ABSTRACTMajor congenital malformations are common, and most cases have no known etiology because of complex interactions between genetic and environmental factors and variable phenotypic outcomes. Congenital NAD Deficiency Disorder (CNDD), a cause of multiple congenital malformations and embryo loss, exemplifies this variability in phenotypic presentation, even between siblings with the same underlying genetic variants. Mouse models show that CNDD is caused by embryonic nicotinamide adenine dinucleotide (NAD) deficiency because of the embryos' genetic inability to synthesize NAD and/or insufficient maternal provision of NAD precursors to embryos. But it is unknown when during pregnancy embryos become susceptible to developing malformations and what drives the malformation variability. Here, we induced CNDD in wild‐type mice via the maternal diet and longitudinally tracked affected and unaffected embryos in utero. We compared 3‐day interval measurements of the maternal blood NAD metabolome with embryo phenotype using Fast Spin Echo Magnetic Resonance Imaging, mass spectrometry, and micro‐computed tomography. Malformations varied between litters, but they correlated with different embryo growth dynamics. Mice with lower maternal NAD Salvage Pathway metabolite levels and minimal levels of derived excretion metabolites from embryonic day 6.5 onward had smaller embryos with more malformations. This showed that altered embryo growth and reduced maternal NAD precursor availability during organogenesis resulted in CNDD. Variability in the timing of maternal metabolic perturbation corresponded to variability in organ and tissue defect types between litters. As embryo phenotypes are directly linked to maternal NAD precursor availability prior to and during organogenesis, this suggests NAD‐derived metabolites are potential biomarkers predicting CNDD.

Retinal detachment (RD) is a sight-threatening emergency requiring urgent intervention to prevent permanent vision loss. While both environmental and genetic risk factors contribute to RD, its complete genetic architecture remains unknown. Here, we performed the largest whole genome sequencing-based case-control study in RD to date, including data from 7,276 RD cases and 236,741 controls in the UK Biobank. Through variant- and gene-level association analyses, we identified VSX2 as a genetic determinant of RD risk while confirming established associations including FAT3, RDH5, and COL2A1. Gene-level collapsing analysis revealed that rare heterozygous missense variants in VSX2 confer a 2.8-fold increased risk of RD (p = 2.4x10-10; odds ratio (OR) = 2.8; 95% confidence interval (CI): [2.1, 3.7]). One missense variant in this gene, p.Glu218Asp, demonstrated a particularly strong effect size (p = 9.3x10-10; OR = 5.9; 95% CI: [3.7, 9.4]). Replication analyses in two additional cohorts, totaling 1,331 cases and 52,355 controls strengthened both the gene- and variant-level associations even further (p = 1.4x10-10 and 1.1x10-11, respectively). Other contributory heterozygous variants included previously reported pathogenic homozygous variants for anophthalmia and microphthalmia. These findings thus reveal a previously unknown gene dosage curve for VSX2, where homozygous mutations cause severe developmental eye disorders and heterozygous mutations cause adult-onset retinal detachment. Extending this observation, we found a significant enrichment for other known recessive Mendelian eye disease genes among nominally significant (p < 0.05) genes associated with RD in the collapsing analysis. This work provides a compelling example of how heterozygous variants in recessive disease genes can be associated with less severe clinical phenotypes.

Individual’s future socioeconomic status (SES) has been reported to be robustly predicted by cognitive ability (IQ). However, research on the genetic and environmental underpinnings of this association in emerging adults remains limited. Utilizing the German TwinLife panel data, the present study examined how IQ at early adulthood at age 23 is associated with SES at age 27 (NMZ = 228 and NDZ−SAME SEX = 212), through 2 measures on educational attainment and 2 on occupational status. Cholesky decomposition models reported the heritability of IQ at approximately 75%, and heritability on all SES outcomes. Genetic factors further explained most of the IQ–SES association (69–98%), and genetic correlations between IQ and SES exceeded environmental correlations. These findings seem to underscore the importance of researchers and policymakers to also considering genetic factors when examining the life outcomes of young adults.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-026-37786-3.

Carbapenem-resistant Acinetobacter baumannii (CRAB) is a critical nosocomial pathogen with limited therapeutic options. This study aimed to describe clonal relationships among CRAB isolates and genomic insights from representative clusters. A total of 128 non-duplicate CRAB isolates were included in the study. Pulsed-field gel electrophoresis (PFGE) was used to assess clonal relationships and as a preliminary clustering tool for isolate selection. Twelve representative isolates from distinct PFGE clusters were selected for whole-genome sequencing using Oxford Nanopore. Genome assembly, annotation, and comparative analyses were performed using Flye, Prokka, and Roary, respectively. Antimicrobial resistance (AMR) genes, plasmids, insertion sequences, integrons and prophages were identified using the CARD, MOB-suite, ISEscan, IntegronFinder, and PHASTEST tools, respectively. Multilocus sequence typing (MLST) and pangenome analyses were conducted to determine genetic diversity and relatedness among the CRAB isolates. Antibiotic susceptibility testing revealed an extensively drug-resistant phenotype, colistin resistance rate was 23.4%. Mutations in lpxC, lpxD, pmrB, and lpxA were identified in colistin-resistant isolates, suggesting a possible role. Most isolates belonged to the globally disseminated clone ST2Pasteur, while others were classified as ST636 and ST78. Genomic comparisons identified diverse resistance genes, mobile genetic elements, plasmids, integrons, and virulence factors. Pangenome analysis uncovered a considerable genomic diversity, with 2700 core genes (42.5%) and 3649 accessory genes (57.5%), including 1864 strain-specific (cloud) genes (29.4%) among the isolates. Overall, our findings demonstrate the complex genomic architecture of CRAB and highlight the potential role of genomic surveillance in local infection control.

The development of endometrial cancer is a gradual malignant transformation process driven by multiple factors, and the immune microenvironment is closely related to clinical outcomes and immunotherapy responses. Under physiological conditions, the immune microenvironment of the normal endometrium undergoes periodic reshaping under the regulation of estrogen and progesterone, maintaining the balance between immune defense and reproductive capacity. However, continuous exposure to risk factors, such as non-antagonistic estrogen, may trigger endometrial intraepithelial neoplasia. During this period, the immune microenvironment becomes dysregulated, supporting malignant progression. For example, estrogen-stimulated interactions between endothelial cells and macrophages, elevated neutrophil/lymphocyte ratios, and the accumulation of regulatory T cells all combine to cause dysregulation of immune microenvironment. The abnormal immune microenvironment that occurs in the precancerous lesion stage interacts with systemic and genetic carcinogenic factors, ultimately shaping the unique immune microenvironment of each molecular subtype of endometrial cancer. POLE-mutated and MSI-H subtype endometrial cancer are immune-infiltrated tumors, whereas the copy-number high subtype is immune-suppressive tumor and the copy-number low subtype is immune-desert tumor. However, still little is known about the immune dysregulation that occurs during the precancerous stage and its impact on subsequent malignant progression. This review systematically describes the changes in the immune microenvironment during the process from normal endometrium to endometrial cancer, emphasizing that endometrial intraepithelial neoplasia is a key stage of immune imbalance, thus paving the way for early immune intervention and precise immunotherapy.

Novel association of HLA-DQA1 and HLA-DPB1 alleles with Acute myeloid leukemia susceptibility in (Central Asian) Kazakhstani Population: A Case-Control study.

Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease/Lewy body dementia (PD/LBD), and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are driven by complex interactions of genetic and environmental factors. While genome wide association studies (GWAS) have uncovered a number of risk gene variants (e.g., APOE, SNCA [encoding α-synuclein], and protein disulfide isomerase [PDI]), these genetic factors alone cannot fully explain disease onset or progression. Emerging evidence suggests that post-translational modifications of proteins, particularly S-nitrosylation (SNO), act as a critical link between environmental stress and neurodegenerative pathology. Here, we review data showing that while physiological protein SNO regulates diverse neuronal processes, aberrant SNO, occurring very commonly in the diseased brain, can disrupt protein function in ways that mimic the deleterious effects of rare genetic mutations. We advance the concept of "mutational mimicry," whereby aberrant SNO of key neuronal or glial proteins reproduces the functional consequences of known specific genetic mutations, ultimately converging on common pathways of synaptic dysfunction emanating from mitochondrial and metabolic impairment, proteostasis, neuroinflammation, and so on. Supporting this framework, proteomic analyses show significant overlap between abnormally S-nitrosylated proteins in diseased brains and known genetic risk factors in AD and PD/LBD as well as in ALS. By linking redox biology to human genetics, this review highlights how environmental factors can phenocopy or enhance genetic susceptibilities. Understanding this convergence not only provides novel insight into disease mechanisms but also suggests new therapeutic targets to intervene in these convergent pathways with the goal of halting neurodegenerative processes.

HFE genetic variants, especially C282Y homozygosity (C282Y+/+), can increase systemic iron and cause hemochromatosis, though expression varies. Excess iron can lead to liver disease and liver cancer, yet factors influencing liver iron beyond HFE genotype remain unclear. We investigated genetic/environmental factors influencing liver iron, including HFE genotype and hemochromatosis diagnosis. We analyzed 37,287 European ancestry UK Biobank participants (mean age 64.1, SD: 7.6) with HFE genotypes and MRI-estimated liver iron concentrations (MRLIC). Linear regression assessed MRLIC associations with genetic and environmental factors, adjusting for age, sex, and genetic covariates. Mean MRLIC was highest in undiagnosed C282Y+/+ males and females (2.56 and 2.31mg/g) versus diagnosed (1.23 and 1.51mg/g, p=0.0001 and 0.0004). Other HFE genotypes had nominal increases versus those without HFE genetic variants. Higher MRLIC was associated with higher alcohol intake (β=0.11, 95% CI: 0.09-0.11, p=6.0×10-128; >30 vs. 1-14 units/wk), frequent red/processed meat consumption (β=0.08, 95% CI: 0.07-0.09, p=3.7×10-54; ≥3 times/week vs. none), high waist-height ratio (β=0.01, 95% CI: 0.006-0.02, p=6.4×10-5; although magnitude was weak) and genetically predicted transferrin saturation (β=0.22, 95% CI: 0.19-0.26, p=3.8×10-46). Lower MRLIC was associated with underweight body mass index (β=-0.06, 95% CI: -0.09 to -0.03, p=1.1×10-4) and proton pump inhibitor use (β=-0.03, 95% CI: -0.04 to -0.03, p=3.5×10-17). Undiagnosed C282Y+/+ individuals had excess liver iron versus diagnosed, likely due to treatment. Genetic and environmental factors influence liver iron beyond C282Y+/+. Tailored lifestyle advice could benefit those at risk of hemochromatosis.

Genetic causes and modifiers of prion diseases.

Abstract Background Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with the characteristics of demyelination and axonal degeneration at a young age. Genetic factors may play an important role in the development of multiple sclerosis. Interleukin 10 (IL-10) is a homodimer anti-inflammatory cytokine. So far, there has been no research on the relationship between the − 1082 (G/A) polymorphism of this gene and the aforementioned disease in a large statistical population and with definitive results. The purpose of this study is to investigate the relationship between the 1082-(G/A) polymorphism in interleukin 10 and the genetic predisposition to MS and the onset of the disease in patients. Method Databases including Google Scholar, PubMed, Scopus and Web of Science were searched to find research on the association between polymorphism − 1082 (G/A) interleukin 10 gene and MS disease. Also, the studies include reporting the genotype frequency between the two experimental and control groups and studies that have sufficient information and genetic distribution to estimate the odds ratio (OR) with a confidence interval (CI) of 95%. Results In total, research was conducted on 1042 subjects and 1299 control subjects. Polymorphism − 1082 (rs1800896) (G/A) of interleukin 10 gene was analyzed. This meta-analysis provides a consolidated examination of the association between the IL-10 -1082 G/A polymorphism and MS by synthesizing data across a broader and more diverse population than previously reported. Conclusion Our findings showed that there is significant relationship between genotypes of polymorphism − 1082 (rs1800896) (G/A) of interleukin 10 gene and MS disease.

Genetic factors, including single-nucleotide variants (SNVs), may modulate disease course and therapeutic efficacy in patients with inflammatory bowel disease (IBD). We investigated the association between four SNVs in cytokine genes and clinical phenotype as well as the response to molecular-targeted drugs in patients with IBD. A total of 197 IBD patients (142 Crohn's disease [CD], 55 ulcerative colitis [UC]) undergoing targeted treatment were enrolled. The SNVs analysed were: TNFA rs1800629 (-308 G>A), TGFB rs1800471 (-codon 10 C>T), IL6 rs1800795 (-174 G>C), and IL10 rs1800896 (-1082 G>A). Biochemical response at 12 months (T12) was defined as C-reactive protein < 5.0 mg/L and faecal calprotectin < 250 μg/g at T12, in the absence of ongoing corticosteroid therapy. Among the SNVs analysed, the IL6 rs1800795 C allele was significantly associated with a younger age at diagnosis (p = 0.049), while the TNFA rs1800629 A allele was more frequently observed in patients with CD than in UC (p = 0.036). Regarding treatment response, 134 patients completed 12 months of molecular-targeted therapy and were included in the per-protocol analysis; 41.0% achieved biochemical remission at T12. The IL10 rs1800896 variant allele was significantly associated with remission (OR = 2.15, 95% CI: 1.03-4.44; p = 0.041). This association remained significant in multivariate analysis (aOR = 4.15, 95% CI: 1.49-11.56; p = 0.007), independently of clinical and treatment-related variables. In conclusion, genotyping of cytokine-related SNVs may help identify patients with a more aggressive disease phenotype and guide personalised treatment strategies in patients with IBD.

Women are vulnerable to depression, with evidence of MAO-A and HTTP gene variations' impact. We studied depression in women at a UAE hospital to analyze hormonal changes, psychological symptoms severity, and gene variations related to MAO and HTTP promoter region polymorphism. This prospective analytical study included 100 participants (50 depressed, 50 non-depressed women aged 18-60 years). Women with thyroid diseases, abnormal mammograms, organic causes, cardiovascular diseases, or atherosclerotic conditions were excluded. Depression severity was assessed using Beck Depression Inventory. Cortisol, serotonin, and leptin levels were measured using ELISA kits. Saliva samples were collected for DNA polymorphism detection using PCR and gel electrophoresis. Statistical analysis used SPSS software. Participants showed simple depression (20%), moderate (13%), severe (10%), and very severe (7%). HTTP cases were L/L (41%), L/S (39%), and S/S (20%). MSP distributions were SA/SG (32%), SA/SA (29%), LA/SA (25%), and SA/LG(14%); MAO were 3/4 (57%), 3/3 (32%), and 4/4 (11%). This UAE study demonstrates hormones and gene variations' influence. HTTP genotyping revealed three groups: S/S, S/L, and L/L alleles. MAO variants were 3/4, 3/3 and 4/4. Genetic factors can guide treatment planning for severe depression.

The sheep as a translational model for neurodevelopmental disorders induced by prenatal maternal immune activation.

Deep neural networks reveal organic pollutants' dominance in global inflammatory bowel disease.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for 80% of cases worldwide. While chronic hepatitis B and C infections remain primary risk factors, emerging evidence highlights the increasing contributions of metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) to HCC development. Genetic predispositions play a crucial role in modulating individual susceptibility to HCC, particularly through variants affecting viral persistence, lipid metabolism, and fibrogenesis. This review aims to summarize key genetic variants associated with precancerous conditions leading to HCC. The genetic risk factors, such as TP53 R249S mutant, TERT promoter mutations, and Wnt/B-catenin pathway alterations, influence disease progression and treatment response in HCC subjects with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. In MASLD-related HCC, variants in PNPLA3, TM6SF2, and MBOAT7 modulate hepatic lipid metabolism and fibrosis. ALD-associated HCC is influenced by polymorphisms in ADH1B, ADH1C, and ALDH2, which affect alcohol metabolism and oxidative stress. Additionally, inherited metabolic disorders, including Wilson's disease and hemochromatosis, further contribute to HCC susceptibility. Despite previous insights into HCC-related genetic cues, challenges such as limited population-specific data, lack of genetic screening programs, and ethical concerns regarding genetic tests hinder the translation of genetic discoveries into personalized HCC prevention strategies. Expanding population-specific studies, improving genetic screening accessibility, and developing standardized risk prediction models will be crucial in shifting traditional medications toward a precision medicine setting for HCC management.

Pathophysiology of Chronic Rhinitis and Chronic Sinusitis With and Without Nasal Polyposis.

A 4-year-old male with Down syndrome was diagnosed with a complete atrioventricularcanal defect type A (Rastelli), ostium primum ASD, and inlet-type VSD. Despite his age,he showed preserved cardiopulmonary function and a positive vasoreactivity test,allowing surgical correction using a single autologous pericardial patch technique.Postoperative follow-up revealed hemodynamic improvement and gradual reduction ofright ventricular pressure under medical therapy. This case highlights late surgicalfeasibility in a patient with trisomy 21 and complete AV canal, possibly influenced byfavorable anatomic and genetic protective factors reported in the literature.Keywords: atrioventricular (AV) canal, Down syndrome, cardiac catheterization,pulmonary hypertension.

Maize seed quality attributes: Exploring genetic, agronomic, and environmental factors for sustainable improvement – A Systematic Review

Dietary regulation of peroxisome proliferator-activated receptors (α and γ) and IL-1R-associated kinase proteins in experimental Trypanosoma cruzi infection: Insights into one health.

Systemic lupus erythematosus (SLE) is a chronic, heterogeneous autoimmune disease influenced by various genetic and environmental factors, and recent advances have established type I interferons (IFN-I) as pivotal drivers. This study comprehensively characterises IFN-I risk gene signatures in SLE. The IFN-I-related genes were obtained from GSE185047, and then Mendelian randomisation analysis using data from the FinnGen cohort (705 SLE cases, 385 509 controls) was utilised as a discovery set to identify IFN-I related risk genes. Single-cell RNA sequencing (scRNA-seq) and external cohorts were used to validate the four key signatures. Univariate and multivariate linear regression models assessed associations between gene expression and clinical parameters. DNA methylation analysis further evaluated epigenetic dysregulation in SLE immune subsets. Thirty-eight IFN-I-related genes were identified, and Mendelian randomisation analysis revealed robust causal associations between four genes (HERC5, IFIT3, IFI44L and IFI6) and SLE risk, with no heterogeneity or pleiotropy. ScRNA-seq demonstrated significant upregulation of these gene signatures in SLE PBMCs and monocytes (except IFIT3 in monocytes), along with altered immune cell proportions-specifically, increased monocytes and decreased T cells. External validation confirmed elevated expression of all four genes in SLE, with high diagnostic accuracy. Clinically, increased expression of these genes correlated with SLEDAI, reduced lymphocyte counts and lower complement C4 levels. Furthermore, DNA hypomethylation of IFI44L was observed across multiple SLE immune subsets, indicating epigenetic dysregulation. This study establishes HERC5, IFIT3, IFI44L and IFI6 as causal IFN-I risk genes in SLE and identifies IFI44L hypomethylation as a key epigenetic driver of IFN-I pathway activation. These findings offer new insights into SLE pathogenesis and highlight potential diagnostic biomarkers and therapeutic targets.