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PubMed2026

Bacteroides cellulosilyticus-derived 2-hydroxyphenylacetic acid rectifies hepatic lipid homeostasis in MASLD by targeting the PPARγ-CD36 axis.

The gut microbiota plays an important role in the occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD), but the specific molecular mechanisms involved have not been fully elucidated. In this study, human cohort studies were performed to identify that the relative abundance of Bacteroides cellulosilyticus (B. cellulosilyticus) was significantly decreased in patients with MASLD. Through the integration of metagenomic and metabolomic analyses, it was confirmed that B. cellulosilyticus and its metabolite 2-hydroxyphenylacetic acid (2HPAA) are key factors regulating the occurrence and development of MASLD. Single-cell sequencing and lipidomic analyses revealed that 2HPAA can enter the liver through the enterohepatic circulation to exert regulatory effects. Specifically, 2HPAA inhibits the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway, thereby suppressing the expression of the fatty acid transporter CD36. Meanwhile, 2HPAA regulates lipid metabolism in hepatocytes by significantly enhancing palmitate conversion efficiency and inhibiting CD36 palmitoylation. This dual regulatory effect on CD36 expression and palmitoylation can reduce lipid accumulation in hepatocytes and ultimately alleviate MASLD progression. These findings reveal the mechanism by which B. cellulosilyticus and 2HPAA alleviate MASLD by targeting the PPARγ-CD36 pathway. This work provides a new perspective for the study of gut microbiota-host interactions in regulating liver diseases.

PPAR gamma↗

PubMed2026

ARX mutation-associated interneuron defects provide insights into mechanisms underlying developmental epilepsies.

Cortical interneuron (cIN) dysfunction is associated with various neurodevelopmental and neurological disorders, including developmental epilepsies, autism spectrum disorders and intellectual disabilities. Mutations in ARX (aristaless-related homeobox) are linked to these conditions, with or without accompanying structural brain anomalies. We previously demonstrated that the loss of Arx in the mouse ganglionic eminence, the birthplace of cINs, is associated with seizures, whereas its loss in cortical excitatory neuron progenitor cells results in structural anomalies but no seizures. To elucidate the pathophysiological role of ARX in cINs and its relationship to seizure phenotype, Arx conditional mutant mouse lines were investigated using Gad2- and Nkx2.1-Cre drivers to target distinct populations in the cIN lineage. Our data demonstrate that ARX abrogation results in defects in cIN density and distribution, as well as perinatal lethality. In these mice, we observed defects in cell cycle exit, a biased loss of the marginal zone migration stream of cINs, shifts in cell fate from caudal ganglionic eminence to medial ganglionic eminence identity, and a reduced number of parvalbumin⁺ and somatostatin⁺ cINs, with parvalbumin⁺ cINs being more severely affected. Single-cell RNA sequencing combined with chromatin immunoprecipitation and sequencing revealed that ARX regulates key processes involved in cell cycle progression, cIN subtype differentiation and cIN migration. Investigation of one downregulated target gene, Lmo1, uncovered a potential mechanism by which ARX regulates the number and distribution of cINs in the cortex. Cortical slice cultures demonstrate that LMO1 inhibits cIN migration by repressing Cxcr4 expression, which encodes a key receptor involved in cortical guidance. These data indicate that ARX positively regulates cIN migration by derepressing LMO1's repressive role. Consistent with our mouse model, we observed a significant loss of parvalbumin+ and somatostatin+ cINs in the brain of a patient carrying a pathogenic variant of ARX, who was diagnosed with developmental epileptic encephalopathy. Together, our data provide novel insights into how ARX and its target genes regulate cIN development and migration and into the pathogenic mechanisms underlying a spectrum of neurodevelopmental disorders linked to loss of ARX.

Animals↗

PubMed2026

RNA splicing and cardiovascular disease: a guide for cardiologists.

Alternative splicing (AS) is a fundamental RNA processing mechanism, which generates different RNA transcripts and consequently different protein isoforms from a single gene. This increases the diversity of proteins within an organism and can fine-tune biological processes. This review examines how cardiac-enriched RNA-binding proteins establish heart-specific splicing programs governing aspects of cardiac development, function, and disease. Developmentally, coordinated sarcomeric isoform switches underpin the foetal-to-adult transition and further isoform rewiring in ion channel and kinase genes determine electrophysiology and excitation-contraction coupling. AS contributes to the pathogenesis of several cardiomyopathies and emerging datasets suggest that pathological hypertrophy engages distinct splicing signatures compared with physiological hypertrophy. This review summarizes diagnostic and prognostic opportunities arising from bulk, long-read, and single-cell/nucleus transcriptomics, which resolve cell type-specific isoforms and disease-associated switches. Circulating RNA biomarkers (including splice ratios and circularRNAs) may signify myocardial remodelling and arrhythmic risk. Integrative approaches that link AS with proteomics and genomics improve variant interpretation, reveal previously unannotated protein isoforms, and enable tracking of disease progression and therapy response. Finally, an outline of therapeutic strategies to modulate AS in cardiovascular disease (CVD), including antisense oligonucleotides, small molecules, and genome-editing modalities (CRISPR, base, and prime editing), is provided. The major challenges that remain before splice-targeting therapeutics can be targeted to treat cardiovascular disease are highlighted. Lessons from neuromuscular indications establish clinical feasibility of splicing correction and motivate translation to cardiology. Together, mechanistic insight, biomarker development, and therapeutic innovation position RNA splicing as a tractable axis for precision cardiovascular medicine.

Humans↗

PubMed2026

Genetic architecture of endometriosis: risk factors, comorbidities and clinical implications.

BACKGROUND: In 1999, Dr Susan Treloar and colleagues conducted a landmark twin study in Australia and reported their estimate of 51% for the heritability of endometriosis. This important result led several groups to begin mapping genetic factors contributing to increased endometriosis risk. Despite early challenges, advances in genome-wide association studies (GWAS) have identified multiple genetic risk factors and some target genes implicated in follow-up studies on genetic regulation of transcription. Access to large publicly available genetic datasets and analysis with endometriosis GWAS results is also providing new opportunities to answer important questions about comorbid conditions associated with endometriosis and their implications for clinical practice. OBJECTIVE AND RATIONALE: The objective of the review is to summarize the last 25 years of genetic studies in endometriosis, outline contributions to our understanding of the disease, and suggest future directions to accelerate biological insights from genetic studies to improve clinical outcomes. SEARCH METHODS: A comprehensive review of scientific literature on the genetics of endometriosis was conducted through searches in PubMed and Google Scholar up to June 2026. Search terms included "endometriosis AND (genetics OR GWAS OR genetic risk factors)", For studies addressing the functional characterization of genetic risk loci, additional searches employed the terms "endometriosis AND (genotype-phenotype associations OR colocalization OR eQTL OR mQTL OR multi omics methods)". To identify studies examining shared genetic risk between endometriosis and comorbid conditions, the search strategy included "endometriosis AND (genetic correlation OR colocalization OR Mendelian randomisation)". Publications reporting discoveries related to genetic risk factors for endometriosis and studies interpreting their biological and clinical significance were critically evaluated, and 144 publications were discussed in the review. OUTCOMES: Discovery of genetic risk factors started slowly and has accelerated in recent years with developments in technology and international collaborations to combine data and increase statistical power. GWAS have mapped 80 genetic risk factors that implicate gene regulation of hormonal targets, development of the reproductive tract, regulation of cell proliferation, and regulation of epithelial cell differentiation. In common with most other complex diseases, effects of individual common genetic risk factors are small. However, several examples demonstrate that small effect sizes are not a good predictor for the impact of drugs developed against genetically validated targets. Genetic risk factors implicate five genes regulating gonadotrophin release and oestrogen action, the major target pathway of current drugs for treatment of endometriosis demonstrating proof-of-principal for biologically meaningful results. Genetic correlation and Mendelian Randomization studies highlight important causal relationships between endometriosis and comorbid conditions including a possible role for testosterone during development and shared genetic risk factors for gynaecological, gastrointestinal, pain, psychiatric, and inflammatory conditions. Understanding causal relationships between endometriosis and related conditions will aid clinical management and more personalized treatments. WIDER IMPLICATIONS: Genetic studies provide novel insights into endometriosis pathogenesis and associations with related comorbid conditions. Genetic factors modifying gene regulation and disease risk likely act in specific cell types, and access to datasets from genetically informed cell-based models, single-cell and spatial omics data are needed to accelerate progress. Future studies should address critical questions of heterogeneity and disease subtypes, expand the search for genetic risk factors to non-European populations, evaluate the role of rare and structural variants, and better integrate data from functional, genomics, genetics, and clinical studies to reduce diagnostic delay, develop novel treatment strategies, and translate discoveries into personalized management strategies for affected individuals. REGISTRATION NUMBER: N/A.

comorbid conditions↗

PubMed2026

Generation of spCAS9 expressing human mesenchymal stem cell line to study gene function during osteoblast differentiation.

Human bone marrow-derived stromal cells (hMSCs) are a great resource for studying how genes influence cell fate and differentiation into various cell types like osteoblasts, adipocytes, and chondrocytes, among other cell types. However, genetic manipulation of primary hMSCs has been challenging due to their short lifespan and cellular senescence after limited passaging. Their low and unstable transfection efficiency also complicates gene delivery or inactivation, hindering long-term functional studies. The limited lifespan has been effectively solved by immortalizing hMSCs with telomerase reverse transcriptase (hMSCs-TERT). The use of these cells is ideal for functional studies of osteoblast and adipocyte differentiation through genetic manipulation, providing a stable and reliable model. Here, we have engineered a stable CAS9 expressing hMSC-TERT cell line (hMSC-TERTCAS9) via lentiviral transduction. The constitutive expression of spCas9 enables efficient and reproducible gene editing. We demonstrate the potential of these hMSC-TERTCAS9 cells for generating gene disruptions using plasmid delivery of guide RNAs as a fast and efficient strategy for targeted genome editing. The edited cells can be sorted and expanded as single cells to obtain homogenous clonal cell lines with mono- as well as bi-allelic gene deletions, a crucial step for producing reliable experimental results. We further validate this cell line as a powerful tool for studying gene function during hMSC proliferation and differentiation, providing 3 distinct examples of its utility. Through the generation of indels, single-cell sorting, and clonal selection, we have efficiently inactivated the vitamin D receptor and created both larger (256 nucleotides) gene disruptions in Forkhead box protein O1 and precise removals of a small genomic sequence (73 nucleotides) coding for microRNA MIR675. This novel hMSC-TERTCAS9 cell line represents a significant advancement, offering a stable, efficient, and versatile platform for advanced genetic studies, high-throughput screening, and the creation of reliable cellular disease models.

CRISPR-Cas9↗

PubMed2026

Genome-Wide Association Analyses Identify Distinct Genetic Architectures for Extreme Early-Onset and Late-Onset T2D.

AIMS: Type 2 diabetes (T2D) is a heterogeneous disorder with substantial variation in age at onset (AAO). This study aimed to characterize the distinct genetic architectures and biological mechanisms underlying extreme AAO-defined T2D subtypes. MATERIALS AND METHODS: Using 74 795 European-ancestry participants from the UK Biobank, we performed genome-wide association studies (GWAS) of relatively early-onset T2D (eoT2D; AAO < 55 years) and late-onset T2D (loT2D; AAO ≥ 70 years). We investigated subtype-specific genetic loci, SNP-based heritability, genetic correlations, Mendelian randomization (MR)-based relationships, polygenic risk scores (PRS) and phenome-wide association studies (PheWAS). Single-cell transcriptomic data from human pancreatic tissues were further used to evaluate cell-type-specific expression patterns of candidate genes. RESULTS: SNP-based heritability was substantially higher for eoT2D than loT2D (11.2% vs. 6.4%), with eoT2D displaying distinct genetic loci related to β-cell function and insulin regulation, including SLC30A8 and IRS1. By contrast, loT2D showed a comparatively lipid-related genetic profile, featuring APOE-associated signals and expression patterns in immune-related cell populations. Linkage disequilibrium score regression (LDSC) and MR analyses further underscored this divergence: eoT2D exhibited broader genetic overlap with cardiometabolic traits, whereas loT2D showed stronger relationships with traditional metabolic risk factors. Finally, subtype-specific PRSs improved risk discrimination beyond conventional covariates, although their clinical utility warrants further evaluation. CONCLUSIONS: Extreme AAO-defined T2D subtypes exhibit partially distinct genetic architectures, highlighting AAO as an important dimension of T2D heterogeneity and providing a framework for future age-stratified genetic risk assessment.

Type 2 diabetes↗

PubMed2026

Intestinal blood vessel-associated macrophages and gut-vascular barrier dysfunction in cirrhosis.

BACKGROUND: Bacterial translocation in cirrhosis can trigger infection and hepatic decompensation, leading to systemic inflammation, organ failure and increased mortality. These infections often originate from the gastrointestinal tract after bacteria breach the intestinal barrier and disseminate to systemic sites. OBJECTIVE: In this study, we explore the mechanisms underlying intestinal barrier dysfunction in cirrhosis using an experimental cirrhosis model and patient-derived intestinal biopsies. DESIGN: We developed a murine model of cirrhosis through chronic administration of carbon tetrachloride for up to 20 weeks. We investigated both the intestinal epithelial and vascular compartments and performed single-cell transcriptomic profiling of myeloid cells isolated from cirrhotic mice and from individuals with compensated and decompensated cirrhosis. RESULTS: Our findings indicate that bacterial translocation in cirrhosis is the result of failure at multiple checkpoints, including aberrant epithelial cell death, vascular barrier damage and dysfunction of gut-vascular macrophages. In a preclinical model of cirrhosis, macrophages exhibited increased levels of monocyte-attracting chemokines, reduced bacterial clearance and impaired interactions with blood vessels. Importantly, depleting vascular-lining macrophages resulted in bacterial translocation to systemic sites, even in the absence of experimental liver disease. Transcriptional profiling of macrophages from duodenal biopsies of patients with cirrhosis indicated similar dysregulation of pathways supporting blood vessels and elevated expression of chemokines. CONCLUSIONS: This study emphasises the critical role of intestinal macrophages in preventing the dissemination of luminal bacteria and highlights the multifaceted breakdown of the intestinal barrier in cirrhosis and the importance of the gut-vascular barrier.

Animals↗

PubMed2026

SDC1+ CAFs secreting CTGF drive tumour metastasis via FGFR3 signalling in cancers.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are key stromal components of the tumour microenvironment (TME) that profoundly influence tumour progression. However, CAFs exhibit pronounced phenotypic and functional heterogeneity, and whether conserved CAF subtypes with shared functional hallmarks exist across different cancer types remains unclear. OBJECTIVE: We sought to uncover universal CAF subtypes that transcend tumour origins, defining their core molecular signatures and pro-tumorigenic functions within the TME. DESIGN: We constructed a pan-cancer CAF atlas through single-cell transcriptomic analysis of 554 specimens across 14 cancer types. To validate the findings, we performed further functional analyses, including in vitro migration and invasion assays, in vivo lymphatic metastasis models and mechanistic studies focusing on candidate signalling pathways. RESULTS: We identified a conserved syndecan 1 (SDC1) + CAF subset associated with advanced tumour stage and poor outcomes. These CAFs enhanced tumour cell migration and invasion in vitro and promoted lymphatic metastasis in vivo. This effect is mediated through connective tissue growth factor (CTGF) secretion, which activates fibroblast growth factor receptor 3 (FGFR3) signalling in tumour cells to induce epithelial-mesenchymal transition (EMT). Blocking CTGF or FGFR3 signalling abrogated these effects. We also found that kruppel like factor 6 (KLF6) directly regulates CTGF in SDC1+ CAFs, establishing a complete KLF6-CTGF-FGFR3 metastatic axis. CONCLUSIONS: Our study establishes SDC1+ CAFs as a universal, metastasis-promoting CAF subset across multiple cancer types and uncovers a novel KLF6-CTGF-FGFR3 axis that drives EMT and tumour dissemination. These findings provide mechanistic insight into CAF-tumour cell crosstalk and highlight actionable stromal targets for anti-metastatic therapies across diverse malignancies.

Humans↗

PubMed2026

The Pathogenesis of Epithelial Ovarian Cancer.

Epithelial ovarian cancer is not a single disease but a group of biologically distinct malignancies that include serous (high-grade and low-grade), endometrioid, clear cell, and mucinous carcinomas, along with other rare subtypes. Integrating clinicopathological analyses, genomic and multiomic data, and experimental investigations in model systems has revealed the pathogenesis of the various histologic subtypes. A unique feature of epithelial ovarian cancer is that most of these tumors are now recognized to arise not from ovarian tissue but from the fallopian tube or endometrium, the latter in the context of ovarian endometriosis. Studies of precursor lesions have revealed complex evolutionary trajectories and the earliest molecular events in their development. Recent single-cell and spatial technologies further elucidate the roles of intratumoral heterogeneity and the tumor microenvironment in disease progression. This review summarizes these advances from the perspective of tissue of origin and highlights their implications for prevention, early detection, and therapeutic development.

Journal Article↗

PubMed2026

Phenotypes of Hereditary Diseases Associated With Rauch-Steindl Syndrome.

PURPOSE: Prenatal phenotypic manifestations of genetic disorders associated with NSD2 variants remain poorly characterized. This study presents our institutional experience with the prenatal diagnosis of NSD2-associated genetic disorders, specifically Rauch-Steindl syndrome (RAUST), aiming to improve understanding of both the molecular and clinical features of RAUST. METHODS: We performed a retrospective analysis of six fetuses and one adult diagnosed with RAUST at our institution and thoroughly reviewed the prenatal ultrasound reports of six fetuses. Prenatal and postnatal phenotypes of RAUST cases were summarized alongside findings from previously published literature. Correlations between NSD2 variant locations, variant types, and phenotypes were analyzed. Additionally, protein modeling was used to visualize structural changes in NSD2 protein before and after C-terminal variants. We integrated single-cell transcriptomic and gene expression data from multiple public databases to investigate spatiotemporal expression patterns of NSD2 during human fetal development. RESULTS: Fetal growth restriction (FGR) was the most prevalent prenatal manifestation in RAUST fetuses, followed by microcephaly. Bilateral renal hypoplasia emerged as a novel prenatal ultrasonographic feature. Postnatally, speech and motor developmental delays were the most commonly reported phenotypes, followed by physical developmental delays and intellectual disability. Genotype-phenotype correlation analysis revealed an association between N-terminal truncating variants in NSD2 and impaired fetal growth parameters. Notably, C-terminal truncating variants-predicted not to directly impact NSD2 functional domains-also exerted disease-causing effects. CONCLUSION: This study provides a comprehensive analysis of prenatal phenotypes in RAUST cases, enriching the prenatal phenotypic spectrum of the disease and facilitating early diagnosis and clinical management of RAUST. Furthermore, our genotype-phenotype correlation findings lay a foundational basis for future research into the complex molecular mechanisms underlying NSD2-associated genetic disorders.

Humans↗

PubMed2026

Impaired Glycolysis Leads to Defective Efferocytosis and Impaired Plaque Resolution in Tet2 Clonal Hematopoiesis.

BACKGROUND: Clonal hematopoiesis (CH) arising from mutations in hematopoietic genes has been identified as an important risk factor for atherosclerotic cardiovascular disease. Despite the established role of some CH mutations in promoting atherosclerosis progression, their role in clinically relevant LDL (low-density lipoprotein) lowering-induced plaque remodeling or regression has not been extensively studied. METHODS: To assess the effects of TET2 (tet methylcytosine dioxygenase 2) CH on plaque resolution, we prepared control or chimeric Tet2+/- CH mice with conditional deletion of Tet2 in hematopoietic stem cells during LDL lowering-induced plaque remodeling. After establishing atherosclerosis by Western diet feeding for 12 weeks in Ldlr-/- mice, Tet2 was deleted by tamoxifen injection, and hypercholesterolemia was either normalized to simulate clinical lipid management, or mice were continued on the Western diet. RESULTS: Unlike control mice, Tet2+/- CH mice failed to significantly reduce necrotic core area or increase fibrous cap thickness and showed impaired macrophage efferocytosis during LDL lowering. Single-cell RNA sequencing and gene set enrichment analysis of aortic cell populations revealed that Tet2 deficient monocyte/macrophage populations were defective in glycolysis, phagocytosis, and actin polymerization. Tet2-deficient bone marrow-derived macrophages and Tet2+/- induced pluripotent stem cell-derived human macrophages showed defective ability to sustain continuing rounds of efferocytosis. Bone marrow-derived macrophages displayed reduced apoptotic cell binding and internalization and impaired activity of Wiskott-Aldrich syndrome protein and SCAR (suppressor of cyclic AMP receptor) homolog complex mediated actin polymerization. We linked these defects to reduced anaerobic glycolysis and lactate levels and rescued them by lactate supplementation or by treatment with the HIF-1α (hypoxia-inducible factor 1α) activator molidustat. Molidustat treatment reversed the defects in necrotic core and fibrous cap formation during LDL lowering-induced plaque remodeling in Tet2+/- CH mice. Reduced plasma lactate levels were also shown in TET2 clonal hematopoiesis of indeterminate potential carriers in the UK Biobank. CONCLUSIONS: Our data identify impaired efferocytosis and glycolysis-lactate-actin polymerization pathways in advanced atherosclerosis as potential therapeutic targets to induce proresolving restructuring of the plaque immune cells and to promote beneficial atherosclerosis remodeling in subjects with TET2 CH.

LDL lowering↗

PubMed2026

Tracking GAD-specific T-cell expansions in Type 1 diabetes by intradermal GAD-Alum challenge.

Identifying and monitoring autoreactive T cells that drive beta cell destruction remains a major obstacle to developing effective immunotherapies for type 1 diabetes (T1D). These cells are extremely rare in peripheral blood and cannot be accessed directly from the pancreas. We used intradermal injection of Glutamic Acid Decarboxylase (GAD)-Alum to recruit GAD-specific T cells to accessible sites in the skin and skin-draining lymph nodes (LNs), sampled by skin suction blisters and ultrasound-guided LN aspiration. Peripheral blood samples obtained before GAD injection were restimulated with GAD in vitro to detect reactive CD4+ T cells. Single-cell RNA sequencing (scRNAseq) followed by re-expression of selected T cell receptors (TCRs) confirmed antigen specificity. Up to 70% of T cells at the skin injection site were clonally-expanded and 4 of 14 (28%) re-expressed TCRs were GAD-reactive. In LNs 1 of 14 (4%) clonally-expanded TCRs was GAD-reactive, representing ~0.08% of all T-cells. GAD-reactive cells across compartments displayed Th1 and Th17-associated transcription signatures. These results demonstrate the intradermal autoantigen challenge and scRNAseq, enable direct identification and molecular profiling of autoreactive T cells in vivo. This minimally invasive approach provides a powerful platform for tracking antigen-specific T cells to monitor disease activity and evaluate immune interventions in T1D.

Autoimmunity↗

PubMed2026

Endothelial cell cycle inhibition enables blood vessel maturation to normalize the tumor vasculature.

Dysfunctional tumor vessels promote disease progression, whereas improved function enhances therapeutic delivery. However, current approaches to normalize tumor vasculature have limited efficacy. In vascular malformations, vessels are similarly dysfunctional, with endothelial cell (EC) hyperproliferation impairing arterial-venous specification. These defects are corrected with palbociclib, a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) that has beneficial effects on tumor and immune cells, but the effects on tumor vasculature are not well characterized. In our studies, murine mammary tumor ECs (TECs) exhibited disrupted cell cycle and specification, and CDK4/6i promoted TEC cycle control, enabling improved tumor vascular function. To investigate transcriptomic changes, we performed single-cell RNA sequencing (scRNAseq) of treated and untreated tumors, and healthy tissues. CDK4/6i-mediated TEC cycle arrest promoted arterial-venous specification, cellular junctions, and pericyte association, and suppressed glycolytic and immunosuppressive gene expression. These effects were associated with increased vessel perfusion, decreased tumor hypoxia, and a more favorable immune landscape with immunotherapy. In scRNAseq datasets from patients treated long-term with CDK4/6i, TECs exhibited similar transcriptomic changes associated with arterial-venous specification, pericyte recruitment, and immune signaling. Thus, in contrast to current strategies, CDK4/6i-mediated vascular changes may be maintained with continued treatment, highlighting the relevance of modulating TEC cycle to improve vessel maturation/function.

Angiogenesis↗

PubMed2026

GIRK Channels Regulate Circadian Rhythms of Excitability in Prokineticin 2 Neurons of the Suprachiasmatic Nucleus and Modulate Behavioral Circadian Rhythms.

The suprachiasmatic nucleus (SCN), the central circadian clock in mammals, generates robust yet adaptable circadian rhythms through electrically mediated coordination among heterogeneous peptidergic neuronal populations with presumed cell type-specific roles. Previous studies have proposed that circadian changes in membrane excitability of individual SCN neurons arise from time-of-day-dependent shifts in the relative balance of subthreshold Na+ and K+ conductances. Although multiple channels have been implicated in these processes, how nocturnally dominant K+ conductances are implemented in a cell type-specific manner remains poorly understood. Prokineticin 2 (Prok2) has been identified as a SCN signaling peptide essential for behavioral circadian regulation; however, the electrophysiological properties of Prok2-expressing neurons and the mechanisms underlying their diurnal rhythmicity remain largely unexplored. Here, using electrophysiological approaches in mice of either sex, we show that Prok2 neurons exhibit diurnal variations in electrical properties, with higher excitability during the day and reduced excitability at night, and that G-protein-coupled inwardly rectifying potassium (GIRK) channel-mediated basal current contributes to nighttime hyperpolarization. Immunofluorescence and single-cell RT-PCR analyses revealed that GIRK1 and GIRK3 are the predominant GIRK subunits expressed in Prok2 neurons. Moreover, Prok2 neuron-specific deletion of GIRK3 using in vivo genome editing resulted in significant nocturnal depolarization and induced abnormalities in behavioral rhythms, including delayed activity onset and circadian period lengthening, with altered SCN network activity. Together, these findings suggest that tonic, G-protein-dependent regulation of GIRK channels provides a night-specific inhibitory mechanism that contributes to intrinsic diurnal neuronal excitability in Prok2 neurons and supports the regulation of behavioral circadian rhythms.

Animals↗

PubMed2026

CDC20B Dysregulation: Links to Tumor Prognosis and Immunity.

OBJECTIVE: This study aimed to clarify the pan-cancer expression pattern, upstream regulatory mechanisms, prognostic relevance, and immune associations of CDC20B. METHOD: Using public databases (GTEx, GEO, and TCGA), we examined CDC20B expression and its associations with prognosis and tumor immunity across multiple cancers. Immunohistochemistry (IHC) on an independent clinical cohort was performed to validate CDC20B upregulation in tumor tissues. Promoter methylation, genetic alterations, and immune infiltration were analyzed using bioinformatics tools (cBioPortal, UALCAN, TIMER2.0, ESTIMATE). Functional enrichment was assessed by GSEA and single-cell state analysis (CancerSEA). RESULTS: CDC20B was markedly upregulated in most tumor types (p < 0.001), with strong diagnostic efficiency (AUC > 0.7 in 15 cancers) and potential regulation by promoter hypomethylation. IHC confirmed its overexpression in clinical tumor tissues. However, the prognostic impact of CDC20B was cancer-type-specific: high expression correlated with poor overall survival in UCS, LGG, KIRC, and OV, but with favorable survival in BRCA, LUAD, and PAAD. CDC20B expression was associated with immune infiltration patterns, showing negative correlations with ImmuneScore in most cancers but positive correlations with CD8+ T cells in PAAD. Functional analyses indicated involvement in EMT, KRAS/NF-κB signaling, and DNA damage response pathways. DISCUSSION: The dual prognostic role of CDC20B suggests context-dependent functions, likely influenced by tumor microenvironment composition and underlying oncogenic programs. Promoter hypomethylation emerges as a potential epigenetic driver of overexpression. The associations with immune modulation and genomic instability suggest that CDC20B is a candidate biomarker, though causal relationships require experimental validation. CONCLUSION: CDC20B may contribute to tumor progression in a context-dependent manner, with its prognostic impact varying across cancer types. Its role in tumor immunity and oncogenic pathways warrants further investigation, particularly in stratified patient populations.

CDC20B↗

PubMed2026

Tumor-Intrinsic Blood and Imaging Correlatives in Advanced Prostate Cancer Treated with Combination Radiopharmaceutical Therapy and Immunotherapy.

The PRINCE trial showed the clinical activity for 177Lu-PSMA-617 in combination with pembrolizumab for metastatic castration-resistant prostate cancer. To refine patient selection and improve response monitoring strategies to this combination, we investigated candidate tumor-intrinsic biomarkers of treatment response and resistance. Methods: We performed circulating tumor DNA (ctDNA), circulating tumor cell (CTC), and PET imaging analyses at baseline, 12 wk on-treatment, and disease progression in participants enrolled in PRINCE (n = 37). We performed targeted sequencing for ctDNA quantification and genomic analysis of more than 70 prostate cancer genes. CTC enumeration was performed on the EpicSciences platform and was combined with selective single-cell whole-genome sequencing. PET imaging included serial PSMA PET as well as 18F-FDG PET imaging at baseline. Results: A low baseline ctDNA fraction and high PSMA avidity in metastatic lesions were linked to superior treatment responses and may have composite biomarker value. Genomic alterations in tumor suppressor genes TP53, RB1, or PTEN were associated with higher 18F-FDG avidity and metabolic tumor volume on 18F-FDG PET imaging and worse prognosis. At 12-wk on-treatment, both ctDNA detection and PSMA PET imaging were strong indicators of response depth and durability. At disease progression, PSMA expression on PET imaging was lower compared with baseline and supported by subclonal remodeling of ctDNA and CTC copy number profiles and by clonal expansions of tumor suppressor gene mutations. Conclusion: We provide the first integrated molecular and imaging insights into determinants of response and resistance to combined radiopharmaceutical therapy and immunotherapy in prostate cancer and propose biomarker strategies to inform future clinical development.

177Lu-PSMA-617↗

PubMed2026

Identification of molecular subtypes in clear cell renal cell carcinoma based on chromatin regulators and tumor immune microenvironment profiling.

In the histological classification of renal cell carcinoma, clear cell renal cell carcinoma (ccRCC) accounts for the highest proportion and is the most common subtype. Despite advances in management, it continues to be associated with considerable incidence and mortality. Although surgery and systemic therapies are available, their efficacy is constrained by pronounced intratumoral heterogeneity and treatment resistance. Identifying robust biomarkers and clarifying the underlying biological mechanisms are therefore essential to improving diagnosis, risk stratification and therapeutic decision-making. In this work, we identified two ccRCC molecular subtypes displaying divergent chromatin regulator (CR) profiles and different clinical prognoses. Using the genes differentially expressed between these subgroups, we constructed a CR-related score (CRS) that effectively stratified patients according to survival. More analysis concluded that the low expression of CR was more linked with the immune-activated tumors, which encompassed the immune pathway enrichment, as well as the elevation of numerous immune cell subtypes. Moreover, elevated CRS was associated with improved immunotherapy responsiveness. Drug-sensitivity analyses nominated several candidate agents, and SMARCD3 knockdown in 786-O cells inhibited proliferation and migration and reduced sensitivity to masitinib. Collectively, these findings support the prognostic and therapeutic relevance of CR-related states in ccRCC and provide a framework for future experimental validation of chromatin-regulated tumor-immune interactions.

Humans↗

PubMed2026

Disentangling covariate effects on single-cell-resolved epigenomes with DeepDive.

Understanding the effects of individual biological factors from single-cell-resolved epigenomic data is hindered by multicollinearity, particularly in human cohorts. We introduce DeepDive, a deep-learning framework designed to systematically disentangle known and unknown sources of variation in single-nucleus ATAC-seq data. DeepDive accurately reconstructs chromatin accessibility, outperforms state-of-the-art methods with incomplete covariate information, and robustly recovers true biological signals from even highly entangled covariates, unlocking counterfactual, "what-if," analyses. Applying DeepDive to pancreatic islet cells, we perform counterfactual analyses to prioritize covariates associated with a type 2 diabetes-linked beta-cell subtype and nominate transcription regulators. DeepDive offers a powerful and unbiased tool for mechanistic discovery in complex human disease cohorts.

disentanglement↗