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PubMed2026

Mapping Wastewater Pathogens and Their Associated Environmental and Public Health Risk Factors: A Systematic Review and Meta-Analysis.

BACKGROUND: Wastewater-based epidemiology (WBE) has emerged as a critical tool for public health surveillance, yet its application across diverse pathogens and geographical settings remains inconsistent. This systematic review synthesizes global evidence on wastewater surveillance to identify associated risk factors. METHODS: Following PRISMA 2020 guidelines (PROSPERO: CRD420261297382), a systematic search was conducted across PubMed, Scopus, Google Scholar, and Web of Science for studies published between 2000 and 2025. RESULTS: Thirty-nine peer-reviewed studies were included. The evidence base is geographically skewed toward the European Region (48.7%) and the Americas (23.1%), with significant underrepresentation in LMICs. Viruses were the primary biological target (89.7%), followed by bacteria (7.7%) and parasites (2.6%). A proportion meta-analysis of 31 eligible studies demonstrated a pooled wastewater pathogen detection prevalence of 62% (95% CI: 47.5-74.6%), with the European Region yielding the highest regional estimate (73%) and the African Region the lowest (8.3%). Conventional PCR and sequencing methods showed higher pooled detection rates (92.4% and 90.1%, respectively) than RT-qPCR (47.9%). CONCLUSION: WBE provides a robust early-warning system indicating a need for broader pathogen diversity, incorporating bacterial and parasitic surveillance and expansion into rural and resource-limited regions.

Contamination↗

PubMed2026

Molecular characterization and biological characteristics of a highly pathogenic recombinant ALV-J strain (HUE2023) with cross-clade gp85 recombination.

Avian leukosis virus subgroup J (ALV-J) has undergone extensive diversification into phylogenetically distinct clades, yet whether recombination between these clades within the gp85 envelope glycoprotein generates variants with altered pathogenicity has received little direct investigation. A field strain (HUE2023) was recovered from breeding roosters displaying vascular tumors. The viral genome was sequenced and subjected to phylogenetic and recombination analyses. The three-dimensional structure of gp85 was predicted with AlphaFold3; electrostatic surface potentials and surface hydrophobicity were computed using the Adaptive Poisson-Boltzmann Solver and the Eisenberg hydrophobicity scale, respectively. Pathogenicity and immunosuppressive effects were assessed in Hy-Line Brown chickens. Recombination analysis revealed that HUE2023 is an inter-clade recombinant derived from Clade 1.1 (major parent: JS14NT01) and Clade 1.2 (minor parent: JS09GY3). A single-residue deletion at position 61 within receptor-binding domain 1 (RBD-1), unique to the recombinant, induced a localized conformational rearrangement that generated a concentrated electronegative surface patch and a contiguous hydrophobic pocket not observed in either parental gp85. Animal challenge showed that HUE2023 is highly pathogenic: female chickens in the high-dose group reached only 61% survival and displayed significant growth retardation (P < 0.05) together with marked immunosuppression. The recombination in the RBD-1 led to local conformational rearrangement, resulting in a concentrated and negatively charged surface area as well as a continuous hydrophobic pocket, which were never present in any of the parental gp85 sequences. These results indicate that gp85 recombination across clades can yield variants with fundamentally altered receptor-binding surfaces and argue for integrating structural surveillance into ALV-J monitoring programmes.

Animals↗

PubMed2026

Synergistic transcriptional modules in Trichoderma asperellum enhance glutathione detoxification to counteract fungal pathogen toxins.

Trichoderma fungi are potent biocontrol agents. However, their defence mechanisms against pathogen-derived toxins remain poorly understood. We identified two synergistic transcription factor modules in T. asperellum that orchestrate the detoxification of cytotoxic secondary metabolites from the poplar blight pathogen Alternaria alternata. Overexpression of the central regulator TasMYB46 reduced disease lesion area by approximately 22% and was associated with decreased pathogen-induced reactive oxygen species (ROS) accumulation. Mechanistically, TasMYB46 directly activates the glutathione S-transferases TasGST61.1 and TasGST56.1 through distinct promoter binding sites (G-box/as-1/MBS), forming dedicated detoxification modules. Crucially, we identified urolithin C as the most abundant phytotoxin in A. alternata metabolites, which is efficiently detoxified through the TasMYB46-TasGST61.1 module. The transcription enhancer TasbHLH53.8 amplifies this system by binding to TasMYB46, boosting TasGST expression and enhancing glutathione-dependent detoxification capacity. This coordinated response elevates glutathione pools and antioxidant enzyme activities (GST/GPx), conferring increased oxidative stress resistance. This study reveals a novel defence mechanism in Trichoderma in which MYB-bHLH-GST modules enable biocontrol agents to neutralise pathogen-derived toxins. Given that Alternaria toxins threaten crops globally (tomatoes, potatoes, citrus), the discovered regulatory synergy represents a strategic advance in developing next-generation biocontrol solutions against toxin-producing plant pathogens.

Alternaria↗

PubMed2026

Pathogenic Variants in HEPACAM Alter Protein Localization and Interactome in Astrocytes of the Developing Mouse Cortex.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy characterized by early-onset macrocephaly, white matter edema, seizures, and motor and cognitive decline. Approximately 25% of MLC patients carry HEPACAM pathogenic variants, many of which are dominant missense variants causing remitting MLC Type 2b. HEPACAM encodes hepatic and glial cell adhesion molecule (hepaCAM), also known as GlialCAM, an astrocyte-enriched transmembrane protein with important roles in astrocyte territory establishment, gap junction coupling, branching organization, synaptic function, and development of the gliovascular unit. The molecular mechanisms through which pathogenic variants in HEPACAM alter hepaCAM protein function in vivo and facilitate MLC pathogenesis during brain development remain largely unknown. Here, we used new viral tools and proximity-based proteomics to examine how three different dominant pathogenic variants alter hepaCAM subcellular localization and protein interactome in astrocytes of the developing mouse cortex. We found dramatic changes in hepaCAM distribution throughout the astrocyte, which were common to all mutants tested. We also observed significant changes in protein interactome between wild type and mutant hepaCAM, including decreased association with previously described hepaCAM-interacting proteins Connexin 43 and CLC-2. Moreover, we identified the epilepsy-associate potassium channel KCNQ2 as a novel hepaCAM interaction partner and found reduced association between KCNQ2 and pathogenic variants. Collectively, our data provide new insights into hepaCAM protein function in astrocytes during brain development, reveal altered protein dynamics of pathogenic variants, and provide a new resource to explore the molecular underpinnings of MLC pathogenesis.

Animals↗

PubMed2026

Conserved host-exclusive oligonucleotide motifs enriched in pathogenic genes of human oncogenic viruses.

Comparative viral genomics can reveal sequence-level constraints influencing virus-host interactions. Relative minimal absent words (rMAWs) are short oligonucleotide motifs present in viral genomes but completely absent from the host, potentially reflecting selective pressures related to host adaptation and immune evasion. Using the EAGLE algorithm and the GRCh38 human reference genome, we systematically screened for prevalent rMAWs (prMAWs) across six major human oncogenic viruses: Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), human T-cell leukemia virus type 1 (HTLV-1), and human herpesvirus 8/Kaposi's sarcoma-associated herpesvirus (HHV-8/KSHV). highly conserved 11- and 12-bp prMAWs were identified in EBV, HBV, HTLV-1, and HHV-8/KSHV, with sequence prevalences ranging from 91.5% to 97.9%. Conversely, no short prMAWs were detected in HCV or HPV, likely reflecting differences in genome architecture, mutation rates, and long-term host adaptation to the human host. Importantly, the identified host-exclusive motifs exhibited non-random genomic distribution and were preferentially embedded within viral genes central to replication, persistence, immune modulation, and oncogenesis, including EBNA-1 (EBV), HBx (HBV), Tax-associated regions (HTLV-1), and lytic replication genes of HHV-8/KSHV. Notably, all detected prMAWs were enriched in GC nucleotides and exhibited marked CpG over-representation, suggesting sequence constraints associated with epigenetic regulation and viral persistence. Collectively, these highly conserved, host-exclusive signatures offer promising, candidates for sequence-directed approaches in the diagnosis, monitoring, and investigation of virus-associated cancers.

Humans↗

PubMed2026

Portable metagenomics for preventive surveillance and outbreak control in livestock and poultry: Pathogen detection, resistome profiling, and antimicrobial stewardship.

Conventional diagnostics for livestock and poultry outbreaks commonly rely on culture or targeted PCR panels, which may be too slow or too narrow to guide early control decisions. Portable metagenomics, particularly real-time nanopore sequencing, offers a route to broad pathogen detection, antimicrobial-resistance gene profiling, and outbreak investigation within an integrated workflow. This implementation-focused review evaluates how near-point-of-care metagenomics may support preventive veterinary medicine through earlier detection, surveillance, cohorting, biosecurity decisions, and antimicrobial stewardship. We synthesize sample-to-answer workflows for enteric and respiratory disease in food-producing animals, including sampling, nucleic-acid extraction, host depletion or target enrichment, library preparation, sequencing, bioinformatics, quality control, and interpretation. Applications in calf diarrhea, bovine respiratory disease, poultry outbreaks, mastitis, and resistome monitoring are considered alongside the central limitation that detection alone does not establish causation. Pathogen and resistance-gene signals must therefore be interpreted with clinical signs, lesions, epidemiology, controls, and confirmatory testing. We also propose a minimum reporting checklist, intended as a practical framework rather than a validated consensus standard. Portable metagenomics is not a replacement for conventional diagnostics, but appropriately validated workflows can reduce uncertainty during time-sensitive outbreaks and support more judicious antimicrobial use.

Animals↗

PubMed2026

[Analysis of clinical phenotypes and pathogenicity of a c.4476+5G>T variant of SCN1A gene in a Chinese pedigree affected with Genetic epilepsy with febrile seizures plus].

OBJECTIVE: To explore the pathogenicity and characteristics of a heterozygous splicing variant of SCN1A gene in a Chinese pedigree affected with Genetic epilepsy with febrile seizures plus (GEFS+). METHODS: A retrospective analysis was carried out on the clinical data and results of genetic testing of a GEFS+ pedigree consisting of 5 members who had visited the First Affiliated Hospital of Zhengzhou University on July 1, 2024. Pathogenicity of the splicing variant of the SCN1A gene was validated with a minigene splicing assay. This study was approved by the Medical Ethics Committee of the the First Affiliated Hospital of Zhengzhou University (Ethics No.: KS-2018-KY-36). RESULTS: The proband, a 24-year-old female, presented with FS in conjunct with focal seizures, and both of her younger brothers had Dravet syndrome. All of the three patients had carried a c.4476+5G>T variant of the SCN1A gene, which was unreported previously. Minigene experiment verified that the variant could cause loss of the first 7 bps of exon 24 and 138 bps from exon 23 of the SCN1A gene, resulting in alteration p.V1447_1495delfs*6 and affecting splicing. Based on the guidelines from American College of Medical Genetics and Genomics (ACMG), the variant was predicted as likely pathogenic (PVS1+PM2_Supporting). CONCLUSION: The c.4476+5G>T variant at an intronic site of the SCN1A gene probably underlay the pathogenesis of GEFS+ in this pedigree.

Adult↗

PubMed2026

Integrin-Linked Kinases 1, 4, and 5 participate in cell wall-mediated innate immunity to leaf and root pathogens.

The cell wall integrity (CWI) pathway is triggered by plasma membrane-localized receptors in plant cells and serves to orchestrate responses to cell wall damage by initiating compensatory changes under stressful environments. The essential role of CWI maintenance as part of plants' interactions with pests or pathogens and during growth is well known. Nevertheless, CWI pathways remain to be fully characterized. Here, we show that altered Integrin-Linked Kinase 1 (ILK1) expression causes widespread defects in the transcriptional program activated by the bacterial elicitor flg22, primarily in genes associated with cell wall integrity and immunity. These transcriptional deficiencies are recapitulated in mutant lines with altered ILK4 or ILK5 expression. Analysis of molecular and cellular defenses in ilk mutants revealed reduced callose accumulation in leaves treated with bacterial (elf18) and plant (pep1) elicitors and increased pathogen susceptibility. Histochemical analysis of cell-wall-associated staining across diverse cells and organs of ilk mutants revealed modified lignin-associated patterns in the root xylem and altered calcofluor staining patterns in the seed coat. All ilk mutants exhibited altered root morphology due to mechano-touch and high-NaCl stress. Based on these results, we propose that ILKs contribute to pathways connecting elicitor-triggered immune signaling with cell-wall-associated stress responses and that ILK-related defense functions may extend to the cotton root-nematode interaction, while the mechanism remains to be elucidated.

Cell Wall↗

PubMed2026

Draft genome sequence of Enterococcus casseliflavus strain MBBL_MP4 isolated from healthy bovine milk.

We report the draft genome sequence of Enterococcus casseliflavus MBBL_MP4, recovered from healthy bovine milk. The 3.45-Mbp genome assembly comprises 27 contigs and indicates low pathogenic potential, with no acquired antimicrobial resistance or known virulence genes. This genome provides a valuable resource for the genomic characterization of bovine-associated E. casseliflavus.

Enterococcus casseliflavus↗

PubMed2026

Pathogenic properties of myasthenia gravis AChR autoantibodies associate with clinical response to efgartigimod.

BACKGROUND: Efgartigimod, a neonatal Fc receptor (FcRn) blocker, effectively reduces total IgG, including pathogenic acetylcholine receptor (AChR) autoantibodies in myasthenia gravis (MG); however, clinical responses vary. To investigate this variability, we studied how efgartigimod impacts AChR-specific autoantibody profiles and associated pathogenic mechanisms, including complement activation, AChR internalisation and ACh-binding site blockade. METHODS: Serum samples (N=150) were sourced from 50 AChR autoantibody-positive generalised MG patients participating in the phase 3 ADAPT study, randomised to receive efgartigimod (N=40) or placebo (N=10) in cycles of 4-weekly infusions. Samples were collected at baseline, day 29 and day 57 during the first cycle. Live cell-based assays quantified AChR-specific IgG subclasses and isotypes and assessed their capacity to mediate pathomechanisms. RESULTS: Efgartigimod decreased all detectable AChR-specific IgG subclasses. At baseline, AChR autoantibody-mediated C3b deposition, AChR internalisation and ACh-binding site blockade were detected in 42 (84%), 41 (82%) and 10 (20%) patients, respectively. After 4-weekly infusions of efgartigimod, the magnitude of all three pathomechanisms was significantly decreased. However, the extent of this reduction varied across individuals. Double responders on both MG-activities of daily living and quantitative MG scores demonstrated a greater reduction in complement activity and AChR internalisation compared with patients who responded on only one score or were double non-responders. In addition, efgartigimod reduced IgG-dependent IgM binding to AChR. CONCLUSIONS: These findings suggest that clinical efficacy may be more closely associated with functional modulation of the AChR-specific autoantibodies than with their absolute quantity alone. These results support the evaluation of mechanistic pathway monitoring as a potential strategy to predict or guide efgartigimod treatment response.

Humans↗

PubMed2026

Evaluating the pathogenic significance of unique chromosomal variants in craniosynostosis using patient-derived induced pluripotent stem cells and mouse modelling.

PURPOSE: Unravelling causal links between unique structural/copy-number variants (SV/CNV) and associated phenotypes is essential for correct genetic counselling. We investigated two families in which patients with craniosynostosis had SV/CNV potentially dysregulating a fibroblast growth factor (FGF)-encoding gene; a 730 kb dup(4)(q21.21) including FGF5; and a complex 568 kb interspersed 13q12.11 duplication, located 841 kb from FGF9. METHODS: We combined bioinformatic predictions of altered topologically-associating domain (TAD) structure, with experimental analysis (RNA- and ATAC- [assay for transposase-accessible chromatin] sequencing) of patient induced pluripotent stem cell lines (iPSCs) differentiated to neural crest (NCC) and osteoprogenitor (OPC) identities. For the dup(4)(q21.21) we generated a mouse bearing an equivalent rearrangement using CRISPR-Cas9 targeting. RESULTS: TAD analysis suggested potential dysregulation of the FGF5/FGF9 gene by bringing it into a novel genomic milieu. The RNA- and ATAC-seq assays demonstrated FGF5/FGF9 upregulation (2.7-18x) and local opening of chromatin, in 3/4 cell lines. For the dup(4)(q21.21), a causal role was supported by the mouse model, whereas interpretation of the 13q12.11 SV is confounded by a co-existing FOXP2 pathogenic variant. CONCLUSION: Patient iPSC-differentiated NCC and OPC lines, combined with TAD-based modelling to generate testable functional hypotheses, provide valuable functional evidence when evaluating causation of unique SV/CNV in craniosynostosis.

copy-number variant↗

PubMed2026

[Pathogenicity analysis and prenatal genetic counseling for five Chinese pedigrees harboring a hemizygous c.-32C>G variant of FGF13 gene].

OBJECTIVE: To explore the pathogenicity and prenatal counseling strategies for five Chinese pedigrees harboring a hemizygous c.-32C>G (NM_001139500.2) variant of fibroblast growth factor 13 (FGF13) gene. METHODS: Five Chinese pedigrees found to carry a hemizygous c.-32C>G variant of the FGF13 gene at the Prenatal Diagnosis Center of Henan Provincial People's Hospital between January 2024 and January 2025 were selected as study subjects. The pedigrees had undergone prenatal diagnosis for a family history of genetic disorders, abnormal fetal ultrasound findings, or advanced maternal age. A retrospective analysis was carried out, wherein clinical data for all members of the pedigrees were obtained through the medical records system and outpatient visit system. Peripheral blood samples were collected from all pedigree members, and amniotic fluid samples were obtained from the probands. Following extraction of genomic DNA, prenatal diagnosis was performed using chromosomal microarray analysis (CMA) and trio whole-exome sequencing (trio-WES). Sanger sequencing was used to determine the carrier status for the candidate variant, and Mini-Mental State Examination (MMSE) was used to assess the cognitive function of hemizygous individuals carrying the FGF13 gene c.-32C>G variant. Pathogenicity of candidate variant was assessed based on guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: 2021-171). RESULTS: CMA and trio-WES revealed no pathogenic variants in all probands, whilst trio-WES and Sanger sequencing had identified 11 male individuals carrying a hemizygous c.-32C>G variant of the FGF13 gene from the five pedigrees, which included six adult males, a young boy, and four fetuses. One fetus had undergone termination of pregnancy due to hydrocephalus, one was born pre-term at 34+1 weeks of gestation owing to maternal hypertension, and other two were delivered at full term. Follow-up of the survived males revealed no phenotypic manifestations related to language or intellectual impairment. Among these, three adult males underwent the MMSE assessment, all of whom showed normal cognitive function. Search of the gnomAD database suggested the carrier frequency of FGF13 c.-32C>G variant in the East Asian population to be 0.125%, with 11 hemizygous males documented. Three male patients harboring the variant showed severe intellectual disability. Both in vitro and in vivo studies suggested that it could reduce the translation levels of FGF13 protein. Based on the ACMG guidelines, it was classified as variant of uncertain significance (BS4+PS3_Supporting). CONCLUSION: There is insufficient evidence to classify the FGF13 c.-32C>G as a pathogenic variant in clinical practice, and its presence should not be considered an indication for pregnancy termination due to major birth defects.

Adult↗

PubMed2026

Evolutionary expansion of the NF-Y gene family in bivalves and divergent subunit responses to thermal and pathogenic stress in the noble scallop.

Nuclear factor Y (NF-Y) is a conserved eukaryotic transcription factor complex that specifically interacts with the CCAAT motif. Prior research has demonstrated that this gene family participates in various biological processes, encompassing growth, development, and stress responses, across a broad spectrum of organisms. However, research on the role of the NF-Y family in bivalves remains limited. In this study, we comprehensively identified the NF-Y family in 34 bivalve species, and further investigated its expression in the noble scallop Chlamys nobilis. A total of 296 NF-Y genes were identified and classified into three subfamilies, NF-YA, NF-YB, and NF-YC. Phylogenetic analysis revealed that NF-YA and NF-YC have remained relatively conserved, whereas NF-YB has undergone significant expansion. Additionally, while substantial disparities in gene copy numbers exist across species, the motif composition and exon-intron structures within each subfamily demonstrate notable conservation. Tissue expression profiling revealed distinct expression patterns among CnNF-Y genes, with several members exhibiting relatively high transcript abundance in gonadal tissues. Furthermore, qRT-PCR results demonstrated that CnNF-YA2, CnNF-YB6, and CnNF-YC were significantly and continuously upregulated under heat stress. Conversely, several genes, particularly CnNF-YA2, CnNF-YB3, and CnNF-YB4, exhibited dynamic transcriptional responses to Vibrio parahaemolyticus exposure. These findings enhance our understanding of the evolutionary trajectory and functional diversification of the NF-Y gene family in bivalves, laying a theoretical foundation for future research on thermal adaptation, immune regulation, and molecular breeding in scallops.

Animals↗

PubMed2026

Multi-omics integrative analysis provides insight into potential molecular responses to sustained high water flow in common carp (Cyprinus carpio) cultured in recirculating aquaculture.

To investigate the potential molecular responses by which water flow intensity affects the growth of common carp (Cyprinus carpio) in a recirculating aquaculture system (RAS), a control group (CG, actual water velocity 0.3 cm/s) and three sustained flow treatment groups were established, including a low-flow group (LF, 1 body length per second, bl/s), a medium-flow group (MF, 2 bl/s), and a high-flow group (HF, 3 bl/s). After 12 weeks of culture in the RAS, growth performance was compared among groups under different flow intensities. The best-performing group and the control group were then selected for the determination of intestinal digestive enzyme activities, as well as transcriptomic and whole-genome bisulfite sequencing analyses of muscle tissue. The results showed that the specific growth rate and feed intake of the HF group were significantly higher than those of the other groups (P < 0.05), whereas no significant difference in feed conversion ratio was observed among groups. Compared with the CG group, lipase activity was significantly higher in the HF group (P < 0.05), while α-amylase and trypsin activities showed increasing trends without significant differences. RNA-seq identified a total of 273 differentially expressed genes, including 72 upregulated genes and 201 downregulated genes in the HF group relative to the CG group. These genes were mainly enriched in glycolysis, pyruvate metabolism, ATP metabolism, the pentose phosphate pathway, the insulin signaling pathway, the PPAR signaling pathway, and the adipocytokine signaling pathway, indicating that sustained high water flow induced a muscle transcriptional response characterized by remodeling of energy metabolism and substrate utilization. Whole-genome bisulfite sequencing analysis showed that DNA methylation in common carp muscle occurred predominantly in the CpG context. Differentially methylated regions between the HF and CG groups were mainly distributed in transcription-related regulatory regions, including promoters, CpG islands, and CpG island shores. In promoter regions, the number of hypermethylated regions in the HF group relative to the CG group was markedly higher than that of hypomethylated regions. Integrated analysis further identified two candidate genes showing both promoter differential methylation and differential expression, namely LOC109094644 and bcorl1, suggesting that adaptation to high water flow may involve IGF-related growth regulation and remodeling of upstream transcriptional programs. The qPCR results were consistent with the transcriptomic data. Taken together, within the tested range, a sustained water flow of 3 bl/s was more conducive to the growth of common carp in the RAS, which may be associated with enhanced lipid digestion and utilization, remodeling of the muscle energy metabolic network, changes in promoter methylation, and the coordinated regulation of key candidate genes. This study provides a theoretical basis for clarifying the exercise adaptation mechanism of common carp in recirculating aquaculture and for optimizing flow velocity parameters.

Animals↗

PubMed2026

The Animal Variant Classification Guidelines v2: An Update With New Criteria and Improved Clarifications.

The Animal Variant Classification Guidelines (AVCG) were developed to standardize and objectify the classification of putative disease-causing variants. These guidelines are sufficiently reproducible and are used to classify previously published and new disease-causing variants across species. Here, the guidelines are updated (AVCG.v2), based on a three-phase decision process. Overall, four new criteria and seven clarifying comments were added. The number of criteria has increased from 23 to 27, with three new criteria supporting pathogenicity and one new criterion supporting benign classification. Pharmacogenomic variants were determined to fall within the scope of the guidelines. These updated guidelines are being used by the Variant Pathogenicity Working Group (VPWG), part of the Animal Genetic Testing Standardization standing committee, which is a committee of elected members of the International Society for Animal Genetics (ISAG). Under the auspices of ISAG, the VPWG retrospectively classifies published putative disease-causing variants. The pathogenicity label for a variant will be presented in the variant tables of Online Mendelian Inheritance in Animals (OMIA; https://omia.org/). The AVCGv.2 criteria and recommendations were developed by the expertise of the animal genetics community and the ISAG Executive Committee through the Animal Genetics Testing Standardization Committee endorses and strongly encourages their use to evaluate the evidence supporting pathogenicity of putative disease-causing variants.

Animals↗

PubMed2026

Reinforcement learning-based dynamic ensemble for missense variant effect prediction and tiered prioritization of VUS.

BACKGROUND: Accurate classification of missense variants remains a challenging task despite major advances in genomics. Numerous computational models have been developed to assist in variant classification, but often require repeated integration and benchmarking efforts. Ensemble methods have been proposed to overcome the limitations of single predictors, but mostly rely on fixed, predefined weights that constrain their ability to capture interactions among predictive signals. METHODS: We present GenixRL, a dynamic ensemble framework that reformulates model fusion as a reinforcement learning optimization problem. GenixRL uses a Q-learning agent to learn a policy that dynamically weights the probabilistic outputs of complementary predictors, including BayesDel (addAF and noAF), ClinPred, and MetaRNN. Replacing static weighting with policy learning allows GenixRL to adaptively identify optimal weightings and substantially improve classification accuracy. RESULTS: In benchmark evaluation against 25 state-of-the-art predictors, GenixRL achieved an AUROC of 0.9644 on an independent ClinVar dataset. On saturation genome editing assays for BRCA1 and BRCA2, GenixRL achieved the best performance and ranked highest on 14 of 17 clinically significant genes in a zero-shot evaluation. Applied to uncertain and conflicting ClinVar variants, GenixRL enabled tiered, evidence-based prioritization of hundreds of thousands of variants as likely pathogenic or pathogenic with high confidence, supported by orthogonal population evidence from gnomAD. CONCLUSION: GenixRL advances pathogenicity prediction for missense variants and provides an adaptive ensemble that sorts variants of uncertain significance into tiered candidates for expert curation and functional validation.

Mutation, Missense↗

PubMed2026

S-layer-phage interaction in Clostridioides difficile.

Successful infection by a bacteriophage requires the injection of the phage genome into the cytoplasm of the host bacterium. To achieve this, an infecting phage must traverse the layers of the host cell envelope, including the membrane(s) and the cell wall. This process is further complicated in bacterial species that produce a proteinaceous S-layer on the outermost surface of the cell. Surprisingly little is known about the mechanistic basis of these early stages in the phage lifecycle, and even less is known about infection of S-layer producing bacteria. Recent advances in structural biology, particularly in cryoEM, have dramatically improved our understanding of the structures of both bacterial S-layers and phage virions separately, but we still lack a molecular view combining both phage and S-layer in the process of infection. Here, we review our current understanding of phage-S-layer interactions, using the human pathogen Clostridioides difficile as an example host.

Clostridioides difficile↗

PubMed2026

Construction of an infectious clone of Spodoptera frugiperda densovirus and its biological characteristics.

Densoviruses are highly pathogenic to their insect hosts and have great potential for biocontrol. Spodoptera frugiperda densovirus (SfDV) was isolated from diseased larvae of Spodoptera frugiperda, while its biological functions remain unclear. Herein, we successfully constructed an infectious clone of SfDV. The S. frugiperda larvae transfected with the infectious clone exhibited anorexia, stunted growth, and reduced activity. Histopathological analysis further showed that the epidermis, fat body and trachea were infected instead of muscle and midgut tissues. Transmission electron microscopy (TEM) revealed that numerous virions of about 22 nm were distributed within both the nucleoplasm and cytoplasm of epidermal cells. Moreover, many virions were also found contained within vesicles in the cytoplasm. The replication kinetics of the rescued SfDV (rSfDV) was similar to that of the parental SfDV. The median lethal dose (LD50) and median lethal time (LT50) values of rSfDV were 6.63 × 107 viral genome copies (vgc), 5.23 d, respectively, which were also comparable to those of the parental SfDV. Taken together, the infectious clone of SfDV provides an important tool for further exploring the genome function, pathogenesis, and interactions with its hosts.

Animals↗