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PubMed2026

Genetic mutations driving ciprofloxacin resistance in laboratory-evolved Salmonella Typhimurium.

Ciprofloxacin resistance in Salmonella Typhimurium is a significant public health concern, and the mechanisms by which the resistance evolves are poorly defined. Here, by serial passaging under antibiotic selection, we isolated ciprofloxacin-resistant S. Typhimurium mutants and subjected them to whole-genome sequencing to reveal the major mutations associated with resistance. The Low CipR mutant acquired four chromosomal mutations in ramR, icdA, lipB, and gyrA, and the High CipR mutant gained additional mutations in gyrB, yaiC, and corA. Functional characterization determined that mutations in ramR resulted in efflux pump upregulation, while disruptions in the TCA cycle caused by mutations in icdA and lipB led to metabolic alterations. These changes indirectly enhanced resistance by increasing the expression of the global regulator MarA and reducing OmpF-dependent membrane permeability. Despite the observation of the G105A substitution in GyrA, enzymatic assays confirmed the failure to support resistance to ciprofloxacin, possibly because the structural alteration remained minimal. GyrB488-489dup was associated with maintained supercoiling under ciprofloxacin and enhanced fluoroquinolone resistance, suggesting a major role in resistance evolution. Other mutations in yaiC impaired biofilm and, in corA, intracellular accumulation of magnesium, possibly stabilizing the bacterial cell envelope under antibiotic pressure. The findings provide novel explanations for the multifaceted mechanisms leading to ciprofloxacin resistance in Salmonella and suggest targets to combat antimicrobial resistance.IMPORTANCEAntibiotic resistance in Salmonella Typhimurium is an increasing public health concern, yet the genetic changes that allow bacteria to become resistant are not fully understood. In this study, we evolved ciprofloxacin-resistant Salmonella in the laboratory and identified the mutations that arise during resistance development. We found that resistance does not result from a single change but from multiple adaptations affecting drug efflux, metabolism, and the antibiotic target. Some mutations increased the activity of pumps that remove antibiotics from the cell, while others altered bacterial metabolism and reduced membrane permeability, making it harder for the drug to enter. A duplication in the DNA gyrase subunit GyrB played a particularly important role in maintaining DNA function under antibiotic stress. Together, these results reveal how diverse genetic changes cooperate to generate ciprofloxacin resistance and provide insights that may help guide strategies to combat drug-resistant Salmonella infections.

DNA gyrase↗
PubMed2026

A hybrid effectiveness-implementation trial to integrate precision skin cancer risk feedback in federally qualified health centers.

BACKGROUND: Skin cancers are the most common type of cancer in the United States, occur in all segments of the population, and are preventable. Our previous research with primary care patients' demonstrated interest in and efficacy of a precision prevention intervention providing feedback on MC1R risk level (higher versus average) in combination with prevention education materials relative to a standard educational intervention. Our current study is a hybrid type 1 effectiveness-implementation trial deployed at six federally-qualified health centers. This paper presents the study protocol. METHODS: A community advisory panel will guide development of study materials and measures. Staff training at each clinic will be completed in-person. Patients will be approached and screened in-person. Those completing genetic testing and the baseline survey will be randomized to the precision versus standard intervention for each risk level with a target sample size of 286 for each combination. Primary outcomes of effectiveness, assessed at 6 and 12 months, include a tanning score (5 items assessing intentional and unintentional tanning), number of sunburns, conduct of a skin self-examination, and electronic health record documentation of clinician-patient communication about skin cancer prevention. Effectiveness comparisons will focus on the precision relative to the standard intervention among higher risk participants. Implementation data will be collected to identify barriers and facilitators. RESULTS: Effectiveness and implementation outcomes will be evaluated following study completion. CONCLUSIONS: Results will guide subsequent scale-up of the precision intervention, including modifications of the intervention as well as methods for implementation. CLINICAL TRIALS IDENTIFIER: NCT07222995.

Humans↗
PubMed2026

Psychological impacts of APOE genotype disclosure among Latinos in New York City: a randomized controlled trial.

INTRODUCTION: Latinos face increased Alzheimer's disease (AD) risk but are underrepresented in studies of APOE genotype disclosure. We evaluated the psychological impacts of APOE disclosure in the Información de la Enfermedad de Alzheimer para Latinos (IDEAL) study, a randomized controlled trial among Latinos in New York City. METHODS: Latino northern Manhattan residents without self-reported AD (mean age 52, 69% women, 49% college graduates) were randomized in the period August 2021 to July 2024 to receive AD risk estimates to age 85 incorporating APOE genotype, family history, and ethnicity (disclosure) or the same factors excluding APOE (non-disclosure). Bilingual genetic counselors delivered risk estimates to both groups, unmasked to randomization. Follow-up surveys were completed 6 weeks, 9 months, and 15 months after risk delivery. Primary outcomes were impact of genetic testing in AD (IGT-AD) and Impact of Event Scale-Revised (IES-R). Secondary outcomes were changes from baseline in depression, anxiety, and perceived AD threat. Analyses used intention-to-treat with multiple imputation. RESULTS: Disclosure (N = 194) and non-disclosure (N = 180) groups did not differ on IGT-AD (mean disclosure-non-disclosure difference [MD] at 6 weeks: -1.5, p = 0.14; 9 months: -1.2, p = 0.35; 15 months: -2.0, p = 0.07), IES-R (MD at 6 weeks: 0.00, p = 0.98; 9 months: 0.01, p = 0.84; 15 months: 0.03, p = 0.64), or change in secondary outcomes. Occurrence of disclosure-related adverse events was similar in the disclosure (N = 2) and non-disclosure (N = 3) groups. DISCUSSION: In this Latino cohort, APOE disclosure did not have clinically significant adverse psychological effects, addressing an important evidence gap. TRIAL REGISTRATION: ClinicalTrials.gov NCT04471779.

Aged↗
PubMed2026

Non-parametric differential methylation analysis characterizes histotype-specific promoter regions in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is a heterogenous disease with frequent late-stage diagnosis and high mortality rates, for which no reliable screening tests exist. In recent years, epigenetic biomarkers in the form of DNA methylation in CpG-rich regions have gained increased attention in the scientific community due to their robust nature and accessibility, allowing for diagnosis without the need for invasive surgery. In this study, we investigated the aberrant methylation of promoter regions in early stage EOC through non-parametric methods, with the purpose of characterizing candidate epigenetic biomarkers. The approach was used on a cohort of early stage EOC samples, and results were compared to existing programs for differential methylation. Significant regions were then used to construct a CpG panel for stratifying EOC histotypes through predictive classification in external data. Identified promoter regions were highly reproducible across cohorts, and the constructed CpG model stratified histotypes in external cohorts through predictive classification. Comparisons against other DMP and DMR callers showed a degree of homogeneity between results but also revealed promoter regions that were overlooked despite clear signs of aberrant methylation. Finally, EOC histotypes were found to differ in their methylation distribution types, and results indicate that methods sensitive to non-normally distributed data may be poorly suited to compare groups with different distribution types. The non-parametric approach identified aberrantly methylated promoter regions that were highly reproducible across cohorts. Results from predictive classification indicate that these regions may be useful for the purpose of EOC histotype stratification.

Humans↗
PubMed2026

Clinical and genetic features of Ph-negative myeloproliferative neoplasms with dual-driver gene positivity.

OBJECTIVES: To investigate the clinical laboratory characteristics and gene mutation features of dual-driver gene positivity in patients with Philadelphia chromosome-negative myeloproliferative neoplasm (Ph-negative MPN). METHODS: We conducted a retrospective analysis of clinical data and genetic test results from 203 newly diagnosed patients with Ph-negative MPN. Of these, 194 had single-driver gene positivity and 9 had dual-driver gene positivity. High-throughput sequencing was used to detect mutations in JAK2, CALR, and MPL. Clinical characteristics and gene mutation profiles were compared between the two patient groups. RESULTS: The incidence of dual-driver gene positivity was 4.4% (9/203), with the most common combinations being JAK2 with CALR (4 patients) and JAK2 with MPL (4 patients). Compared with the single-driver group, the dual-driver group had a significantly higher risk of bleeding [4.1% (8/194) vs. 33.3% (3/9), P = 0.008] and a higher proportion of uncommon mutations [3.6% (7/194) vs. 33.3% (3/9), P = 0.006]. No statistically significant differences were observed between the two groups regarding age, thrombosis incidence, splenomegaly, or routine blood test indicators. During follow-up, 1 patient in the dual-driver group died from cerebrovascular disease. No leukaemia transformation or disease-related deaths occurred among the remaining patients. DISCUSSION: The increased bleeding risk in dual-driver patients may be related to a higher proportion of CALR mutations, elevated platelet counts, and higher variant allele frequencies, though these findings require validation in larger cohorts due to the small sample size. The higher prevalence of uncommon mutations suggests a more complex mutational landscape in this subgroup. CONCLUSION: Patients with Ph-negative MPN and dual-driver gene positivity may have a higher risk of bleeding and a more complex gene mutation profile.

Humans↗
PubMed2026

Somatic mutations: recent advances in brain aging and neurodegeneration.

Somatic mutations are genetic variants that occur after the single-cell phase of development and have been implicated in disease pathogenesis. While most DNA lesions are detected and repaired, examination of healthy tissue has revealed that some lesions escape repair, leading to somatic mutations that accumulate at a consistent rate, including in human brain tissue and postmitotic neurons. Emerging methodological and analytical advances have revealed the presence of persistent mutagenic mechanisms during healthy brain aging as well as mutational pattern shifts in the context of neurodegenerative diseases. Here, we highlight recent methodological advances, summarize our current understanding of somatic mutagenesis in neurotypical brain aging, and examine the role of somatic mutations in neurodegenerative diseases.

Humans↗
PubMed2026

Pharmacogenomics of antipsychotic-induced weight gain: A systematic review.

BACKGROUND: Antipsychotic-induced weight gain (AIWG) is a major clinical concern, affecting approximately 30% of patients. Clinical predictors explain only part of AIWG risk. Genetic and molecular variations are hypothesized to contribute to susceptibility. The purpose of this review is to summarize recent results to identify replicated and novel findings. STUDY DESIGN: Applying PRISMA guidelines, we searched MEDLINE, Embase, and PsycINFO (May 2018-May 2026) for studies on genetic and molecular associations with AIWG, extending our prior review. Reviews, editorials, and conference abstracts were excluded. We extracted study characteristics (design, diagnosis, antipsychotic exposure, sample size, ancestry, genetic variants, and AIWG outcomes) (e.g., ≥7% weight gain, BMI change). RESULTS: Fifty-three studies met inclusion criteria. In candidate gene studies, the most consistently replicated genes associated with AIWG were observed for DRD2, HTR2C, and MC4R. Multiple novel associations were identified by genome-wide association studies (GWAS) (e.g., MAP2K1, ZDBF2, PEPD), polygenic risk scores (PRS) (e.g., body mass index PRS), gene expression (e.g., CYP3A4, EP300), and epigenetic analyses (e.g., cg12034943 at CRTC1). CONCLUSIONS: Polymorphisms in candidate genes related to neurotransmission and appetite regulation continue to be investigated for associations with AIWG, while novel findings have emerged from GWAS, gene expression, and epigenetic studies. Evidence remains inconsistent due to limited replication, methodological variability, sparse ancestry data, and geographical underrepresentation. No single genetic variant is ready for clinical use, and multi-omic and multi-ancestry models are needed to improve prediction and clinical utility.

Humans↗
PubMed2026

Cis-regulatory variation in the MdCKX6 promoter is associated with allele-specific expression and fruit size in apple.

Fruit size is a key determinant of apple fruit quality and market value and is strongly influenced by phytohormone-regulated cell proliferation and expansion during early fruit development. Cytokinin oxidase/dehydrogenase (CKX) enzymes regulate cytokinin homeostasis by irreversibly degrading active cytokinins, but the contribution of natural variation in CKX genes to fruit size remains poorly understood. Here, we identified MdCKX6 as a candidate regulator of fruit growth in apple (Malus domestica). MdCKX6 exhibited pronounced allele-specific expression during fruit development in the cultivar 'Royal Gala'. Sequence analysis identified a promoter SNP associated with differential promoter activity and allele-specific expression. Genotyping of diverse apple cultivars and wild Malus accessions revealed a significant association between MdCKX6 promoter genotype and fruit size. Cultivars carrying low-expression alleles produced larger fruits, whereas high-expression alleles were associated with smaller fruits. To investigate gene function, MdCKX6 was overexpressed in tomato, resulting in reduced fruit size. Histological analyses of the transgenic tomato fruit revealed smaller pericarp cells. Transcriptome analysis of transgenic fruits revealed widespread changes in genes associated with cell-cycle regulation, cell wall modification, hormone-related processes, and transcriptional regulation. Together, these results identify MdCKX6 as a potential negative regulator of apple fruit growth and reveal an association between cis-regulatory variants, gene expression, and fruit size. This study provides new insights into the role of cytokinin metabolism in fruit development and highlights regulatory variation in MdCKX6 as a potential target for apple breeding.

Malus↗
PubMed2026

Mortality of Individuals With PRNP Variants Associated With Prion Disease in the United States, 1998-2024.

BACKGROUND AND OBJECTIVES: To characterize the survival of individuals with pathogenic PRNP variants-including to estimate annual hazards, to judge the accuracy of previously reported survival data, and to evaluate the utility of public record searches in determining vital status. METHODS: In this single-center cohort study, we gathered data on individuals who received positive antemortem PRNP genetic tests at the US National Prion Disease Pathology Surveillance Center (NPDPSC), including both diagnostic tests in symptomatic individuals, and predictive tests in asymptomatic individuals. Genetic test and autopsy results were queried from the NPDPSC database, and public record searches were conducted using online tools. RESULTS: Four hundred four individuals received positive genetic test results. Of 206 cases symptomatic at the time of genetic testing, 188 are likely now deceased based on typical disease duration for their genetic variants. Combined autopsy and public record searches in combination confirmed 174 of these deaths, for an estimated 92.6% sensitivity. We evaluated the age-dependent penetrance of the reportedly highly penetrance variants D178N and E200K and the reportedly low-penetrance variant V210I. Among 99 initially asymptomatic individuals with the pathogenic E200K variant, more than 936 person-years of follow-up, 18 deaths were observed, significantly fewer than 27.4 expected according to life tables based on retrospective data. The age-dependent penetrance of E200K calculated from these longitudinal data was significantly lower than that from retrospective data, with 69% penetrance by age 80 and a median age at death of 75. For the pathogenic D178N variant, the median age at death was 57, which was numerically later, but not significantly different from, that seen in retrospective data. For V210I, just 2 deaths occurred, both after age 90, consistent with minimal penetrance. DISCUSSION: Our data support high penetrance of PRNP D178N and E200K variants and low penetrance of V210I. For E200K, the age at onset distribution appears to be shifted slightly later, and lifetime risk slightly lower, than previously reported. Autopsy data and public death records in combination were sensitive and concordant for determining long-term outcomes, but additional prospective data should be gathered to support future preventive trials.

Journal Article↗
PubMed2026

Antagonistic regulation by mango MiSPL9a and MiSPL9b regulates flowering time, drought and salt stress in Arabidopsis.

SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) transcription factors, which are unique to plants, contain a highly conserved SBP domain that regulates gene expression by binding to downstream targets. They play critical roles in various biological processes, especially in the regulation of flowering in plants. In this study, two SPL-like genes (MiSPL9a and MiSPL9b) were identified from mango genomic and transcriptomic data, and their sequence, expression and function were further analyzed. Sequence analysis revealed that MiSPL9a and MiSPL9b have open reading frames of 1173 bp and 1158 bp, respectively, with slight differences in the number of cis-regulatory elements within their promoter regions. Expression analysis under stress conditions revealed distinct patterns: MiSPL9a expression significantly differed under drought stress but did not significantly differ under salt stress, whereas MiSPL9b expression responded significantly to salt stress but changed minimally under drought stress. Phenotypic analysis of the transgenic Arabidopsis lines revealed that MiSPL9a overexpression delayed flowering, whereas MiSPL9b overexpression promoted early flowering. Under stress conditions, compared with wild-type plants, MiSPL9a-overexpressing plants presented increased drought tolerance but did not significantly differ. In contrast, MiSPL9b-overexpressing plants were sensitive to salt stress, with no notable phenotypic differences observed under drought conditions. Physiological assays revealed that under drought stress, MiSPL9a transgenic plants presented significantly reduced levels of malondialdehyde (MDA) and hydrogen peroxide (H2O2) and increased proline (Pro) content and superoxide dismutase (SOD) activity. Under salt stress, MiSPL9b transgenic plants presented opposite trends in terms of these physiological markers. In summary, both MiSPL9a and MiSPL9b are involved in the regulation of plant flowering time and stress responses, but their functions differ.

Arabidopsis↗
PubMed2026

XsiAMT1.1a was identified as a novel ammonium uptake functional gene and its overexpression combined with GA4 application significantly increased yield in Arabidopsis thaliana.

Nitrogen (N) is a key limiting factor for plant yield. Ammonium is one of the main N forms absorbed by plants. Overexpression of ammonium uptake functional genes, such as ammonium transporter (AMT), can increase yield. However, the AMTs reported to enhance yield significantly is still limited. No researches have focused on the effect of overexpressing AMT combined with hormone application on yield improvement. In this study, we first investigated the role of XsiAMT1.1a, a potential ammonium uptake functional gene in an ammonium preference plant Xanthium sibiricum, in ammonium uptake by the analysis of bioinformatics, gene expression and subcellular localization, and the determination of ammonium uptake rate in endogenous silencing and heterologous overexpression plants. Subsequently, the effect of XsiAMT1.1a overexpression combined with hormone application on yield increase was further investigated in model plant Arabidopsis thaliana. Our results showed that XsiAMT1.1a shared the same conserved domains with AtAMT1 subfamily members and localized on the plasma membrane. XsiAMT1.1a was induced by N deficiency and highly expressed during the reproductive period. XsiAMT1.1a endogenous silencing and heterologous overexpression significantly decreased and increased ammonium uptake rates in X. sibiricum and A. thaliana, respectively. Overexpression of XsiAMT1.1a significantly improved total N accumulation, biomass and yield in A. thaliana, while XsiAMT1.1a overexpression combined with GA4 application had a stronger promoting effect on the above indicators. Our research identified a novel ammonium uptake functional gene, XsiAMT1.1a, and provided a new yield-increasing strategy which was verified in A. thaliana.

Arabidopsis↗
PubMed2026

Integrative multi-omics reveals a fibroblast-centered, ZFHX3-prioritized regulatory framework linking sick sinus syndrome and atrial fibrillation.

OBJECTIVE: To define shared genetic and multi-scale mechanisms underlying comorbidity between sick sinus syndrome (SSS) and atrial fibrillation (AF). METHODS: We integrated genome-wide association study (GWAS) summary statistics for SSS and AF with Genotype-Tissue Expression (GTEx) expression and splicing quantitative trait loci (eQTL/sQTL), atrial single-cell and spatial transcriptomics, and epigenomics. We identified trait-relevant tissues and pathways, prioritized shared cell types, quantified genome-wide and local genetic sharing, detected joint loci by cross-trait meta-analysis, and linked loci to regulatory programs via colocalization and cell-prioritized co-expression networks. RESULTS: Both traits showed strongest enrichment in cardiac tissue, especially Heart Atrial Appendage. Fibroblasts from the left atrial appendage were consistently prioritized as the key shared cell population. SSS and AF displayed significant positive genome-wide genetic correlation, with multiple locally shared regions, including six major loci. Cross-trait meta-analysis identified eight joint-phenotype SNPs implicating four susceptibility genes. ZFHX3 was the leading tissue-cell-gene candidate, acting as a hub in fibroblast co-expression modules and colocalizing with cardiac regulatory signals. CONCLUSION: Shared liability for SSS and AF is highly tissue- and cell-specific, converging on regulatory networks in atrial appendage fibroblasts, with ZFHX3 serving as a central mechanistic and biomarker node.

Humans↗
PubMed2026

Polygenic risk scores in major depressive disorder: A systematic review across diagnostic, treatment, course/severity, and subtype domains.

BACKGROUND: Major depressive disorder (MDD) is heterogeneous across diagnostic, treatment-related, course/severity, and subtype domains. Polygenic risk score (PRS) studies have examined these domains, but differences in PRS sources, samples, methods, and endpoint definitions have fragmented the evidence. We synthesised findings and examined potential contributors to heterogeneity. METHODS: PubMed/MEDLINE, Embase, PsycINFO, and Web of Science were searched for studies published from January 2016 through 25 November 2025. Result records were synthesised using SWiM, and certainty was assessed with an adapted GRADE framework. RESULTS: Sixty studies contributed 493 retained records; 450 were descriptively classified as positive, null, or reverse, although records were not independent. Positive findings accounted for 44/56 diagnostic, 61/273 treatment-related, 64/100 course/severity, and 14/21 subtype records. For MDD/depression-derived PRSs and case-control MDD status, all 10 contributing studies showed higher liability in cases (exploratory exact sign test p = 0.002; FDR q = 0.004). The same PRS group showed positive findings for overall depressive symptom severity (14/18), although the study-level test was imprecise (5/5 studies; p = 0.063). Pharmacological response/remission findings for these PRSs were mostly null or directionally mixed (10 positive, 18 null, and 9 reverse). Treatment-resistant depression (TRD) findings differed by operational definition. Atypical and psychotic subtype signals arose mainly from single-study PRS and endpoint contrasts. CONCLUSIONS: PRS evidence was clearest for MDD diagnostic status and showed a tentative pattern for overall symptom burden. Treatment and subtype findings were less consistent or less replicated. Larger, ancestrally diverse studies with standardised endpoints and transparent PRS methods are needed.

Humans↗
PubMed2026

Introgression shapes the genomic conflict landscape of Malus, providing evidence for a reticulate backbone in a woody crop lineage.

Phylogenomic discordance is widespread across plants, but its evolutionary significance is often obscured when conflict is treated primarily as analytical noise rather than as evidence of underlying processes. In woody lineages in particular, incomplete lineage sorting, introgression, and genome duplication can interact over long timescales to produce complex genomic histories that are not adequately summarized by a strictly bifurcating tree. Here, we use Malus as a model woody genus to investigate how these processes structure conflict across a genus-scale, accession-based phylogenomic framework. Using broad taxon sampling, hundreds of nuclear loci, plastid genomes, and genome-wide SNP summaries, we reconstruct a robust nuclear backbone for sampled Malus lineages and evaluate where discordance is concentrated and which processes best explain it. Nuclear analyses resolve eight major clades, whereas conflict is non-random and localized to recurrent hotspots rather than evenly distributed across the tree. Cytonuclear discordance is similarly concentrated, especially around Clade H, represented by sampled accessions of M. tschonoskii, where localized plastid-nuclear disagreement is consistent with candidate plastid capture or organellar introgression. Multiple complementary analyses further indicate that the strongest conflict is not explained by ILS alone, but instead reflects lineage-structured introgression, while polyploid complexes represent additional localized sources of evolutionary complexity. Together, these results provide evidence for a reticulate genomic backbone in Malus and show how integrating nuclear, plastid, and genome-wide conflict analyses can help distinguish background discordance from process-specific signals in woody plant radiations. Several lineage-level reticulation hypotheses identified here should now be tested with broader population-level sampling and curated reference accessions.

Malus↗
PubMed2026

Diverse structures of mcr-10-bearing plasmids and high colistin resistance in Enterobacter cloacae complex clinical isolates from South Korea.

BACKGROUND: The emergence of mcr-mediated colistin resistance in Enterobacter cloacae complex (ECC) poses a significant threat to antimicrobial therapy. Among mcr variants, mcr-10 has been identified in various environments, but its genetic diversity, structural context, and functional role in colistin resistance remain unclear. METHODS: We investigated 183 ECC isolates and identified 60 colistin-resistant strains through minimum inhibitory concentration (MIC) testing. The presence of mcr-10 was screened using reference genomes from NCBI, and whole plasmid sequencing was conducted on mcr-10-positive isolates. The genetic environment of mcr-10 was analyzed via synteny and structural annotation. RESULTS: Whole-plasmid sequencing of eight mcr-10-positive ECC isolates identified three replicon types among the mcr-10-harboring plasmids: IncFIB (n=3), IncFII (n=3), and IncFII/IncFIB (n=2). Although all plasmids shared the xerC-mcr-10 cassette, they lacked a conserved backbone and showed diverse genetic contexts with variable insertion sequences near mcr-10, indicating marked structural heterogeneity. No additional antimicrobial resistance genes were detected on these plasmids. When introduced into E. coli DH5α, the plasmids increased colistin MICs only modestly, whereas representative plasmids transferred into colistin-susceptible E. roggenkampii and E. kobei conferred high-level resistance comparable to that of the parental mcr-10-positive isolates. Consistently, qRT-PCR showed higher mcr-10 expression in ECC transformants than in E. coli under colistin exposure, supporting a hostdependent effect on mcr-10-mediated colistin resistance. CONCLUSION: These findings highlight the diversity of mcr-10-carrying plasmids and suggest that mcr-10-mediated colistin resistance is shaped by the host genetic background. Further studies are needed to clarify the mechanisms underlying mcr-10 expression.

Colistin↗
PubMed2026

Genome-Wide Characterization of β-Glucosidase (TaBGLU) Genes in Bread Wheat and Their Expression Under Drought, Cold, and Combined Stress.

Glycoside hydrolase 1 (GH1) β-glucosidases were known to activate hormone conjugates and defense metabolites, yet their genomic organization and stress-response dynamics in wheat remained incompletely defined. We therefore performed an integrated characterization of TaBGLUs spanning phylogeny, gene structure and conserved motifs, subcellular localization, promoter cis-elements, Gene Ontology enrichment, protein-protein interaction networks, and targeted expression profiling. Wheat TaBGLUs partitioned into well-supported clades that shared canonical GH1 catalytic residues and a largely conserved motif scaffold. Subcellular localization predictions indicated predominant nuclear and chloroplast targeting, with a smaller cohort directed to secretory or endomembrane compartments. Promoters were enriched for light-responsive, hormone-related (ABA, JA/SA, auxin, GA) and stress-associated (MYB/WRKY, heat, low temperature) cis-elements, and functional annotations were consistent with roles in carbohydrate and cell-wall metabolism, hormone homeostasis, and defense. Network analysis revealed a densely connected TaBGLU submodule embedded within broader carbohydrate and defense interaction networks, suggesting coordinated or cooperative functions. Expression profiling under cold, drought, and combined drought and cold demonstrated broad stress inducibility, with early activation detected by 6 h, cold-responsive maxima typically at 12 h, drought-responsive peaks predominating at 24 h, and combined stress eliciting both earlier and more sustained expression maxima between 12-24 h. Representative strongly responsive genes included TaBGLU20, TaBGLU44, TaBGLU6, and TaBGLU23, which showed pronounced late induction under combined stress, TaBGLU30, which exhibited an earlier combined-stress peak, and TaBGLU12, which displayed a marked late drought-specific response. Taken together, this integrated genomic, regulatory, and expression atlas refined the wheat BGLU repertoire relative to previous gene model inventories, highlighted candidate TaBGLUs with central network positions and strong stress inducibility, and provided concrete entry points for functional validation and breeding for improved stress resilience.

Triticum↗
PubMed2026

In Vivo Genome Editing Approach to Disrupt Hydroxyacid Oxidase 1 for the Treatment of Primary Hyperoxaluria Type 1.

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder that leads to kidney and liver failure. PH1 is caused by a mutation in the alanine glyoxylate aminotransferase (AGXT) gene, which encodes a key metabolic enzyme that converts glyoxylate to glycine in the liver. Inability to metabolize glyoxylate leads to oxalate overproduction, yielding insoluble calcium oxalate crystals; accumulation of these crystals leads to progressive organ failure. Here, we used a novel, minimally disruptive genome-editing approach to disrupt the mechanism of action of hydroxyacid oxidase 1 (HAO1), an upstream enzyme in the glyoxylate metabolic pathway. Successful gene editing and disruption of the HAO1 gene is expected to increase levels of glycolate, a harmless intermediate of the glycine metabolic pathway, thereby preventing the formation of calcium oxalate crystals. We intravenously administered an adeno-associated virus (AAV) vector expressing the M1HAO1 meganuclease to both wild-type and Agxt-/- mice, a mouse model of PH1. We observed >30% editing of HAO1 in Agxt-/- mice, correlating with a dose-dependent increase in serum glycolate levels. At the highest dose tested, urine glycolate levels increased by 79%, with a concomitant 75% decrease in urine oxalate levels. We also evaluated in vivo targeting in rhesus macaques injected with AAV expressing two different versions of the HAO1 meganuclease. Dose-dependent editing of hepatic DNA and RNA was achieved, and serum glycolate levels changed in a manner consistent with successful liver editing; additionally, the treatment was well tolerated. Our results indicate that AAV-delivered meganucleases can effectively target HAO1 in mice and nonhuman primates to achieve high levels of HAO1 gene editing. Moreover, increased glycolate levels in serum indicate that this intervention significantly impacts the HAO1-mediated glycolate-to-glyoxylate pathway. These data suggest that this approach may represent an effective treatment for PH1.

Hyperoxaluria, Primary↗