty liver by promoting fatty acid Ξ²-oxidation, energy consumption, and bile acid metabolism. These findings provide new insights into the mechanism of ZGJTQGF in the treatment of diabetic fatty liver disease.

PMID:41962267 | DOI:10.1016/j.phymed.2026.158128

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