Natural killer (NK) cells are critical for both innate and adaptive immunity, and their effective regulation holds significant promise for tumor immunotherapy. The terminal maturation of NK cells is closely associated with enhanced effector functions, but the role of epigenetic mechanisms in this process remains incompletely understood. Here, we identify the histone methyltransferase EHMT2 as an epigenetic regulator that restrains NK cell maturation and function. EHMT2 expression is markedly downregulated upon cytokine activation in human NK cells and inversely correlated with effector gene expression across tissues and cancer types. NK cell-specific deletion of Ehmt2 in mice promotes terminal NK cell maturation, augmenting IFN-γ production and cytotoxicity both in vitro and in vivo. Integrated RNA-seq and H3K9me2 CUT&Tag profiling reveal that Ehmt2 loss reduces the repressive histone mark H3K9me2 and derepresses transcriptional programs associated with NK cell differentiation and cytotoxicity. Pharmacological inhibition of EHMT2 recapitulated these effects in both human umbilical cord blood (hUCB)-hematopoietic stem cell (HSC)-derived NK cells and peripheral blood NK cells, promoting terminal maturation and tumor cell killing. These findings define EHMT2-dependent H3K9me2 deposition as a key epigenetic barrier to NK cell effector programming and suggest that targeting EHMT2 may potentiate NK cell-based immunotherapies.

In China, non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens remain widely utilized as first-line antiretroviral therapy (ART) despite issues of low resistance barriers and significant side effects, leading to frequent treatment interruptions and virologic failures. Timely drug-resistance testing is often inaccessible, complicating subsequent treatment management. This trial aims to fill this critical gap by comparing the efficacy, safety, and tolerability of the single-tablet regimen (STR) of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) with the multi-tablet regimen (MTR) of dolutegravir plus lamivudine plus tenofovir disoproxil fumarate (DTG+3TC+TDF) in people living with HIV (PLWH) experiencing virologic failure. This multicenter, open-label, randomized controlled non-inferiority trial will enroll 374 PLWH experiencing virologic failure of first-line NNRTI-based therapy from 14 clinics across China. Participants will be randomized 1:1 to receive either a once-daily STR of BIC/FTC/TAF or a once-daily MTR of DTG+3TC+TDF. The primary endpoint is the proportion achieving viral suppression (HIV-1 RNA < 50 copies/mL) at week 48. Secondary endpoints include the time to viral suppression, emergence of resistance-associated mutations (RAMs), immunologic markers, treatment adherence, patient-reported outcomes, and safety profiles. Data will be analyzed using intention-to-treat (ITT) and per-protocol (PP) populations, with non-inferiority defined using a margin of 12

Coral reef fishes, distinguished by remarkable species diversity and unique speciation mechanisms, offer an exceptional framework for understanding evolutionary diversification. As ecologically dominant predators, groupers (family Epinephelidae) exemplify high diversity in coral reef ecosystems, yet their phylogenetic relationships remain partially unresolved in previous studies based on mitochondrial and nuclear markers. Here, we performed a comprehensive phylotranscriptomic analysis of 92 specimens representing 32 species across seven genera of Epinephelidae. Leveraging concatenated nucleotide data analyzed with maximum likelihood and Bayesian inference, we first reconstructed a robust transcriptomic phylogeny with markedly enhanced resolution and nodal support compared to traditional marker-based frameworks. Our results revealed Plectropomus as the earliest diverging lineage, resolving a longstanding debate regarding the basal divergence within this family, and robustly supported the non-monophyly of Epinephelus and Cephalopholis. The origin and early diversification of Epinephelidae, currently distributed across the Indian and Pacific Oceans, may have occurred in the West Pacific during the Paleocene, followed by subsequent dispersal mediated by prevailing ocean currents. Furthermore, we found that the vicariance and speciation of major clades were likely driven by repeated episodes of sea level regression associated with glacial cycles. Enhanced upwelling and elevated primary productivity in recent periods may have further promoted the rapid radiation of groupers. To our knowledge, this represents the first application of phylotranscriptomics in the phylogenetic study of Epinephelidae, providing new insights into its phylogeny and evolutionary history.

Lower respiratory infections (LRIs) are the foremost cause of infection-related mortality worldwide. However, the specific aetiological agents responsible for high hospitalisation rates and elevated coinfection risks across different populations have not been systematically investigated, primarily constrained by clinical practices that often target few pathogens and employ inconsistent testing methods across hospitals. Here, we collected 695,142 bronchoalveolar lavage fluid (BALF) samples from patients hospitalised with LRIs across 4758 hospitals of Chinese mainland between January 2022 and May 2025 and analysed 28 common respiratory pathogens using targeted next-generation sequencing (tNGS). Based on the real-world pathogen spectrum, we stratified the hospitalised patients undergoing BALF sampling into eight distinct age groups, corresponding to eight life-stages, and established life-stage-specific patterns of pathogen distribution. Subsequently, we identified 124 coinfecting pathogen pairs and three characteristic co-detection networks. 79.03% of observed co-detections occurred within these networks. Furthermore, our analysis revealed that bacteria and fungi such as KPN, PJ, and ABA were more frequently detected in hospitalised male patients, which indicates sex-specific differences in detection patterns. We also observed that males aged 0-4 years and 35+ years were more frequently represented among hospitalised patients with severe LRIs. These findings may inform age- and sex- stratified infectious disease prevention, control, and clinical management. Specifically, they may support public health practitioners in optimizing vaccination strategies; assist diagnostic developers in creating life-stage-specific diagnostic panels that prioritize commonly detected pathogens; and aid clinicians in assessing patterns of hospitalisation and co-detection based on nationwide data from BALF-sampled hospitalised LRI cases.

Oral squamous cell carcinoma (OSCC) is a prevalent malignancy with poor prognosis due to therapeutic resistance and tumor heterogeneity. N6-methyladenosine (m6A) modification, mediated by methyltransferase-like 3 (METTL3), drives OSCC progression via the HNRNPA2B1/FOXQ1 axis. STM2457, a selective METTL3 inhibitor, and Astragalus polysaccharide (APS), a traditional Chinese medicine with antitumor properties, hold promise for enhancing OSCC treatment, but their combined efficacy remains unexplored. In CAL27 OSCC cells, optimal concentrations of STM2457 (15 µM) and APS (100 µg/mL) were determined using EdU assays. Effects on m6A levels, METTL3, HNRNPA2B1, and FOXQ1 expression, and mRNA stability were assessed via RT-qPCR, Western blot, and RIP-qPCR. Cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) were evaluated using EdU, wound healing, and Transwell assays. In vivo efficacy was tested in nude mouse xenografts treated with STM2457 (50 mg/kg/day) and APS (80 mg/kg/day), with tumor growth and FOXQ1 expression analyzed. Combined STM2457 and APS treatment significantly reduced m6A levels, METTL3, HNRNPA2B1, and FOXQ1 expression, and mRNA stability compared to single-drug treatments, approaching or surpassing METTL3 silencing effects. The combination markedly suppressed cell proliferation, migration, invasion, and EMT, with increased E-cadherin and decreased N-cadherin levels. Regarding the role of APS in regulating m6A, we acknowledge that the current evidence is speculative and requires further mechanistic validation. In vivo, combination therapy significantly reduced tumor growth and FOXQ1 expression, outperforming single-drug treatments. STM2457 and APS enhance the inhibitory effects on OSCC progression by targeting the METTL3/HNRNPA2B1/FOXQ1 axis, offering a potential therapeutic strategy that integrates precision oncology with traditional herbal medicine. Further mechanistic and clinical studies are warranted to validate these findings.

Minimally invasive D2 lymphadenectomy for gastric cancer is technically demanding, and its quality varies across patients, surgeons, platforms, and institutions. Conventional endpoints, including lymph node yield, margin status, operative time, blood loss, postoperative morbidity, and survival, remain essential but do not consistently capture intraoperative procedural fidelity, safety-critical deviations, or case complexity. This narrative framework review synthesized evidence from MEDLINE, Embase, and Web of Science from inception to May 10, 2026, focusing on technical difficulty, surgical quality assessment, pathology-centered oncologic adequacy, risk-adjusted outcomes, and artificial intelligence (AI)-enabled audit. Technical difficulty was conceptualized as a case- and context-dependent risk-adjustment layer shaped by anatomical complexity, vascular variation, therapy-altered tissue planes, visceral adiposity, operative platform, team workflow, and learning stage. Surgical quality was defined as a multidomain construct integrating process metrics, pathology metrics, and risk-adjusted clinical outcomes. The proposed framework provides audit-oriented guidance for identifying a simplified minimum dataset, prioritizing high-risk D2 segments for selective process review, and interpreting process, pathology, and outcome indicators together after adjustment for technical difficulty. AI may support scalable audit through video indexing, phase and step recognition, extraction of high-risk operative segments, assisted event logging, and structured feedback. However, AI outputs should be treated as candidate measurement signals requiring human confirmation, expert surgical review, pathology-based assessment, external validation, governance, and post-deployment monitoring. Future validation should proceed stepwise, from feasibility testing and inter-rater reliability assessment to prospective workflow evaluation and multicenter assessment of audit efficiency, benchmarking validity, and process- or patient-level outcomes. Quality assessment in minimally invasive D2 lymphadenectomy should shift from isolated surrogate endpoints toward an auditable, difficulty-adjusted framework that makes “D2 achieved” more measurable, reviewable, and clinically meaningful.

Background and Objectives:Asthma represents a heterogeneous chronic respiratory condition. Type 2 (T2) inflammation is the most crucial pathological event in asthma. In terms of whether T2 inflammation is dominant or not, asthma can be classified into T2-high and T2-low asthma. Currently, there exists a significant gap in our understanding of the heterogeneity of treatment-naive T2-high asthma patients. Moreover, no studies have examined the impacts of inhaled corticosteroids (ICS) on the airway microenvironment and metabolism of T2-high asthma during the early stage of treatment. This study, by employing multi-omic techniques, investigated the pathophysiological features and heterogeneity of untreated T2-high asthma, as well as the effects of ICS treatment. This study provided more in-depth insights into the pathophysiological mechanisms underlying T2-high asthma heterogeneity. Methods:Thirty-one treatment-naive T2-high asthma patients and fourteen healthy individuals were enrolled in this study. On the basis of hierarchical clustering analysis of T2 inflammation markers, fractional exhaled nitric oxide (FeNO) level and blood eosinophil count (BEC), the T2-high asthma patients were divided into three subgroups in terms of FeNO levels (≤ 25 ppb, 26-50 ppb, and > 50 ppb). All asthma patients underwent asthma control scoring, pulmonary function tests, and FeNO measurement at baseline and during a regular 3-month follow-up. Induced sputum and plasma were collected. Other tests included 16S rRNA microbiome profiling of the induced sputum, Luminex xMAP immunoassays of cytokines, and plasma metabolomic analysis using Q-Exactive liquid chromatography-mass spectrometry (LC-MS/MS). Meanwhile, data from the healthy population were also harvested. Results:T2-high asthma patients differed significantly from healthy controls in terms of airway inflammatory cytokines, airway microbial community structure, and plasma metabolic profiles. At baseline, T2-high asthma patients with different FeNO levels exhibited remarkable similarities in clinical symptoms, pulmonary function indices, airway cytokines, airway microbial diversity, and metabolites. After treatment with ICS, symptoms improved in T2-high asthma patients. The levels of FeNO, blood eosinophils, and total immunoglobulin E (tIgE) decreased significantly, while pulmonary function did not show substantial improvement. Some indices of airway cytokines underwent changes. No differences were found in airway microbial diversity; however, the abundance of Actinomyces increased. Moreover, the levels of glycerophospholipids and arachidonic acid metabolites decreased. Differentially expressed metabolites were enriched in arachidonic acid metabolism. The effect of ICS treatment varied among different T2-high asthma subgroups. Conclusions:The airway local microenvironment and systemic metabolic profiles of treatment-naive T2-high asthma patients were distinctly different from those of healthy individuals. Limited heterogeneity was observed among patients stratified in terms of T2-inflammatory burden. ICS altered the airway microenvironment and rectified the lipid/arachidonic acid metabolic dysregulation. However, ICS effects varied across various T2-high subgroups.

Preoperative assessment of lymph node dissection (LND) difficulty in gastric cancer remains challenging. Conventional clinical indicators are relatively coarse and may not adequately reflect tissue-related complexity within the surgical field. This study aimed to develop and validate a preoperative CT-based radiomics approach using suprapancreatic adipose tissue for predicting high-difficulty LND in gastric cancer. This single-center retrospective study included 192 patients with gastric cancer who underwent laparoscopic radical D2 gastrectomy between January 2022 and December 2024. Patients were randomly assigned to a training cohort (n = 134) and a validation cohort (n = 58). High-difficulty LND was defined as suprapancreatic LND time exceeding the 75th percentile (32.68 min) and/or unqualified suprapancreatic dissection according to KLASS-02-QC. A single-slice ROI was manually delineated in the suprapancreatic adipose tissue on portal venous-phase CT images. Radiomics features were extracted, followed by feature selection and model development. Four radiomics models, a clinical model, and a combined model were constructed. Sensitivity analyses were further performed using alternative time thresholds and in the subgroup without neoadjuvant chemotherapy (NCT). A total of 81 of 192 patients (42.2

Background: Krukenberg tumors (KTs) represent a distinct form of ovarian metastasis originating from gastric cancer (GC) and are associated with dismal clinical outcomes. Despite their clinical significance, the molecular landscape and underlying mechanisms driving KTs development remain largely undefined. Our goal was to delineate the molecular landscape and metastatic evolutionary pattern of KTs, thereby informing the development of therapeutic strategies. Methods: We conducted whole-exome sequencing (WES) on paired primary gastric and metastatic ovarian tumors from 11 patients with KTs in a retrospective cohort. Results: TP53 (54.5%) and EIF1AX (45.5%) were the most frequently mutated genes in KTs. Mutational signatures analysis revealed associations with age and mismatch repair deficiency. Mutations in TP53, EIF1AX, and FBXW7, along with MYC-amplification, were highly consistent between matched primary tumors and KTs. Importantly, compared to primary GC, KTs harbored distinct mutational landscapes, including mutually exclusive receptor tyrosine kinase (RTK) gene amplifications and a significantly higher burden of copy number variations (CNVs). Furthermore, patients exhibiting high-level CNVs or TP53 mutations had worse survival outcomes. Genomic comparisons between matched tumors demonstrated low concordance (median shared mutations: 6.3%), supporting the hypothesis of early clonal divergence and a parallel progression model of metastasis. Conclusions: Frequent TP53 and EIF1AX mutations may play a critical role in the ovarian metastasis of GC. KTs demonstrate distinct mutational profiles compared with their primary counterparts, consistent with a parallel progression model, highlighting the need for tailored therapeutic approaches targeting metastasisspecific alterations.

Monkeypox virus (MPXV), a zoonotic orthopoxvirus (OPXV), re-emerged as a global public health concern following the 2022 multi-country outbreak that disproportionately affected people with human immunodeficiency virus (HIV). In July 2023, the U.S. National Institutes of Health classified MPXV as an AIDS-defining opportunistic infection, underscoring the urgency of understanding immune features in immunocompromised populations. Existing studies provide limited data on the durability and coordination of MPXV-specific humoral and cellular immunity in people with HIV (PWH). Moreover, whether concomitant MPXV infection modulates HIV-specific immunity in PWH remains unclear. We aimed to evaluate the durability of immune responses against MPXV, compare immune profiles between PWH and people without HIV (PWoH), and assess the impact of MPXV coinfection on HIV-specific immunity. We conducted a prospective immunological analysis involving 28 PWH and 13 PWoH with confirmed MPXV infection. Peripheral blood samples were collected at 1–2 weeks, 1–6 months, and 12–18 months post-infection. Plasma IgG levels against MPXV antigens were measured using ELISA. Poxvirus- and HIV-specific memory T (Tm) cell responses were assessed using activation-induced marker and intracellular cytokine staining assays via flow cytometry. MPXV infection elicited durable humoral and cellular immune responses for up to 18 months, regardless of HIV status. However, PWH demonstrated attenuated MPXV-specific antibody responses, lower frequencies of poxvirus-specific Tm cells, and reduced polyfunctionality compared to PWoH. Notably, immune coordination in PWH was impaired, as evidenced by weakened concordance between humoral and cellular responses, disrupted interactions between CD4+ and CD8+ Tm cell subsets, and diminished consistency among antibody levels. Additionally, HIV-specific Tm cell responses remained stable in antiretroviral-treated PWH, irrespective of prior MPXV infection. MPXV infection induced long-lasting cellular and humoral immunity in both PWH and PWoH. However, HIV-mediated immune dysregulation compromised the strength and coordination of these responses.

Cardiac fibrosis is a hallmark of various cardiovascular diseases and is characterized by excessive extracellular matrix (ECM) deposition and progressive tissue stiffening. Emerging evidence suggests that ECM stiffening is not merely a mechanical consequence of fibrosis but also an active driver of pathological cellular responses. Among the mechanosensitive cells within the myocardium, macrophages play a central role in sensing and responding to mechanical cues. Through defined mechanotransduction pathways, macrophages undergo phenotypic and functional reprogramming that shapes inflammatory signaling and the progression of fibrosis. In this review, we summarize current knowledge on ECM stiffening in cardiac fibrosis and its impact on macrophage behavior. We also highlight key mechanosensors that mediate macrophage responses to biomechanical stress. Finally, we discuss emerging therapeutic strategies targeting macrophage mechanotransduction and ECM remodeling and explore their potential as antifibrotic interventions in cardiovascular disease.

Background:Viral infection induces host cells to enter a state of "virus-induced senescence (VIS)", which provides a stable cellular environment for viral replication. However, it is unclear about the molecular mechanism of this process. Here, we identified cellular protein DAP5 and its N-terminal fragment DAP51-451 as sensors to viral infection. Methods:Upon SARS-CoV-2 infection, cellular apoptosis and senescence levels were assessed. This led to the identification of DAP5 as a pivotal proteolytic substrate that links viral protease activity to host cell fate determination. The specific cleavage site on DAP5 targeted by the non-structural protein 5 (NSP5) encoded by SARS-CoV-2 was mapped using Western Blot and Fluorescence Resonance Energy Transfer (FRET) analysis. The functional role of the resulting N-terminal fragment DAP51-451 was then characterized through a series of molecular biology experiments, including ChIP-seq, dual-luciferase reporter assays, and co-immunoprecipitation (Co-IP). Furthermore, ubiquitination assays and protein stability analyses were conducted to delineate the degradation pathway responsible for clearing this N-terminal fragment DAP51-451. Results:Viral infection-activated caspase 3 cleaves DAP5, which contributed to positive feedback loops, reinforcing apoptotic process. NSP5 interrupted the apoptotic process by NSP5-specific cleavage of DAP5 that led to the production of the N-terminal fragment DAP51-451, which initiated the cellular senescence program, achieving an "apoptosis→senescence" fate transformation and thereby promoting viral replication of SARS-CoV-2. Mechanistically, DAP51-451 interacted with the transcription factor p53 to enter the nucleus and bind to CDKN1A locus to increase its expression, thereby triggering cell cycle arrest. Additionally, DAP51-451 activated the NF-κB signaling pathway and promoted the production of senescence-associated secretory phenotype (SASP) factors. E3 ubiquitin ligase TRIM7 encoded by host cells degraded the N-terminal fragment DAP51-451 by Glutamine C-degron-mediated ubiquitination and protein degradation, and restricted viral replication. Conclusions:Our findings clarify the mechanism of SARS-CoV-2 induced VIS and establish a model of host cells inhibiting VIS through protein degradation and limiting viral replication, which provides a basis for subsequent immunological studies of emergent pathogenic microbial infection.

Comprehensive molecular profiling is essential for modern precision oncology but remains hindered by prohibitive costs, specimen exhaustion, and protracted turnaround times. While pathology foundation models (PFMs) have demonstrated potential for inferring molecular phenotypes from routine hematoxylin and eosin (H E) whole-slide images (WSIs), current architectures primarily rely on vision-centric self-supervised learning or vision-language alignment, lacking the spatially resolved molecular supervision required to connect subtle morphological features with underlying genomic alterations. Spatial transcriptomics (ST) emerges as a transformative technology that enables transcriptomic quantification within intact tissue sections, thereby preserving the precise spatial link between histology and molecular profiles. In this study, we present a Spatial Transcriptomics-guided Alignment framework for Molecular Profiling (STAMP), which endows PFMs with intrinsic molecular awareness. To support this paradigm, we curated HumanST-1k, a human ST dataset spanning diverse anatomical organs and sequencing platforms. This atlas yields 1.8 million pairs of H E patches and corresponding transcriptomic profiles, providing a corpus that links histological structures with their molecular states. To mitigate the technical noise inherent to raw transcriptomics, STAMP applies a pathway-informed alignment strategy that aggregates transcriptomic data into biologically functional pathways, which are subsequently integrated into PFMs via parameter-efficient fine-tuning. This alignment enriches the representation space of PFMs and unlocks their capacity to resolve sub-visual molecular signatures. The clinical utility of these augmented representations was validated through a multi-tier evaluation framework.

Proximal gastrectomy (PG) for proximal gastric cancer (PGC) is associated with complications such as gastroesophageal reflux. The double-flap technique (DFT) has been proposed as an effective anti-reflux reconstruction method. This systematic review aims to compare the safety and short-term outcomes of DFT versus other reconstruction methods for proximal gastrectomy. The present meta-analysis was conducted, following PRISMA guidelines. Studies comparing DFT with other reconstruction methods for proximal gastric cancer were included. Outcomes assessed included surgical parameters (operative time and intraoperative blood loss), postoperative reflux incidence (subjective reflux symptoms, objective evaluation using endoscopy and proton pump inhibitor (PPI) intake), and other short-term postoperative indicators (postoperative complications and length of postoperative hospital stay). Data were extracted from PubMed, Web of Science, EMBASE, and the Cochrane Library through June 1st, 2025. Risk of bias was assessed using the Newcastle-Ottawa Scale. We performed meta-analyses using Review Manager 5.4, presenting mean differences (MD) and odds ratios (OR) with 95

Epidemiological studies of Talaromyces marneffei (T. marneffei) infection are largely confined to HIV-positive populations and specific geographic regions, whereas its population-scale characteristics and environmental factors associated with infection in China are lacking. This study investigates spatiotemporal patterns, host susceptibility, and environmental correlates of T. marneffei detection in Chinese mainland. Targeted next-generation sequencing (tNGS) data from patients hospitalized for acute respiratory tract infections (ARTIs) from 2022 to 2024 were used for epidemiological, spatiotemporal, and co-detection analyses. Geographical detector models with the q-statistic were employed to quantify the associations of meteorological, host distribution, and social factors on detection risk, where the q-statistic measures the proportion of spatial variance explained by each factor. Among 2,316 reported cases, we identified significant spatial clustering, with bimodal seasonal peaks in detection rate. Males and individuals aged 41–50 showed the highest susceptibility. Pneumocystis jirovecii was the predominant co-detected pathogen; 5 pathogens were positively and 16 were negatively correlated with T. marneffei. Univariate analysis using the q-statistic revealed that dew point temperature had the strongest explanatory power for T. marneffei detection at 48.55