Functional & Integrative Genomics最新文献

Tumor-adjacent mucosa is commonly used as a normal reference in colorectal cancer (CRC) transcriptomic studies, but its relationship with distant normal mucosa and tumor tissue remains unclear. Here, we performed bulk RNA sequencing of paired distant normal, adjacent, and tumor tissues from 25 patients with CRC and used these three tissue states to construct an ordered normal–adjacent–tumor (N-A-T) expression continuum. Although adjacent mucosa was globally closer to distant normal mucosa and showed no significant differential expression by pairwise analysis, a limma-based linear trend model identified widespread monotonic transcriptional changes along the N-A-T continuum. Tumor-directed genes were enriched in translation, RNA processing, cell-cycle activity, and proliferation-related pathways, whereas genes decreasing along this axis were associated with oxidative metabolism and epithelial homeostasis. A trend gene-based N-A-T score positioned adjacent mucosa between normal and tumor tissues in external bulk cohorts and was associated with proliferative and immune-low molecular states in CRC. Single-cell RNA-seq analysis localized this signal mainly to epithelial cells and associated higher scores with proliferative and stem-like epithelial states. In conclusion, CRC-adjacent mucosa is not fully equivalent to distant normal mucosa but carries coordinated tumor-directed transcriptional changes mainly associated with epithelial-cell programs.

Transcript-derived metabolic representations connect gene expression with pathway state, but interpretation depends on sampling unit, endpoint, cohort, and validation evidence. NeuroMetBench is a patient-aware methodology that keeps target quantity, independent unit, endpoint mapping, coverage, uncertainty, transport, numerical diagnostics, and provenance separate rather than collapsing them into a universal score. A frozen three-gene serine score showed RNA-protein rank concordance in 89 lung squamous cell carcinoma (LSCC) patients (Spearman (rho =0.9071), 95% confidence interval (CI) 0.8496 to 0.9388) and in a patient-disjoint 90-patient central nervous system/high-grade-glioma (CNS/HGG) cohort ((rho =0.6266), 95% CI 0.4697 to 0.7507). Reviewer-driven age/sex sensitivities remained positive in complete cases (LSCC (n=86), partial (rho =0.9118); CNS/HGG (n=69), partial (rho =0.7058)), but CNS/HGG complete-case selection was associated with the frozen RNA-score distribution and cannot rule out demographic confounding. A preanalysis-frozen Tel Aviv glioblastoma test was NOT RUN because public RNA/proteomics deposits yielded zero source-documented patient cross-matches (minimum (n=10)). A separately frozen Sun Yat-sen University Cancer Center (SYSUCC) analysis found 20 exact RNA/protein-matched glioblastomas and positive concordance ((rho =0.5984), 95% CI 0.1252 to 0.9101; permutation (p=0.00637)). By contrast, RNA score correspondence with measured L-serine in 75 same-cohort patients was weak and uncertain ((rho =0.1534), 95% CI -0.0803 to 0.3737; permutation (p=0.1853)). Evidence strength is therefore axis-specific: cross-modal proxy concordance does not establish metabolic flux, biochemical validation, universal method superiority, framework-wide external validation, or calibration.

Polyploidization serves as a major driver of plant genome evolution and functional innovation. However, how it influences genome structural remodeling and functional divergence remains unclear. In this study, we selected six species with different ploidy levels in the genus Panax as research materials. By integrating pan-genome and gene duplication analyses, we systematically evaluated the evolutionary patterns under distinct ploidy backgrounds. The results showed that, under their respective ploidy-specific pan-genome frameworks, tetraploid species had a higher proportion of core genes than diploid species. This compositional difference, combined with extensive gene family remodeling in tetraploid lineages, suggests that polyploidization was accompanied by systematic genome structural reorganization, likely driven by distinct selective pressures corresponding to different modes of gene duplication. The composition of duplication types differed extremely significantly among ploidy levels, and WGD as well as TRD were significantly elevated in tetraploid species. Further analysis revealed that WGD contributed predominantly to core genes, whereas DSD and TRD were more involved in the formation of dispensable and private genes. Functional analysis indicated that duplicated genes in tetraploids were involved in a broader range of metabolic and cellular processes, among which private genes derived from DSD were significantly enriched in DNA replication and repair pathways. These findings suggest that polyploidization promotes functional diversification while maintaining core functional stability by regulating different duplication mechanisms, thereby driving genome structural reorganization and adaptive evolution in Panax. These findings provide a genomic framework for understanding the diversity of bioactive compounds and may support future breeding and quality improvement of Panax medicinal resources.

Atopic dermatitis (AD) and asthma frequently co-occur, yet the regulatory mechanisms connecting cutaneous and airway inflammation remain unclear. We integrated European genome-wide association statistics for AD (22,474 cases; 774,187 controls) and asthma (56,167 cases; 352,255 controls) with expression and splicing quantitative trait loci (QTLs), immune single-cell expression QTLs, single-cell transcriptomes, and spatial transcriptomics. The AD dataset compared lesional skin with healthy controls, whereas the asthma dataset paired allergen and diluent challenges in four participants. Each was analyzed within its own design, and cross-disease comparison used independently derived annotations and gene sets. Regulatory QTL enrichment implicated skin, lung, fibroblast, and immune-related tissues. Cell-stratified Mendelian randomization identified multi-instrument associations in memory B cells (odds ratio = 1.35, 95% confidence interval 1.18–1.56; false discovery rate = 1.1 × 10⁻⁴) and immature/naïve B cells (1.26, 1.10–1.45); single-instrument estimates were exploratory regardless of false discovery rate, and no association has been independently replicated. T-cell co-expression analysis identified three cross-disease module overlaps—translational, metabolic–cytoskeletal, and cytotoxic effector—each significant after multiple-testing correction across 42 module comparisons. Airway transcripts in the asthma T-cell compartment were attributed predominantly to ambient RNA. Bayesian colocalization identified signals at 19 AD and 72 asthma loci and 112 shared genes. Integrated evidence prioritized SLC22A4, CTSW, IL1R1, RMI2, and IRF1; four ranked in the top five under all eight scoring schemes and IRF1 under seven, and all five retained top-ten ranking in ≥ 98.9% of 10,000 moderately concentrated randomized weightings. These results prioritize shared regulatory candidates for validation.

Single-cell transcriptomics resolves immune-cell heterogeneity, but whether cluster boundaries or coordinated programmes are the more transferable unit across donors remains uncertain. We reanalyzed 14,414 circulating memory B cells from four untreated rheumatoid arthritis donors. Harmony increased mean local donor entropy from 0.506 to 0.912, while original labels showed only moderate agreement with uncorrected and Harmony reclustering (adjusted Rand indices 0.508 and 0.473). Conditional label permutations and analyses based on pan-B-centred residuals or state-marker genes supported donor-level consistency for most major states, but identified C3-PECAM1 and the rare C10-IFN state as weakly specific or quality-control-sensitive. In training-only donor-held-out transfer, accuracy was 66.0–70.5% and adjusted Rand index was 0.432–0.525, indicating partial transfer rather than independent state recovery. Removal of DoubletFinder-predicted doublets preserved 15–20 of each state’s top 20 pseudobulk markers and did not change programme rank order across states. Rank-based UCell scores agreed with AddModuleScore in both datasets. In an independent cohort of 5,725 memory B cells from 34 donors, adapted programme scores could be quantified, but no disease-activity or serological association remained significant after correction; treatment and unavailable disease-duration data limited clinical interpretation. These results distinguish recurrent donor-level transcriptional structure from analysis-sensitive state boundaries and support programme-level interpretation without claiming independent cell-state validation or biomarker utility.

Owing to the nonspecific nature of early symptoms of gastric cancer, the high postoperative recurrence rate, and considerable interindividual heterogeneity, accurate prognosis assessment is essential for optimizing individualized clinical management. BAP31 is closely associated with gastric cancer, and the progression of this malignancy is exacerbated by elevated levels of BAP31 expression. This study aims to investigate the relationship between miRNAs derived from BAP31-overexpressing exosomes (BAP31-exos) and prognostic models in gastric cancer. High-throughput sequencing was used to detect the expression levels of miRNAs in BAP31-exos to screen for differentiated miRNAs. The effects of differentiated miRNAs on cell proliferation were evaluated by CCK-8 and colony formation assays. The target genes of the miRNAs were predicted and protein‒protein interaction (PPI) network was analyzed using the STRING database and visualized through Cytoscape. LASSO regression analysis was conducted on the predicted target genes to construct a prognostic risk scoring model, which was verified through Cox regression analyses, receiver operating characteristic (ROC) curve analysis, and Kaplan‒Meier analysis, and the prognostic model was visualized using a nomogram. Three significant miRNAs were screened from the BAP31-exos. Exosomes promoted the proliferation of GCs via these three miRNAs. The predicted target genes were significantly enriched in tumor-related signaling pathways, leading to the identification of hub genes. A gastric cancer risk scoring model was established. This study reveals the important role of BAP31-related miRNAs in the prognosis of GC. A reliable risk prognosis scoring model for gastric cancer was established, facilitating the development of individualized diagnosis strategies.

Antibiotic residues in aquatic environments are an increasing concern because they may retain antibacterial activity, promote antibiotic resistance and generate transformation products with uncertain ecological risks. In this study, marine-derived bacteria were screened for their ability to degrade representative β-lactam antibiotics. Strain PP1, identified as Bacillus cereus, was selected for detailed characterization because of its outstanding degradation capacity toward piperacillin, ceftiofur and cephalexin, especially its efficient removal of piperacillin at a high initial concentration of 100 mg/L. During a 48-h incubation, B. cereus PP1 completely degraded piperacillin and reduced the antibacterial activity of the treated solution against representative Gram-negative and Gram-positive bacteria. UHPLC-MS/MS analysis indicated that piperacillin was transformed mainly through β-lactam ring opening, together with side-chain cleavage and downstream fragmentation reactions. The degradation products showed no obvious hemolytic activity under the tested conditions, whereas live PP1 exhibited hemolysis, highlighting the need for biosafety evaluation before live-cell application. Whole-genome sequencing revealed that PP1 contains a single circular chromosome of 5,285,738 bp and has broad metabolic potential. CARD, CAZy and VFDB annotations indicated antibiotic tolerance, hydrolytic enzyme resources and virulence-associated features. Targeted mining using a local β-lactamase database identified two candidate β-lactamase genes, PP1_BLA_A and PP1_BLA_B, assigned to class A and class B β-lactamases, respectively. Structure prediction and molecular docking further suggested that both enzymes can accommodate piperacillin, but with distinct binding modes. These findings indicate that B. cereus PP1 is a valuable source for β-lactamase discovery and enzyme-based β-lactam bioremediation.

Seed size is a complex quantitative trait governed by coordinated developmental, hormonal, and metabolic pathways, yet its regulatory architecture in makhana (Euryale ferox Salisb.) remains largely unknown. This study integrated comparative genomics with developmental transcriptomics to construct a systems-level framework for investigating seed development in makhana. Genome-wide analyses identified 543 genes across ten conserved gene families containing established regulators of seed development and related growth processes, with WGD/segmental duplication contributing substantially to their expansion and duplicated genes predominantly evolving under purifying selection. Despite extensive evolutionary constraint, only 193 genes met the expression criterion during seed development. Temporal profiling revealed dynamic stage-specific reprogramming, with NAC and WRKY genes prominently represented among development-associated expression patterns across seed maturation. Co-expression network analysis identified six positively associated development modules, with the blue module containing the largest proportion of candidate genes and showing enrichment for ubiquitin-mediated protein turnover, calcium signalling, vacuolar trafficking, and autophagy. Leave-one-sample-out (LOSO) analysis further supported hub-gene stability, with 61 of 64 development-associated hubs retaining the module-membership criterion in at least 11 of 12 runs. Integrating these LOSO-stable hubs with genes upregulated between the earliest and latest developmental stages prioritized 51 high-confidence seed-development-associated candidate genes from the NAC, WRKY, EXPANSIN, ARF, AP2, AUX/IAA, and SWEET families. This study establishes a comprehensive framework linking gene-family evolution with developmental transcriptional and co-expression dynamics in makhana, providing a prioritized resource for functional investigation of seed-development-associated candidates and future genomics-assisted molecular breeding.

Graphical Abstract

Sedentary chromosomal integrons (SCIs) are large integrons that harbor extensive arrays of gene cassettes and constitute major reservoirs of bacterial genetic diversity. In Vibrio, SCI cassettes are flanked by species-associated attC repeats, here referred to as Vibrio species repeats (VXRs). Although SCIs have been proposed as ancestral sources of antibiotic resistance genes (ARGs), the extent to which SCI-associated ARGs are exchanged among Vibrio species remains poorly understood. To investigate the dynamics of SCI-associated ARGs, we analyzed 37,812 genomes representing 181 Vibrio species. Using VXR mapping, comparative phylogenetics, and genome screening, we identified 8,679 putative ARG cassettes distributed across 8,517 genomes from 11 species. Despite the diversity of VXRs identified in SCIs, ARG cassettes were predominantly associated with a small subset of related VXRs shared among phylogenetically distant species, suggesting horizontal transfer of ARG-associated cassettes across the genus. Comparative analyses further suggested that members of the Cholera clade may act as potential sources of SCI-associated ARG dissemination. Five major ARG families were identified within SCIs, including catB, qnrVC, bla_CARB, dfrA, and vatF, some of which displayed phylogenetic patterns consistent with interspecies transfer. Functional characterization of a SCI-associated qnrVC4 cassette from Vibrio mimicus confirmed its ability to confer reduced susceptibility to ciprofloxacin in a heterologous host. Together, our findings indicate that a conserved subset of VXR backbones, mainly from the Cholera clade, plays a role in ARG dissemination across Vibrio species, highlighting SCIs as active reservoirs contributing to the emergence and spread of antimicrobial resistance.