Search Results (4,073)

Myotonic dystrophy type 1 (DM1) is caused by an expansion of CTG repeats in the DMPK gene. In a proportion of patients, the expanded allele contains variant repeats, which have been associated with later disease onset and different clinical presentation, although their full impact remains incompletely defined. We compared sociodemographic, neuromuscular, and multisystem clinical features between DM1 patients with pure CTG expansions (n = 66) and those with variant repeats (n = 9), who formed a consecutive cohort of unrelated index cases evaluated at the age of diagnosis in routine clinical practice. Patients with variant repeats were nine years older at diagnosis than patients with pure repeat expansions (p = 0.025), had more years of formal education (p = 0.024), and showed reduced muscle strength in proximal lower limbs (p = 0.049). No childhood or juvenile forms were observed among patients with variant repeats. Sex, disease duration, and most other clinical parameters, including multisystem involvement, did not differ between groups. The results of our exploratory study support variant repeats as disease modifiers in both age at onset and pattern of muscle involvement, and imply a two-sequential-component hypothesis in DM1 pathogenesis. Full article

Background: Coronary artery disease (CAD) arises from the convergence of genetic susceptibility, lipid dysregulation, and modifiable environmental exposures. The polymorphism rs4977574, located proximal to the CDKN2A/CDKN2B gene cluster, has been repeatedly implicated in CAD risk across several populations, yet its relationship to intermediate cardiometabolic phenotypes and pharmacological treatment patterns in Saudi individuals remains poorly characterized. Objective: This study aimed to evaluate the association of rs4977574 with CAD status, lipid-related phenotypes, smoking history, obesity, and atorvastatin exposure in a Saudi cardiovascular cohort, and to assess the robustness of observed associations through sensitivity-adjusted analyses excluding participants with major metabolic confounders. Methods: A case–control genetic association study was conducted in Saudi participants with clinically confirmed CAD and healthy controls. Genomic DNA was genotyped for rs4977574 using TaqMan^® allelic discrimination assays. Genotype–phenotype associations were examined using chi-square testing, binary logistic regression under additive and dominant inheritance models, and one-way ANOVA for continuous lipid traits. Hardy–Weinberg equilibrium (HWE) was assessed in controls. Sensitivity analyses were conducted by sequentially excluding participants with obesity, smoking, diabetes mellitus, hypertension, dyslipidaemia, and statin use. Results: After covariate adjustment, rs4977574 was not independently associated with CAD case–control status under any inheritance model. Genotype-stratified analyses identified significant differences in HDL-cholesterol and triglyceride concentrations among cases, with no equivalent effects on total cholesterol or LDL-cholesterol. A significant association was observed between rs4977574 genotype and atorvastatin prescribing patterns. Sensitivity-adjusted analyses were directionally consistent with primary findings. HWE deviation persisted in controls after sequential metabolic exclusions, implicating population stratification or regional genetic heterogeneity rather than sample selection bias. Conclusions: Although rs4977574 did not associate independently with CAD susceptibility, its relationship with HDL-cholesterol, triglycerides, and atorvastatin exposure indicates that this locus contributes to cardiometabolic phenotypic heterogeneity in this Saudi cohort. These findings support phenotype-oriented and pharmacogenetically informed approaches in regional cardiovascular genetics and highlight the need for larger, ancestry-stratified investigations across Middle Eastern populations. Full article

Trachoma, caused by Chlamydia trachomatis (Ct), persists as a major cause of preventable blindness despite the global SAFE strategy. Understanding how Ct genovars and genovariants influence infection dynamics and clinical outcomes is crucial for sustaining elimination efforts and informing vaccine development. A four-year longitudinal study was conducted in a trachoma-endemic region of Tanzania across multiple rounds of mass drug administration (MDA) with azithromycin. Ct infections were genotyped by ompA sequencing to identify genovars and genovariants. Associations between genetic variants, bacterial load, and clinical signs of trachoma were assessed. Following MDA, a shift in Ct genovar prevalence occurred from genovar B to genovar A. Genovar B was associated with more severe clinical signs, including follicles, papillae, and scarring, whereas genovar A infections exhibited higher bacterial loads. Among 121 individuals with recurrent infections, 94% were re-infected with the same genovar, indicating limited protective immunity and incomplete clearance despite MDA coverage exceeding 60%. The genovariants B2, B9, and A2 predominated, with an A → T amino acid substitution in B9 potentially modifying antigenic recognition. Post-MDA, normalized genovariant diversity increased, suggesting ongoing transmission or strain reintroduction. Distinct genovar-associated clinical and immunological patterns underscore the need to elucidate genovar-specific virulence and immune evasion mechanisms. These findings provide key insights for optimizing trachoma control and advancing vaccine development. Full article

Obesity and metabolic dysregulation are closely associated with chronic low-grade inflammation, in which interleukin-6 (IL-6) plays a key regulatory role. Genetic variation in the IL-6 gene may influence inflammatory responses and metabolic homeostasis. To identify single-nucleotide variants (SNVs) in the IL-6 gene in a cohort of Colombian high-performance athletes and to evaluate their potential functional and structural consequences using bioinformatic prediction and protein-modeling approaches. A descriptive observational study was conducted in a cohort of 23 high-performance Colombian athletes from Valle del Cauca representing cycling, karate, and weightlifting disciplines. Genomic Deoxyribonucleic Acid (DNA) extracted from peripheral blood samples was analyzed using Next-Generation Sequencing (NGS). Identified variants were evaluated using several in silico prediction tools, including Basic Local Alignment Search Tool (BLAST version 2.16.0), Expert Protein Analysis System (ExPASy version 4.0), Open Reading Frame Finder (ORFfinder version 0.4.3), and population databases such as Genome Aggregation Database (gnomAD version 4.0). Structural modeling was used to explore the potential impact of amino-acid substitutions on IL-6 protein stability. Eight single-nucleotide variants were identified in the IL-6 gene. Among them, the rs1524107 variant generated a missense substitution predicted to modify the amino-acid sequence of the IL-6 protein. Structural modeling suggested a potential alteration in protein stability associated with this variant. The rs1524107 variant may influence IL-6 protein structure according to computational predictions. These findings provide preliminary hypothesis-generating evidence regarding the potential role of IL-6 genetic variation in inflammatory regulation; however, functional validation and larger cohort studies are required to determine their biological significance. Full article

Calcium alginate is an anionic polysaccharide that forms an ionically crosslinked hydrogel network with encapsulation properties to nucleic acids and nutrients for the amelioration of osmotic stress, ion toxicity and nutrient imbalance in saline–alkali soils. Traditional soil reclamation methods, including salt leaching, incorporation of organic matter, and gypsum application, are water-intensive under a changing climate, ultimately necessitating transformative bio-based solutions for food security. Calcium alginate-based biohydrogel represents a versatile platform with a tunable macromolecular architecture, ionic crosslinking via an “egg box” mechanism and potentially promising to deliver engineered co-encapsulated nutrients and genetically modified cargoes. The mannuronic (M) and guluronic (G) acid (M/G) ratios govern ion exchange capacity, rheological behavior and release kinetics in saline- and alkali-stressed environments. Recent studies on alginate-based nutrient encapsulation showed reduced oxidative damage and a 15–50% increase in plant-available water. The irrigation intervals extended from 7 to 14 days and yield gains by 24% in wheat, with comparable improvements in maize, tomato, rice and cotton. Calcium alginate hydrogels encapsulated salt tolerance genes (HKT1, SOS1, AVP1) encoding proteins mainly involved in Na⁺ retrieval from xylem, Na⁺ extrusion from root cells and vacuolar Na⁺ sequestration, which have achieved yield gains of 40 to 75% across wheat, rice and maize. Future research should focus on optimizing mechanical strength, crosslinking chemistry and smart bioencapsulation strategies for sustainable development so that crops are capable of withstanding variable climate stresses. Full article

Objective: This study aims to examine the association between the frailty index (FI) and stroke risk among Chinese adults, describe the burden of stroke in China, and explore the causal role of FI in ischemic stroke through Mendelian randomization. Methods: Data from the China Health and Retirement Longitudinal Study (CHARLS) included 13,473 participants aged 45 years and older without a history of stroke. Cox models, restricted cubic splines, and sensitivity analyses were employed to assess the association between the modified frailty index (mFI) and incident stroke. Additionally, data from the Global Burden of Disease (GBD) 2021 data report were utilized to describe stroke trends in China from 1990 to 2021. Two-sample Mendelian randomization was conducted to evaluate the causal effects of FI on ischemic stroke subtypes. Results: During a median follow-up period of approximately 7 years, 811 incident strokes were recorded. Each 0.1-point increase in mFI was associated with a 16% increase in stroke risk (HR = 1.16, 95% CI: 1.06–1.27), demonstrating a linear dose–response relationship. From 1990 to 2021, the proportion of ischemic stroke rose from 46.9% to 63.2%. Mendelian randomization analysis provided genetic evidence supporting a causal association between FI and ischemic stroke (OR = 1.191, 95% CI: 1.046–1.357), particularly driven by large-artery atherosclerotic (OR = 1.852) and small-vessel stroke (OR = 1.415), but not by cardioembolic stroke. Conclusions: A higher FI is associated with an increased risk of stroke among Chinese adults, with genetic evidence supporting a causal role in ischemic stroke. Therefore, FI may serve as a valuable addition to existing risk assessment tools. Full article

Ribonucleotides are frequently incorporated into DNA during the replication of genetic information and, if missed during ribonucleotide excision repair, they may undergo phosphodiester bond rearrangement or cleavage. These changes can in turn lead to deformation of the spatial geometry of the local double helix and potentially interfere with charge transfer through ds-DNA. This process is believed to support long-range communication between proteins involved in genome replication and repair. This study theoretically explores how a single embedded riboadenosine (A₃) affects the structure, electronic properties, and charge-transfer properties of double-stranded DNA ([A₁G₂A₃G₄A₅]*[T₅C₄T₃C₂T₁]). In particular, the study focuses on four products formed at the ribonucleotide site: native 3′,5′-linkage (R-DNA), the 2′,3′-cyclic phosphate intermediate (IM-R-DNA), rearranged 2′,5-linked (RE-R-DNA), and the single-strand-break cleavage product (SSB-R-DNA). This theoretical investigation was performed at the M06-2X/6-31++G**//M06-2X/D95** level of theory in the aqueous phase. Significant spatial geometry perturbations were found at the central part of ds-oligonucleotides, i.e., the A₃T₃|G₄C₂ region, where the modified linkage affected the base overlap and stacking interactions most strongly; in the rearranged and cleaved forms, stacking at this site decreased by about 7 kcal•mol⁻¹ relative to native DNA. Global electronic analysis showed that R-DNA had the highest ionisation potential and the lowest electron affinity, whereas SSB-R-DNA displayed the lowest adiabatic ionisation potential and the highest adiabatic electron affinity, indicating a much greater tendency to stabilise excess charge. At the base-pair level, G₂C₄ was usually the preferred hole sink, except in RE-R-DNA, where G₄C₂ was favoured. In contrast, electron localisation was generally favoured at G₄C₂, while, in SSB-R-DNA, the A₃T₃ pair became the most favourable electron-accepting site. Overall, the results show that even a single ribonucleotide, depending on its linkage chemistry, can substantially reshape charge migration through ds-DNA and may therefore influence lesion recognition, repair efficiency, and genome stability. Full article

The rapid proliferation of genetically modified (GM) crops and the uncontrolled distribution of GM-based food and feed have become a growing global concern, posing new challenges for regulatory oversight and traceability. The traditional PCR detection method cannot simultaneously meet the needs of high-throughput, high-specificity and high-sensitivity detection of transgenic organisms. In this study, a multiplex fluorescence PCR-capillary electrophoresis platform was developed by labeling primers of endogenous and exogenous genes with different fluorescent groups. The system enabled the simultaneous detection of 27 GM-related genes and events in a single analytical workflow. The results demonstrated accurate identification of all seven GM maize events, with correct detection achieved for each individual strain. In addition, the method enabled precise discrimination of a mixed sample containing five GM maize varieties. The assay also achieved a detection sensitivity of 0.1% in gradient mixtures with different GM contents. Our platform integrates a larger number of targets into a single PCR reaction, thereby simplifying the detection workflow while maintaining high analytical performance. Furthermore, the combination of multicolor fluorescence labeling and capillary electrophoresis provides high-resolution fragment discrimination and robust multiplex detection capability. This platform provides a novel and effective tool for rapid detection in food safety of transgenic crops and related areas, and can be applied in import/export inspection, quarantine, and biosafety surveillance. Full article

Epidermolysis bullosa (EB) comprises a group of rare inherited genodermatoses characterized by fragility and blistering of the skin and mucous membranes, chronic wounding, and significant morbidity including increased risk of squamous cell carcinoma in severe subtypes. Key unmet priorities include reducing diagnostic latency, establishing objective wound monitoring, enabling early detection of malignant transformation within chronic ulcerations, and developing therapies that durably modify disease progression. Artificial intelligence (AI) encompassing machine learning (ML), and deep learning (DL) is increasingly integrated into EB research and clinical practice to address these unmet needs. This structured narrative review synthesises current evidence on AI applications in EB spanning genetic diagnostics, wound assessment, inflammatory endotyping, drug repurposing, and emerging therapeutic technologies, and integrates evidence from registered clinical trials. In genomics, DL-based splicing prediction models and variant prioritisation frameworks accelerate pathogenic variant detection and reduce diagnostic latency. In wound care, convolutional neural networks-based platforms enable automated lesion segmentation and remote monitoring, while multimodal AI models predict healing trajectories and support stratification of wounds by chronicity. Computational transcriptomic analyses have identified candidate repurposing agents by reversing pathogenic gene expression signatures in EB tissue. Emerging convergence of AI with biosensors-integrated wound dressings and three-dimensional bioprinting of genetically corrected skin substitutes represents a transformative future direction. Translational barriers include limited EB-specific training datasets, algorithmic bias across diverse skin phototypes, the interpretability deficit of DL systems, and evolving regulatory frameworks for AI as a medical device. Expansion of internationally interoperable EB disease registries with standardised wound imaging protocols is identified as the single most impactful intervention to accelerate AI adoption. A minimum endpoint set for AI-assisted EB wound assessment, incorporating wound area trajectory, wound type classification, tissue composition, and paired patient-reported pain and itch scores, is proposed to standardise outcome reporting across future studies. Full article

Background/Objectives: Depression is a heterogeneous disorder shaped by both inherited liability and environmental exposures. Physical activity is a scalable, modifiable behavior consistently linked to lower depressive symptoms and reduced incident depression, but interpretation is complicated by measurement error, genetic confounding, and bidirectional pathways in which depression can also reduce activity. This systematic review synthesizes evidence on gene–physical activity interplay in depression across four complementary frameworks: (i) candidate–gene interaction studies, (ii) genome-wide susceptibility indexed by depression polygenic risk scores (PRS), (iii) lifestyle-context and activity-architecture analyses (e.g., timing and accumulation patterns), and (iv) Mendelian randomization (MR) studies testing bidirectional causal effects between activity-related traits and depression. Methods: A PRISMA-aligned search and narrative synthesis were conducted due to substantial heterogeneity in populations, exposure measurement (self-report vs. accelerometer), genetic approaches, and depression phenotypes. Twenty-seven studies met inclusion criteria. Results: Across designs, the most consistent pattern was that higher physical activity (or lower inactivity) tracked with lower depression risk or symptom burden even when genome-wide genetic susceptibility was modeled, supporting largely additive contributions of PRS and activity rather than strong, generalizable PRS × activity interactions. MR evidence most consistently supported a protective effect of physical activity on depression when activity was indexed by accelerometer-derived phenotypes, whereas self-reported activity instruments yielded weaker or more heterogeneous findings. Bidirectional genetic evidence also indicated that depression liability can causally suppress physical activity, consistent with a feedback loop relevant for prevention and intervention. Candidate-gene moderation effects were mixed and typically emerged only in specific contexts (e.g., stress history, developmental stage, sex, or treatment setting), underscoring limited replicability and sensitivity to how activity is operationalized. Conclusions: Overall, the literature supports physical activity as broadly protective across levels of genetic risk, while emphasizing that robust inference depends on objective exposure measurement, careful handling of confounding and reverse causation, and improved generalizability beyond predominantly European-ancestry genetic resources. Full article

Cancer-associated cachexia (CAC) is a complex metabolic syndrome characterised by progressive skeletal muscle loss, systemic inflammation, reduced treatment tolerance, and poor survival. Marked interindividual variability in CAC susceptibility suggests that host genetic factors may contribute to its development. Vitamin D plays an important role in muscle metabolism and inflammatory control through activation of the vitamin D receptor (VDR). VDR signalling influences myogenesis, mitochondrial function, insulin-like growth factor pathways, and pro-inflammatory cytokine expression, all of which are implicated in CAC pathogenesis. Hence, VDR variants, including the rs731236 (A>G) polymorphism, which modifies receptor activity, may affect CAC pathogenesis. Thus, this study investigated the association between the polymorphism and susceptibility to CAC as well as patient survival in a cohort of 140 adult cancer patients. Briefly, the rs731236 GG genotype was significantly associated with a lower prevalence of CAC across disease diagnostic approaches (chi-square tests, p < 0.05). Furthermore, GG genotype carriers demonstrated significantly improved survival compared with carriers of AA/AG genotypes (Log-rank and Tarone–Ware tests, p < 0.05). In summary, these findings suggest that the rs731236 polymorphism influences both susceptibility to CAC and survival outcomes in patients with cancer, further supporting a clinically relevant role for vitamin D signalling in supportive oncology care. Full article

Cerebellar ataxia is clinically and genetically heterogeneous, and candidate variant prioritization is particularly difficult when only a single affected animal is available. We combined structural MRI of one affected Border Collie and six controls with whole-genome sequencing of the affected dog and 31 comparison dogs. MRI revealed widened cerebellar folial spaces and reduced bilateral cerebellar gray matter volume, without global brain atrophy or spinal cord lesioning. Parallel heterozygous and recessive variant screens, together with identity-by-descent, runs-of-homozygosity, structural-variant, and repeat-expansion analyses, narrowed the candidates to six non-MODIFIER variants. Among these, a heterozygous PACSIN1 splice-donor variant (chr12:3,985,222 T > G) was private to the affected dog in the analyzed cohort and affects a conserved residue in the F-BAR domain. No segregation, replication, or functional validation data are currently available. These results prioritize the PACSIN1 variant as a testable candidate and demonstrate the utility of imaging-guided genomic prioritization in underpowered veterinary cohorts. Full article

Acute aortic syndrome (AAS) comprises acute aortic dissection, intramural haematoma, penetrating atherosclerotic ulcer, and limited intimal tear, conditions that require rapid recognition because mortality and resource use are strongly influenced by time to diagnosis, anatomical extent, malperfusion, and the need for emergency surgical or endovascular intervention. This revised narrative review synthesizes contemporary evidence on clinical, genetic, environmental, and health-system determinants of prolonged hospitalisation, intensive care unit (ICU) utilisation, bed occupancy, and costs in patients with AAS. Beyond summarising established risk factors, the review adds a resource-oriented framework that links hypertension, advanced age, female sex, smoking-related comorbidity, hereditary aortopathies, haemodynamic instability, malperfusion, delayed diagnosis, operative complexity, and postoperative complications to measurable downstream outcomes such as ICU length of stay, total hospital length of stay, reoperation, readmission, and longitudinal imaging surveillance. We searched PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar for relevant studies, registries, guideline documents, and cost analyses published between January 2000 and May 2026, with particular emphasis on studies from the last five years. The review was not designed as a meta-analysis; therefore, effect estimates are interpreted according to study design and generalisability. AAS imposes a disproportionate burden on hospital systems because high-risk patients often require advanced imaging, prolonged haemodynamic monitoring, complex open or endovascular repair, ICU care, and lifelong follow-up. Earlier diagnosis, structured risk stratification, targeted genetic evaluation, aggressive control of modifiable risk factors, and system-level pathways such as dedicated aortic networks may shorten hospital stay and reduce avoidable costs. Full article

Human fertility has declined sharply since 1950, and a growing body of evidence suggests that while conventional socioeconomic factors are well-established drivers of the broader demographic transition, they do not fully account for the timing and breadth of this trend. This review examines the Circadian-Light-Hygiene hypothesis, which proposes that daily light exposure is a fundamental regulator of reproductive health. We synthesize findings from photobiology, endocrinology, reproductive medicine, and epidemiology to evaluate how artificial light at night, insufficient daytime light, and irregular light–dark patterns may disrupt the hormonal timing systems that support reproduction. The available evidence indicates that such disruption can alter melatonin signaling, circadian gene regulation, and neuroendocrine rhythms, with downstream effects on ovulation, sperm quality, endometriosis, polycystic ovary syndrome, pregnancy outcomes, and developmental programming. Urbanization, screen use, and shift work appear to amplify these effects, while genetic variation may modify individual susceptibility. Although direct causal evidence in humans remains limited for several endpoints, the convergence of observational, experimental, and translational data supports circadian-light misalignment as a plausible, additional modulator of fertility decline, and a potentially modifiable contributor. Optimizing daily light exposure may therefore represent a low-cost and scalable strategy for improving reproductive health. Full article

Heart failure (HF) in the setting of diabetes represents a distinct cardiometabolic phenotype characterized by profound disturbances in myocardial glucose metabolism, mitochondrial function, and energetic efficiency. Growing evidence indicates that sirtuins, a family of nicotinamide adenine dinucleotide (NAD⁺)-dependent deacylases, play a central role in coordinating glucose utilization, oxidative metabolism, and stress responses in the heart. Findings from genetically modified animal models and cardiomyocyte studies demonstrate that sirtuin impairment, often driven by NAD⁺ depletion and redox imbalance, further suppresses metabolic activity and promotes metabolic inflexibility, whereas restoration of NAD⁺ availability or sirtuin activity improves mitochondrial efficiency and metabolic coordination. Human studies, including analyses of myocardial tissue and circulating biomarkers, provide supportive but largely associative evidence, highlighting a substantial translational gap. In this review, we synthesize experimental and clinical data linking sirtuin signaling to the metabolic remodeling observed in diabetic HF, with particular emphasis on glycolysis–oxidation uncoupling, pyruvate dehydrogenase regulation, and mitochondrial dysfunction. We critically discuss context-dependent effects, apparent contradictions, and current limitations of the field, emphasizing differences between diabetic and non-diabetic HF, as well as phenotype- and stage-specific considerations. Finally, we explore therapeutic implications and outstanding questions, positioning the NAD⁺–sirtuin axis as a unifying mechanistic framework that links systemic metabolic disease to cardiac energetic failure and underscores the potential for metabolism-informed, precision strategies in diabetic HF. Full article