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The detection of circulating tumor cells (CTCs) through liquid biopsy offers a non-invasive approach for accurately monitoring cancer dissemination and evaluating therapeutic efficiency. However, their rarity and heterogeneity limit conventional tumor antigen labelling-based methods in identifying and tracing CTCs. Here, we developed a novel metric, termed chromatin unwinding state (CUS), which leverages activated transcriptional regions related to cell-identity processes from single-cell transcriptomic data while overcoming technical variances. Using CUS features, we trained attention-based neural network models, panCTC, to in situ identify and lineage trace rare single CTCs directly from 5 mL of peripheral blood mononuclear cells scRNA-seq without enrichment. We benchmarked panCTC on various in silico-simulated, public, and in-house sequenced data, demonstrating its robustness across sample types and platforms. PanCTC could provide real-time scRNA-seq profiles of fresh CTCs, supporting early cancer detection and targeted anti-metastatic therapy.

Gut microbiome alterations are increasingly associated with hepatocellular carcinoma (HCC), highlighting the gut-liver axis as a key contributor to tumor progression and prognosis. Taxon-based HCC microbiome studies have shown limited reproducibility because they are affected by database dependency, taxonomic ambiguity, and overlooked ecological interactions. The Two Competing Guilds (TCG) model, based on stable gut microbiome interactions, provides a structurally grounded framework for robust, generalizable biomarkers. Using shotgun metagenomic data from a newly recruited cohort of 120 surgically resectable HCC cases and 76 benign liver tumor controls, we constructed co-abundance networks to identify stably correlated genome pairs and assembled a hepatic cancer-TCG (HCC-TCG) model composed of 142 genomes. Functionally, one Guild had more genes for butyrate production from carbohydrate fermentation while the other Guild was enriched in genes for virulence factors and antibiotic resistance, highlighting its potential proinflammatory roles. Classifiers trained on the abundance profiles of HCC-TCG genomes successfully distinguished HCC from benign liver tumors (area under the receiver operating characteristic, AUROC = 0.70) and from colorectal liver metastases (CRLM) (AUROC = 0.78). In an external validation cohort, the model further discriminated against HCC from intrahepatic cholangiocarcinoma (iCCA) (AUROC  =  0.72), and from healthy controls (AUROC  =  0.79-0.85), demonstrating its broad applicability for tumor stratification across clinical contexts. Moreover, HCC-TCG profiles predicted post-resection recurrence risk and response to adjuvant therapies (AUROC up to 0.83). Importantly, external validation in two independent cohorts of advanced HCC patients treated with PD-1/PD-L1 inhibitors demonstrated consistent predictive performance (AUROC  =  0.64-0.73), confirming the model's generalizability in nonsurgical and immunotherapy contexts. This genome-specific, ecologically structured, and database-independent framework identifies a conserved Guild-based microbiome signature for HCC. Our findings demonstrate that a fixed genome-resolved ecological structure retains transferable discriminatory signal across clinical contexts. The HCC-TCG framework provides a genome-specific, interaction-based foundation for future development of non-invasive microbiome stratification strategies requiring prospective validation.

Immune checkpoint inhibitors (ICIs) have shown promising antitumor efficacy in certain types of solid tumors. However, the efficacy of ICIs remains unsatisfactory owing to the dysregulation of signaling pathways in local tumor tissues. Here, we reveal that diacylglycerol kinase α (DGKα)-derived phosphatidic acid (PA) directly binds to nuclear factor-κB (NF-κB) and enhances the transcriptional activity of NF-κB to increase the expression of programmed cell death 1-ligand 1 (PD-L1) and facilitate the immune evasion of tumor cells and orchestrate immune microenvironment. Inhibition of DGKα activity decreases the intratumoral PD-L1 level and induces cytotoxic T lymphocytes (CTLs) infiltration and resultantly enhances the antitumor efficacy of ICIs. Plasma PA can function as a biomarker to evaluate the efficacy of ICIs in gastrointestinal cancers. Overall, our results identify the DGKα/PA axis as a metabolic driver of immune evasion and CTLs exclusion, representing a promising target to enhance ICIs' efficacy in gastrointestinal cancer treatments.

We utilized single-cell RNA sequencing (scRNA-seq) to investigate cellular heterogeneity and signaling networks in aortic dissection (AD) tissues compared to adjacent normal tissues. The analysis identified five smooth muscle cell (SMC) subtypes, with SMC2 linked to fibrosis and SMC3 associated with inflammation. Thrombus-positive AD samples showed upregulated angiopoietin-like 4 (ANGPTL4) and increased M2 macrophages, indicating an immunosuppressive microenvironment. Cell-cell communication analysis revealed a shift in vascular endothelial growth factor A (VEGFA) signaling from SMCs to fibroblasts, disrupting vascular homeostasis. In vitro experiments confirmed SMC2-induced endothelial-to-mesenchymal transition and SMC3-driven inflammatory responses via mitogen-activated protein kinase (MAPK) pathways. Immunofluorescence validated elevated insulin-like growth factor binding protein 2 (IGFBP2), procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2), and VEGFA in AD tissues, supporting their roles in matrix remodeling and angiogenesis. These findings highlight SMC phenotypic switching and altered VEGFA signaling as key drivers of AD, proposing novel therapeutic targets to restore vascular integrity.

Nontargeted metagenomic surveillance of the poultry enteric virome reveals underrecognized threats to poultry health and productivity in intensive production systems. In South Asia, avian rotavirus A (AvRV-A) and avian orthoreovirus (ARV) are frequently detected in broilers by conventional diagnostics, whereas chicken megrivirus genotype C (ChMeV-C) is often identified through metagenomic surveillance. Often present in both clinical disease and coinfections, these viruses may impair gut function, immune responses, and growth performance, yet their genomic diversity and evolutionary dynamics in poultry remain poorly characterized. Here, we report complete genomes of AvRV-A, ARV, and ChMeV-C strains co-detected via nontargeted metagenomic next-generation sequencing (ntNGS) in a pooled cloacal sample comprising 150 commercial broiler chickens (19 and 33 days old) collected from three commercial farms in Kamrup Rural District, Assam, Northeast India. Despite routine vaccination, all three flocks experienced > 10% mortality, poor weight gain, and postmortem lesions including pale kidneys and hepatomegaly. Phylogenetic analyses revealed segmental clustering in ARV and AvRV-A consistent with reassortment-driven divergence, though not supported by detectable recombination, while ChMeV-C clustered within a distinct C1 sublineage, suggesting intercontinental lineage connectivity and highlighting the need to expand regional genomic baseline data. We also identified nonsynonymous single nucleotide polymorphisms in several key viral proteins, including RNA-dependent RNA polymerases (VP1 of AvRV-A, λB of ARV, and 3D of ChMeV-C), capsid proteins (VP2 and VP7 of AvRV-A, λA and σB of ARV, and VP0 and VP1 of ChMeV-C), and replication-associated nonstructural proteins. These findings expand the genomic baseline for poultry enteric viruses in South Asia, reveal novel polymorphic signatures, and underscore the value of ntNGS-based metagenomic surveillance in virus detection, diversity monitoring, and informing vaccine and biosecurity strategies.

FluNexus is a versatile platform for the antigenic prediction and visualization of influenza A viruses, including: (i) Online data preprocessing module. (ii) Online antigenic prediction module. (iii) Visualization module for mapping antigenic evolution.

Porcine deltacoronavirus (PDCoV) is a significant pathogen of swine with a global distribution, leading to severe gastrointestinal disease and substantial economic losses. Furthermore, PDCoV poses a potential threat to human health, as evidenced by the recent identification of three cases of infection in Haitian children. This study aimed to investigate the effects of PDCoV infection on host intestinal microbiota and bile acid metabolism, as well as the antiviral effects of lithocholic acid (LCA) in vitro and in vivo. Our results revealed that PDCoV infection caused microbiota dysbiosis in piglets, significantly reducing the intestinal abundance of Bacteroides fragilis (B. fragilis), a reduction that correlated with disruptions in bile acid metabolism. Colonization with bile salt hydrolase (BSH)-producing B. fragilis increased the levels of unconjugated bile acids and inhibited PDCoV infection, highlighting the role of microbiota-associated bile acid metabolism in viral pathogenesis. LCA, a prominent unconjugated bile acid, was shown to effectively inhibit PDCoV infection in porcine small intestinal epithelial cells and porcine intestinal enteroids. Notably, LCA inhibited PDCoV replication independently of bile acid receptor signaling and innate immune modulation. Mechanistic studies indicated that LCA prevents PDCoV infection by disrupting the viral entry process, specifically inhibiting the binding between the PDCoV spike protein and its cellular receptor, aminopeptidase N. In vivo experiments further confirmed that LCA significantly inhibited PDCoV infection in piglets. These results collectively highlight the potential of LCA as a therapeutic agent against PDCoV by targeting and disrupting the viral entry process, providing a novel strategy to control zoonotic PDCoV infections.

Plant growth-promoting rhizobacteria (PGPR) represent a sustainable method to improve crop productivity. Synthetic microbial consortia have emerged as a powerful tool for engineering rhizosphere microbiomes. However, designing functionally stable consortia remains challenging due to an insufficient understanding of bacterial social interactions. In this study, we investigated the effects of Bacillus velezensis SQR9 (i.e., a commercially important PGPR) on social interactions within the rhizosphere community, particularly among Bacillus species. SQR9 inoculation significantly enhanced cucumber plant growth and altered the structure of rhizosphere Bacillus and its related bacterial communities. The results of swarm boundary and carbon utilization assays, revealed that phylogenetically closer Bacillus strains exhibited increased social cooperation and increased metabolic niche overlap. Building on these social interactions, we designed 30 consortia comprising both highly related (HR) and moderately related (MR) types across four richness levels (1, 2, 3, and 4 strains), with MR consortia demonstrating superior PGP effects through enhanced plant growth, root colonization, indole-3-acetic acid production, and siderophore production, than the HR consortia. Expanding these findings to 300 consortia across four richness levels (1, 2, 4, and 8 strains) confirmed enhanced PGP effects in MR consortia with increasing richness. These findings highlight the importance of bacterial interactions and phylogenetic relationships in shaping rhizosphere communities and designing synthetic microbial consortia. Specifically, this study provides a framework for assembling Bacillus consortia that enhance cooperation, which would aid in improving their stability and effectiveness in agricultural applications.

Hepatocellular carcinoma (HCC) is associated with high mortality rates despite the widespread application of radiofrequency ablation (RFA), which has limited therapeutic efficacy as a monotherapy. This study investigated ribonucleotide reductase M2 (RRM2) upregulation in post-RFA HCC tissues and developed a targeted nanoco-delivery system (red blood cell membrane/cRGD-modified pH-sensitive liposomes [sS@RBCM/cRGD-phLips]) to increase RFA efficacy through specific RRM2 knockout. RRM2 knockout synergistically amplified RFA-induced tumor cell death by promoting ferroptosis and immunogenic cell death. Mechanistically, RRM2 knockout upregulated the STAT1-IRF1-ACSL4 axis, which potentiated lipid peroxidation and ferroptosis. Furthermore, the nanocarrier system enhanced dendritic cell maturation and cytotoxic T cell infiltration, thereby remodeling the tumor immune microenvironment. In vivo experiments revealed that the combination of RFA and RRM2-targeted nanoparticles significantly suppressed tumor growth and prolonged survival in HCC-bearing mice with minimal systemic toxicity. Notably, the dual-loaded nanoparticles also enhanced the efficacy of anti-programmed cell death protein 1 therapy, suggesting a promising combinatorial approach for HCC treatment. This study presents a novel therapeutic strategy that integrates RRM2-targeted gene editing with RFA, offering a robust and synergistic approach for improving HCC outcomes.

Homoharringtonine (HHT) is widely used in combination regimens for acute myeloid leukemia (AML), yet its direct cellular targets remain undefined, limiting precision application. Here, we identified EWS RNA-binding protein 1 (EWSR1) as the primary target of HHT through chemical proteomics and biophysical validation. HHT bound the RNA recognition motif of EWSR1 with micromolar affinity, inducing an allosteric conformational switch that promoted oligomerization and liquid-liquid phase separation (LLPS). EWSR1 condensates selectively recruited the N6-methyladenosine (m6A) reader YTHDF2, forming cytoplasmic hubs where HHT disrupted YTHDF2-mRNA interactions. This sequestration attenuated m6A-mediated RNA decay, stabilizing key transcripts such as TNFRSF1B and HMOX1, and thereby impairing AML cell proliferation. Integrated transcriptomics and single-cell RNA-seq analyses revealed that EWSR1 was markedly upregulated in AML, particularly in hematopoietic progenitor and myeloid subpopulations, and high EWSR1 expression correlated with poor prognosis and enhanced HHT sensitivity. In vivo, the anti-leukemic efficacy of HHT was significantly diminished upon EWSR1 knockdown, demonstrating that EWSR1 was required for therapeutic response. Collectively, these findings uncover a phase separation-centric mechanism by which HHT exerts anti-AML activity, establish the EWSR1-YTHDF2-m6A axis as a critical regulator of leukemia progression, and position EWSR1 as both a functional target and a predictive biomarker for optimizing HHT-based therapies.

Multi-omics approaches revealed how nanoplastics with different surface charges influence antibiotic resistance in Escherichia coli K12. Positively charged nanoplastics enhanced antibiotic resistance by upregulating genes and proteins linked to oxidative stress tolerance and efflux pumps, and promoted antibiotic resistance genes transfer via conjugation and transformation. In contrast, negatively charged nanoplastics disrupted biofilm formation and metabolism, potentially reducing antibiotic resistance. These findings highlight the critical role of nanoplastics' surface properties in shaping microbial resistance dynamics and highlight emerging risks posed by nanoplastics to public health through accelerated antibiotic resistance propagation.

The intratumoral microbiome is an emerging hallmark of cancer, yet its multi-kingdom host-microbiome ecosystem in colorectal cancer (CRC) remains poorly characterized. Here, we conducted an integrated analysis using deep shotgun metagenomics and proteomics on 185 tissue samples, including adenoma (A), paired tumor (T), and para-tumor (P). We identified 4057 bacterial, 61 fungal, 108 archaeal, and 374 viral species in tissues and revealed distinct intratumor microbiota dysbiosis, indicating a CRC-specific multi-kingdom microbial ecosystem. Proteomic profiling uncovered four CRC subtypes (C1-C4), each with unique clinical prognoses and molecular signatures. We further discovered that host-microbiome interactions are dynamically reorganized during carcinogenesis, where different microbial taxa converge on common host pathways through distinct proteins. Leveraging this interplay, we identified 14 multi-kingdom microbial and 8 protein markers that strongly distinguished A from T samples (area under the receiver operating characteristic curve (AUROC) = 0.962), with external validation in two independent datasets (AUROC = 0.920 and 0.735). Moreover, we constructed an early- versus advanced-stage classifier using 8 microbial and 4 protein markers, which demonstrated high diagnostic accuracy (AUROC = 0.926) and was validated externally (AUROC = 0.659-0.744). Functional validation in patient-derived organoids and murine allograft models confirmed that enterotoxigenic Bacteroides fragilis and Fusobacterium nucleatum promoted tumor growth by activating Wnt/β-catenin and NF-κB signaling pathways, corroborating the functional potential of these biomarkers. Together, these findings reveal dynamic host-microbiome interactions at the protein level, tracing the transition from adenoma to carcinoma and offering potential diagnostic and therapeutic targets for CRC.

The vaginal microbiome is central to reproductive health, yet large-scale studies in East Asian populations remain scarce. Here, we characterized the vaginal microbiota of 6423 Chinese women of reproductive age across 18 provinces and assessed associations with 33 host factors. We observed a striking compositional transition around age 40, marked by declining Lactobacillus crispatus and enrichment of dysbiosis-associated taxa including Gardnerella vaginalis, independent of lifestyle or sociodemographic influences. Sexual behavior, contraceptive use, and educational attainment emerged as key determinants of community structure, differentially shaping Lactobacillus crispatus and Lactobacillus iners. Despite these associations, host factors explained less than 2% of overall variation, highlighting the resilience and individuality of the vaginal microbiome. To quantify vaginal health, we derived a microbiome balance score, validated it in external cohorts, and demonstrated its predictive power for incident bacterial vaginosis and sexually transmitted infections. Our findings establish a national-scale reference for the vaginal microbiome in Chinese women, reveal a midlife inflection point in microbial composition, and introduce a clinically actionable metric for risk stratification. These insights advance mechanistic understanding of host-microbiome interactions and inform strategies for precision interventions to preserve vaginal health.

Antimicrobial resistance (AMR) disseminates throughout the soil-plant continuum via complex microbial interactions. Plants shape root- and leaf-associated microbiomes that sustain plant health; however, soil-borne legacies-enriched with antibiotic-producing microbes and resistance genes-govern AMR dynamics across agroecosystems. Using 16S rRNA gene sequencing, shotgun metagenomics, and high-throughput quantitative PCR, we profiled antibiotic resistance genes (ARGs), mobile genetic elements, and virulence factor genes across bulk soil, rhizosphere, phyllosphere, and root endosphere within soil-tomato and soil-strawberry continua. Recurrent bacterial wilt amplified the resistome, particularly polypeptide resistance genes, thereby establishing the rhizosphere as a major hotspot of ARG accumulation. Multidrug-resistant Ralstonia solanacearum (R. solanacearum) strains acted as major ARG reservoirs, harboring resistance determinants on both chromosomes and megaplasmids. Collectively, these findings demonstrate that pathogen-driven restructuring of the plant microbiome accelerates ARG dissemination, establishing soil-borne diseases as critical amplifiers of AMR across agricultural ecosystems.

We used snRNA-seq to construct a high-resolution atlas of pectoral muscle development in broiler chickens from neonatal to adult stages. This analysis revealed pronounced molecular heterogeneity among satellite cells across developmental phases and uncovered a previously uncharacterized Runx1 + satellite cell subpopulation. By integrating pseudotime trajectory reconstruction, gene set enrichment analysis, dynamic expression profiling and loss-of-function assays, we established a critical regulatory role for RUNX1 in muscle hypertrophy. Mechanistically, RUNX1 promotes myotube hypertrophy by transcriptionally repressing Pik3r1, thereby reducing PI3K p85α levels, destabilizing PTEN, and activating the PI3K/AKT/mTOR signaling cascade, which enhances protein synthesis and drives myotube growth.

The human microbiome is now recognized as a central regulator of cancer biology, intricately shaping tumor development, immune dynamics, and therapeutic response. This comprehensive review delineates the multifaceted roles of bacteria, viruses, and fungi in modulating the tumor microenvironment and systemic immunity across diverse cancer types. We synthesize current evidence on how microbial dysbiosis promotes carcinogenesis via chronic inflammation, metabolic reprogramming, genotoxic stress, immune evasion, and epigenetic remodeling. This review emphasizes organ-specific microbiome signatures and highlights their potential as non-invasive biomarkers for early detection, treatment stratification, and prognosis. Furthermore, we explore the impact of intratumoral microbiota on cancer therapies, uncovering how microbial metabolites and host-microbe interactions shape therapeutic efficacy and resistance. Finally, advances in microbiome-targeted strategies, such as probiotics, fecal microbiota transplantation, and engineered microbes offer new avenues for adjunctive cancer therapy. This review provides a roadmap for future investigation and underscores the transformative promise of microbiome modulation in cancer prevention and treatment.

Using culturomics and metagenomics, we demonstrate the existence of non-pathogenic microbiota in the internal organs of healthy experimental mice, challenging the traditional dogma of organ sterility. Based on the analysis of 104 commercially sourced mice (C57BL/6J, BALB/c, ICR), the study reveals that over 20% of the analyzed mice harbored a high microbial burden in the internal organs and identified a total of 463 microbial species. Several species, including Ligilactobacillus murinus, Alcaligenes faecalis, Micrococcus luteus, Pseudochrobactrum asaccharolyticum, Escherichia coli, and Microbacterium sp., were frequently identified and were abundant in the mouse tissues. Further investigation implies that microorganisms in the "sterile" tissues could be associated with the gut microbiota. Given the wide use of experimental mice in medical and biological research, these findings of resident microorganisms in the animal's internal organs raise concerns about potential variability in experimental outcomes.

Gemcitabine resistance drives bladder cancer recurrence and progression. Using high-throughput drug screening in bladder cancer cells, we identified Bavachalcone (Bava) as a potent gemcitabine sensitizer. Mechanistically, Bava simultaneously targets transferrin receptor (TFRC) and epidermal growth factor receptor (EGFR). It competes with transferrin (Tf) for TFRC binding, reducing cellular iron influx, and inhibits EGFR-mediated phosphorylation of TFRC at tyrosine 20 (Y20). These actions disrupt mitochondria iron utilization and impairs respiration. The combination of Bava and gemcitabine synergistically inhibits the repair of gemcitabine-induced DNA damage, while suppressing the iron-dependent ATR-CHEK1-E2F1 pathway and downregulating RRM1 expression. Patient-derived xenograft models confirmed the superior antitumor efficacy of the Bava-gemcitabine co-treatment compared to monotherapies. Clinically, elevated TFRC and RRM1 expression correlates with poor prognosis, supporting their utility as biomarkers of bladder cancer. Our study identified Bava as the first small-molecule TFRC inhibitor that overcomes gemcitabine resistance through iron modulation, providing both mechanistic insights and a promising therapeutic strategy for bladder cancer.