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PubMed2026

Patterns of antimicrobial resistance genes in pathogens across One Health sectors in Ireland: an in silico approach.

As part of a rapid risk assessment, an in silico approach was used to detect antimicrobial resistance (AMR) in pathogenic isolates from humans, animals, and the environment. A total of 11,670 genomic data sets were retrieved from the NCBI Pathogen Detection system for Ireland, which represented 47 pathogenic species, including Salmonella enterica, Escherichia coli/Shigella spp., Staphylococcus aureus, Klebsiella pneumoniae, and Enterococcus faecium. Identifying the most critical pathogenic strains over time is essential, as these organisms significantly contribute to mortality, morbidity, and hospitalization. The analysis identified 799 antimicrobial resistance genes (ARGs), including their allelic diversity, 117 plasmid replicons, and 274 virulence factors. Several critical ARGs, particularly those conferring resistance to beta-lactams, aminoglycosides, quinolones, and colistin, were common across isolates originating from human, animal, and environmental sources, suggesting shared resistance profiles across One Health sectors. Klebsiella pneumoniae, E. coli/Shigella spp., S. enterica, and S. aureus were the dominant hosts of these ARGs and associated mobile genetic elements. Increasing resistance across major antibiotic classes aligned with trends reported across other European countries. This study provides a national-scale in silico comparison of AMR across pathogens and One Health sectors using publicly available genomic data. The findings help reinforce Ireland's AMR surveillance by showing which resistance genes are present and how they spread across critical pathogens in humans, animals, and the environment. These findings highlight the urgent need for improved antibiotic stewardship and integrated One Health surveillance to limit the emergence and spread of AMR.IMPORTANCEAntimicrobial resistance (AMR) is a growing threat to human, animal, and environmental health. This study used publicly available genomic data to identify antimicrobial resistance genes (ARGs) in key bacterial pathogens circulating in Ireland. By analyzing over 11,000 genomes from humans, animals, and the environment, we found that several dangerous resistance genes, including those against last-resort antibiotics, were widespread across different sources. The study highlights which bacteria and resistance genes are most critical and how they may spread between humans, animals, and the environment. These insights provide a national snapshot of AMR, supporting more effective monitoring and prevention strategies. By revealing patterns of resistance and modes of transmission, our findings underscore the importance of coordinated antibiotic stewardship and One Health approaches to slow the emergence and spread of resistant infections, protecting public health and ensuring antibiotics remain effective.

Humans↗

PubMed2026

Exploiting Omic Data to Advance Predictive Ecotoxicology.

Predicting species-specific chemical sensitivity using in silico approaches has the potential to transform environmental risk assessment, conservation, and biomonitoring, while reducing, and ultimately replacing, animal testing. Genomic and transcriptomic data capture extensive sensitivity-relevant variation, including differences in molecular targets, xenobiotic metabolism, and damage mitigation pathways. Large-scale sequencing initiatives therefore offer an unprecedented opportunity to address ecotoxicology's "too many species" problem. Although existing omic-based predictive tools provide proof of concept, they have so far been applied to a narrow set of relatively straightforward prediction scenarios. To achieve broader applicability, current and future tools must be firmly grounded in the diverse molecular mechanisms underlying differential chemical responses. Here, we critically evaluate the emerging field of predicting species sensitivity using molecular variation inferred from omic data. We analyze the strengths and limitations of current omic-based approaches and identify major sequence and ecotoxicological data gaps, as well as critical bioinformatic challenges. We then review the current knowledge of how molecular biology underlies differential chemical sensitivity, outlining research paths to allow the next generation of sensitivity prediction tools to exploit ever expanding omic data.

Ecotoxicology↗

PubMed2025

Whole-Genome Sequencing Uncovers Chromosomal and Plasmid-Borne Multidrug Resistance and Virulence Genes in Poultry-Associated Escherichia coli from Nigeria.

BACKGROUND: Broad and unregulated antibiotic use in livestock production, particularly poultry farming, has increased the development and persistence of multidrug-resistant (MDR) bacterial strains in animals. These resistant pathogens and their antibiotic resistance genes (ARGs) can spread to humans through environmental exposure and the food chain, posing serious public health risks. Whole-genome sequencing (WGS), alongside phenotypic antimicrobial susceptibility testing (AST), enables a comprehensive understanding of resistance mechanisms and informs antimicrobial stewardship strategies, particularly in resource-limited settings. AIM: This study aimed to characterize the phenotypic and genotypic antimicrobial resistance profiles, plasmid content, and virulence factors of an MDR E. coli strain (S3) isolated from a poultry farm in Enugu State, Nigeria, to elucidate potential risks to public health and the role of poultry as a reservoir for resistance determinants. METHODS: E. coli strain S3 was isolated from chicken droppings using standard microbiological methods and confirmed by MALDI-TOF mass spectrometry. AST was assessed using disc diffusion and broth microdilution to determine minimum inhibitory concentrations (MICs) for ten antibiotics across multiple classes. WGS was performed with a hybrid approach combining Illumina and Nanopore platforms, followed by genome assembly and annotation. ARGs, plasmid replicons, and virulence factors were identified in silico using AMRFinderPlus, starAMR, RGI/CARD, PlasmidFinder, MOB-suite, and the Virulence Factor Database (VFDB). RESULTS: Phenotypic testing revealed extensive resistance, with complete resistance to six of seven tested antibiotics (cefotaxime, ampicillin, erythromycin, gentamicin, ciprofloxacin, and doxycycline). MICs exceeded clinical breakpoints for multiple classes, confirming an MDR phenotype. Genome analysis indicated a 5.33 Mb genome distributed across five contigs, including one chromosome and four plasmid-associated contigs. The strain harboured numerous ARGs, including bla CTX-M-15, bla OXA-1, bla TEM-1, aac(6')-Ib-cr, aadA5, aph(3")-Ib, sul1/sul2, tet(A), dfrA17, and mph(A), co-localized on plasmids indicative of horizontal gene transfer (HGT) potential. Plasmid types included Col156, IncF, and two rep clusters. Virulence profiling revealed genes associated with adhesion (pap cluster, ECP), iron acquisition (enterobactin, yersiniabactin, aerobactin, heme uptake), and toxins (sat, senB), highlighting the isolate's potential for urinary tract and intestinal infections. CONCLUSION: This study highlights the significant role of poultry-associated bacteria as reservoirs of AMR genes, particularly those harboured on mobile plasmids with potential for HGT. E. coli strain S3 exhibits extensive multidrug resistance and carries a complex plasmid repertoire facilitating horizontal transfer of ARGs. Coupled with a rich virulence gene profile, this strain underscores the public health risk posed by poultry-associated E. coli in Nigeria. These findings demonstrate the urgent need for stringent antimicrobial stewardship, regulatory oversight, and genomic surveillance in poultry production milieus to mitigate the dissemination of MDR pathogens.

Escherichia coli↗

PubMed2026

Probiogenomic analysis of functional potential and safety of L. plantarum 8p-a3 and DMC-S1 strains: in silico vs in vitro and in vivo data.

The molecular basis of the beneficial effects and the causes of the negative effects of probiotics are not entirely clear. Clarifying these issues is important for understanding the biology and assessing the safety of the microbes. Omics technologies have opened up new resources for obtaining relevant knowledge. Here, for the first time, we present the results of a comparative analysis of the functional potential and safety of two L. plantarum strains: the approved probiotic 8p-a3 and the Drosophila intestinal resident, which exhibit opposite effects on D. melanogaster as the model host organism. Through genomic analysis, extracellular vesicle studies, and in vitro and in vivo assays, we have identified the common and specific characteristics of the strains. The strains proved to be similar in a set of genes that determine benefits to the host organism, as well as in the presence of some risk factors. Significant differences between the strains are related to genes responsible for adhesion, sialic acid metabolism, mucin degradation, antimicrobial peptides, tannin resistance, and immunomodulation. In silico data correlated with in vitro and in vivo data, with the exception of antimicrobial sensitivity. Pronounced differences between the strains were found in terms of the composition and biological effects of their vesicles. In vivo data on the effects of the strains correlate with the corresponding data of their vesicles in the fruit fly model. The results obtained open up new facets in L. plantarum strains relevant for evaluating the functionality and safety of probiotics.IMPORTANCEUsing a probiogenomic approach, common and specific features regarding functionality and safety were identified in the strains (the approved probiotic strain L. plantarum 8p-a3 and the Drosophila intestinal bacterium L. plantarum DMC-S1), which exhibit opposite effects on the model host organism (D. melanogaster). The genomic analysis was supplemented by the analysis of extracellular vesicles of the strains. Comparative analysis of in silico data in combination with in vitro and in vivo studies was performed, and unexpected capabilities of the strains were discovered. Novel factors, essential for evaluating the safety of probiotics, were identified. New facets in the interplay of probiotic bacterium with host organism have been revealed.

Animals↗

PubMed2026

De novo chromatin remodelling variants in sporadic Chiari 1 malformation.

Chiari 1 malformation (CM1) is the most common congenital malformation of the human hindbrain. Although prior studies have implicated chromatin-remodeling genes in CM1, the de novo genetic architecture and underlying neurodevelopmental mechanisms remain incompletely defined. To investigate the molecular genetics of a novel familial form of CM1 linked with syringomyelia and tethered cord and determine whether rare, damaging de novo variants (DNVs) contribute to sporadic CM1 risk with gene- and pathway-level resolution, we performed whole-exome sequencing in an ultra-rare multigenerational family with CM1 and associated spinal pathology, and in the largest assembled trio-based cohort to date, comprising 1,585 proband-parent trios with sporadic, idiopathic CM1 (2017-2025). The comparison cohort included 1,798 unaffected control siblings. Clinical phenotyping was by systematic medical record review. Structural domain mapping, in silico modeling, and integration with single-cell transcriptomic data from developing human cerebellum was conducted to assess biological plausibility. A heterozygous loss-of-function variant in CHD3 segregated with CM1 and syringomyelia in a multigenerational family. In the trio-based cohort, rare protein-altering DNVs were significantly enriched across multiple chromodomain helicase DNA-binding (CHD) genes, including CHD1, CHD3, CHD4, and CHD8, exceeding gene-specific mutation expectations (protein-damaging variants: P = 1.3 × 10-9; predicted loss-of-function variants: P = 8.6 × 10-5). CHD1 contained two pathogenic DNVs (p.A999D and p.E984K). CHD4 (p.D744N, p.T1813P, and p.I1102T) and CHD8 (p.R1402X, p.R1472X, and p.R2035X) each contained three new DNVs. Variants clustered within conserved ATPase, helicase, and chromodomain regions essential for chromatin remodeling, and these patients frequently had comorbid developmental delay and related neurodevelopmental features. Single-cell transcriptomic analyses demonstrated enrichment in Purkinje cells and inhibitory neurons of midgestational cerebellum, where CHD gene products form a coherent chromatin-regulatory network. Rare, large-effect DNVs that disrupt chromatin-remodeling programs contribute to sporadic CM1, implicating genetically encoded dysregulation of cerebellar development as a central disease mechanism. Exome sequencing may complement surgical evaluation of children with sporadic CM1, particularly when accompanied by neurodevelopmental concerns, informing prognosis and family counseling.

de novo variants↗

PubMed2025

Creating an atlas of variant effects to resolve variants of uncertain significance and guide cardiovascular medicine.

Cardiovascular diseases are leading global causes of death and disability, often presenting as interrelated phenotypes of atherosclerotic vascular disease, heart failure and arrhythmias. Cardiovascular diseases arise from interactions between environmental factors and predisposing genotypes and include common Mendelian lipid disorders, cardiomyopathies and arrhythmia syndromes. The identification of a pathogenic variant through genetic testing can inform disease diagnosis, risk prediction, treatment and family screening. However, a major roadblock in genomic medicine is that for many variants, especially missense variants, we lack sufficient evidence to enable a definitive classification, and therefore these variants are deemed as 'variants of uncertain significance'. In this Review, we describe how multiplexed assays of variant effects can enable the functional assessment of nearly all coding variants in a target sequence, potentially offering a proactive approach to identifying the functional significance of gene variants that are observed later in a patient. We discuss validation, including the role of in silico variant effect predictors, and how multiplexed experimental methods are informing cardiovascular disease biology and ultimately resolving the problem of variants of uncertain significance at scale.

Humans↗

PubMed2026

Proteome-wide curation of experimentally validated HPV T-cell epitopes identifies key gaps in our understanding of cellular immunity to HPV and informs vaccine design.

BACKGROUND: Human papillomavirus (HPV) drives both malignant and benign tumours. Current prophylactic vaccines are type-restricted, not optimised for T-cell induction, and lack therapeutic efficacy. Although T-cells are critical for both preventing and clearing HPV infection, experimentally validated HPV T-cell epitopes remain fragmented across the literature, limiting systematic evaluation of cellular immune targets. METHODS: We curated experimentally validated HPV T-cell epitopes from the Immune Epitope Database (IEDB). Epitopes were mapped across HPV proteins and genotypes, and analysed for response rate, sequence conservation across 454 representative HPV genomes, and HLA restriction patterns. RESULTS: 485 unique experimentally validated HPV epitopes have been described (133 studies; 1,494 functional assays). Consistent with research focus and viral biology, E6 and E7 proteins account for >60% of known HPV epitopes despite accounting for ~10% of the viral proteome. High-risk HPV types, especially HPV16 and HPV18, were the most studied (p <.001) and were enriched for CD8+ epitopes (p <.001). We identified major knowledge gaps, including: underrepresentation of structural proteins such as L2; limited epitope coverage for low-prevalence HPV genotypes; a bias towards common HLA alleles. In silico analysis indicated greater conservation of epitopes in L1/L2 and across high-risk HPV types. Conserved, commonly detected, and HLA-promiscuous epitopes were highlighted and we provide panels of candidate epitopes for consideration in immune monitoring, broad-spectrum prophylactic vaccines, and high-risk targeted therapeutic vaccines. CONCLUSION: This study provides the first comprehensive atlas of experimentally validated HPV T-cell epitopes and ranked epitope candidates for translational application. We demonstrate that our understanding of HPV T-cell immunity is constrained by biases in antigen, genotype and HLA focus and by incomplete epitope mapping. Addressing these gaps will be essential for a comprehensive assessment of cellular immunity and for utilising T-cells in next-generation vaccines.

Epitopes, T-Lymphocyte↗

PubMed2026

Stromal ARHGEF15 Correlates With Inflammatory EMT and Stromal-Immune Crosstalk During Inflammatory Bowel Disease-To-Colorectal Cancer Progression.

Patients with inflammatory bowel disease (IBD) have an increased risk of colorectal cancer (CRC), but how chronic intestinal inflammation drives malignant transformation remains unclear. We retrospectively reanalyzed published single-cell transcriptomic datasets from intestinal biopsies of healthy individuals and patients with IBD; differential expression was assessed using independent t tests with Benjamini-Hochberg false discovery rate correction. We then integrated those single-cell findings with the Cancer Genome Atlas bulk transcriptomes and pharmacogenomic cohorts to trace stromal programs across the IBD-to-cancer continuum. ARHGEF15 emerged as a stromal gene enriched in CD74hi HLA-DRB1hi arterial pericytes within inflamed tissue. Its expression rose steadily from IBD to CRC and tracked with epithelial-mesenchymal transition (EMT) activity. In CRC, higher ARHGEF15 expression was associated with shorter overall and progression-free survival. These retrospective, in silico findings identify ARHGEF15 as an exploratory stromal biomarker associated with inflammatory EMT and stromal-immune remodeling during IBD-to-CRC progression. Prospective experimental and clinical validation is required to establish its prognostic or therapeutic relevance.

ARHGEF15↗

PubMed2026

Multitarget interactions of bisphenol A in polycystic ovary syndrome: evidence from integrated network toxicology, mendelian randomization, and molecular docking.

OBJECTIVE: To study the potential pathogenic mechanisms of bisphenol A (BPA) in polycystic ovary syndrome (PCOS) using an integrative computational strategy. DESIGN: Integrative computational study combining network toxicology, Mendelian randomization (MR), and molecular docking. SUBJECTS: For MR analysis, genetic data were sourced from large European-ancestry cohorts, including plasma protein quantitative trait loci data and genome-wide association study summary statistics for PCOS (3,045 cases and 267,780 controls). EXPOSURE: In silico exposure to BPA for target prediction; genetically predicted plasma protein levels for causal inference. MAIN OUTCOME MEASURES: Identification of overlapping targets between BPA and PCOS; functional enrichment pathways; causal effects of prioritized proteins on PCOS risk (odds ratios with 95% confidence intervals); binding affinities between BPA and core targets (kcal/mol). RESULTS: Network toxicology identified 310 overlapping targets between BPA and PCOS. Enrichment analyses revealed significant involvement in endocrine signaling, inflammatory pathways (eg, IL-17), and cellular processes. MR demonstrated that genetically elevated levels of RET, CXCL8, HTR6, MMP1, MMP9, NTRK1, and TNNI2 were significantly associated with increased PCOS risk, whereas higher PSAP and SHBG levels were protective. Molecular docking confirmed stable binding between BPA and all nine key targets, with strongest affinity for SHBG (-8.4 kcal/mol), followed by NTRK1, TNNI2, and RET. CONCLUSION: This integrative investigation suggests that BPA may contribute to PCOS pathogenesis through multitarget interactions involving inflammatory mediators, endocrine regulators, and tissue remodeling proteins. The findings provide prioritized targets and mechanistic insights for future experimental validation and environmental risk assessment.

Female↗

PubMed2026

Cross-tissue Mendelian randomization prioritizes RAB27B as a brain-derived candidate protein for postpartum depression.

OBJECTIVE: Postpartum depression (PPD) is one of the most common and debilitating complications of childbirth, yet the candidate proteins linking genetic risk to disease remain poorly defined. Building on recent genome-wide association studies (GWAS), we sought to integrate cross-tissue proteogenomic data to identify candidate proteins for PPD and explore therapeutic opportunities. METHODS: We conducted two-sample Mendelian randomization (MR) using genome-wide significant cis-protein QTLs from brain (n = 608 proteins), cerebrospinal fluid (CSF; n = 214), and plasma (n = 612). PPD summary statistics were obtained from FinnGen R8 (13,657 cases, 236,178 controls) and replicated in an independent GWAS. Phenome-wide association (PheWAS) was used to assess pleiotropy. Potential therapeutic targets were evaluated through DSigDB drug repurposing, molecular docking, and molecular dynamics simulations. RESULTS: Among all proteins tested, RAB27B was the only brain-derived protein surpassing Bonferroni correction (OR = 1.60; 95% CI: 1.30-1.96; P = 6.6 × 10⁻⁶), whereas no significant proteins were identified in CSF or plasma. This association was replicated in an independent GWAS (OR = 1.27; 95% CI: 1.02-1.58; P = 0.037). PheWAS identified no pleiotropic associations at genome-wide significance. In silico drug repurposing identified pregnenolone as a candidate ligand with computationally predicted stable binding to RAB27B, providing a starting point for future experimental validation. CONCLUSION: This study provides the first cross-tissue proteogenomic evidence that RAB27B is a brain-derived, reproducible candidate protein genetically associated with PPD. By extending GWAS signals to functional protein-level mechanisms and therapeutic inference, our findings nominate RAB27B and pregnenolone as promising directions for postpartum psychiatric research.

Humans↗

PubMed2026

In silico analysis of metal resistance genes in Pseudomonas extremaustralis 2E-UNGS: Genomic insights and safety assessment for wastewater biotreatment.

Pseudomonas extremaustralis 2E-UNGS is a non-pathogenic strain isolated from the polluted Reconquista River basin (Buenos Aires Metropolitan Area, Argentina), with a 20-year history of study focused on its survival strategies that have enabled its application in various processes such as waste biotreatment and biosensing. Regarding bacterial-metal interactions, P. extremaustralis 2E-UNGS is capable of biosorbing Cd(II), Zn(II), and Cu(II), and biotransforming Cr(VI) to Cr(III), facilitating both the removal of these metals from aqueous systems and their use in biosensor development. The complete circular chromosome (6,372,594 bp) has been annotated in the NCBI GenBank under accession number NZ_CP091043.1. The aim of this work was to perform an in-depth exploration of the P. extremaustralis 2E-UNGS genome to support the optimization of sustainable bioprocesses within the One Health framework. To this end, the integration of experimental evidence with a detailed in silico analysis of key genes involved in metal-microorganism interactions, antibiotic resistance, and their interconnections provides valuable insights for the optimization of future biotechnological applications. Considering its antibiotic resistance profile, together with the activation of efflux pumps induced by metal stimuli-particularly observed under Zn(II) exposure-P. extremaustralis 2E-UNGS can be regarded as suitable for the design of confined bioreactor processes, minimizing the risk of potential accidental environmental releases. Therefore, modulation of gene expression emerges as a promising approach to enhance the efficiency of metal-loaded wastewater biotreatments.

Pseudomonas↗

PubMed2026

Integrated functional, metabolomic, and biotransformation profiling of mycotoxin hepatotoxicity in 2D and 3D human hepatic models.

Mycotoxins pose a major risk to food safety and human health, yet their hepatotoxic mechanisms remain incompletely characterized due to limitations in conventional in vitro models. In this study, we systematically compared mycotoxin-induced hepatotoxicity and metabolomic profiling across two human hepatic models cultured under 2D monolayer and 3D spheroid conditions. The various mycotoxins (Aflatoxin B1, Citrinin, Deoxynivalenol, Ochratoxin A, Patulin, and Zearalenone) exhibit distinct metabolic signatures, thereby serving as an appropriate panel for comprehensively evaluating diverse hepatotoxic mechanisms. Mycotoxin exposure induced concentration-dependent hepatotoxicity accompanied by functional impairment and structural disruption in hepatic models. Metabolomic profiling revealed distinctive regulatory patterns between 2D and 3D hepatic models, with 3D spheroids showing consistent down-regulation across multiple intracellular metabolic pathways and altered extracellular metabolite release, whereas 2D monolayers predominantly exhibited global metabolic activation. In silico-assisted MS/MS analysis further demonstrated that Phase I biotransformation was largely conserved across models, whereas Phase II conjugation reactions were more frequently detected and exhibited greater model specificity in 3D spheroids. Overall, these findings indicate that 3D hepatic spheroids capture more integrated and coordinated hepatotoxic and metabolic responses to mycotoxins compared with 2D monolayer systems. These distinctive regulatory dynamics support their value as a physiologically relevant platform for toxicity assessment and mechanistic investigation.

3D hepatic spheroids↗