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TIGFlow-GRPO: Trajectory Forecasting via Interaction-Aware Flow Matching and Reward-Guided Optimization
ASTROREPOMICS: A curated transcriptomic database for reproductive biology in space
iScience. 2026 Mar 10;29(4):115309. doi: 10.1016/j.isci.2026.115309. eCollection 2026 Apr 17.
ABSTRACT
Spaceflight imposes substantial physiological stress on reproductive systems, yet relevant transcriptomic data remain fragmented across repositories. To address this need, we developed ASTROREPOMICS, a web-based platform that integrates 17 rigorously normalized and batch-corrected transcriptomic datasets spanning multiple species and reproductive tissues. The platform supports reproducible cross-study and cross-species analyses through standardized metadata and an intuitive user interface. We highlight its utility through two example analyses: (1) irradiated mouse sperm exhibited suppression of RNA splicing and protein-processing pathways alongside activation of interferon- and GPCR-associated programs; and (2) a multi-species intersected-DEG assessment between irradiated rat mammary tissue and microgravity-exposed zebrafish embryos uncovered conserved signatures involving RNA metabolism, cytokine signaling, and angiogenesis. By consolidating dispersed datasets and offering tailored analytical capabilities, ASTROREPOMICS provides a centralized resource for hypothesis generation and strengthens the research infrastructure needed to advance reproductive health studies in space, supporting long-term efforts to safeguard fertility during deep-space exploration.
PMID:41940322 | PMC:PMC13049440 | DOI:10.1016/j.isci.2026.115309
Cell-type-specific transposon demethylation and TAD remodeling in aging mouse brain
TSHA: A Benchmark for Visual Language Models in Trustworthy Safety Hazard Assessment Scenarios
Generative AI in Action: Field Experimental Evidence from Alibaba's Customer Service Operations
ContractSkill: Repairable Contract-Based Skills for Multimodal Web Agents
Robust transcriptomic hallmarks targeting intratumor heterogeneity in intrahepatic cholangiocarcinoma
Cell Rep Med. 2026 Mar 30:102708. doi: 10.1016/j.xcrm.2026.102708. Online ahead of print.
ABSTRACT
Intratumor heterogeneity (ITH) undermines transcriptome-based stratification in intrahepatic cholangiocarcinoma (iCCA). Here, we integrate multi-omics data from multi-region, single-region, and single-cell RNA sequencing cohorts to systematically characterize gene expression ITH. We uncover that immune and stromal heterogeneity are primary drivers of ITH, leading to misclassification of a median 27.8% of tumors by existing subtyping systems. To overcome this, we identify a low-intratumor-heterogeneity/high-intertumor-variability (LIHV) gene set and develop an ITH-insensitive classification system defining five subgroups: inflammatory (SI), metabolic (SII), atypical (SIII-1), immune-silent (SIII-2), and neurodegenerative (SIII-3). These subgroups exhibit distinct clinical outcomes, molecular features, immune landscapes, and therapeutic vulnerabilities. GPRC5A and VTCN1 serve as robust immunohistochemical biomarkers for SI and SIII tumors, while serum CEA and CA19-9 identify inflammatory iCCA. Therapeutically, HSP90 inhibition synergizes with anti-PD1 in inflammatory iCCA, whereas combined anti-PD1 and anti-TIM3 suppresses neurodegenerative iCCA. Collectively, our study provides a robust molecular framework and actionable therapeutic strategies for iCCA.
PMID:41916296 | DOI:10.1016/j.xcrm.2026.102708
Doxorubicin promotes the production of inflammatory cytokines in tumor-associated macrophages through activating lactate dehydrogenase A
Cell Death Discovery, Published online: 31 March 2026; doi:10.1038/s41420-026-03014-0
Doxorubicin promotes the production of inflammatory cytokines in tumor-associated macrophages through activating lactate dehydrogenase AProposed Role of Circadian Clock Genes in Pathogenesis of HCC: Molecular Subtyping and Characterization
Biomedicines. 2026 Mar 12;14(3):645. doi: 10.3390/biomedicines14030645.
ABSTRACT
Background: Hepatocellular carcinoma (HCC) stands as a prevalent global health issue with increasing incidence and mortality rates. Hepatocellular carcinoma (HCC) exhibits profound molecular and clinical heterogeneity, which limits the effectiveness of current therapeutic strategies. Circadian rhythm disruption has been implicated in metabolic reprogramming, proliferation, and immune modulation in cancer, but its role in shaping HCC heterogeneity remains poorly defined. Methods: Four public HCC transcriptomic cohorts (TCGA-LIHC, CHCC, LIRI, LICA) were integrated using RMA normalization and ComBat for batch correction. Consensus clustering based on 31 core circadian clock genes (CCGs) identified robust molecular subtypes. Multi-omics characterization-including genomic alterations, pathway activity (GSEA/GSVA), immune microenvironment profiling (CIBERSORT, EPIC, MCP-counter, xCell), and drug-sensitivity prediction (pRRophetic/oncoPredict)-was performed to delineate subtype-specific biological properties. A nine-gene CCG-based RiskScore model was constructed using LASSO Cox regression to internally validate subtype robustness and intra-subtype risk stratification. Results: Using consensus clustering of 31 core CCGs in TCGA-LIHC and three independent validation cohorts (CHCC, LIRI, LICA), we identified three reproducible subtypes-Cluster-1 (metabolic-quiescent), Cluster-2 (transition-intermediate), and Cluster-3 (proliferation-inflammatory)-which were recapitulated across cohorts and showed distinct overall survival (Cluster-3 worst; log-rank p values significant across datasets). Multi-omic characterization revealed that Cluster-3 exhibits the highest tumor mutational burden and CNV burden with enrichment of TP53/AXIN1/TERT alterations, strong activation of cell-cycle, E2F, and G2M programs, and an immune-hot yet immunosuppressed microenvironment enriched for TAMs, Tregs and MDSCs. By contrast, Cluster-1 shows relative genomic stability, dominant hepatic metabolic signatures (fatty-acid oxidation, bile-acid and xenobiotic metabolism) and an immune-cold phenotype. Single-cell mapping linked ALAS1 expression to malignant hepatocytes predominating in Cluster-1, whereas NONO and CSNK1D localized to stromal (CAFs/TECs) and both malignant/immune compartments respectively in Cluster-3, providing a cellular mechanism for subtype-specific metabolism, angiogenesis and immune modulation. Finally, a nine-gene CCG-based RiskScore validated prognostic stratification and drug-sensitivity predictions indicated subtype-specific therapeutic vulnerabilities (notably increased predicted TKI sensitivity in Cluster-3). Conclusion: In conclusion, this study proposes a robust circadian rhythm-based molecular classification of hepatocellular carcinoma, revealing three biologically and clinically distinct subtypes characterized by divergent genomic alterations, metabolic programs, immune microenvironment states, and prognostic patterns. By integrating bulk and single-cell transcriptomic data, we identify subtype-specific roles of key circadian regulators-including ALAS1, NONO, and CSNK1D-in shaping tumor metabolism, proliferation, stromal remodeling, and immune suppression. These findings highlight circadian dysregulation as a potential upstream factor associated with HCC heterogeneity and provide a conceptual framework for developing subtype-tailored mechanistic studies and circadian-informed therapeutic strategies.
PMID:41898292 | PMC:PMC13024568 | DOI:10.3390/biomedicines14030645
SVNeoPP: A Workflow for Structural-Variant-Derived Neoantigen Prediction and Prioritization Using Multi-Omics Data
Biology (Basel). 2026 Mar 19;15(6):492. doi: 10.3390/biology15060492.
ABSTRACT
BACKGROUND: Tumor neoantigens are key targets for personalized vaccines and T-cell therapies, yet most pipelines focus on neoantigens derived from SNV/small indel and often yield a limited number of high-quality candidates. SVs are prevalent in tumors and can generate novel chimeric sequences and neopeptides, making them a promising additional source of neoantigens. However, SV-derived neoantigen prediction remains challenging due to breakpoint uncertainty, isoform-dependent coding inference, and limited integration of multi-dimensional evidence and reproducibility.
METHODS: We developed SVNeoPP (Structural Variant Neoantigen Prediction and Prioritization), an end-to-end workflow for SV-derived neoantigen analysis. SVNeoPP takes WGS and RNA-seq as inputs, performs SV calling and annotation, and reconstructs altered transcripts and coding sequences in a traceable, isoform-aware manner to generate candidate peptides. Candidates are prescreened by integrating antigen-processing features with HLA binding prediction, and then hierarchically filtered and prioritized based on transcript expression, LC-MS/MS proteomics evidence, immunogenicity predictions, and sequence similarity to experimentally validated neoantigen databases. SVNeoPP is implemented in Snakemake to enable modular extension, checkpoint-based restarts, and end-to-end reproducibility.
RESULTS: Using a hepatocellular carcinoma (HCC) multi-omics dataset as a proof of concept, we demonstrated the performance of SVNeoPP and obtained a high-priority shortlist of candidate peptides. Compared with other methods, SVNeoPP substantially expanded the candidate search space for SV-derived neoantigens and showed more favorable distributions of antigen-processing and HLA binding features.
CONCLUSIONS: SVNeoPP provides a reusable, traceable, and interpretable multi-dimensional evidence-driven framework for SV-derived neoantigens. As a complementary module to SNV/small-indel pipelines, it broadens the neoantigen candidate repertoire and generates ranked candidates with interpretable evidence to facilitate downstream prioritization and decision-making.
PMID:41892252 | PMC:PMC13024079 | DOI:10.3390/biology15060492
ImplicitRM: Unbiased Reward Modeling from Implicit Preference Data for LLM alignment
Hierarchical Long Video Understanding with Audiovisual Entity Cohesion and Agentic Search
When Models Judge Themselves: Unsupervised Self-Evolution for Multimodal Reasoning
SIRT3 deacetylates STEAP4 to modulate cuproptosis sensitivity via mitochondrial metabolic reprogramming in HBV-related HCC
Cell Death Differ. 2026 Mar 16. doi: 10.1038/s41418-026-01713-w. Online ahead of print.
ABSTRACT
Hepatitis B virus (HBV) infection remains a leading etiological driver of hepatocellular carcinoma (HCC). Cuproptosis is a recently defined copper-dependent form of regulated cell death that selectively eliminates mitochondria-dependent cells; whether HBV rewires this vulnerability remains unknown. Here we unveil a novel HBV X protein (HBx)-driven mechanism of cuproptosis evasion. Integrative analysis of clinical specimens, HBx-transgenic (HBx-Tg) mice, and multi-omics datasets revealed marked downregulation of STEAP4 (six-transmembrane epithelial antigen of prostate 4), a metalloreductase essential for cuproptosis sensitivity, in HBV-positive HCC. Mechanistically, HBx attenuates sirtuin 3 (SIRT3), impairing deacetylation of STEAP4 at lysine 404 and abolishing its mitochondrial targeting. Consequently, cells switch from the tricarboxylic acid (TCA) cycle respiration to glycolysis, reducing sensitivity to the copper ionophore elesclomol (ES). Restoring STEAP4 expression or pharmacological activation of SIRT3 with honokiol (HKL) re-instated mitochondrial STEAP4 localization and re-sensitized HBV-related HCC cells to cuproptosis; combination with ES produced synergistic tumor suppression in vitro and in orthotopic models. Collectively, our findings establish the SIRT3-STEAP4 axis as a novel regulator of cuproptosis resistance in HBV-related HCC. HBx-mediated repression of SIRT3 disrupts STEAP4 deacetylation and mitochondrial targeting, fostering metabolic reprogramming and evasion of copper-induced cell death. The results provide a pre-clinical rationale for copper-directed combination strategies in HBV-associated HCC.
PMID:41840161 | DOI:10.1038/s41418-026-01713-w