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Received — 8 April 2026 ⏭

IC3-Evolve: Proof-/Witness-Gated Offline LLM-Driven Heuristic Evolution for IC3 Hardware Model Checking

✇cs.AI, q-bio.NC updates on arXiv.org
By: Mingkai Miao · Guangyu Hu · Ziyi Yang · Hongce Zhang
7 April 2026 at 12:00
arXiv:2604.03232v1 Announce Type: new Abstract: IC3, also known as property-directed reachability (PDR), is a commonly-used algorithm for hardware safety model checking. It checks if a state transition system complies with a given safety property. IC3 either returns UNSAFE (indicating property violation) with a counterexample trace, or SAFE with a checkable inductive invariant as the proof to safety. In practice, the performance of IC3 is dominated by a large web of interacting heuristics and implementation choices, making manual tuning costly, brittle, and hard to reproduce. This paper presents IC3-Evolve, an automated offline code-evolution framework that utilizes an LLM to propose small, slot-restricted and auditable patches to an IC3 implementation. Crucially, every candidate patch is admitted only through proof- /witness-gated validation: SAFE runs must emit a certificate that is independently checked, and UNSAFE runs must emit a replayable counterexample trace, preventing unsound edits from being deployed. Since the LLM is used only offline, the deployed artifact is a standalone evolved checker with zero ML/LLM inference overhead and no runtime model dependency. We evolve on the public hardware model checking competition (HWMCC) benchmark and evaluate the generalizability on unseen public and industrial model checking benchmarks, showing that IC3-Evolve can reliably discover practical heuristic improvements under strict correctness gates.

Multi-omics integration and machine learning reveal gut-immune signatures in idiopathic pulmonary fibrosis: insights from bulk RNA-seq, single-cell profiles, spatial transcriptomics, and experimental validation

✇(Multiomics OR Omics) AND (Lung OR gastric OR Hepatocellular)
By: Zhengyu Hu · Jiaqi Wang · Jialin Yu · Zheqing Hu · Jing Xue · Zhanbing Ma · Miaomiao Nian · Ruixin Qi · Tingting Zhao · Xia Cao · Hongxia Xin · Xiuyan Wang · Guilan Yang · Zhenzhen Gui · Xiaoming Liu · Juan Chen
6 April 2026 at 18:00

Front Immunol. 2026 Mar 19;17:1730289. doi: 10.3389/fimmu.2026.1730289. eCollection 2026.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with limited treatment options and a poor prognosis. Recent studies suggest a critical role for the gut-immune-lung axis in IPF, yet the underlying molecular mechanisms remain unclear.

METHODS: The current study performed in silico multi-omics integration of publicly available datasets, including bulk RNA-seq, single-cell and spatial transcriptomics, as well as peripheral blood multi-omics data to uncover key molecular signatures in IPF. Furthermore, machine learning techniques were utilized to identify core genes, whereas functional analyses and Mendelian randomization were conducted to evaluate the causal relationships among gut microbiota, immune cells, and IPF. Additionally, experimental validation using qPCR and ELISA assays was conducted in vitro, in vivo, and in patient plasma to confirm the expression patterns of key genes.

RESULTS: Across integrated public bulk, single-cell, spatial, and blood multi-omics, CXCL13, IL33, TLR4, and IGF1 were identified as core IPF genes consistently linked to immune infiltration and fibrotic remodeling. Deconvolution, scRNA-seq, and spatial mapping localized their dysregulation to fibroblasts and immune compartments (notably B-cell, macrophage, and mast-cell axes), highlighting fibroblast-immune crosstalk in fibrotic foci. A four-gene model robustly distinguished IPF from controls across cohorts. Mendelian randomization supported a gut-immune-lung axis, indicating causal effects of specific gut taxa on IPF risk via immune phenotypes. qPCR/ELISA in TGF-β1-stimulated fibroblasts, bleomycin mouse lungs, and patient plasma corroborated upregulation of IL33, CXCL13, IGF1 and downregulation of TLR4. Drug-signature reversal nominated cucurbitacin I and temsirolimus; molecular docking was performed as a preliminary in silico, computer-simulation-based assessment of potential ligand-protein interactions between these compounds and the four core targets.

CONCLUSION: This study provides new insights into the importance of gut-immune-lung axis in IPF and identifies CXCL13, IL33, TLR4, and IGF1 as diagnostic signatures and therapeutic targets. By integrating public multi-omics resources with experimental validation, our findings offer a foundation for future diagnostic and treatment strategies aimed at modulating the gut microbiota and immune system in IPF.

PMID:41939867 | PMC:PMC13043422 | DOI:10.3389/fimmu.2026.1730289

Multi-omics integration and machine learning reveal gut-immune signatures in idiopathic pulmonary fibrosis: insights from bulk RNA-seq, single-cell profiles, spatial transcriptomics, and experimental validation

✇Omics In Lung
By: Zhengyu Hu · Jiaqi Wang · Jialin Yu · Zheqing Hu · Jing Xue · Zhanbing Ma · Miaomiao Nian · Ruixin Qi · Tingting Zhao · Xia Cao · Hongxia Xin · Xiuyan Wang · Guilan Yang · Zhenzhen Gui · Xiaoming Liu · Juan Chen
6 April 2026 at 18:00

Front Immunol. 2026 Mar 19;17:1730289. doi: 10.3389/fimmu.2026.1730289. eCollection 2026.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with limited treatment options and a poor prognosis. Recent studies suggest a critical role for the gut-immune-lung axis in IPF, yet the underlying molecular mechanisms remain unclear.

METHODS: The current study performed in silico multi-omics integration of publicly available datasets, including bulk RNA-seq, single-cell and spatial transcriptomics, as well as peripheral blood multi-omics data to uncover key molecular signatures in IPF. Furthermore, machine learning techniques were utilized to identify core genes, whereas functional analyses and Mendelian randomization were conducted to evaluate the causal relationships among gut microbiota, immune cells, and IPF. Additionally, experimental validation using qPCR and ELISA assays was conducted in vitro, in vivo, and in patient plasma to confirm the expression patterns of key genes.

RESULTS: Across integrated public bulk, single-cell, spatial, and blood multi-omics, CXCL13, IL33, TLR4, and IGF1 were identified as core IPF genes consistently linked to immune infiltration and fibrotic remodeling. Deconvolution, scRNA-seq, and spatial mapping localized their dysregulation to fibroblasts and immune compartments (notably B-cell, macrophage, and mast-cell axes), highlighting fibroblast-immune crosstalk in fibrotic foci. A four-gene model robustly distinguished IPF from controls across cohorts. Mendelian randomization supported a gut-immune-lung axis, indicating causal effects of specific gut taxa on IPF risk via immune phenotypes. qPCR/ELISA in TGF-β1-stimulated fibroblasts, bleomycin mouse lungs, and patient plasma corroborated upregulation of IL33, CXCL13, IGF1 and downregulation of TLR4. Drug-signature reversal nominated cucurbitacin I and temsirolimus; molecular docking was performed as a preliminary in silico, computer-simulation-based assessment of potential ligand-protein interactions between these compounds and the four core targets.

CONCLUSION: This study provides new insights into the importance of gut-immune-lung axis in IPF and identifies CXCL13, IL33, TLR4, and IGF1 as diagnostic signatures and therapeutic targets. By integrating public multi-omics resources with experimental validation, our findings offer a foundation for future diagnostic and treatment strategies aimed at modulating the gut microbiota and immune system in IPF.

PMID:41939867 | PMC:PMC13043422 | DOI:10.3389/fimmu.2026.1730289

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