Search Results (5,610)

Brugada syndrome is a rare inherited heart disease characterized by ventricular arrhythmias and characteristic ST segment elevation, which increases the risk of sudden death. Studies have shown that the pathogenesis of this disease involves a variety of gene mutations, including abnormal functions of sodium, calcium, and potassium ion channels, resulting in cardiac electrophysiological disorders. These variants affect excitability and conduction of cardiomyocytes, thereby increasing the susceptibility to ventricular arrhythmias and sudden death. However, many genetic variants remain of uncertain significance or are insufficiently characterized, necessitating further investigation. This review summarizes the genetic variants associated with Brugada syndrome and discusses their potential implications for improving diagnosis and therapeutic approaches. Full article

Predominantly antibody deficiencies (PADs) are the most prevalent types of inherited errors of immunity (IEI) and are characterized by a broad range of clinical manifestations, such as recurrent infections, autoimmunity, lymphoproliferation, atopy and malignancy. The aim of this study was to identify genetic defects associated with PADs in order to improve diagnosis and personalized care. Twenty patients (male/female: 12/8, median age of disease onset: 16.5 years, range: 1–50) were analyzed by next-generation sequencing (NGS) using a custom panel of 30 genes associated with PADs and their possible disease phenotype. The detected variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines and inheritance, and the penetrance patterns were evaluated by PCR–Sanger sequencing. Novel and rare mutations associated with the phenotype of common variable immunodeficiency (CVID) in genes encoding the transcription factors NFKB1, NFKB2 and IKZF1/IKAROS were identified. Alphafold3 protein structure prediction was utilized to perform a comprehensive visualization strategy and further delineate the mutation-bearing domains and elucidate their potential impact on protein function. This study highlights the value of genetic testing in PADs and will guide further research and improvement in diagnosis and treatment. Full article

As power grids scale and aging assets edge toward obsolescence, grounding grid corrosion has become a critical vulnerability. Conventional diagnosis must fit high-dimensional electrical data to a physical model, typically yielding a nonlinear under-determined system fraught with computational burden and uncertainty. We propose the Enhanced Biomimetic Hippopotamus Optimization (EBOHO) algorithm, which distills the river-dwelling hippo’s ecological wisdom into three synergistic strategies: a beta-function herd seeding that replicates the genetic diversity of juvenile hippos diffusing through wetlands, an elite–mean cooperative foraging rule that echoes the way dominant bulls steer the herd toward nutrient-rich pastures, and a lens imaging opposition maneuver inspired by moonlit water reflections that spawn mirror candidates to avert premature convergence. Benchmarks on the CEC 2017 suite and four classical design problems show EBOHO’s superior global search, robustness, and convergence speed over numerous state-of-the-art meta-heuristics, including prior hippo variants. An industrial case study on grounding grid corrosion further confirms that EBOHO swiftly resolves the under-determined equations and pinpoints corrosion sites with high precision, underscoring its promise as a nature-inspired diagnostic engine for aging power system infrastructure. Full article

This work presents a multiscale, microstructure-aware framework for predicting fatigue strength distributions in additively manufactured (AM) alloys—specifically, laser powder bed fusion (L-PBF) AlSi10Mg and Ti-6Al-4V—by integrating density functional theory (DFT), instrumented indentation, and Bayesian inference. The methodology leverages principles common to all 3D printing (additive manufacturing) processes: layer-wise material deposition, process-induced defect formation (such as porosity and residual stress), and microstructural tailoring through parameter control, which collectively differentiate AM from conventional manufacturing. By linking DFT-derived cohesive energies with indentation-based modulus measurements and a MAP-based statistical model, we quantify the effect of additive-manufactured microstructural heterogeneity on fatigue performance. Quantitative validation demonstrates that the predicted fatigue strength distributions agree with experimental high-cycle and very-high-cycle fatigue (HCF/VHCF) data, with posterior modes and 95 % credible intervals of ${\widehat{\sigma }}_f^{\mathrm{AlSi}10\mathrm{Mg}}={86}_{-7}^{+8}\mathrm{MPa}$ and ${\widehat{\sigma }}_f^{\mathrm{Ti}–6\mathrm{Al}–4\mathrm{V}}={115}_{-9}^{+10}\mathrm{MPa}$, respectively. The resulting Woehler (S–N) curves and Paris crack-growth parameters envelop more than 92 % of the measured coupon data, confirming both accuracy and robustness. Furthermore, global sensitivity analysis reveals that volumetric porosity and residual stress account for over 70 % of the fatigue strength variance, highlighting the central role of process–structure relationships unique to AM. The presented framework thus provides a predictive, physically interpretable, and data-efficient pathway for microstructure-informed fatigue design in additively manufactured metals, and is readily extensible to other AM alloys and process variants. Full article

Hyperekplexia (OMIM 149400), a sensorimotor syndrome of perinatal clinical relevance, causes newborns to display an energic startle reflex in response to certain trivial stimuli. This condition can be lethal due to apnea episodes. The disease is caused by a blockade of glycinergic neurotransmission. Glycinergic interneurons preserve their identity by the activity of the surface glycine transporter GlyT2, which supplies glycine to presynaptic terminals to maintain glycine content in synaptic vesicles. Loss-of-function mutations in the GlyT2 gene (SLC6A5) cause a presynaptic form of human hyperekplexia. Here, we describe a new GlyT2 variant found in an infantile patient diagnosed with hyperekplexia. A missense mutation in the open reading frame of the GlyT2 gene inherited in homozygosity caused the substitution G449E in a residue highly conserved across the phylogenetic scale. The sequences of the glycine receptor genes GLRA1 and GLRB did not show abnormalities. We expressed the recombinant GlyT2 variant in heterologous cells and analyzed its pathogenic mechanism. The transporter was totally inactive, behaving as a bona fide loss-of-function mutant. Furthermore, the mutation promoted the abnormal insertion of the protein into the membrane, leading to its large incorporation into lipid rafts. However, there was no apparent alteration of wild-type trafficking upon mutant coexpression, as the mutant was prematurely degraded from the endoplasmic reticulum. Rescue with chemical chaperones was not possible for this mutant. Proteomics demonstrated that the expression of the mutant induced the unfolded protein response and interfered with raft-dependent processes. Therefore, the new variant causes a loss of function regarding GlyT2 activity but a gain of function as a cell proteostasis disturber. Full article

The research on the effect of feed with probiotic additives on the growth and functional state of young steelhead salmon (Salmo gairdneri) is presented in this study. For the first time, target strains selected not only by antagonism to pathogens but also by their ability to produce lytic enzymes or secondary metabolites with antioxidant activity were used to create probiotic preparations for aquaculture. This study presents findings showing that groups of fish fed probiotic feeds showed an improved growth performance and higher survival rate compared to the control. It was noted that the weights of fish in the first variant and the second variant of the experiment were higher by 8.8% and 6.8%, respectively. This research showed that juvenile steelhead salmon reared with probiotic-supplemented feeds had an improved ability to survive in high salinity and sublethal temperatures. This indicates that probiotics may play a significant role in enhancing the adaptive system of fish. Full article

Vitamin D plays a crucial role in bone health and immune function, with serum 25(OH)D levels influenced by genetic, dietary, and metabolic factors. Background/Objectives: This study investigated the impact of VDR rs731236, CYP2R1 rs10741657, and GC rs2282679 polymorphisms, body mass index (BMI), and dietary vitamin D intake on vitamin D status. Methods: A total of 230 adults were classified into four BMI categories: normal weight (NW), overweight (OW), obesity class I (OB), and obesity class II/III (OP). Participants completed a Food Frequency Questionnaire (FFQ) and a 7-day Food Frequency Diary (FFD). Genotyping was performed using TaqMan assays, and serum 25(OH)D was quantified via spectrophotometry. Statistical analyses included ANOVA and multiple linear regression. Results: The VDR rs731236 CC genotype, CYP2R1 rs10741657 AG/GG, and GC rs2282679 AC/CC were associated with lower serum vitamin D levels. A higher BMI was significantly correlated with reduced serum 25(OH)D (p < 0.001), with BMI emerging as the strongest predictor of vitamin D status. FFQ-based dietary intake showed a modest positive correlation with 25(OH)D (r = 0.47, p < 0.001). Conclusions: BMI and genetic variants in VDR, CYP2R1, and GC significantly influence vitamin D metabolism. Personalized interventions addressing genetic predispositions and weight management may improve vitamin D status. Full article

Fanconi anemia (FA) is a DNA repair deficiency disorder associated with genomic and chromosomal instability and a high cancer risk. In a small percentage of cases, FA is caused by biallelic pathogenic variants (PVs) in the BRCA2/FANCD1 gene, defining the FA-D1 subtype. Experimental and epidemiologic data indicate that the complete absence of BRCA2 is incompatible with viability. Therefore, cells from individuals affected with FA caused by biallelic BRCA2 PVs must have a residual BRCA2 function. This activity may be maintained through hypomorphic missense mutations, translation termination–reinitiation associated with a translational stop mutation, or other non-canonical or uncommon translation initiation and elongation events. In some cases, however, residual BRCA2 function is provided by alternatively or aberrantly spliced BRCA2 transcripts. Here, we review and debate aspects of the contribution of splicing in the 5′ segment to BRCA2 functions in the context of PVs affecting this largely intrinsically disordered protein region, with a focus on recent findings in individuals with FA-D1. In this Perspective, we also discuss some of the broader biological implications and open questions that arise from considering 5′-terminal BRCA2 splicing in light of old and new findings from FA-D1 patients and beyond. Full article

Insulin-degrading enzyme (IDE) plays a critical role in regulating insulin levels in various tissues, including the brain, liver, and kidneys. In type 2 diabetes mellitus (T2DM), key features include insulin resistance, elevated insulin levels in the blood, and hyperglycemia. In this context, the function of IDE becomes particularly important; however, in T2DM, IDE’s function can be impaired. Notably, individuals with T2DM have a higher risk of developing Alzheimer’s disease (AD), suggesting that impaired IDE function may contribute to both diabetes and neurodegeneration. IDE has been studied for its ability to degrade Amyloid-β peptides, the primary constituents of amyloid plaques in AD. However, its role in Aβ clearance in vivo remains debated due to limited enzymatic efficacy under physiological conditions and differences in subcellular localization between IDE and its putative substrate. Other proteases, such as neprilysin, appear to play a more prominent role in preventing plaque formation. Additionally, the long-standing hypothesis that insulin competes with Aβ for IDE activity has been questioned, as brain insulin levels are too low to inhibit Aβ degradation significantly. Genetic variants in the IDE gene have been associated with increased AD risk, although the mechanisms by which they alter enzyme function are not yet fully understood. A deeper understanding of IDE’s role in the context of both metabolic and neurodegenerative diseases may provide valuable insights for the development of new therapeutic strategies. Full article

Rapeseed meal, a byproduct of oil extraction, is increasingly recognised as a valuable source of plant protein and health-promoting peptides. This study aimed to identify key proteins in cold-pressed rapeseed meal and assess their potential to release bioactive peptides through in silico hydrolysis using plant-derived proteases, namely papain, bromelain, and ficin. Proteomic profiling via two-dimensional electrophoresis and MALDI-TOF/TOF mass spectrometry revealed cruciferin as the dominant protein, along with other metabolic and defence-related proteins. In silico digestion of these sequences using the BIOPEP database generated thousands of peptide fragments, of which over 50% were predicted to exhibit bioactivities, including ACE and DPP-IV inhibition, as well as antioxidant, neuroprotective, and anticancer effects. Among the evaluated enzymes, bromelain exhibited the highest efficacy, yielding the greatest quantity and diversity of bioactive peptides. Notably, peptides with antihypertensive and antidiabetic properties were consistently identified across all of the protein and enzyme variants. Although certain rare functions, such as anticancer and antibacterial activities, were observed only in specific hydrolysates, their presence underscores the broader functional potential of peptides derived from rapeseed. These findings highlight the potential of rapeseed meal as a sustainable source of functional ingredients while emphasising the necessity for experimental validation to confirm the predicted bioactivities. Full article

Minimizing energy consumption remains a critical challenge in wireless sensor networks (WSNs) because of their reliance on nonrechargeable batteries. Clustering-based hierarchical communication has been widely adopted to address this issue by improving residual energy and balancing the network load. In this architecture, cluster heads (CHs) are responsible for data collection, aggregation, and forwarding, making their optimal selection essential for prolonging network lifetime. The effectiveness of CH selection is highly dependent on the choice of metaheuristic optimization method and the design of the fitness function. Although numerous studies have applied metaheuristic algorithms with suitably designed fitness functions to tackle the CH selection problem, many existing approaches fail to fully capture both the spatial distribution of nodes and dynamic energy conditions. To address these limitations, we propose the binary secretary bird optimization clustering (BSBOC) method. BSBOC introduces a binary variant of the secretary bird optimization algorithm (SBOA) to handle the discrete nature of CH selection. Additionally, it defines a novel multiobjective fitness function that, for the first time, considers the Voronoi diagram of CHs as an optimization objective, besides other well-known objectives. BSBOC was thoroughly assessed via comprehensive simulation experiments, benchmarked against two advanced methods (MOBGWO and WAOA), under both homogeneous and heterogeneous network models across two deployment scenarios. Findings from these simulations demonstrated that BSBOC notably decreased energy usage and prolonged network lifetime, highlighting its effectiveness as a reliable method for energy-aware clustering in WSNs. Full article

Background: Lynch syndrome (LS) is an autosomal dominant disease caused by germline pathogenic variants in one of the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene. LS patients harboring genetic variants in one of the MMR genes display a heterogeneous phenotype in terms of cancer penetrance (lifetime cancer risk) and expressivity (malignancies in gastrointestinal or other specific organs). Methods: DNA samples from the index cases of Family 1 and Family 2 were analyzed using a next-generation sequencing (NGS) multigene panel comprising 25 genes involved in major hereditary cancer predisposition syndromes. This NGS analysis revealed a variant of uncertain significance (VUS) in the PMS2 gene (NM_000535.7: c.184G>A; p.Gly62Arg) of both index cases, which was validated by Sanger sequencing. The structural and functional impact of this VUS was evaluated in silico using twelve different prediction tools and by immunohistochemical analysis of MMR proteins. Results: Based on the personal and family history of the two families, tumor pathology, and protein in silico analysis, the novel PMS2 gene variant described in this study may be associated with hereditary LS. Considering the low penetrance of PMS2 gene variants in LS-associated tumors and the intrafamilial variability of the associated clinical phenotypes, the multidisciplinary approach proposed in this study could significantly support the evaluation of suspected LS cases carrying PMS2 variants. Full article

This theoretical research study proposes a novel hybrid algorithm that integrates an improved quasi-dynamical oppositional learning mutation scheme into the Mountain Gazelle Optimization method, augmented with chaotic sequences, for the thermal and economical design of a shell-and-tube heat exchanger operating with nanofluids. The Mountain Gazelle Optimizer is a recently developed metaheuristic algorithm that simulates the foraging behaviors of Mountain Gazelles. However, it suffers from premature convergence due to an imbalance between its exploration and exploitation mechanisms. A two-step improvement procedure is implemented to enhance the overall search efficiency of the original algorithm. The first step concerns substituting uniformly random numbers with chaotic numbers to refine the solution quality to better standards. The second step is to develop a novel manipulation equation that integrates different variants of quasi-dynamic oppositional learning search schemes, guided by a novel intelligently devised adaptive switch mechanism. The efficiency of the proposed algorithm is evaluated using the challenging benchmark functions from various CEC competitions. Finally, the thermo-economic design of a shell-and-tube heat exchanger operated with different nanoparticles is solved by the proposed improved metaheuristic algorithm to obtain the optimal design configuration. The predictive results indicate that using water + SiO₂ instead of ordinary water as the refrigerant on the tube side of the heat exchanger reduces the total cost by 16.3%, offering the most cost-effective design among the configurations compared. These findings align with the demonstration of how biologically inspired metaheuristic algorithms can be successfully applied to engineering design. Full article

Background/Objectives: To investigate associations between Follistatin (FST) gene polymorphisms (SNPs) and baseline musculoskeletal traits, and their interactions with 16-week exercise interventions. Methods: A cohort of 470 untrained Northern Han Chinese adults (208 males, 262 females), sourced from the “Research on Key Technologies for an Exercise and Fitness Expert Guidance System” project, was analyzed. These participants were previously randomly assigned to one of four exercise groups (Hill, Running, Cycling, Combined) or a non-exercising Control group, and completed their respective 16-week protocols. Body composition, bone mineral content (BMC), bone mineral density (BMD), and serum follistatin levels were all assessed pre- and post-intervention. Dual-energy X-ray absorptiometry (DXA) was utilized for the body composition, BMC, and BMD measurements. FST SNPs (rs3797296, rs3797297) were genotyped using matrix assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF MS) or microarrays. To elucidate the biological mechanisms, we performed in silico functional analyses for rs3797296 and rs3797297. Results: Baseline: In females only, the rs3797297 T allele was associated with higher muscle mass (β = 1.159, 95% confidence interval (CI): 0.202–2.116, P_{_adj} = 0.034) and BMC (β = 0.127, 95% CI: 0.039–0.215, P_{_adj} = 0.009), with the BMC effect significantly mediated by muscle mass. Exercise Response: Interventions improved body composition, particularly in females. Gene-Exercise Interaction: A significant interaction occurred exclusively in women undertaking hill climbing: the rs3797296 G allele was associated with attenuated muscle mass gains (β = −1.126 kg, 95% CI: −1.767 to −0.485, P_{_adj} = 0.034). Baseline follistatin correlated with body composition (stronger in males) and increased post-exercise (primarily in males, Hill/Running groups) but did not mediate SNP effects on exercise adaptation. Functional annotation revealed that rs3797297 is a likely causal variant, acting as a skeletal muscle eQTL for the mitochondrial gene NDUFS4, suggesting a mechanism involving muscle bioenergetics. Conclusions: Findings indicate that FST polymorphisms associate with musculoskeletal traits in Northern Han Chinese. Mechanistic insights from functional annotation reveal potential pathways for these associations, highlighting the potential utility of these genetic markers for optimizing training program design. Full article

Anticoagulants, including warfarin, are often administered to patients who are exhibiting early symptoms of thromboembolic episodes or who have already experienced such episodes. However, warfarin has a limited therapeutic index and might cause bleeding and other clinical problems. Warfarin inhibits the vitamin K epoxide reductase complex subunit 1 (VKORC1), an enzyme essential for activating vitamin K, in the coagulation cascade. Genetic factors, such as polymorphisms, can change the natural function of VKORC1, causing variations in the medication reaction among individuals. Hence, before prescribing warfarin, the patient’s genetic profile should also be considered. In this study, an electrochemical genosensor capable of detecting the VKORC1 1639 G>A polymorphism was designed and optimized. This analytical approach detects the electric current obtained during the hybridization reaction between two 52 base pair complementary oligonucleotide sequences. Investigating public bioinformatic platforms, two DNA sequences with the A and G single-nucleotide variants were selected and designed. The experimental protocol of the genosensor implied the formation of a bilayer composed of a thiolate DNA and an alkanethiol immobilized onto gold electrodes, as well as the formation of a DNA duplex using a sandwich-format hybridization reaction through a fluorescein labelled DNA signalling probe and the enzymatic amplification of the electrochemical signal, detected by chronoamperometry. A detection limit of 20 pM and a linear range of 0.05–1.00 nM was obtained. A clear differentiation between A/A, G/A and G/G genotypes in biological samples was successfully identified by his novel device. Full article