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Purpose: To investigate the causality between periodontitis and non-alcoholic fatty liver disease (NAFLD) using a two-sample bidirectional Mendelian randomisation (MR) analysis. Materials and Methods: Genetic variations in periodontitis and NAFLD were acquired from genome-wide association studies (GWAS) using the Gene-Lifestyle Interaction in Dental Endpoints, a large-scale meta-analysis, and FinnGen consortia. Data from the first two databases were used to explore the causal relationship between periodontitis and NAFLD (“discovery stage”), and the data from FinnGen was used to validate our results (“validation stage”). We initially performed MR analysis using 5 single nucleotide polymorphisms (SNPs) in the discovery samples and 18 in the replicate samples as genetic instruments for periodontitis to investigate the causative impact of periodontitis on NAFLD. We then conducted a reverse MR analysis using 6 SNPs in the discovery samples and 4 in the replicate samples as genetic instruments for NAFLD to assess the causative impact of NAFLD on periodontitis. We further implemented heterogeneity and sensitivity analyses to assess the reliability of the MR results. Results: Periodontitis was not causally related to NAFLD (odds ratio [OR] = 1.036, 95% CI: 0.914–1.175, p = 0.578 in the discovery stage; OR = 1.070, 95% CI: 0.935–1.224, p = 0.327 in the validation stage), and NAFLD was not causally linked with periodontitis (OR = 1.059, 95% CI: 0.916–1.225, p = 0.439 in the discovery stage; OR = 0.993, 95% CI: 0.896–1.102, p = 0.901 in the validation stage). No heterogeneity was observed among the selected SNPs. Sensitivity analyses demonstrated the absence of pleiotropy and the reliability of our MR results. Conclusion: The present MR analysis showed no genetic evidence for a cause-and-effect relationship between periodontitis and NAFLD. Periodontitis may not directly influence the development of NAFLD and vice versa. [ABSTRACT FROM AUTHOR]

[This corrects the article DOI: 10.3389/fmicb.2023.1154664.].

Atrial fibrillation (AF), the most common arrhythmia, has been associated with different electrophysiological, molecular, and structural alterations in atrial cardiomyocytes. Therefore, more studies are required to elucidate the genetic and molecular basis of AF. Various genome-wide association studies (GWAS) have strongly associated different single nucleotide polymorphisms (SNPs) with AF. One of these GWAS identified the rs13376333 risk SNP as the most significant one from the 1q21 chromosomal region. The rs13376333 risk SNP is intronic to the KCNN3 gene that encodes for small conductance calcium-activated potassium channels type 3 (SK3). However, the functional electrophysiological effects of this variant are not known. SK channels represent a unique family of K+ channels, primarily regulated by cytosolic Ca2+ concentration, and different studies support their critical role in the regulation of atrial excitability and consequently in the development of arrhythmias like AF. Since different studies have shown that both upregulation and downregulation of SK3 channels can lead to arrhythmias by different mechanisms, an important goal is to elucidate whether the rs13376333 risk SNP is a gain-of-function (GoF) or a loss-of-function (LoF) variant. A better understanding of the functional consequences associated with these SNPs could influence clinical practice guidelines by improving genotype-based risk stratification and personalized treatment. Although research using native human atrial cardiomyocytes and animal models has provided useful insights, each model has its limitations. Therefore, there is a critical need to develop a human-derived model that represents human physiology more accurately than existing animal models. In this context, research with human induced pluripotent stem cells (hiPSC) and subsequent generation of cardiomyocytes derived from hiPSC (hiPSC-CMs) has revealed the underlying causes of various cardiovascular diseases and identified treatment opportunities that were not possible using in vitro or in vivo studies with animal models. Thus, the ability to generate atrial cardiomyocytes and atrial tissue derived from hiPSCs from human/patients with specific genetic diseases, incorporating novel genetic editing tools to generate isogenic controls and organelle-specific reporters, and 3D bioprinting of atrial tissue could be essential to study AF pathophysiological mechanisms. In this review, we will first give an overview of SK-channel function, its role in atrial fibrillation and outline pathophysiological mechanisms of KCNN3 risk SNPs. We will then highlight the advantages of using the hiPSC-CM model to investigate SNPs associated with AF, while addressing limitations and best practices for rigorous hiPSC studies.

Background: The health effects of alcohol consumption, particularly regarding potential protective benefits of light to moderate intake compared to abstinence, remain a subject of ongoing debate. However, epidemiological studies face limitations due to imprecise exposure measurements and the potential for bias through residual confounding and reverse causation. To address these limitations, we conducted a systematic review of Mendelian Randomization (MR) studies examining the causal relationship between alcohol consumption and cancers, cardiovascular, liver, and neurological diseases. Methodology: We searched PubMed, ScienceDirect and Embase and Europe PMC up to 05/2024 for MR studies investigating the association of genetically predicted alcohol consumption with cancers, cardiovascular, liver and neurological diseases. We assessed methodological quality based on key elements of the MR design a genetic association studies tool. Results: We included 70 MR studies that matched our inclusion criteria. Our review showed a significant association of alcohol consumption with multiple cancers such as oral and oropharyngeal, esophageal, colorectal cancers, hepatocellular carcinoma and cutaneous melanoma. While the available studies did not consistently confirm the adverse or protective effects of alcohol on other cancers, such as lung cancer, as suggested by observational studies. Additionally, MR studies confirmed a likely causal effect of alcohol on the risk of hypertension, atrial fibrillation, myocardial infraction and vessels disease. However, there was no evidence to support the protective effects of light to moderate alcohol consumption on cognitive function, Alzheimer's disease, and amyotrophic lateral sclerosis, as reported in observational studies while our review revealed an increased risk of epilepsy and multiple sclerosis. The available studies provided limited results on the link between alcohol consumption and liver disease. Conclusions: Despite the valuable insights into the causal relationship between alcohol consumption and various health outcomes that MR studies provided, it is worth noting that the inconsistent ability of genetic instrumental variables to distinguish between abstainers, light and moderate drinkers makes it difficult to differentiate between U or J-shaped vs. linear relationships between exposure and outcome. Additional research is necessary to establish formal quality assessment tools for MR studies and to conduct more studies in diverse populations, including non-European ancestries. Systematic Review Registration: www.crd.york.ac.uk/prospero/display%5frecord.php?ID=CRD42021246154 , Identifier: PROSPERO (CRD42021246154). [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is a prevalent multifactorial arrhythmia associated with specific single-nucleotide polymorphisms (SNPs). Pulmonary vein (PV) isolation is an established treatment for AF; however, recurrence risk remains caused by AF triggers beyond the PVs. Understanding the embryological origins of these triggers could improve treatment outcomes. This study aimed to investigate the association between embryologically categorized AF triggers, clinical and genetic backgrounds, and postablation prognosis. In cohort 1, comprising 3,067 patients with AF undergoing PV isolation, the clinical characteristics and outcomes were analyzed. Among them, 815 patients underwent genetic analysis using AF-associated SNPs (cohort 2). Patients were delineated based on the developmental origin of the AF triggers: common PV, sinus venosus (SV), and primitive atrium (PA). SV-origin extra-PV AF triggers occurred in 20.3% (n = 622) of patients, whereas PA-origin triggers occurred in 11.9% (n = 365) of patients in cohort 1. Multivariate analysis of cohort 2 revealed that female sex, lower body mass index, absence of hypertension, rs2634073 near PITX2 , and rs6584555 in NEURL1 were associated with SV-AF, whereas nonparoxysmal AF and rs2634073 near PITX2 were predictors of PA-AF. The PA group had a significantly higher arrhythmia recurrence rate after repeated procedures than the common PV (HR: 1.75; 95% CI: 1.34-2.29; P < 0.001) and SV-AF (HR: 1.31; 95% CI: 1.19-1.45; P < 0.001) groups with more de novo AF triggers. However, the incidence of adverse events did not differ significantly among the 3 groups. SV-derived AF triggers may have hereditary factors with a favorable postablation prognosis, whereas PA-derived triggers are linked to AF persistence and poor ablation response. Variants near PITX2 may play a pivotal role in extra-PV triggers. [Display omitted] [ABSTRACT FROM AUTHOR]

Risk stratification in Brugada syndrome (BrS) is based on the occurrence of dynamic factors, such as unexplained syncope and documentation of spontaneous type 1 pattern. At odds with other channelopathies, the role of nonmodifiable risk factors such as sex or genetics remains uncertain. This study aims to identify nonmodifiable risk factors for the occurrence of life-threatening arrhythmic events (LAEs) and define their clinical utility. Clinical and genetic data from consecutive, unrelated Italian patients with Brugada syndrome screened on the sodium voltage-gated channel alpha subunit 5 (SCN5A) gene and 3 pivotal single-nucleotide variations (formerly single-nucleotide polymorphisms) associated with BrS (rs11708996, rs10428132, and rs9388451) were analyzed using multivariable Cox proportional hazards model. In 2,182 unrelated patients with BrS (81% males; median age at diagnosis: 41.6 years [Q1-Q3: 33.4-50.3 years]), male sex (HR: 3.6; 95% CI: 1.9-6.9; P = 0.0001), missense SCN5A mutations in BrS-enriched domains (HR: 2.3; 95% CI: 1.2-4.3; P = 0.008), nonmissense SCN5A mutations (HR: 3.2; 95% CI: 1.8-5.7; P < 0.001), and polygenic risk score for BrS (HR: 1.3; 95% CI: 1.0-1.6; P = 0.041) were all independently associated with a significantly higher risk of a first LAE since birth. Based on these results, we derived the nonmodifiable risk of each patient with BrS, and the division of nonmodifiable risk into tertiles identified 3 distinct risk profiles. In an analysis at follow-up, nonmodifiable risk was independently associated with LAE at follow-up (HR: 1.8; 95% CI: 1.1-2.7; P = 0.014), alongside classical predictors including: history of LAE before diagnosis (HR: 13.8; 95% CI: 8.1-23.7; P < 0.0001), history of unexplained syncope before diagnosis (HR: 4.1; 95% CI: 2.4-6.8; P < 0.0001), and spontaneous type 1 pattern at diagnosis (HR: 2.1; 95% CI: 1.2-3.8; P = 0.010). The model was internally validated, and we derived the equation permitting to calculate the granular 5-year risk of experiencing an LAE at follow-up for each patient with BrS, which may be used to facilitate clinical decision-making. Our data show that male sex, type of SCN5A mutation, and polygenic risk score for BrS define the nonmodifiable risk of each patient with BrS. Nonmodifiable risk is independently associated with LAE, regardless of symptoms or pattern type. [ABSTRACT FROM AUTHOR]

Introduction: Chronic obstructive pulmonary disease (COPD) is one of the world's major public health problems. It is characterized by a major inflammatory response, where vitamin D, due to its role in regulating the immune system, and genetic variants involved in its metabolism may play an essential role. The aim of this study is to evaluate the association between 13 polymorphisms related to vitamin D metabolism and the COPD risk. Material and methods: A retrospective longitudinal study was designed in which 152 cases of COPD diagnosed at the University Hospital Virgen de las Nieves and 456 controls without the pathology, matched by age and sex, were included. The determination of the 13 polymorphisms was carried out using TaqMan™ probes. Results: Statistical analysis showed that the AA genotype and the A allele of the CYP27B1 rs4646536 polymorphism may be associated with an increased risk of developing COPD according to genotypic models (OR = 2. 6; 95% CI = 1.38-5.22; p = 0.004), dominant (OR = 1.69; 95% CI = 1.15-2.5; p = 0.008), recessive (OR = 2.24; 95% CI = 1.22-4.41; p = 0.013) and additive (OR = 1.56; 95% CI = 1.18-2.08; p = 0.020) models. Likewise, the AA genotype and the A allele of the CYP2R1 rs10741657 polymorphism were also associated with the risk of developing COPD according to the genotypic (OR = 1.9; 95% CI = 1.06-3.36; p = 0.028) and additive (OR = 1.37; 95% CI = 1.04-1.81; p = 0.027) models. Likewise, an association was found between GATG (p = 0.002; OR = 2.05; 95%CI = 1.32-3.20) and AGGT (p < 0.0001; OR = 2.1e46; 95%CI = 2.1e46-2.1e46) haplotypes and an increased risk of COPD. Conclusions: We can therefore conclude that those variants could be used in the early detection of the disease in the future. [ABSTRACT FROM AUTHOR]

Background Objectives Materials and methods Results Discussion Conclusion It is not known whether bone marrow stem cells when injected intravenously for a bone marrow transplant colonize the human testicular epithelium. No previous studies of sperm genotype after bone marrow transplantation are reported.To differentiate host from donor genotype in spermatozoa of men who have undergone successful bone marrow transplants.Triplet DNA samples (spermatozoa, blood, and hair) obtained from men who had recovered sperm production after bone marrow transplant were genotyped using 44 autosomal and three sex‐related single nucleotide polymorphisms to determine the tissue genotype in pairwise comparisons of DNA profiles.Participants were 14 men at a median of 5.5 years after allogeneic bone marrow transplant who had a median sperm output of 77 million spermatozoa/ejaculate. In 14/14 the donor (leukocyte) DNA genotype differed significantly from the spermatozoa and hair genotypes whereas hair and sperm genotypes showed no variations.These data suggest that paternity after a successful bone marrow transplant is likely to be of the host and not the donor's genetic origins. The study's small sample size reflects the paucity of eligible man with recovered spermatogenesis after bone marrow transplant and represents preliminary evidence. A large‐scale epidemiological analysis to estimate the frequency of bone marrow donor stem cell colonization of the testicular germinal epithelium based on progeny sex ratio and frequency of female donors is proposed.Successful colonization of the testicular germinal and hair follicle epithelia by allogeneic bone marrow transplant donor stem cells is rare or does not occur. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusions This study investigates the gender‐specific genetic influence of the single nucleotide polymorphism (SNP) rs1111875 on diabetes risk within the Taiwanese population using data from the Taiwan Biobank. Diabetes mellitus, particularly type 2 diabetes (T2D), is influenced by genetic factors, and the rs1111875 SNP near the hematopoietically expressed homeobox (HHEX) gene has been linked to T2D susceptibility.The study included 69,272 participants after excluding those from arsenic‐polluted areas and those with incomplete data. Logistic regression models were used for analyses.The analyses revealed that the CT genotype of rs1111875 was associated with an increased risk of diabetes (OR = 1.092, 95% CI = 1.030–1.157, P = 0.003), as was the TT genotype (OR = 1.280, 95% CI = 1.165–1.407, P < 0.001). The effect was more pronounced in women (CT: OR = 1.118, 95% CI = 1.036–1.207, P = 0.004; TT: OR = 1.404, 95% CI = 1.243–1.585, P < 0.001). Men exhibited a higher overall risk of diabetes (OR = 1.565, 95% CI = 1.445–1.694, P < 0.001) and had a higher prevalence (12.71% vs 7.80%, P < 0.001) compared to women.The findings underscore the importance of considering gender differences in genetic studies of diabetes and suggest that personalized diabetes management strategies should account for both genetic and gender‐specific risk factors. This research contributes to the broader understanding of genetic determinants of diabetes and their interaction with gender, aiming to enhance personalized healthcare strategies for diabetes prevention and treatment. [ABSTRACT FROM AUTHOR]

Objective: Single nucleotide polymorphisms (SNPs) are linked to carcinogenesis. Pathogenic variants in the CDH1 gene are associated with gastric cancer. This study examines the genotype and allele frequencies of three SNPs (rs16260, rs13689, and rs9929218) in the CDH1 gene and their relationship with gastric cancer risk. Materials and methods: The study involved 105 gastric cancer patients with pathology results and 105 healthy controls. Clinical, histopathological, and demographic data were collected and compared between the two groups. Results: No significant differences were found for rs16260 (− 160 C > A) and rs9929218 (G > A) between patients and controls (p > 0.05). For rs13689 (T > C), the T allele frequency was 90% in patients versus 69% in controls, while the C allele frequency was 10% in patients versus 31% in controls. A significant difference was observed for this SNP, with a higher T allele frequency in patients (OR = 4.03 CI95% 2.4–6.7, p < 0.0001) compared with controls, suggesting a fourfold increased risk of gastric cancer. Genotype frequencies were 80% wild-type (TT) and 20% heterozygous-type (TC) in patients, and 58% TT, 22% TC, and 20% mutant-type (CC) in controls (p < 0.0001). The frequencies of non-C allele carriers (TT) were present in 80% of patients versus 58.1% of controls (OR = 2.88 CI95% 1.56–5.34, p = 0.0006). Conclusion: This study is the first to link the rs13689 SNP's T allele and TT genotype with increased gastric cancer risk. Our results suggest that the rs13689 T allele may contribute significantly to disease susceptibility, while the rs16260 CC genotype and rs9929218 GG genotype may influence risk in smokers. [ABSTRACT FROM AUTHOR]

Tyrosinase, a copper-containing oxidase, plays a vital role in the melanin biosynthesis pathway. Mutations in the tyrosinase gene can disrupt the hydroxylation of tyrosine, leading to decreased production of 3,4-dihydroxyphenylalanine (DOPA). Consequently, this impairs the subsequent formation of dopaquinone, a key precursor in melanin pigment synthesis. This study aimed to identify the deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) within the TYR gene that exert an influence on the human TYR protein. Additionally, we evaluated the impact of 10 FDA-approved drugs on the protein stability of mutated structures, exploring the potential for inhibitory pharmaceutical interventions. Through various bioinformatics tools, we detected 47900 nsSNPs, particularly K142M, I151N, M179R, S184L, L189P, and C321R, which were found to be the most deleterious variants, decreasing the protein stability. These drugs (Sapropterin, Azelaic Acid, Menobenzone, Levodopda, Mequinol, Arbutin, Hexylresorcinol, Artenimol, Alloin and Curcumin) interacted with the binding sites in four mutant models K142M, I151N, M179R, and S184L proving that these ligands directly bind with the active site of mutant tyrosinase protein to inhibit it's working. On the other hand, two mutant models L189P and C321R did not show any binding site residue interaction with any ligands. In conclusion, this in-silico analysis of deleterious nsSNPs in the TYR gene, coupled with the evaluation of ligands/drugs on mutated tyrosinase structures not only advances our understanding of molecular variations but also highlights promising pathways for targeted inhibitory interventions in the intricate network of melanin biosynthesis. [ABSTRACT FROM AUTHOR]

Background: Genetic diversity is crucial for conservation efforts as well as breeding programs targeted at the development of improved varieties. Taro, a climate-resilient crop, plays a vital role in the nutritional and economic livelihoods of many households in Nigeria, but its yield is very low due to inadequate genetic improvement efforts. A diversity assessment of Nigerian taro is therefore required to create a premise for its improvement in yield, quality and disease tolerance. In this study, the genetic diversity and population structure of 490 taro cultivars comprising two main gene pools: Dasheen (215) and Eddoe (275), collected from farmers and marketers across seven states in Nigeria was assessed using 3047 Diversity Array Technology single nucleotide polymorphism (DArT-SNP) markers. A subset of 114 taro cultivars, comprising 30 Dasheens and 84 Eddoes were further phenotyped using 24 agro-morphological descriptors. Results: Both phenotypic and molecular characterization revealed higher genetic diversity among the Eddoes than Dasheens. Estimates of gene flow (Nm = 0.353) revealed intermixing of cultivars among the States of collection, with the highest gene flow occurring between cultivars from Anambra and Ondo states and the lowest between Anambra and Kwara states. Population structure and Ward's minimum variance hierarchical cluster based on DArT-SNPs identified four groups, one comprising Dasheen and three comprising Eddoe cultivars. Hierarchical clustering based on phenotypic traits delineated three clusters. Variation between gene pools (49%) was higher than within gene pools (32%). Variation among States of collection was high (41%), while variation among individuals within gene pools (18%) and States of collection (19%) was relatively low. Correlation between phenotypic and genotypic diversity assessments was low (r = 0.01), indicating that both approaches were necessary for assessing genetic diversity in taro. However, genotypic assessment provided better information about genetic diversity of the taro cultivars. Conclusion: This is the first study that represented germplasm collection across the major taro growing regions of Nigeria. The findings from this study based on agro-morphological characterization and DArT-SNP genotyping are critical for genetic characterization, conservation and breeding of taro in Nigeria, mainly initiating hybridization between the two genepools after careful assessment of ploidy levels of the accessions collected in this study. This will facilitate in developing improved taro varieties with desirable traits, such as higher yield, better disease resistance, and improved nutritional quality. [ABSTRACT FROM AUTHOR]

Background and Objectives Methods Results Conclusions and Scientific Significance Both β‐arrestin2 and nicotinic acetylcholine receptor (nAChR) have been implicated in cognitive processes, particularly in relation to psychiatric disorders, including addiction. Previous studies have suggested that nAChR may be regulated by β‐arrestin2. However, no study has investigated the interaction of β‐arrestin2 and nAChR on cognition. We aimed to examine the main and interactive effects of their respective encoding genes, ARRB2 and CHRNA5, on cognitive function in MUD patients.We recruited 559 patients with methamphetamine use disorder (MUD) and 459 healthy controls, assessed their cognitive functioning using the Chinese version of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and genotyped ARRB2 rs1045280 and CHRNA5 rs3829787 polymorphisms in MUD patients.Compared to healthy controls, MUD patients scored significantly lower on all RBANS indexes. Neither ARRB2 rs1045280 nor CHRNA5 rs3829787 had main effects on cognitive function in MUD patients, but there were significant interactive effects between the two single nucleotide polymorphisms (SNPs) on multiple RBANS indexes, including immediate memory, visuospatial/constructional, delayed memory, and total score. In detail, among carriers of CHRNA5 rs3829787 T allele, ARRB2 rs1045280 TT carriers had higher RBANS scores than the C allele carriers, whereas among carriers of CHRNA5 rs3829787 CC genotype, ARRB2 rs1045280 TT carriers performed worse in RBANS.Our study identified for the first time an interactive effect between ARRB2 and CHRNA5 on cognitive function in MUD patients, which would enlarge our knowledge of genetic interaction on cognitive function. [ABSTRACT FROM AUTHOR]

BACKGROUND RESULTS CONCLUSION Recent shifts in consumer dietary preferences have led to a significant decline in rice consumption in Korea, resulting in surplus rice production. To address this issue, rice flour has been proposed as a substitute for wheat flour. However, the physical, chemical and structural differences between rice and wheat, particularly in grain hardness, pose challenges in using rice flour as an alternative. Understanding the genetic factors that influence rice grain hardness is crucial for improving the milling process and producing high‐quality rice flour suitable for wheat flour substitution.In this study, various grain traits, including length, width, thickness, length‐to‐width ratio and hardness, were measured in a population of brown and milled rice. Quantitative trait locus (QTL) analysis revealed a significant association between grain hardness and thickness, with QTLs for grain hardness mapped on chromosomes 1 and 12 for brown and milled rice, respectively. A total of 20 candidate genes related to grain hardness were identified through QTL analysis. Among them, OsFLOq12 (LOC_Os12g43550) was identified as a key gene influencing grain hardness, which encodes a Ras small GTPase. Phenotypic analysis showed differences in endosperm appearance and particle size between lines with low and high grain hardness.The genetic analysis of OsFLOq12 revealed a single nucleotide polymorphism associated with grain hardness. This study provides valuable insights into the genetic background of grain hardness, offering a foundation for breeding rice varieties optimized for flour production as a viable substitute for wheat flour. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethodsResultsConclusionClinical studies involving observation have uncovered a mutual relationship between allergic disorders and diabetes, yet the precise causal link remains undetermined.We conducted two-sample bidirectional Mendelian randomization analyses using single nucleotide polymorphisms (SNPs) associated with allergic conditions (asthma, allergic rhinitis, atopic dermatitis) from genome-wide studies and SNPs related to type 2 diabetes from FinnGen. Initially, we evaluated the causal link between allergic disorders and type 2 diabetes through a univariate Mendelian randomization study, incorporating inverse variance weighting, MR-Egger, and the weighted median estimator. To address potential confounding, we employed multivariate Mendelian randomization. Finally, we validated mediators influencing the correlation between asthma and type 2 diabetes.The Inverse variance weighte method showed that asthma genetically increased the risk of type 2 diabetes (Asthma- type 2 diabetes: β(95%CI)＝0.892(0.152～1.632), P = 0.018). Allergic rhinitis and type 2 diabetes exhibit a mutual protective effect: β(95% CI)＝-1.333(-2.617 to -0.049), P = 0.042；type 2 diabetes - Allergic rhinitis: β(95%CI)＝-0.002(-0.004 to -0.000), P = 0.018). The Multivariable Mendelian randomization study results showed that after after excluding confounding factors, asthma still demonstrates statistical significance in relation to type 2 diabetes. Through mediation analysis, it was discovered that lung function and the percentage of monocytes in leukocytes exert an inhibitory effect on the mediation between asthma and type 2 diabetes.The Multivariable Mendelian randomization study indicates asthma as a risk factor for type 2 diabetes.Lung function, and the percentage of monocytes in leukocytes, play an inhibitory role in asthma and type 2 diabetes mediating effects. [ABSTRACT FROM AUTHOR]

Although patterns of population genomic variation are well‐studied in animals, there remains room for studies that focus on non‐model taxa with unique biologies. Here we characterise and attempt to explain such patterns in mygalomorph spiders, which are generally sedentary, often occur as spatially clustered demes and show remarkable longevity. Genome‐wide single nucleotide polymorphism (SNP) data were collected for 500 individuals across a phylogenetically representative sample of taxa. We inferred genetic populations within focal taxa using a phylogenetically informed clustering approach, and characterised patterns of diversity and differentiation within‐ and among these genetic populations, respectively. Using phylogenetic comparative methods we asked whether geographical range sizes and ecomorphological variables (behavioural niche and body size) significantly explain patterns of diversity and differentiation. Specifically, we predicted higher genetic diversity in genetic populations with larger geographical ranges, and in small‐bodied taxa. We also predicted greater genetic differentiation in small‐bodied taxa, and in burrowing taxa. We recovered several significant predictors of genetic diversity, but not genetic differentiation. However, we found generally high differentiation across genetic populations for all focal taxa, and a consistent signal for isolation‐by‐distance irrespective of behavioural niche or body size. We hypothesise that high population genetic structuring, likely reflecting combined dispersal limitation and microhabitat specificity, is a shared trait for all mygalomorphs. Few studies have found ubiquitous genetic structuring for an entire ancient and species‐rich animal clade. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal symptoms are now detected early in the clinical course of many dementia patients, and studies of the microbiome-gut-brain axis have confirmed bidirectional interactions between the gut and the brain. However, the causal relationship between gut microbiota and cognitive impairment has not been fully established. Therefore, this study conducted a bidirectional Mendelian randomization study to elucidate the potential causal relationship of gut microbiota to cognitive impairment. Objective: Using Mendelian randomization to identify gut flora with a genetic causal effect on the development of cognitive impairment. Methods: This study utilized publicly available genome-wide association study summary data to perform MR analysis, with gut microbiota as the exposure and various cognitive function indicators as well as scores for Alzheimer's disease as outcomes. This study selected single nucleotide polymorphisms as instrumental variables based on p-values, F-statistics, and r2. Bidirectional Mendelian randomization was conducted using methods such as inverse variance weighted, MR-Egger, simple mode, and weighted mode to assess the causal relationship. Concurrently, this study carried out Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis to identify potential heterogeneity and horizontal pleiotropy. Results: This study identified a total of 31 gut microbes that have a causal relationship with cognitive impairment, which include 1 phylum, 4 classes, 3 orders, 2 families, and 21 genera. Conclusions: This study unveiled specific gut microbiota associated with cognitive impairment, offering new insights and approaches for the prevention and treatment of cognitive impairment through gut microbiota such as Bifidobacterium and Ruminococcus gnavus group. [ABSTRACT FROM AUTHOR]

Background: Genetic variations in a common single nucleotide polymorphism in the ninth intron of the KIBRA gene have been linked to memory performance and risk of Alzheimer's disease (AD). Objective: We examined the risk of AD related to presence of KIBRA T allele (versus CC homozygote) and to memory performance. The role of established genetic risk factors APOE ε4 and BDNF Met was also considered. Methods: Participants were cognitively healthy individuals (n = 19), participants with amnestic mild cognitive impairment (aMCI) due to AD (n = 99) and AD dementia (n = 37) from the Czech Brain Aging Study. Binary and multinomial logistic regressions compared odds of belonging to a certain diagnostic category and multivariate linear regressions assessed associations with memory. Results: KIBRA T allele was associated with increased AD dementia risk (odds ratio [OR] = 5.98, p = 0.012) compared to KIBRA CC genotype. In APOE ε4 negative individuals, KIBRA T allele was associated with a greater risk of both aMCI due to AD (OR = 6.68, p = 0.038) and AD dementia (OR = 15.75, p = 0.009). In BDNF Met positive individuals, the KIBRA T allele was associated with a greater risk of AD dementia (OR = 10.98, p = 0.050). In AD dementia, the association between KIBRA T allele and better memory performance approached significance (β = 0.42; p = 0.062). The link between possessing the KIBRA T allele and better memory reached statistical significance only among BDNF Met carriers (β = 1.21, p = 0.027). Conclusions: Findings suggest that KIBRA T allele may not fully protect against AD dementia but could potentially delay progression of post-diagnosis cognitive deficits. [ABSTRACT FROM AUTHOR]

Rs768705 (TMEM161B) is one of the identified single nucleotide polymorphisms related to major depressive disorder (MDD). Paranoid personality traits are independently associated with the risk of MDD. This study aimed to investigate the interaction effect between rs768705 (TMEM161B) and paranoid personality traits on the new-onset risk of MDD in Chinese freshmen. A longitudinal study was conducted among 7642 Chinese freshmen without lifetime MDD at baseline in 2018. 158 new-onset MDD cases were ascertained in 2019. DNA samples were extracted to detect the genotype of rs768705. The diagnostic and statistical manual of mental disorders-IV criteria were used to determine MDD and personality disorder traits. Multiplicative interaction was assessed by logistic regression models. Tomas Andersson's method for calculating biological interactions was used to estimate the additive interaction. Rs768705(AG) (OR = 1.88, 95 % CI: 1.24–2.83) and paranoid personality traits (OR = 3.68, 95 % CI: 2.57–5.26) were significantly associated with the risk of MDD. The multiplicative interaction model with the product term of rs768705 and paranoid personality trait traits had a significant interaction effect (OR = 4.20, 95 % CI:1.62–10.91). There was also a significant additive interaction effect (RR = 7.08, 95 % CI:4.31–11.65) for the incidence of MDD. Seventy seven percent patients among new MDD cases were attributed to the additive interaction effect between rs768705 and paranoid personality traits. Rs768705 (AG) may interact with paranoid personality traits to increase the incidence of MDD among Chinese college students. Schools and psychosocial health organizations should pay more attention to individuals with paranoid personality traits for MDD intervention and prevention. • This was a 1-year longitudinal study conducted among 7642 Chinese freshmen. • There was an addictive interaction effect between rs768705 (AG) and paranoid personality traits on occurrence of MDD. • 77% of new MDD patients were attributed to the interaction effect of rs768705 (AG) & paranoid personality traits. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a highly heritable brain dementia, along with substantial failure of cognitive function. Large-scale genome-wide association studies (GWASs) have led to a set of SNPs significantly associated with AD and related traits. GWAS hits usually emerge as clusters where a lead SNP with the highest significance is surrounded by other less significant neighboring SNPs. Although functionality is not guaranteed even with the strongest associations in GWASs, lead SNPs have historically been the focus of the field, with the remaining associations inferred to be redundant. Recent deep genome annotation tools enable the prediction of function from a segment of a DNA sequence with significantly improved precision, which allows in-silico mutagenesis to interrogate the functional effect of SNP alleles. In this project, we explored the impact of top AD GWAS hits around APOE region on chromatin functions and whether it will be altered by the genetic context (i.e., alleles of neighboring SNPs). Our results showed that highly correlated SNPs in the same LD block could have distinct impacts on downstream functions. Although some GWAS lead SNPs showed dominant functional effects regardless of the neighborhood SNP alleles, several other SNPs did exhibit enhanced loss or gain of function under certain genetic contexts, suggesting potential additional information hidden in the LD blocks. [ABSTRACT FROM AUTHOR]

Background: Ischemic stroke (IS) is a commonly seen cerebrovascular disease which seriously endangers the health of middle age and old people. However, its etiology and pathogenesis have not yet fully comprehended. miR-30 gene is a novel gene which may be involved in IS. However, no studies have investigated the relationship between IS and the single-nucleotide polymorphisms (SNPs) of miR-30. Therefore, this study examined the relationship between miR-30 polymorphisms (rs2222722, rs1192037, rs10095483 and rs16827546) and the risk of IS. Methods: Totally 248 IS patients and 230 age-, sex- and race-matched controls were involved in this study. Based on SNPscan technique, four polymorphisms (rs2222722, rs1192037, rs10095483 and rs16827546) were genotyped. Results: There exists a significant association between rs2222722 polymorphism and the risk of IS according to analyses of genotypes, models and alleles (GA vs. GG: adjusted OR = 1.616, 95% CI: 0.943–2.768, P = 0. 081); (AA vs. GG: adjusted OR = 2.447, 95% CI: 1.233–4.858, P = 0.011); dominant model: adjusted (OR = 1.806, 95% CI, 1.082–3.016, P = 0.024); (G vs. A: adjusted OR = 1.492, 95% CI: 1.148–1.939, P = 0.003). Besides, miR-30a expression was significantly higher in patients undergoing IS relative to that in controls (P < 0.05). Conclusions: To conclude, the rs2222722 polymorphism of the miR-30 gene shows a significant relationship to elevate the risk of IS in Chinese population. [ABSTRACT FROM AUTHOR]

The spinal muscular atrophy (SMA) phenotype strongly correlates with the SMN2 gene copy number. However, the severity and progression of the disease vary widely even among affected individuals with identical copy numbers. This study aimed to investigate the impact of genetic variability in oxidative stress, inflammatory, and neurodevelopmental pathways on SMA susceptibility and clinical progression. Genotyping for 31 genetic variants across 20 genes was conducted in 54 SMA patients and 163 healthy controls. Our results revealed associations between specific polymorphisms and SMA susceptibility, disease type, age at symptom onset, and motor and respiratory function. Notably, the TNF rs1800629 and BDNF rs6265 polymorphisms demonstrated a protective effect against SMA susceptibility, whereas the IL6 rs1800795 was associated with an increased risk. The polymorphisms CARD8 rs2043211 and BDNF rs6265 were associated with SMA type, while SOD2 rs4880, CAT rs1001179, and MIR146A rs2910164 were associated with age at onset of symptoms after adjustment for clinical parameters. In addition, GPX1 rs1050450 and HMOX1 rs2071747 were associated with motor function scores and lung function scores, while MIR146A rs2910164, NOTCH rs367398 SNPs, and GSTM1 deletion were associated with motor and upper limb function scores, and BDNF rs6265 was associated with lung function scores after adjustment. These findings emphasize the potential of genetic variability in oxidative stress, inflammatory processes, and neurodevelopmental pathways to elucidate the complex course of SMA. Further exploration of these pathways offers a promising avenue for developing personalized therapeutic strategies for SMA patients. [ABSTRACT FROM AUTHOR]

Reversing cancer cachexia remains a challenge. Genetic biomarkers for the early detection of the disease have been explored in order to enable the implementation of preventive measures. We therefore genotyped candidate genes based on cachexia phenotype and quantified adiponectin and GDF-15 levels in cachectic patients with gastrointestinal cancer. Patients with a diagnosis of gastrointestinal cancer were divided into a cachectic and a non-cachectic group after the start of chemotherapy. A control group (no cancer) was also included. We genotyped the following single nucleotide polymorphisms (SNPs) by quantitative PCR: FOXO3 (rs1935949), FOXO3 (rs4946935), ACVR2B (rs2268757), and SELP (rs6136). In addition, we quantified adiponectin and GDF-15 levels by ELISA. The rs2268757 SNP in the ACVR2B gene was associated with the weight loss phenotype in cachectic patients with gastrointestinal cancer (non-cachectic, P = 0.004). Plasma adiponectin levels were higher in cachectic patients compared to controls (P = 0.01) and non-cachectic patients (P = 0.004). GDF-15 was also elevated in cachectic patients compared to controls (P < 0.0001) and non-cachectic patients (P = 0.001). Analysis by sex showed elevated adiponectin levels in men (control, P = 0.01) and cachectic women (control, P = 0.04; non-cachectic, P = 0.01), as well as elevated GDF-15 levels in men (control, P = 0.002) and cachectic women (control, P = 0.002; non-cachectic, P = 0.007). However, there was no significant difference in the levels of these cytokines between cachectic men and women. The results suggest the rs2268757 SNP in the ACVR2B gene, adiponectin, and GDF-15 as potential biomarkers of cachexia in gastrointestinal cancer. [ABSTRACT FROM AUTHOR]

Potassium ion channels play a fundamental role in regulating cell membrane repolarization, modulating the frequency and shape of action potentials, and maintaining the resting membrane potential. A growing number of studies have indicated that dysfunction in potassium channels associates with the pathogenesis and treatment of depression. However, the involvement of potassium channels in the onset and treatment of depression has not been thoroughly summarized. In this review, we performed a comprehensive analysis of the association between multiple potassium channels and their roles in depression, and compiles the SNP loci of potassium channels associated with depression, as well as antidepressant drugs that target these channels. We discussed the pivotal role of potassium channels in the treatment of depression, provide valuable insights into new therapeutic targets for antidepressant treatment and critical clues to future drug discovery. [ABSTRACT FROM AUTHOR]

Background: Although caffeine (CAF) supplementation has been shown to improve exercise performance, its dose-dependent effect on CAF metabolism has not been sufficiently investigated. The aim of this study was to evaluate the effects of 3, 6 and 9 mg of CAF/kgBM on changes of CAF and paraxanthine (PRX) in the serum and saliva at four time-points. Methods: In a randomized, double-blind, placebo-controlled crossover design, acute pre-exercise supplementation in 26 moderately-trained athletes, participating in high-intensity functional training (HIFT), was examined. The study protocol involved CAF/PRX biochemical analyses of serum and saliva with respect to CYP1A2 polymorphism and CYP1A2 enzyme activity. Results: Despite significant differences between the serum and saliva levels of CAF and PRX, there was no difference in the PRX/CAF ratio. The interaction effect of dose and time-points for PRX concentration was revealed. The main effects of dose were observed for CAF and the PRX/CAF ratio. The main effect of time-points was registered only for serum CAF. Conclusions: Dose- and time-dependent effect of CAF supplementation on CAF and PRX in the serum and saliva of athletes was confirmed, but there was no effect of the CAF dose on CYP1A2 enzyme activity, nor was there an interaction of CYP1A2 with enzyme inducibility. The CAF/PRX correlation indicated the possibility of interchangeable use of serum and/or saliva analyses in exercise studies. Clinical trial registration: This trial was registered prospectively at ClinicalTrials.gov (NCT03822663, registration date: 30/01/2019). [ABSTRACT FROM AUTHOR]

Stripes and bands are common colour patterns in snakes. Some species are known to exhibit colour polymorphism and that includes expressing it in the bands and stripes. Bridal snake, Dryocalamus is a medium‐sized arboreal snake in South to Southeast Asia and most species of the genus are banded, but including two striped species. In Borneo, banded D. subannulatus and striped D. tristrigatus occur sympatrically and the two species are similar morphologically except for their colour patterns. We hypothesized the two species in Borneo exhibit a significant colour dimorphism of one species and conducted morphological and genetical analysis to test the hypothesis. Morphological examinations revealed that D. subannulatus and D. tristrigatus are not distinguishable in Borneo by scalation. Mitochondrial phylogenetic analysis and nuclear SNP analysis showed D. subannulatus and D. tristrigatus from Borneo formed clades or clusters by region not by species. Dryocalamus subannulatus and D. tristrigatus in Borneo are morphologically and genetically indistinguishable and Bornean D. subannulatus should be treated as a colour morph of D. tristrigatus. This is a rare example of sympatrically distinct banded/striped dimorphism in snakes. Relative abundance of banded/striped morph of the genus is probably different depending on region, and any ecological factor may contribute to it. [ABSTRACT FROM AUTHOR]

The Sardo Negro cattle (SN) is the only zebu cattle breed developed in Mexico. Since its development, the selection could have led to an increase in the homozygosity level in some regions of the genome and made differentiation with other cattle populations. We aimed to identify and characterize selection signatures in SN using medium-density SNP data using four approaches: 1) Runs of homozygosity (ROH) 2) Nucleotide Diversity 3) Tajima's D and 4) the Wright's fixation index (FST). A sample of 555 SN animals genotyped for 65k SNPs was used to obtain ROH segments considered regions under selection. The FST values were estimated by comparing the sample of genotyped SN animals with samples of genotyped animals from the Gir, Brahman, and Ongole breeds. Only one region mapped to 35.78–42.51 Mb on BTA6 was considered a selection signature by the ROH method. This selection signature overlapped with the lowest diversity, negative values of Tajima's D and a diversification region between SN and the other Zebu breeds by FST. We found several candidate genes (LCORL, NCAPG, and SLIT2) related to growth and other economically important productive traits in this common region. Using the FST method, different regions, such as regions on BTA8 (8:93.4–93.9 Mb), BTA11 (11:99.2–99.7), and BTA14 (14: 26.1–26.8) related to growth and milk traits also were defined as candidate selection signatures. The selective signals identified in this study reflected the direction of the selection pressure that primarily involves the increase of live weight traits in the Sardo Negro cattle breeding program. [ABSTRACT FROM AUTHOR]

Premise Methods Results Discussion Leveraging DNA markers, particularly single‐nucleotide polymorphisms (SNPs), in parentage analysis, sib‐ship reconstruction, and genomic relatedness analysis can enhance plant breeding efficiency. However, the limited availability of genomic information, confined to the most commonly used species, hinders the broader application of SNPs in species of lower economic interest (e.g., most tree species). We explored the possibility of using universal target capture probes, namely Angiosperms353, to identify SNPs and assess their effectiveness in genomic relatedness analysis.We tested the approach in 11 tree species, six of which had a half‐sib family structure. Variants were called within species, and genomic relatedness analysis was conducted in species with two or more families. Scalability via amplicon sequencing was tested by designing primers and testing them in silico.Adequate SNPs for relatedness analysis were identified in all species. Relatedness values from Angiosperms353‐based SNPs highly correlated with those from thousands of genome‐wide DArTseq SNPs in Cordia africana, one of the species with a family structure. The in silico performance of designed primers demonstrated the potential for scaling up via amplicon sequencing.Utilizing universal target capture probes for SNP identification can help overcome the limitations of genomic information availability, thereby enhancing the application of genomic markers in breeding plant species with lower economic interest. [ABSTRACT FROM AUTHOR]

Introduction: Powdery mildew (PM) poses an extreme threat to wheat yields and quality.[Methods] In this study, 262 recombinant inbred lines (RILs) of Doumai and Shi 4185 cross were used to map PM resistance genes across four environments. A high-density genetic linkage map of the Doumai/Shi 4185 RIL population was constructed using the wheat Illumina iSelect 90K single-nucleotide polymorphism (SNP) array. Results: In total, four stable quantitative trait loci (QTLs) for PM resistance, QPm.caas-2AS, QPm.caas-4AS, QPm.caas-4BL, and QPm.caas-6BS, were detected and explained 5.6%–15.6% of the phenotypic variances. Doumai contributed all the resistance alleles of QPm.caas-2AS, QPm.caas-4AS, QPm.ca as-4BL, and QPm.caas-6BS. Among these, QPm.caas-4AS and QPm.caas-6BS overlapped with the previously reported loci, whereas QPm.caas-2AS and QPm.caas-4BL are potentially novel. Additionally, six high-confidence genes encoding the NBS-LRR-like resistance protein, disease resistance protein family, and calcium/calmodulin-dependent serine/threonine-kinase were selected as the candidate genes for PM resistance. Three kompetitive allele-specific PCR (KASP) markers, Kasp_PMR_2AS for QPm.caas-2AS, Kasp_PMR_4BL for QPm.caas-4BL, and Kasp_PMR_6BS for QPm.caas-6BS, were developed, and their genetic effects were validated in a natural population including 100 cultivars. Discussion: These findings will offer valuable QTLs and available KASP markers to enhance wheat marker-assisted breeding for PM resistance. [ABSTRACT FROM AUTHOR]

Milk production traits play an important role in dairy cattle breeding, and single nucleotide polymorphisms can be used as effective molecular markers for milk production trait marker-assisted breeding in dairy cattle. Based on the results of the preliminary GWAS, candidate genes SPP1 and NCAPG associated with milk production traits were screened. In this study, the aim was to screen and characterize the SNPs of SPP1 and NCAPG genes about milk production traits. Two SNPs and one haplotype block of the SPP1 gene and four SNPs and one haplotype block of the NCAPG gene were obtained by amplification, sequencing and association analysis, and all six SNPs were located in the exon region. Association analysis showed that all six SNPs were significantly associated with milk protein percentage. Linkage disequilibrium analysis showed that 2 SNPs of SPP1 (g. 36,700,265 C > T and g. 36,693,596 C > A) constituted a haplotype that correlated with milk protein percentage, and the dominant haplotype was H2H2, which was CCTT. 4 SNPs of NCAPG (g. 37,342,705 C > A, g. 37,343,379 G > T, g. 37,374,314 C > A and g. 37,377,857 G > A) constituted a haplotype associated with milk protein percentage, 305-days milk protein yield and 305 days milk yield. Tissue expression profiling results revealed that SPP1 and NCAPG had the highest expression in mammary tissue. Interference with SPP1 and NCAPG inhibited the proliferation of Bovine mammary epithelial cells. (BMECs), down-regulated the expression of PCNA , CDK2 and CCND1 , up-regulated the expression of BAX and BAD , and promoted apoptosis. Reduced triglyceride synthesis in BMECs, down-regulated the expression of DGAT1 , DGAT2 , LPIN1 , and AGPAT6. SPP1 and NCAPG are involved in the synthesis of milk proteins, and interfering with SPP1 and NCAPG decreased the secretion of β -casein, κ -casein, and αs1-casein, as well as up-regulated the CSN2 and CSN3 expression. The above results indicate that the SNP loci of SPP1 and NCAPG can be used as potential molecular markers to improve milk production traits in dairy cows, laying the foundation for marker-assisted selection. It also proves that SPP1 and NCAPG can be used as candidate key genes for milk production traits in dairy cows, providing new insights into the physiological mechanisms of lactation regulation in dairy cows. [ABSTRACT FROM AUTHOR]

Introduction: Reproductive efficiency in dairy cattle bred by artificial insemination (AI) or via embryo transfer (ET) is important as a means of facilitating the rate of genetic improvement by utilizing superior genetics from sires and donor dams. Fertility is especially challenging in primiparous cows as they have recently calved, are still growing, and are lactating. Fertility, measured by the conception rate from the first service (CCR1), is the number of cows that become pregnant as a result of the first AI or ET compared to all cows serviced, whereas times bred (TBRD) is the number of inseminations cows bred by AI needed to achieve a successful pregnancy. Methods: This study aimed to identify the loci associated with and gene sets enriched for the CCR1 in primiparous cows that were bred by AI (n = 882) or were ET recipients (n = 353), and to identify the loci associated with the TBRD (n = 1,851) in primiparous cows. A genome-wide association analysis and gene set enrichment analysis were performed using single-nucleotide polymorphism (SNP) data for the CCR1 and TBRD in primiparous cows. In cows bred by AI, two loci containing five positional candidate genes were associated with the CCR1 (p < 1 × 10−5) and one gene set with 18 leading-edge genes was enriched (NES ≥3) for the CCR1. Results and discussion: In cows that were ET recipients, five loci were associated with the CCR1, but no gene sets were enriched for the CCR1. For the second phenotype, five loci with nine positional candidate genes were associated with the TBRD and two gene sets with eight leading-edge genes were enriched for the TBRD. Identifying the loci associated with or gene sets enriched for the CCR1 and TBRD provides an opportunity to better understand embryonic loss in AI-bred and ET-recipient cows and to use this information to select for higher reproductive efficiency. [ABSTRACT FROM AUTHOR]

Background: Numerous observational studies consistently highlight a strong association between serum uric acid (sUA) levels and atrial fibrillation (AF). However, the causal relationship and the direction of this association remain elusive, despite extensive research efforts. Objective: This study aimed to investigate the bidirectional causal relationships between sUA, gout, and the risk of AF using the two-sample Mendelian randomization (MR) approach. Methods: We conducted a comprehensive analysis utilizing publicly available genome-wide association studies (GWAS) summary statistics, employing stringent criteria to meticulously select genetic variants associated with sUA, gout, and AF. Our primary analytical approach was the inverse-variance weighted (IVW) method, complemented by some sensitivity analyses, including MR-Egger, weighted median, simple mode, and weighted mode, to estimate the causal effects. To identify potential violations, we conducted Egger regression and leave-one-SNP-out analyses. We assessed the strength of instrumental variables using F values to evaluate weak instruments. Additionally, we referenced the Phenoscanner database to exclude single nucleotide polymorphisms (SNPs) associated with confounding factors or outcomes. Results: Our forward Mendelian randomization analysis suggests that there is no causal relationship between UA levels/gout from different populations and the risk of AF [IVW OR 1.03, 95% CI: 0.97–1.08; p = 0.335; IVW OR 0.99, 95% CI: 0.97–1.02; p = 0.583; and IVW OR 1.07, 95% CI: 0.84–1.37; p = 0.575], respectively. We did not detect significant heterogeneity or potential pleiotropy, and we also excluded the possibility of weak instrumental variables. Furthermore, we did not find any reverse causal effects of AF on sUA levels and gout risk. Conclusion: Our findings challenge the widely held belief that lowering urate levels is uniformly effective in reducing the risk of atrial fibrillation (AF). Our study fails to substantiate the existence of a causal link between uric acid (UA) levels or gout and the development of AF, regardless of direction. [ABSTRACT FROM AUTHOR]

Background: Despite the growing number of studies investigating the connection between host genetics and the rumen microbiota, there remains a dearth of systematic research exploring the composition, function, and metabolic traits of highly heritable rumen microbiota influenced by host genetics. Furthermore, the impact of these highly heritable subsets on lactation performance in cows remains unknown. To address this gap, we collected and analyzed whole-genome resequencing data, rumen metagenomes, rumen metabolomes and short-chain fatty acids (SCFAs) content, and lactation performance phenotypes from a cohort of 304 dairy cows. Results: The results indicated that the proportions of highly heritable subsets (h2 ≥ 0.2) of the rumen microbial composition (55%), function (39% KEGG and 28% CAZy), and metabolites (18%) decreased sequentially. Moreover, the highly heritable microbes can increase energy-corrected milk (ECM) production by reducing the rumen acetate/propionate ratio, according to the structural equation model (SEM) analysis (CFI = 0.898). Furthermore, the highly heritable enzymes involved in the SCFA synthesis metabolic pathway can promote the synthesis of propionate and inhibit the acetate synthesis. Next, the same significant SNP variants were used to integrate information from genome-wide association studies (GWASs), microbiome-GWASs, metabolome-GWASs, and microbiome-wide association studies (mWASs). The identified single nucleotide polymorphisms (SNPs) of rs43470227 and rs43472732 on SLC30A9 (Zn2+ transport) (P < 0.05/nSNPs) can affect the abundance of rumen microbes such as Prevotella_sp., Prevotella_sp._E15-22, Prevotella_sp._E13-27, which have the oligosaccharide-degradation enzymes genes, including the GH10, GH13, GH43, GH95, and GH115 families. The identified SNPs of chr25:11,177 on 5s_rRNA (small ribosomal RNA) (P < 0.05/nSNPs) were linked to ECM, the abundance alteration of Pseudobutyrivibrio_sp. (a genus that was also showed to be linked to the ECM production via the mWASs analysis), GH24 (lysozyme), and 9,10,13-TriHOME (linoleic acid metabolism). Moreover, ECM, and the abundances of Pseudobutyrivibrio sp., GH24, and 9,10,13-TRIHOME were significantly greater in the GG genotype than in the AG genotype at chr25:11,177 (P < 0.05). By further the SEM analysis, GH24 was positively correlated with Pseudobutyrivibrio sp., which was positively correlated with 9,10,13-triHOME and subsequently positively correlated with ECM (CFI = 0.942). Conclusion: Our comprehensive study revealed the distinct heritability patterns of rumen microbial composition, function, and metabolism. Additionally, we shed light on the influence of host SNP variants on the rumen microbes with carbohydrate metabolism and their subsequent effects on lactation performance. Collectively, these findings offer compelling evidence for the host-microbe interactions, wherein cows actively modulate their rumen microbiota through SNP variants to regulate their own lactation performance. C1VA69ck9huqCRa2wNrTKW Video Abstract [ABSTRACT FROM AUTHOR]

The study published in the Blood Cancer Journal explores the relationship between genetically determined telomere length (gdLTL) and the risk of developing monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Using single nucleotide polymorphisms (SNPs) as proxies for measuring gdLTL, the study found that longer gdLTL was associated with an increased risk of developing MM. Additionally, the study observed a significant association between longer gdLTL and improved survival in MM patients. The findings suggest that gdLTL may serve as a marker for MM risk and potentially influence the development of pre-malignant conditions like MGUS. [Extracted from the article]

Genomic Selection (GS) in tree breeding optimizes genetic gains by leveraging genomic data to enable early selection of seedlings without phenotypic data reducing breeding cycle and increasing selection intensity. Traditional assessments of the potential of GS in forest trees have typically focused on model performance using cross-validation within the same generation but evaluating effectively realized predictive ability (RPA) across generations is crucial. This study estimated RPAs for volume growth (VOL), wood density (WD), and pulp yield (PY) across four generations breeding of Eucalyptus grandis. The training set spanned three generations, including 34,461 trees with three-year growth data, 6,014 trees with wood quality trait data, and 1,918 trees with 12,695 SNPs (single nucleotide polymorphisms) data. Employing single-step genomic BLUP, we compared the genomic predictions of breeding values (GEBVs) for 1,153 fourth-generation full-sib seedlings in the greenhouse with their later-collected phenotypic estimated breeding values (EBVs) at age three years. RPAs were estimated using three GS targets (individual trees, trees within families, and families), two selection criteria (single- and multiple-trait), and training populations of either all 1,918 genotyped trees or the 67 direct ancestors of the selection candidates. RPAs were higher for wood quality traits (0.33 to 0.59) compared to VOL (0.14 to 0.19) and improved for wood traits (0.42 to 0.75) but not for VOL when trained only with direct ancestors, highlighting the challenges in accurately predicting growth traits. GS was more effective at excluding bottom-ranked candidates than selecting top-ranked ones. The between-family GS approach outperformed individual-tree selection for VOL (0.11 to 0.16) and PY (0.72 to 0.75), but not for WD (0.43 vs. 0.42). Furthermore, higher levels of relatedness and lower genotype by environment (G × E) interaction between training and testing populations enhanced RPAs for VOL (0.39). In summary, despite limited effectiveness in ranking top VOL individuals, GS effectively identified low-performing individuals and families. These multi-generational findings underscore GS's potential in tree breeding, stressing the importance of considering relatedness and G × E interaction for optimal performance. [ABSTRACT FROM AUTHOR]

Pepper (Capsicum spp.) is one of the most important crops worldwide. Understanding the species' genetic background is key to preserve agrodiversity on-farm, to contribute to a more diverse and resilient agrifood sector, and to find new sources of variation that could be useful in future breeding programs. In this regard, varietal groups bred in insular environments have gained special interest as they have evolved quite isolated from continental forms, with a limited genetic exchange. The present work explores the diversity of a plethora of Balearic landraces, corresponding to different local varietal types, through phenotyping and genotyping-by-sequencing (GBS). Mallorca and Eivissa landraces were phenotyped according to a comprehensive list of descriptors for plant, leaf, flower, fruit, pollen, and seed and were genotyped with single nucleotide polymorphism (SNP) markers; population structure and their patterns of diversity were studied. The results showed a considerable morphological diversity for most traits analyzed, within and between landraces. On the whole, in regard to genetic patterns, relatively low levels of heterozygosity and moderate genetic diversity for the studied landraces were found although some of them exhibited diverse patterns. The materials were not grouped in specific clusters associated with each island, but mainly according to varietal types. These findings can serve as the basis for studying divergent evolutionary patterns associated with the corresponding populations. Finally, the results can contribute to further elucidation of the genetic basis of Balearic landraces and serve as an inspiring case of study for other insular endemisms of cultivated species. [ABSTRACT FROM AUTHOR]

Introduction: Human brucellosis is a severe public concern in Shaanxi Province, China, and investigating the epidemiological relationship and transmission pattern of B. melitensis is necessary to devise control strategies. Methods: In this study, a conventional bio-typing approach and whole genome sequencing of single-nucleotide polymorphisms (SNPs) were employed to identify 189 strains. Results: Based on the conventional bio-typing, 189 Brucella strains were identified as B. melitensis , of which 14 were in bv. 1, 145 were in bv. 3, and 30 were variant, and the Brucella strains were distributed in all ten cities in Shaanxi Province. SNP analysis was used to identify genetic variation in 189 B. melitensis genomes, and maximum-likelihood was used to generate a phylogeny that identified two clades (A and B) and 19 sequence types (STs). The two clades were highly diverse and exclusively of Eastern Mediterranean origin. Clade B contained 18 STs (2-19), with most isolates originating from a broad swath, implying that multiple B. melitensis lineages circulated in Shaanxi. The 19 STs were composed of 3 to 46 strains isolated from different counties and years, suggesting that multiple cross-county brucellosis outbreak events are driven by multiple B. melitensis lineages. Global phylogenetic analysis revealed that clade A was close to GTIIb, and clade B was placed in the GTIIh lineage, expanding the known diversity of B. melitensis from China. Conclusion: The human brucellosis epidemic in Shaanxi is driven by multiple indigenous circulating B. melitensis lineages, the knowledge of which will contribute to devising a control strategy and providing the foundation for a comprehensive regional phylogeny of this important zoonotic pathogen. [ABSTRACT FROM AUTHOR]

AbstractBeta-thalassemia is an inherited disorder prevalent in Thailand and Southeast Asia. Several molecular techniques for identifying β-thalassemia mutations have been reported. Next-generation sequencing (NGS) is a type of effective molecular testing with high throughput and accuracy. Hence, this study aims to evaluate a novel barcode-tagged NGS approach based on a short-read assay. A total of 258 samples with 54 different β-thalassemia genotypes related to 32 mutations were gathered and evaluated. A library was constructed with the BTSeqTM kit and sequencing was performed on the Illumina NGS machine. The validation results showed 98.45% concordance with conventional genotypes. Less discordant results (1.55%) were limited to insertional mutations and included one case of each of the following: HBB:c.27dupG, HBB:c.85dupC, HBB:c.216dupT, and HBB:c.440_441dupAC. Five single-nucleotide polymorphisms that derived from the NGS results were also analyzed in terms of allele frequency and revealed significant differences between the wild types and other β-genotypes. Furthermore, this paper is the first to describe rare single-nucleotide polymorphisms including IVS II-109 (C/T), IVS II-258 (G/A), IVS II-613 (T-C), and IVS II-806 (G/C). Interestingly, the C allele of IVS II-806 was found to have 100% linkage with two cases of Hb Tak. The haplotype and phylogenetic analysis was also constructed based on variants and revealed three clusters in the Hb variants, which represented their evolution and genetic background. Finally, NGS with the barcode-tagged method has a high throughput, which is suitable for large population screening. Its cost effectiveness and less complicated process promote its application in further works. [ABSTRACT FROM AUTHOR]

Background: Many clinical variables might impact the pharmacokinetics of calcineurin inhibitors (CIs). Different alleles of cytochromes P450 (CYP)3A4/5 and drug transporter P-glycoprotein are the main variables. Other variables include relocated type, treatment duration after transplantation, age, sex, dietary consumption, medications used and renal or hepatic impairment. Tacrolimus and cyclosporine are two main CIs extensively used in organ transplantation. Both drugs are metabolized by CYP3A4 and CYP3A5 isoforms, and single-nucleotide polymorphisms in these genes have been displayed to influence CIs pharmacokinetics. Another important gene is the pregnane X receptor (PXR), which manages the statement of a variety of genes including CYP3A4 genes. PXR has a clinical significance in CIs metabolism. The liver is the essential site for CIs metabolism. A decreased clearance with a prolonged CIs half-life was occurred in patients with impaired liver compared with patients with normal liver function. The presence of different genetic and clinical factors that may affect calcineurin inhibitors trough levels will consequently affect their immunosuppressant effect after liver transplantation. Purpose: This study aims to determine the effect of different genetic polymorphisms in CYP3A4 1B rs2740574 and PXR A7635G rs6785049 and other clinical factors that may affect calcineurin inhibitors pharmacokinetics after liver transplantation. Results: The presence of T allele in CYP3A4 gene was associated with elevated DATLs with P values of 0.00, 0.00, 0.007 and 0.00 after tacrolimus doses 4, 30, 60 and 90, respectively. Regarding PXR gene, the presence of G allele was associated with elevated DATLs in cyclosporine. About 432 correlations were tested in both drugs. In CYP3A4 genotype CC, male sex was associated with elevated DATLs interpreted by strong positive correlations and statistically significant difference in all DATLs, except DATL 60 (P value 0.374). No strong association was found between low hemoglobin levels and DATLs in almost all the follow-up periods. There were many positive relations between increased total and direct bilirubin and increased DATLs. Conclusions: Studying the various genetics and clinical factors that may affect calcineurin inhibitors serum concentrations is very essential for successful treatment plans after organ transplantation. These different factors may interact with each other and these complicated interactions may complicate the patient's conditions post-transplantation. Considering all these complicated interactions is very crucial in monitoring treatment plans, especially in the presence of other comorbidities or chronic diseases. More studies with large number of patients should be conducted to explore more consequences of these interacting variables of treatment plans of these patients and all studied parameters in this study should be considered while monitoring patients after transplantation. [ABSTRACT FROM AUTHOR]

Understanding the genetic diversity of crops is of fundamental importance for the efficient use and improvement of germplasm resources. Different molecular genotyping systems have been implemented for population structure and phylogenetic relationships analyses, among which, microsatellites (SSRs) and single nucleotide polymorphisms (SNPs) markers have been the most widely used. This study reports the efficacy of SNPs detected via double-digest restriction-site-associated DNA sequencing (ddRADseq) and SSRs analyzed via capillary electrophoresis (CE) and high-resolution melting (HRM) in tomato. In total, 21,020 high-quality SNPs, 20 CE-SSRs, and 17 HRM-SSR markers were assayed in a panel of 72 accessions that included a diversified set of landraces, long-shelf-life cultivars and heirlooms with different origins and fruit typology. The results showed how the population structure analysis was consistent using the three genotyping methods, although SNPs were more efficient in distinguishing cultivar types and in measuring the degree of accessions' similarity. Compared to CE-SSR, the analysis of microsatellites via HRM yielded a slightly higher number of alleles (98 vs. 96). HRM-SSR demonstrated a distinction between European and non-European germplasm, better resolving the collection's diversity and being more consistent with SNP data. Phylogenetic trees drawn with independent marker data, detected specific groups of accessions showing robust clusters, highlighting how heirlooms were less heterogeneous than landraces. In addition, the fixation index (FST) revealed a high genetic differentiation between heirlooms and long-shelf-life cultivars, with SNP and SSR-HRM data emphasizing the distinction between cherry and plum types and CE-SSR data between cherry and oxheart types. In all instances, a greater molecular variance was found within the different considered biological statuses, provenances, and typologies rather than among them. This work presents the first attempt to compare the three tomato genotyping techniques in tomato. Findings highlighted how the markers used are complementary for genetic diversity analysis, with SNPs providing better insight and HRM-SSR as a viable alternative to capillary electrophoresis to dissect the genetic structure. [ABSTRACT FROM AUTHOR]

Background: Interferon-induced helicase C domain-containing protein 1 (IFIH1) is one of the main pattern recognition receptors that sense viral RNA and activate host cells to mount an effective antiviral immunity. Methods: A case–control study (90 patients with mild/moderate COVID-19 and 90 matched controls) was performed to explore the association of two variants of the IFIH1 gene with COVID-19 risk using the tetra-primer amplification refractory mutation system-polymerase-chain-reaction method. The first is a missense variant, rs1990760 C/T, and the second is an intergenic variant, rs2111485 A/G. In addition, serum IFIH1 levels were assessed using an ELISA kit. Results: Mutant alleles (T and G, respectively) and corresponding homozygous genotypes (TT and GG, respectively) of both variants were significantly associated with increased risk of COVID-19. IFIH1 levels were significantly higher in patients compared to controls and were favorably affected by the rs1990760 and rs2111485 mutant-type genotypes. Conclusion: IFIH1 protein showed up-regulated levels in the serum of patients with mild/moderate COVID-19. In addition, the IFIH1 gene variants rs1990760 C/T and rs2111485 A/G were associated with susceptibility to COVID-19, and the study suggests that their mutant-type genotypes are not only associated with increased risk of COVID-19 but also contributed to higher serum IFIH1 levels. [ABSTRACT FROM AUTHOR]

Tuberculosis disease (TB), caused by Mycobacterium tuberculosis (Mtb), is a major global public health problem, resulting in > 1 million deaths each year. Drug resistance (DR), including the multi-drug form (MDR-TB), is challenging control of the disease. Whilst many DR mutations in the Mtb genome are known, analysis of large datasets generated using whole genome sequencing (WGS) platforms can reveal new variants through the assessment of genotype-phenotype associations. Here, we apply tree-based ensemble methods to a dataset comprised of 35,777 Mtb WGS and phenotypic drug-susceptibility test data across first- and second-line drugs. We compare model performance across models trained using mutations in drug-specific regions and genome-wide variants, and find high predictive ability for both first-line (area under ROC curve (AUC); range 88.3–96.5) and second-line (AUC range 84.1–95.4) drugs. To aggregate information from low-frequency variants, we pool mutations by functional impact and observe large improvements in predictive accuracy (e.g., sensitivity: pyrazinamide + 25%; ethionamide + 10%). We further characterise loss-of-function mutations observed in resistant phenotypes, uncovering putative markers of resistance (e.g., ndh 293dupG, Rv3861 78delC). Finally, we profile the distribution of known DR-associated single nucleotide polymorphisms across discretised minimum inhibitory concentration (MIC) data generated from phenotypic testing (n = 12,066), and identify mutations associated with highly resistant phenotypes (e.g., inhA − 779G > T and 62T > C). Overall, our work demonstrates that applying machine learning to large-scale WGS data is useful for providing insights into predicting Mtb binary drug resistance and MIC phenotypes, thereby potentially assisting diagnosis and treatment decision-making for infection control. [ABSTRACT FROM AUTHOR]

CRISPR/Cas12a is a highly promising detection tool. However, detecting single nucleotide variations (SNVs) remains challenging. Here, we elucidate Cas12a specificity through crRNA engineering and profiling of single- and double-base mismatch tolerance across three targets. Our findings indicate that Cas12a specificity depends on the number, type, location, and distance of mismatches within the R-loop. We also find that introducing a wobble base pair at position 14 of the R-loop does not affect the free energy change when the spacer length is truncated to 17 bp. Therefore, we develop a new universal specificity enhancement strategy via iterative crRNA design, involving truncated spacers and a wobble base pair at position 14 of the R-loop, which tremendously increases specificity without sacrificing sensitivity. Additionally, we construct a PAM-free one-pot detection platform for SARS-CoV-2 variants, which effectively distinguishes SNV targets across various GC contents. In summary, our work reveals new insights into the specificity mechanism of Cas12a and demonstrates significant potential for in vitro diagnostics. A new ultra-specific enhancement strategy for Cas12a via iterative crRNA design. A PAM-free one-pot detection platform for SARS-CoV-2 variants demonstrates significant potential for in vitro diagnostics. [ABSTRACT FROM AUTHOR]

Whole-genome sequencing studies of parent–offspring trios have provided valuable insights into the potential impact of de novo mutations (DNMs) on human health and disease. However, the molecular mechanisms that drive DNMs are unclear. Studies with multi-child families can provide important insight into the causes of inter-family variability in DNM rates but they are highly limited. We characterized 2479 de novo single nucleotide variants (SNVs) in 13 multi-child families of Mexican-American ethnicity. We observed a strong paternal age effect on validated de novo SNVs with extensive inter-family variability in the yearly rate of increase. Children of older fathers showed more C > T transitions at CpG sites than children from younger fathers. Validated SNVs were examined against one cancer (COSMIC) and two non-cancer (human germline and CRISPR-Cas 9 knockout of human DNA repair genes) mutational signature databases. These analyses suggest that inaccurate DNA mismatch repair during repair initiation and excision processes, along with DNA damage and replication errors, are major sources of human germline de novo SNVs. Our findings provide important information for understanding the potential sources of human germline de novo SNVs and the critical role of DNA mismatch repair in their genesis. Mutational signature analyses of de novo mutations in multi-child human families suggest that inaccurate DNA mismatch repair, DNA damage, and replication errors are major sources of age-related increases in germline mutations. [ABSTRACT FROM AUTHOR]

Objective: Analyze the ultrasound findings, single nucleotide polymorphism array (SNP-array) results, and pregnancy outcomes of fetuses with 7q11.23 deletions and duplications in the second and third trimesters. Investigate the prenatal ultrasound characteristics and follow up information of these fetuses. Methods: Seven fetuses were diagnosed with 7q11.23 deletion and six with 7q11.23 duplication via SNP-array at the prenatal diagnosis center of a single Chinese tertiary medical center from January 2017 to May 2024. Maternal demographics, ultrasound findings, SNP-array results, pregnancy outcomes, and follow-up information were comprehensively reviewed and analyzed. Results: The copy number variations (CNVs) ranged from 1.43 Mb to 1.78 Mb in cases of 7q11.23 deletions and from 1.42 Mb to 1.68 Mb in cases of 7q11.23 duplications. These CNVs encompassed 29 OMIM-listed genes, including ELN, DNAJC30, GTF2IRD1, and GTF2I. Among the seven cases of 7q11.23 deletion syndrome, six exhibited ultrasound abnormalities. The main clinical phenotypes included three cases of intrauterine growth restriction and four cases of cardiovascular system abnormalities, specifically two cases with ventricular septal defects, one case with aortic narrowing, and one case with supravalvular pulmonary stenosis. One case was particularly notable, exhibiting complex multi-organ structural malformations. Out of six cases of 7q11.23 duplication syndrome, five exhibited ultrasound abnormalities. These included two cases of cardiovascular abnormalities: one case with a widened left ventricle and another case with a shortened fetal humerus length. One case revealed complex multi-organ structural malformations, including hydronephrosis, a microgallbladder, and a cleft lip and palate. All seven cases of 7q11.23 deletions and three cases of 7q11.23 duplications opted for termination of the pregnancy. The remaining three cases of 7q11.23 duplications chose to continue the pregnancy. One case underwent surgical treatment for a ventricular septal defect after birth, and the prognosis was favorable. Another case involved a full-term delivery, this child was followed up at the age of 4 and exhibited a phenotype of poor language expression ability. Conclusion: Our study broadened the clinical phenotype spectrum of fetuses with 7q11.23 deletions and duplications. Additionally, it conducted a preliminary evaluation of prenatal ultrasound findings and postnatal clinical phenotypes in follow-up cases. The clinical phenotype of fetuses with 7q11.23 deletion and duplication syndromes involves multiple systems and is relatively complex. Cardiovascular abnormalities and intrauterine growth restriction are the most common clinical manifestations observed in prenatal 7q11.23 deletion syndrome. Fetuses with 7q11.23 duplications exhibit a wide range of clinical phenotypes that lack specificity. [ABSTRACT FROM AUTHOR]

Background: Xinglong buffalo, as an indigenous breed in Hainan province of China, possesses characteristics such as high humidity tolerance, disease resistance and high reproductive capacity. Combined with whole genome sequencing technology, comprehensive investigation can be undertaken to elucidate the genomic characteristics, functions and genetic variation of Xinglong buffalo population. Results: Xinglong buffalo has the highest genetic diversity, lowest runs of homozygosity average length, and fasted decay of linkage disequilibrium in our study population. Phylogenetic tree results revealed that Xinglong buffalo was gathered together with Fuzhong buffalo firstly. The population genetic structure analysis indicates that at K = 3, the Xinglong buffalo for the first time showed a distinct ancestral origin from other water buffalo. Furthermore, compared to different populations, candidate genes displaying significantly distinct patterns of single nucleotide polymorphisms (SNPs) (e.g., RYR2, COX15, PCDH9, DTWD2, FCRL5) distribution have been identified in the Xinglong buffalo. Conclusions: Based on the whole genome sequencing data, this study identified a substantial number of SNPs and assessed the genetic diversity and selection signatures within the Xinglong buffalo population. These results contribute to understanding the genomic characteristics of Xinglong buffalo and their genetic evolutionary status. However, the practical significance of these signatures for genetic enhancement still requires confirmation through additional samples and further experimental validation. [ABSTRACT FROM AUTHOR]

Background: Embryonic genome activation (EGA) is a critical step in early embryonic development, as it marks the transition from relying on maternal factors to the initiation of transcription from embryo's own genome. The factors associated with EGA are not well understood and need further investigation. PRD-like (PRDL) homeodomain transcription factors (TFs) are considered to play crucial roles in this early event during development but these TFs have evolved differently, even within mammalian lineages. Different numbers of PRDL TFs have been predicted in bovine (Bos taurus); however, their divergent evolution requires species-specific confirmation and functional investigations. Results: In this study, we conducted molecular cloning of mRNAs for the PRDL TFs ARGFX, DUXA, LEUTX, NOBOX, TPRX1, TPRX2, and TPRX3 in bovine oocytes or in vitro fertilized (IVF) preimplantation embryos. Our results confirmed the expression of PRDL TF genes in early bovine development at the cDNA level and uncovered their structures. For each investigated PRDL TF gene, we isolated at least one homeodomain-encoding cDNA fragment, indicative of DNA binding and thus potential role in transcriptional regulation in developing bovine embryos. Additionally, our cDNA cloning approach allowed us to reveal breed-related differences in bovine, as evidenced by the identification of a high number of single nucleotide variants (SNVs) across the PRDL class homeobox genes. Subsequently, we observed the prediction of the 9aa transactivation domain (9aaTAD) motif in the putative protein sequence of TPRX3 leading us to conduct functional analysis of this gene. We demonstrated that the TPRX3 overexpression in bovine fibroblast induces not only protein-coding genes but also short noncoding RNAs involved in splicing and RNA editing. We supported this finding by identifying a shared set of genes between our and published bovine early embryo development datasets. Conclusions: Providing full-length cDNA evidence for previously predicted homeobox genes that belong to PRDL class improves the annotation of the bovine genome. Updating the annotation with seven developmentally-important genes will enhance the accuracy of RNAseq analysis with datasets derived from bovine preimplantation embryos. In addition, the absence of TPRX3 in humans highlights the species-specific and TF-specific regulation of biological processes during early embryo development. [ABSTRACT FROM AUTHOR]

Streptococcus suis serotypes 2 and 14 are the most common zoonotic strains, but previous identification methods made distinguish these two serotypes from other S. suis serotypes difficult. To effectively prevent and control them, there is an urgent need for a highly sensitive and specific method to identify these two serotypes. In this study, a fluorescent probe was designed for the single nucleotide polymorphism site at cpsK 483 of Streptococcus suis type 2 and type 14 compared with other serotypes, and an enzyme-activated probe quantitative PCR (EA-probe qPCR) method was established for the detection of Streptococcus suis type 2 and type 14 by combining with the specific hydrolysis characteristics of the RNase H2 enzyme. The results showed that the optimal probe concentration for this method was 0.5 µM and the optimal RNase H2 enzyme concentration was 25 mU.This method showed no reactivity with genomic DNA from Streptococcus suis strains 1/2, 5, 7, 9, 23, 28, 29, and 31, confirming its high specificity. And its sensitivity can reach 18.4 CFU. In addition, 19 clinical strains of Streptococcus suis type 2 or type 1/2 were tested. The results showed 100% agreement with the gene sequencing method. In conclusion, this method can meet the needs of accurate laboratory testing of Streptococcus suis serotypes 2 and 14 and has value for clinical prevention. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) are complex, multifactorial conditions that require personalized assessment and treatment. Advancements in multi-omics technologies, namely RNA sequencing and whole-genome sequencing, have provided translational researchers with a comprehensive view of the human genome. The efficient synthesis and analysis of this data through integrated approach that characterizes genetic variants alongside expression patterns linked to emerging phenotypes, can reveal novel biomarkers and enable the segmentation of patient populations based on personalized risk factors. In this study, we present a cutting-edge methodology rooted in the integration of traditional bioinformatics, classical statistics, and multimodal machine learning techniques. Our approach has the potential to uncover the intricate mechanisms underlying CVD, enabling patient-specific risk and response profiling. We sourced transcriptomic expression data and single nucleotide polymorphisms (SNPs) from both CVD patients and healthy controls. By integrating these multi-omics datasets with clinical demographic information, we generated patient-specific profiles. Utilizing a robust feature selection approach, we identified a signature of 27 transcriptomic features and SNPs that are effective predictors of CVD. Differential expression analysis, combined with minimum redundancy maximum relevance feature selection, highlighted biomarkers that explain the disease phenotype. This approach prioritizes both biological relevance and efficiency in machine learning. We employed Combination Annotation Dependent Depletion scores and allele frequencies to identify variants with pathogenic characteristics in CVD patients. Classification models trained on this signature demonstrated high-accuracy predictions for CVD. The best performing of these models was an XGBoost classifier optimized via Bayesian hyperparameter tuning, which was able to correctly classify all patients in our test dataset. Using SHapley Additive exPlanations, we created risk assessments for patients, offering further contextualization of these predictions in a clinical setting. Across the cohort, RPL36AP37 and HBA1 were scored as the most important biomarkers for predicting CVDs. A comprehensive literature review revealed that a substantial portion of the diagnostic biomarkers identified have previously been associated with CVD. The framework we propose in this study is unbiased and generalizable to other diseases and disorders. [ABSTRACT FROM AUTHOR]

In military populations, gene-environment interactions can influence performance and health outcomes. Brain-derived neurotrophic factor (BDNF) is a central nervous system protein that is important for neuronal function and synaptic plasticity. A BDNF single nucleotide polymorphism, rs6265, leads to an amino acid substitution of valine (Val) with methionine (Met) at codon 66 (Val66Met), which may influence an individual's response to occupational stress, and predispose military members to psychological disorders. Telomere length (TL), a novel measure of biological aging, can be used as a biomarker of stress. Accordingly, telomere shortening may be a surrogate indicator of physiological weathering due to chronic disease and stressful life events. To increase our understanding about the potential effect of the Val66Met mutation on the human stress response, we evaluated the relationships between Val66Met, TL, and mental health symptoms in a military population. In this pilot study (N = 164), we observed an association between Val66Met and reduced TL (p = 0.048). There was no relationship between Val66Met and mental health symptoms. These results support the investigation of gene-environment interactions, and their potential influence on TL due to occupational stress such as military service. [ABSTRACT FROM AUTHOR]