PubMed Health⌕ Search

Biomedical subjects

Browse citations

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

At least 325 records · Page 18Linked to original sources
PubMed2026

Profilin promotes lamellipodium protrusion by tuning the antagonistic activities of capping protein and VASP.

Cell migration frequently employs protrusions termed lamellipodia, constituting the prime model system for generation of branched actin filament networks. Here we utilize genome editing to explore the functional connections between the actin monomer-binding protein profilin (Pfn), the filament nucleating Arp2/3 complex, its co-factor heterodimeric capping protein (CP) and Ena/VASP family polymerases in lamellipodial actin assembly. We show that Pfn counters Ena/VASP but promotes Arp2/3 complex activity, while Ena/VASP and CP mutually antagonize each other. While Pfn promotes Arp2/3 complex activity irrespective of Ena/VASP, sensitivity of CP to Pfn removal vanishes in the absence of Ena/VASP. Our findings establish Pfn as master regulator of Arp2/3 complex-dependent actin network formation, differentially regulating VASP and its antagonizer CP. Mathematical modeling of our data suggest Ena/VASP and CP to compete for recruitment to lamellipodial edges. Our work provides critical insights into the molecular logic of branched actin network assembly in protrusion and force generation.

Profilins↗
PubMed2026

Scalable near-real-time Bayesian phylogenetics for outbreaks with Delphy.

Pathogen genomic analysis is central to tracking, understanding and containing outbreaks1-13, but the complexity and cost of state-of-the-art phylogenetic tools limit global access and impact. Here we introduce Delphy, an exact reformulation of Bayesian phylogenetics14-17 designed to transform its speed, scalability and accessibility while retaining Bayesian state-of-the-art accuracy. Delphy's central data structure, an explicit mutation-annotated tree, takes advantage of the high sequence similarity of large-scale epidemic datasets18-20 for efficient tree exploration and convergence. By reproducing key analyses from recent major epidemics, including Ebola1,21, Zika2, SARS-CoV-2 (ref. 22), mpox3,4 and H5N1 (refs. 23,24), we demonstrate state-of-the-art accuracy with up to 2-3 orders of magnitude improvements in speed. Assessing Delphy's scalability, we show that a simulated dataset of 100,000 sequences can be analysed within a day. We distribute Delphy as a client-side web application that enables local, interactive analysis of raw data on the user's machine. Delphy automatically identifies key viral lineages and mutations, as well as their emergence and prevalence through time, with quantified uncertainties grounded in Bayesian theory. Delphy establishes Bayesian phylogenetics as a fast, accessible frontline tool for future outbreak response.

Journal Article↗
PubMed2026

A retinoic acid autoregulatory loop governing prefrontal-motor arealization.

The frontal lobe comprises the prefrontal association cortex (PFC), which supports complex cognition and goal-directed behaviour, and the motor cortex (MC), which executes movement1-14. The establishment of distinct regional identities and connections along the sensorimotor-to-association axis provides a fundamental scaffold for cortical areal organization and function15-19. Retinoic acid (RA) signalling has emerged as a key regulator of PFC development19-26. However, the mechanisms that spatially confine RA signalling within the developing PFC, and the downstream RA-responsive gene networks, remain poorly understood. Here we define an RA-associated gene regulatory network in the developing human PFC and identify MEIS2, which encodes a transcription factor linked to intellectual disability and autism spectrum disorder, as a key hub of this network. Conditional deletion of Meis2 in postmitotic cortical excitatory neurons in mice results in a partial respecification of prospective prefrontal association territories towards motor-like molecular and connectivity features, highlighting a critical role of postmitotic neurons in establishing and maintaining cortical areal identities. Concomitant with Meis2 loss, the population of excitatory neurons expressing the RA-synthesizing enzyme ALDH1A3, and consequently RA signalling itself, is substantially reduced in the developing medial PFC (mPFC). These findings reveal a conserved autoregulatory loop, RA → MEIS2 → ALDH1A3 → RA, that reinforces a PFC-enriched RA gradient and organizes the MC-PFC axis. Together, our findings reveal a postmitotic mechanism by which specific features of neuronal identity reinforce RA signalling to define key features of prefrontal and motor cortical territories, linking a classic morphogen to transcriptional identity, neural circuit formation and function, and potentially to neuropsychiatric disorders.

Journal Article↗
PubMed2026

Targeted genomic integration and rearrangement using prime assembly.

Although therapeutic genome editing holds great potential to remedy diverse inherited and acquired disorders, targeted installation of medium-to-large genomic modifications in therapeutically relevant cells remains challenging1. Here we develop prime assembly, an approach that permits DNA sequence assembly and integration in human cells leveraging CRISPR-targeted dual flap synthesis. This method enables RNA-programmable site-specific integration of single or double-stranded DNA fragments. Unlike homology-directed repair, prime assembly is similarly active in dividing and non-dividing cells. We applied prime assembly to perform targeted exon recoding, transgene integration and megabase-scale rearrangements, including at therapeutically relevant loci in primary human cells. Prime assembly expands the capabilities of genome engineering by enabling the targeted integration of medium to large-sized DNA sequences without relying on double-stranded DNA donors, nuclease-driven double-strand breaks or cell cycle progression.

Journal Article↗
PubMed2026

Cohesin reshapes replication fork contacts to aid fork slowing and reversal.

DNA replication forks can be challenged by cancer chemotherapeutic treatments, leading to accumulation of single-stranded DNA and slowdown of DNA synthesis. The marked plasticity of replication forks under replication stress ensures fork stability, damage tolerance and complete genome duplication1. Initiation and progression of replication forks occur in a three-dimensionally organized genome. DNA loop extrusion by the cohesin complex organizes the genome2 and regulates the initiation and positioning of DNA replication origins3,4. Although transient interaction of sister forks was recently reported during unperturbed replication5, the functional relevance of fork contacts during replication stress and the role of cohesin in this context remain unknown. Here we show that cohesin-mediated loop extrusion rearranges nascent DNA contacts at stressed replication forks to promote genome stability. Using auxin-inducible degron6, separation-of-function mutants7-9 and a newly developed Micro-C-based technique to capture chromatin contacts at nascent DNA (Repli-C), we found that loop-extruding cohesin accumulates at stalled replication forks, limiting sister-fork coupling in favour of inter-replicon contacts. This process promotes active fork slowing and reversal by preventing PRIMPOL action on single-stranded DNA1. These findings show that the replication stress response is not merely an accumulation of individual regulatory events, but is topologically integrated across the genome through cohesin loop extrusion. While providing a new function for loop-extruding cohesin, our results indicate the potential impact on cancer therapy of frequent cohesin mutations in tumours10.

Journal Article↗
PubMed2026

Evolution and heterogeneity of lethal metastatic bladder cancer subtypes.

Histological variation is a prognostic feature of metastatic urothelial cancer1-3, but its evolutionary trajectory remains poorly defined. We developed a metastatic bladder cancer rapid autopsy programme enriched in histological subtypes4 to profile individuals with terminal disease. Here by reconstructing the evolutionary histories of patient tumours, we show that metastasis-to-metastasis seeding is the dominant pattern of cancer spread and that increased polyclonal migration predicts poor prognosis. The burden, heterogeneity and timing of genomic alterations differ markedly among histological subtypes. Plasmacytoid and neuroendocrine variants develop early driver alterations associated with shorter survival. Mutational signature analyses and experimental models demonstrated that plasmacytoid tumours uniquely use the Fanconi anaemia pathway to mitigate chemotherapy-induced genomic scarring. Single-nucleus profiling revealed mixed cell states in histological subtypes and an association between transcriptional heterogeneity and patient survival. Characterization of the tumour microenvironment uncovered distinct immune states across subtypes, with plasmacytoid tumours exhibiting immune-inflamed profiles, whereas squamous tumours are predominantly immunosuppressive. Last, we demonstrate that post-mortem cell-free DNA captures genomic and transcriptional heterogeneity of the subtypes, which provides a potential strategy for noninvasive assessment of tumour identity and aggressiveness. Our results provide new insights into how tumour heterogeneity shapes the evolutionary history of disease progression in bladder cancer histological subtypes.

Journal Article↗
PubMed2026

Reimagining research papers as interactive and reliable AI agents.

Here we introduce Paper2Agent, an automated framework that converts research papers into artificial intelligence (AI) agents. Paper2Agent transforms research output from passive artefacts into active systems that accelerate use and discovery. Conventional research papers require readers to understand and adapt the paper's code, data and methods to their work, creating barriers to dissemination and reuse. Paper2Agent addresses this challenge by converting a paper into an AI agent that functions as a virtual corresponding author, exposing its manuscript, supplementary materials, datasets, code and workflows as active, agent-native knowledge rather than static text. It analyses the paper and codebase using multiple agents to construct a model context protocol (MCP) server, then generates and runs tests to refine and increase robustness of the MCP. These paper MCPs can be connected to a chat agent (such as Claude Code) to carry out complex scientific queries through natural language while invoking tools and workflows from the paper. We demonstrate Paper2Agent's effectiveness through case studies. Paper2Agent created an agent that leveraged AlphaGenome1 to interpret genomic variants and agents based on Scanpy2 and TISSUE (transcript imputation with spatial single-cell uncertainty estimation)3 to conduct single-cell and spatial transcriptomics analyses. We validate that these agents reproduce the results of the original papers and carry out novel user queries. Paper2Agent created multiple agents that collaborate to prioritize a causal gene for psoriasis. By turning static papers into interactive AI agents, Paper2Agent introduces a paradigm for knowledge dissemination and a collaborative ecosystem of AI co-scientists.

Journal Article↗
PubMed2026

Sex without crossovers mimics clonal reproduction in Rhynchospora tenuis.

Meiotic recombination ensures accurate chromosome segregation and promotes genetic diversity by generating crossovers between homologous chromosomes1. Although essential in most sexually reproducing organisms, recombination is variably regulated and can be absent in some lineages, a condition known as achiasmy2. However, obligate achiasmy in both sexes of a sexual species has not been documented. Here we investigate Rhynchospora tenuis, a flowering plant with the lowest known chromosome number and inverted meiosis3. Combining genomics with molecular experiments, we show that R. tenuis undergoes obligate, genome-wide achiasmy in both male and female meiosis. Despite normal early meiotic axis formation, synapsis fails, crossovers are undetectable cytologically and genetically, and univalents persist at metaphase I. Haplotype-specific accumulation of transposable elements generates segregation distortion favouring the transmission of larger, repeat-rich chromosomes. Sexual reproduction is nevertheless retained: fertilization yields viable seeds only when translocation-compatible gametes meet, indicating strong post-meiotic selection against incompatible homozygous combinations. As a result, all surviving offspring are genetically identical, effectively maintaining heterozygosity by sexual reproduction with parental genotype restitution mimicking clonal reproduction. We propose that recombination loss, a low chromosome number, inverted meiosis and selection for compatible gamete combinations together enable faithful segregation and clonal-like inheritance despite sexual reproduction. These findings blur the boundary between sex and clonality, linking genome architecture, recombination loss and transmission bias.

Journal Article↗
PubMed2026

Mechanisms of Transcriptional Regulation by Salicylic Acid Receptors.

Salicylic acid (SA) is a key phytohormone that activates plant defense responses 1-3. In Arabidopsis, NPR1 (also known as NIM1) and NPR3/NPR4 have been identified as dual SA receptors responsible for perceiving SA 4-6. However, the mechanisms of how SA binding to the NPR proteins leads to induction of defense gene expression remain unclear. Here, we elucidate how SA triggers transcriptional activation via NPR1 and relieves transcriptional repression mediated by NPR3/NPR4. We identified Mediator Complex Subunit 15A (MED15A) as a bridge between NPR1 and the Mediator complex governing transcription. SA induces direct interaction of NPR1 with MED15A. Structural and functional analysis showed that the binding of NPR1 to MED15A is essential for NPR1-mediated transcriptional activation. Meanwhile, SA relieves transcriptional repression mediated by NPR3/NPR4. NIM1-interacting 1 (NIMIN1) interacts with NPR3/NPR4 and the Topless (TPL) co-repressor, connecting them to Polycomb Repressive Complex 2 (PRC2) to mediate H3K27 trimethylation of SA-responsive genes. SA inhibits the interactions between NPR3/NPR4 and NIMIN1, reduces H3K27 trimethylation levels and increases histone acetylation of the target genes to release NPR3/NPR4-mediated repression. Our study offers a comprehensive view of SA-mediated defense gene activation. These findings lay a foundation for designing more effective SA analogs as agrochemicals and for engineering crop resistance by manipulating SA perception and signaling.

Journal Article↗
PubMed2026

Liquid biopsy for early detection of pancreatic ductal adenocarcinoma.

There is no clinically relevant blood-based assay for the detection of early-stage pancreatic ductal adenocarcinoma (PDAC), a solid malignancy characterized by poor outcomes. Here we developed, validated and tested a blood-based microRNA (miRNA) assay (which included hsa-miR-142-3p, hsa-miR-30c-5p, hsa-miR-335-5p, hsa-miR-340-5p, hsa-miR-200b-3p, hsa-miR-1260b, hsa-miR-145-3p, hsa-miR-145-5p, hsa-miR-429 and hsa-miR-200a-3p) and a composite score, PANXEON (PANcreatic cancer eXosome Early detectiON), that integrates the miRNA signature with carbohydrate antigen 19-9 for the detection of early-stage PDAC. We conducted an international, multicenter, observational, prospective biomarker study that involved 1,785 individuals with and without PDAC from four countries. The miRNA signature achieved an area under the receiver operating characteristic curve of 88.6% in the testing cohort, with a sensitivity of 83.8% for early-stage PDAC, while showing minimal cross-reactivity with other gastrointestinal cancers. In a cohort of 19 individuals, the miRNA signature levels decreased during neoadjuvant chemotherapy and after surgery and increased before disease recurrence. When combined with carbohydrate antigen 19-9 levels, this blood assay demonstrated a sensitivity of 86.8% for stage I-II PDAC, false-positive rates of 3.2% in low-risk controls and 15.6% in high-risk controls in the testing cohort. PANXEON demonstrates potential for detecting high-grade dysplasia in individuals with high-risk pancreatic cysts (64.3%). Collectively, we present a composite biomarker that may complement existing strategies for the detection of early-stage PDAC and warrants further large-scale prospective studies. ClinicalTrials.gov registration: NCT06388967 .

Journal Article↗
PubMed2026

Factor IX Padua AAV gene therapy in adolescents with hemophilia B: a phase 1 trial.

Adeno-associated virus (AAV)-mediated factor IX Padua gene therapy has demonstrated good safety and efficacy in adult patients with hemophilia B, but its safety and efficacy in adolescent patients with hemophilia B remain unknown. Here we report a multicenter, single-arm, phase 1 study involving 11 adolescent participants (aged 12-18 years) with severe or moderately severe hemophilia B (factor IX coagulant activity (FIX:C) ≤2 IU dl-1) in China. All of them received the AAV gene therapy BBM-H901 at a dose of 5 × 1012 vector genomes per kilogram of body weight and were then enrolled in a 52-week follow-up. The primary endpoint was safety. No dose-limiting toxicity was observed throughout the study. The most common adverse events included elevation of white blood cell count, elevation of neutrophil count and rash associated with corticosteroid use. One serious adverse event and two grade 3 adverse events occurred. Abnormal liver function was observed in one participant, with elevated alanine aminotransferase (197.0 U l-1) and aspartate aminotransferase (75.0 U l-1) levels, which returned to normal 4 weeks after immunosuppression therapy. The key secondary endpoints included the mean (s.d.) FIX:C at week 52 following infusion, which was 41.8 (30.1) IU dl-1 (one-stage SynthASil method), and the mean annualized bleeding rate, which decreased from 13.9 to 0.5. In this study, we show that the gene therapy drug BBM-H901 for hemophilia B is safe in adolescent patients, providing initial insights into its efficacy. ClinicalTrials.gov identifier: NCT05709288 .

Journal Article↗
PubMed2026

Sex-specific biological aging clocks across organs and omics.

Sex differentially shapes aging, neurodevelopment and neurodegenerative diseases such as Alzheimer's disease (AD). However, most biological aging clocks (artificial intelligence-predicted age minus chronological age) were trained on sex-pooled samples and implicitly assume sex invariance.Here we developed 38 sex-specific biological aging clocks across 15 organ systems. We first demonstrate the importance of sex-stratified training for constructing sex-specific healthy normative references and then reveal marked divergence between female and male clocks. Key genetic parameters and Mendelian randomization results indicate that organ-specific aging liability and its relationships to cardiometabolic, endocrine and mental traits are configured differently in females and males. Proteomic analyses identify distinct, organ-resolved synaptic, immune, vascular and metabolic networks that differentially track female and male biological aging. In longitudinal survival analyses, sex-specific clocks predict whole-body systemic diseases and all-cause mortality in a sex-dependent and organ-dependent manner. Further analyses reveal sex-dependent associations between the brain aging clock and cognitive decline trajectory during a preclinical AD clinical trial. Sex-stratified clocks may offer distinct value by defining biological age against sex-appropriate normative references and revealing sex-dependent genetic, molecular and clinical signatures that pooled models may obscure. Meanwhile, sex-pooled and sex-interaction approaches remain valuable, as human aging and disease also share fundamental biological similarities between females and males. Together, these findings reveal sex-specific biological aging signatures in aging, AD and systemic health, highlighting the need for explicitly sex-stratified modeling approaches.

Journal Article↗
PubMed2026

EBV reactivation priming of the peripheral immune system in multiple sclerosis relapse.

Despite decades of research, the cellular and molecular events preceding multiple sclerosis (MS) relapse remain incompletely understood. Here, in this observational study of longitudinal blood samples from patients with relapsing-remitting MS, we used single-cell RNA sequencing, bulk transcriptomics, multiparameter flow cytometry and targeted viral reverse transcription quantitative polymerase chain reaction (RT-qPCR) to construct a time-resolved atlas of immune perturbations surrounding relapse. A reproducible pre-relapse signature in monocytes and B cells, emerging up to 3 months before clinical onset, was enriched for host genes responsive to Epstein-Barr virus (EBV) lytic reactivation factors. RT-qPCR confirmed elevated EBV LMP-1 transcripts in pre-relapse B cells, and flow cytometry demonstrated expansion of CD11c+ atypical B cell populations displaying EBV surface protein gp350. Pre-relapse transcriptional modules overlapped with MS genome-wide association study (GWAS) risk loci and EBNA-2-bound enhancers, suggesting that inherited MS susceptibility and EBV-responsive programs operate through shared regulatory elements. How this peripheral activation relates to central nervous system lesion formation remains to be established. These findings nonetheless suggest that EBV reactivation, when occurring within a genetically predisposed peripheral immune environment, is a proximal precursor of MS relapse.

Journal Article↗
PubMed2026

The TUBG meshwork is associated with centromere dynamics and micronuclear organization.

This study investigates how γ-tubulin and the centrosome contribute to interphase centromere dynamics and nuclear organization. Although classically associated with mitotic microtubule nucleation, here we show that γ-tubulin associates with chromatin and is enriched within centromere-defined volumes. Using live-cell imaging, immunofluorescence, and chromatin immunoprecipitation sequencing, we detect γ-tubulin-associated signal at satellite-rich, centromere-proximal chromatin. Reduced γ-tubulin levels are associated with increased centromere fluorescence intensity and reduced mobility, linking the γ-tubulin network to centromere organization. Under acute cisplatin-induced stress, centromere mobility increases, whereas centromere clustering is observed in separate fixed-cell analyses. Ser131 phosphorylation is associated with γ-tubulin self-assembly and centromere-related dynamics. Additionally, γ-tubulin accumulates in micronuclei, coinciding with increased replication-associated signal and DNA fluorescence. In primary clear cell renal cell carcinoma cells, stress is associated with higher γ-tubulin fluorescence intensity within centromere-defined volumes. Together, these findings support an association between the γ-tubulin meshwork and centromere organization, chromatin compartmentalization, and responses to genomic stress.

Centromere↗
PubMed2026

Non-coding regulatory variants in adolescent idiopathic scoliosis risk and pathogenesis.

Adolescent idiopathic scoliosis is a common pediatric musculoskeletal disease that has significant impacts on childhood quality of life. Recent genome-wide association studies have identified dozens of genetic risk loci and hundreds of risk variants that primarily reside in non-coding regions of the genome. Follow up studies suggest a complex genetic architecture in which several tissues may be affected, however few causal disease variants have been identified. Here we review the functional AIS-associated variants that have been identified, how they may contribute to disease etiology, and necessary advancements that will link the effects of non-coding variants to disease mechanisms.

Humans↗