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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]

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]

Lifetime productivity is a trait of great importance to dairy cattle populations, as it combines information from production and longevity variables. Therefore, we investigated the genetic background of lifetime productivity in high-producing dairy cattle by integrating genomics and transcriptomics datasets. A total of 3,365,612 test-day milk yield records from 134,029 Chinese Holstein cows were used to define 6 lifetime productivity traits, including lifetime milk yield covering full lifespan and 5 cumulative milk yield traits covering partial lifespan. Genetic parameters were estimated based on univariate and bivariate linear animal models and the restricted maximum likelihood method. Genome-wide association studies and weighted gene co-expression network analyses (WGCNA) were performed to identify candidate genes associated with lifetime productivity based on genomic data from 3,424 cows and peripheral blood RNA-sequencing data from 23 cows, respectively. Lifetime milk yield averaged 24,800.8 ± 14,396.6 kg (mean ± SD) across an average of 2.4 parities in Chinese Holstein population. The heritability estimates for lifetime productivity traits ranged from 0.05 (±0.01 for SE) to 0.10 (±0.02 for SE). The estimate of genetic correlation between lifetime milk yield and productive life is 0.88 (±0.3 for SE), whereas the genetic correlation with 305-d milk yield in the first lactation was 0.49 (±0.08 for SE). Absolute values for most genetic correlation estimates between lifetime productivity and type traits were lower than 0.30. Moderate genetic correlations were found between udder related traits and lifetime productivity, such as with udder depth (0.33), rear udder attachment height (0.33), and udder system (0.34). Some single nucleotide polymorphisms and gene co-expression modules significantly associated with lifetime milk yield were identified based on GWAS and WGCNA analyses, respectively. Functional enrichment analyses of the candidate genes identified revealed important pathways related to immune system, longevity, energy utilization, and metabolism, and FoxO signaling. The genes NTMT1 , FNBP1 , and S1PR1 were considered to be the most important candidate genes influencing lifetime productivity in Holstein cows. Overall, our findings indicate that lifetime productivity is heritable in Chinese Holstein cattle, and important candidate genes were identified by integrating genomic and transcriptomic datasets. The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. [ABSTRACT FROM AUTHOR]

Farmstead dairy processing facilities may be particularly susceptible to Listeria spp. contamination due to the close physical proximity of their processing environments (PE) to associated dairy farm environments (FE). In this case study, we supported the implementation of interventions focused on improving (1) cleaning and sanitation efficacy, (2) hygienic zoning, and (3) sanitary equipment and facility design and maintenance in a farmstead dairy processing facility, and evaluated their effect on Listeria spp. detection in the farmstead's PE over 1 yr. Detection of Listeria spp. in the farmstead's PE was numerically reduced from 50% to 7.5% after 1 yr of intervention implementation, suggesting that these interventions were effective at improving Listeria spp. control. In addition, environmental samples were also collected from the farmstead's FE to evaluate the risk of the FE as a potential source of Listeria spp. in the PE. Overall, detection of Listeria spp. was higher in samples collected from the FE (75%, 27/36) compared with samples collected from the PE (24%, 29/120). Whole-genome sequencing performed on select isolates collected from the PE and FE supported the identification of 6 clusters (range of 3 to 15 isolates per cluster) that showed ≤ 50 high-quality single nucleotide polymorphism differences. Of these 6 clusters, 3 (i.e., clusters 2, 4, and 5) contained isolates that were collected from both the PE and FE, suggesting that transmission between these 2 environments was likely. Moreover, all cluster 2 isolates represented a clonal complex of L. monocytogenes commonly associated with dairy farm environmental reservoirs (i.e., CC666), which may support that the farmstead's FE represented an upstream source of the cluster 2 isolates that were found in the PE. Overall, our data underscore that although the FE can represent a potential upstream source of Listeria spp. contamination in a farmstead dairy processing facility, implementation of targeted interventions can help effectively minimize Listeria spp. contamination in the PE. The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. [ABSTRACT FROM AUTHOR]

[Display omitted] • The first chromosome-contiguous genome for an Australian strain of Haemonchus contortus (Haecon-5) was identified. • This genome and associated transcriptomic and proteomic resources underpin future fundamental and applied investigations. • There was marked genetic variation within H. contortus , both within and between strains. • A subset of conserved, essential genes were identified as potential intervention targets. Millions of livestock animals worldwide are infected with the haematophagous barber's pole worm, Haemonchus contortus , the aetiological agent of haemonchosis. Despite the major significance of this parasite worldwide and its widespread resistance to current treatments, the lack of a high-quality genome for the well-defined strain of this parasite from Australia, called Haecon-5, has constrained research in a number of areas including host-parasite interactions, drug discovery and population genetics. To enable research in these areas, we report here a chromosome-contiguous genome (∼280 Mb) for Haecon-5 with high-quality models for 19,234 protein-coding genes. Comparative genomic analyses show significant genomic similarity (synteny) with a UK strain of H. contortus , called MHco3(ISE).N1 (abbreviated as "ISE"), but we also discover marked differences in genomic structure/gene arrangements, distribution of nucleotide variability (single nucleotide polymorphisms (SNPs) and indels) and orthology between Haecon-5 and ISE. We used the genome and extensive transcriptomic resources for Haecon-5 to predict a subset of essential single-copy genes employing a "cross-species" machine learning (ML) approach using a range of features from nucleotide/protein sequences, protein orthology, subcellular localisation, single-cell RNA-seq and/or histone methylation data available for the model organisms Caenorhabditis elegans and Drosophila melanogaster. From a set of 1,464 conserved single copy genes, transcribed in key life-cycle stages of H. contortus , we identified 232 genes whose homologs have critical functions in C. elegans and/or D. melanogaster , and prioritised 10 of them for further characterisation; nine of the 10 genes likely play roles in neurophysiological processes, germline, hypodermis and/or respiration, and one is an unknown (orphan) gene for which no detailed functional information exists. Future studies of these genes/gene products are warranted to elucidate their roles in parasite biology, host-parasite interplay and/or disease. Clearly, the present Haecon-5 reference genome and associated resources now underpin a broad range of fundamental investigations of H. contortus and could assist in accelerating the discovery of novel intervention targets and drug candidates to combat haemonchosis. [ABSTRACT FROM AUTHOR]

Despite current research primarily centering on point mutations in the Pfk13 gene, artemisinin resistance (AR) bears many characteristics of a complex, cumulative genetic trait. This trait is shaped by a combination of nonsynonymous single-nucleotide polymorphisms (nsSNPs), intron mutations, promoter indels, long noncoding RNAs (lncRNAs), and epigenetic factors, which collectively regulate gene expression and modulate distinct phenotypic responses to the drug. AR parasites, both in vivo and in vitro , show a broad but distinct transcriptional profile, allowing them to better survive brief drug pressures. Population dynamics, including heteroresistance, transmission, recombination rates, and environmental factors form an integral part of the genetics of drug resistance in the malaria parasite. To match the complex life cycle of Plasmodium falciparum , studies of genetic resistance should extend beyond single point mutations. The genetics of Plasmodium as an intracellular, mostly haploid, sexually reproducing, eukaryotic organism with a complex life cycle, presents unprecedented challenges in studying drug resistance. This article summarizes current knowledge on the genetic basis of artemisinin resistance (AR) – a main component of current drug therapies for falciparum malaria. Although centered on nonsynonymous single-nucleotide polymorphisms (nsSNPs), we describe multifaceted resistance mechanisms as part of a complex, cumulative genetic trait that involves regulation of expression by a wide array of polymorphisms in noncoding regions. These genetic variations alter transcriptome profiles linked to Plasmodium's development and population dynamics, ultimately influencing the emergence and spread of the resistance. [ABSTRACT FROM AUTHOR]

This study aimed to identify the specific vaccine strain associated with herpes zoster (HZ) in children following a series of diagnosed cases and to explore whether differences in single nucleotide polymorphisms (SNPs) among various vaccine strains are linked to an increased incidence of herpes zoster after vaccination. From February 2021 to March 2024, children <12 years old suspected of vaccine-related varicella-like rash or HZ were included. Varicella zoster virus DNA isolated from the patients were sequenced to differentiate vaccine type versus wild-type. 3D protein structures of pORF62 were simulated using open reading frame 62 sequences extracted from whole genome sequencing of vOka, MAV/06, Oka/SK vaccines, and pOka reference. A total of 27 children with a median age of 2.1 (interquartile range, 1.5–3.4) years old presented with vaccine-related varicella-like rash (n = 4/27, 14.8%) or HZ (n = 23/27, 85.2%). One patient with varicella-like rash and 34.8% (n = 8/23) with HZ had disseminated skin involvement. All were immunized with the Oka/SK strain varicella vaccine. Genotyping showed 88.2% (n = 15/17) had SNPs specific to the Oka/SK strain, and two had SNPs considered pOka type contained within the Oka/SK vaccine. Despite accumulations of SNPs in ORF 62 of Oka/SK, the translated amino acid sequence and 3D protein structure were identical to wild-type pOka's pORF62. In vOKA and MAV/06, changes in amino acids occurred at two positions, S628G and R958G, within pORF62. The predicted 3D protein structure of vOka and MAV/06's pORF62 showed that the α helical structure within region I undergoes conformational change, potentially increasing difficulties in interactions with infection-related proteins and thereby decreasing virulence. pORF62 in pOka and Oka/SK exhibited more stable structure complex of the α helical structure. Lack of structural alternations in region I of pORF62 due to the absence of critical genetic polymorphisms in open reading frame 62 could be associated with the heightened incidence of adverse events. [ABSTRACT FROM AUTHOR]

• The first use of MR to evaluate the association between neuroticism and IAs. • Using large GWAS data, with a large sample size, results are more reliable. • Further validate the reliability of the results using multiple databases. The aim of this study was to assess the potential causal relationship between neuroticism and 12 neuroticism items with intracranial aneurysms (IAs) and aneurysmal subarachnoid hemorrhage (aSAH) using a two-sample Mendelian randomization (MR) approach. Study data were obtained from the Genome-Wide Association Study (GWAS) pooled dataset, and we extracted summary statistics for neuroticism, 12 neuroticism items, and IAs, which were categorized into ruptured and unruptured aneurysms (IA), aSAH, and unruptured IAs (uIA). Single nucleotide polymorphisms (SNPs) were used as instrumental variables (IVs) to explore the causal relationship between exposure and outcome using five Mendelian randomization methods, with Inverse variance weighted (IVW) as the primary study method. Horizontal multiple validity tests, sensitivity analyses, and inverse MR ensured the stability of the results. The two-sample MR showed a genetically predictive association between neuroticism and IA [odds ratio (OR) = 1.16; 95 % confidence interval (95 % CI): 1.04–1.30; p = 0.009], aSAH (OR = 1.17; 95 % CI: 1.03–1.33; p = 0.013) and uIA (OR = 1.30; 95 % CI: 1.07–1.59; p = 0.009) were all genetically predictive of association. Ivw showed a positive association between 5 neuroticism items and IA risk, 5 neuroticism items and aSAH risk as well as no genetically predictive association between neuroticism items and uIA. Sensitivity analysis and inverse MR confirmed the robustness of the results. Our Mendelian randomization analysis demonstrated genetic causality between neuroticism and neuroticism items with intracranial aneurysms, aneurysmal subarachnoid hemorrhage, and unruptured intracranial aneurysms, and further studies are needed to confirm these results and explore potential mechanisms of action. [ABSTRACT FROM AUTHOR]

A 44-year-old man with hypertension and dyslipidemia presented with pain in the buttocks. The patient was diagnosed with perianal ischiorectal fossa abscesses and cellulitis. He was subsequently diagnosed with a perineal subcutaneous abscess after a week, a right lower leg impetigo after a month, right periorchitis, a scrotal abscess, and Fournier's gangrene after two months. The patient was treated with various antimicrobials and underwent incisional drainage. Methicillin-resistant Staphylococcus aureus (MRSA) was detected in all draining specimens. Her daughter and son, who lived with the patient, presented with subcutaneous abscesses caused by MRSA. Suspecting repeated infections and household infections by virulent types of MRSA, such as PVL-positive strains, we performed genetic analyses of his and his son's strains. The results showed that the genotype and toxin gene profiles [ST8/t008/SCCmec type IVc/Panton-Valentine leucocidin (PVL) (+)/arginine catabolic mobile element (ACME) (−)] of both strains matched. single nucleotide polymorphism (SNP) analysis confirmed genetic homology between the two, concluding that home transmission by the same clone had occurred. In addition, the strain in this case differed from USA300 [ST8/t008/SCCmec type IVa/PVL (+) ACME (+)], which is a PVL-positive MRSA worldwide, including Japan, and its genetic profile matches that of USA300-LV, which is detected mainly in South America. Furthermore, SNP analysis showed that this strain is similar to USA300-LV/J (derived from USA300-LV) detected on Ishigaki Island, Okinawa Prefecture, Japan. This is the first report of refractory infections and household transmission of USA300-LV/J. Therefore, it is necessary to closely monitor both the USA300 and the USA300-LV. [ABSTRACT FROM AUTHOR]

Aquaporin-4 (AQP4) is hypothesized to be a component of the glymphatic system, a pathway for removing brain interstitial solutes like amyloid-β (Aβ). Evidence exists that genetic variation of AQP4 impacts Aβ clearance, clinical outcome in Alzheimer's disease as well as sleep measures. We examined whether a risk score calculated from several AQP4 single-nucleotide polymorphisms (SNPs) is related to Aβ neuropathology in older cognitively unimpaired white individuals. We used a machine learning approach and explainable artificial intelligence to extract information on synergistic effects of AQP4 SNPs on brain amyloid burden from the ADNI cohort. From this information, we formulated a sex-specific AQP4 SNP-based risk score and evaluated it using data from the screening process of the A4 study. We found in both cohorts significant associations of the risk score with brain amyloid burden. The results support the hypothesis of an involvement of the glymphatic system, and particularly AQP4, in brain amyloid aggregation pathology. They suggest also that different AQP4 SNPs exert a synergistic effect on the build-up of brain amyloid burden. • AQP4 SNPs exert a synergistic effect on the build-up of brain amyloid burden. • AQP4 SNP based risk score is related to Aβ burden in healthy white individuals. • Explainable AI could extract information on synergistic effects of SNPs. [ABSTRACT FROM AUTHOR]

The dysfunction of the ABO glycosyltransferase (GT) enzyme, which is caused by mutations in the ABO gene, can lead to weak ABO phenotypes. In this study, we have discovered a novel weak ABO subgroup allele and investigated the underlying mechanism to causing its A weak phenotype. The ABO phenotyping and genotyping were performed by serological studies and direct DNA sequencing of ABO gene. The role of the novel single nucleotide polymorphism (SNP) was evaluated by 3D model, predicting protein structure changes, and in vitro expression assay. The total glycosyltransferase transfer capacity in supernatant of transfected cells was examined. The results of serological showed the subject was A weak phenotype. A novel SNP c.424A > G (p. M142V) based on ABO∗A1.02 was identified, and the genotype of the subject was AW-var/O.01 according to the gene analysis. In silico analysis showed that the SNP c.424A > G on the A allele may change the local conformation by damaging the hydrogen bonds and reduce the stability of GT. In vitro expression study showed that SNP p.M142V impaired H to A antigen conversion, although it did not affect the generation of A glycosyltransferase (GTA). One novel AW allele was identified and the SNP c.424A > G (p.M142V) can cause the A weak phenotype through damaging the hydrogen bonds and reducing stability of the GTA. [ABSTRACT FROM AUTHOR]

[Display omitted] Many clustered regularly interspaced short palindromic repeat and CRISPR-associated protein 12b (CRISPR-Cas12b) nucleases have been computationally identified, yet their potential for genome editing remains largely unexplored. In this study, we conducted a GFP-activation assay screening 13 Cas12b nucleases for mammalian genome editing, identifying five active candidates. Candidatus hydrogenedentes Cas12b (ChCas12b) was found to recognize a straightforward WTN (W = T or A) proto-spacer adjacent motif (PAM), thereby dramatically expanding the targeting scope. Upon optimization of the single guide RNA (sgRNA) scaffold, ChCas12b exhibited activity comparable to SpCas9 across a panel of nine endogenous loci. Additionally, we identified nine mutations enhancing ChCas12b specificity. More importantly, we demonstrated that both ChCas12b and its high-fidelity variant, ChCas12b-D496A, enabled allele-specific disruption of genes harboring single nucleotide polymorphisms (SNPs). These data position ChCas12b and its high-fidelity counterparts as promising tools for both fundamental research and therapeutic applications. [ABSTRACT FROM AUTHOR]

The objective of this study was to analyze the causal relationship between Neuroticism and aortic aneurysm using Mendelian randomization (MR). The study aimed to establish a foundation for the development of effective prevention and treatment strategies. Genetic association data for Neuroticism were obtained from the UK Biobank, which included 393,411 individuals and 11,968,760 single nucleotide polymorphisms (SNPs). Genetic association data for aortic aneurysm were obtained from a genome-wide association study (GWAS), which included 479,194 individuals and 24,191,825 SNPs. Heterogeneity was assessed using the Cochran's Q statistic test. The study also utilized the MR Pleiotropy RESidual Sum and Outlier (Mr-PRESSO) test, as well as the MR-Egger regression method, to examine horizontal pleiotropy and determine the reliability of the findings through the leave-one-out method. Forward MR analysis showed that the risk of aortic aneurysm was elevated in individuals with genetically predicted Neuroticism compared to those without Neuroticism (OR = 1.1315, 95 % CI: 1.0269–1.2468; P = 0.0126). The Cochran's Q test showed no heterogeneity (P > 0.05), and the MR-PRESSO test did not identify instrumental variables of horizontal pleiotropy (P > 0.05). The MR analysis remained robust after removing SNPs one by one. Inverse MR analysis did not observe an association between aortic aneurysm and having Neuroticism OR = 1.030, 95 % CI: 0.9459–1.118, P = 0.488). Our study has established a clear causal relationship between genetically determined Neuroticism and the development of aortic aneurysms. It is therefore important to intensify screening and prevention efforts for aortic aneurysms in neurotic patients. It also opens new avenues for exploring the disease's pathogenesis. • Existing Evidence Gap: Psych trait-cardiovascular studies common, but few MR analyses explore neuroticism-aortic aneurysm link. • Novel Contribution: Forward MR shows higher neuroticism genetically linked to increased aortic aneurysm risk. • Clinical Significance: Findings suggest intensified screening & prevention for aortic aneurysms in neurotic individuals. • Future Directions: Study prompts deeper investigation into aortic aneurysm mechanisms & discovery of new genetic pathways. [ABSTRACT FROM AUTHOR]

• MTHFR C677T polymorphism was associated with T2DM microangiopathy. • The study discovered that the MTHFR A1298C polymorphism is related to microangiopathy in T2DM. • Study findings aid early T2DM microangiopathy diagnosis and treatment. Extensive case-control association studies have been conducted over the past few decades to investigate the relationship between MTHFR polymorphism and type 2 diabetes mellitus (T2DM) microangiopathy. However, the strength of the evidence and clinical significance are unclear. Consequently, a meta-analysis was performed to examine the correlations between two prevalent MTHFR single nucleotide polymorphisms, MTHFR C677T and A1298C, and T2DM microangiopathy. Randomized controlled trials were systematically searched in PubMed, Cochrane, Embase, Web of Science, CNKI, VIP database, China Biology Medicine, and Wanfang until August 2023. A total of 42 studies were included. Random-effect models were utilized to estimate odds ratios (ORs) with 95% confidence intervals (CIs) to assess the association between MTHFR polymorphisms and T2DM microangiopathy susceptibility. T2DM microangiopathy was significantly associated with the MTHFR C677T polymorphism in the overall population (T vs C, OR = 1.43, 95% CI = 1.25-1.64; TT + CT vs CC: OR = 1.56, 95% CI = 1.30-1.88; TT vs CT + CC: OR = 1.66, 95% CI = 1.38-1.99; TT vs CC: OR = 2.03, 95% CI = 1.58-2.60). Additionally, the dominant model revealed that the MTHFR A1298C polymorphism was associated with T2DM microangiopathy (OR = 1.27, 95% CI: 1.09-1.47). This meta-analysis revealed that MTHFR may be involved in the pathogenesis of T2DM microangiopathy, providing a reference for early diagnosis and treatment of T2DM. Our meta-analysis of 42 studies found that C677T/A1298C polymorphism wes associated with T2DM microangiopathy. T2DM microangiopathy was significantly associated with the MTHFR C677T polymorphism in the overall population (Allele: T vs C, Dominant: TT + CT vs CC, Recessive: TT vs CT + CC, Homozygote: TT vs CC: P OR <.001). Additionally, the dominant model revealed that the MTHFR A1298C polymorphism was associated with T2DM microangiopathy (Dominant: CC + AC vs AA: P OR =.002). Abbreviations: RCTs, randomized controlled trials; T2DM, type 2 diabetes mellitus. [Display omitted] [ABSTRACT FROM AUTHOR]

The TMPRSS2 protease plays a key role in the entry of the SARS-CoV-2 into cells. The TMPRSS2 gene is highly polymorphic in humans, and some polymorphisms may affect the susceptibility to COVID-19 or disease severity. rs75603675 (c.23G > T) is a missense variant that causes the replacement of glycine with valine at position 8 (p.G8V) in the TMPRSS2 isoform 1. According to GnomAD v4.0.0 database, the allele frequency of the rs75603675 on a global scale is 38.10 %, and range from 0.92 % in East Asian to 40.77 % in non-Finnish European (NFE) population. We analyzed the occurrence of the rs75603675 in two cohorts of patients, the first with severe/critical COVID-19 enrolled in a French hospital (42 patients), and the second with predominantly asymptomatic/pauci-symptomatic/mild COVID-19 enrolled in an Italian hospital (69 patients). We found that the TMPRSS2 -c.23T minor allele frequency was similar in the two cohorts, 46.43 % and 46.38 %, respectively, and higher than the frequency in the NFE population (40.77 %). Chi-square test provided significant results (p < 0.05) when the genotype data (TMPRSS2 -c.23T/c.23T homozygotes + TMPRSS2 -c.23G/c.23T heterozygotes vs. TMPRSS2 -c.23G/c.23G homozygotes) of the two patient groups were pooled and compared to the expected data for the NFE population, suggesting a possible pathogenetic mechanism of the p.G8V substitution. We explored the possible effects of the p.G8V substitution and found that the N-terminal region of the TMPRSS2 isoform 1 contains a signal for clathrin/AP-2-dependent endocytosis. In silico analysis predicted that the p.G8V substitution may increase the accessibility to the endocytic signal, which could help SARS-CoV-2 enter cells. • Polymorphism rs75603675 is a missense variant that causes the replacement of glycine with valine at position 8 in TMPRSS2 • Minor allele of rs75603675 is associated with increased susceptibility to COVID-19 in a retrospective cohort analysis. • G8V substitution affects the stability of the N-terminal region of the TMPRSS2 as revealed by molecular dynamic simulation. • In silico analysis shows that an endocytic signal may be more exposed in TMPRSS2-p.8V variant, helping the virus enter cells. [ABSTRACT FROM AUTHOR]

Triglyceride-rich lipoproteins and remnants (TRL/remnants) have a causal, but not yet quantified, relationship with coronary heart disease (CHD): myocardial infarction plus revascularization. The authors sought to estimate TRL/remnant per-particle atherogenicity, investigate causal relationships with inflammation, and determine whether differences in the atherogenicity of TRL/remnants and low-density lipoprotein (LDL) impact the causal association of non–high-density lipoprotein cholesterol (non–HDL-C) with CHD. Single nucleotide polymorphisms (SNPs) (N = 1,357) identified by genome-wide association in the UK Biobank were ranked into 10 clusters according to the effect on TRL/remnant-C vs LDL-C. Mendelian randomization analysis was used to estimate for each SNP cluster CHD ORs per 10 mg/dL apolipoprotein B (apoB) and per 0.33 mmol/L non–HDL-cholesterol, and to evaluate association of TRL/remnants with biomarkers of systemic inflammation. SNPs in cluster 1 predominantly affected LDL-C, whereas SNPs in cluster 10 predominantly affected TRL/remnant-C. CHD risk per genetically predicted increase in apoB and in non–HDL-C rose across clusters. ORs per 10 mg/dL higher apoB was 1.15 (95% CI: 1.11-1.19) in cluster 1 vs 1.70 (95% CI: 1.52-1.90) in cluster 10. Comparing ORs between these TRL/remnant-predominant and LDL-predominant clusters, we estimated that TRL/remnants were at least 3.9 (95% CI: 2.8-5.4) times more atherogenic than LDL on a per-particle basis. For non–HDL-C, CHD ORs per 0.33 mmol/L rose from 1.15 (95% CI: 1.11-1.19) for cluster 1 to 1.40 (95% CI: 1.30-1.50) for cluster 10. TRL/remnants exhibited causal relationships with inflammation, but this did not explain their greater atherogenicity. TRL/remnants are about 4 times more atherogenic than LDL. Variation in the causal association of non–HDL-C with CHD indicates that adjustment for percentage TRL/remnant-C may be needed for accurate risk prediction. [ABSTRACT FROM AUTHOR]

To explore the feasibility of using cold plasma as a mutagenesis breeding technology for forage crops, in this study we used the Medicago sativa L. cultivar, Zhongcao No. 3, as the experimental material. The effects of plasma treatments on Medicago sativa L. were analyzed through the use of plasma and activated water. Treatments with plasma and activated water inhibited plant height but promoted root growth. By creating a closed environment, adding a dielectric barrier plate, and combining these two treatment methods, the greatest impact can be had on the growth of Medicago sativa L. seeds. After treatment, the plant heights were approximately half those of the control group, and the root lengths were approximately 1.6 times those of the control group. Through emission spectroscopy, it was found that active particles such as O, NO 2 , and N 2 * were present and could be considered to have produced plasma-activated water through contact with the water surface, thus affecting the survival and growth of the seeds. Whole-genome resequencing (WGRS) was performed on the wild-type and selected mutants after treatment, with an average sequencing depth of 115.93×, an average genome alignment rate of 91.72 %, and an average genome coverage rate of 91.85 %. Various types of mutations were detected and annotated. After filtering, 7,822,324 SNP (single nucleotide polymorphisms) sites, 2,161,917 indel sites, 200,544 SV sites, 238 CNV (copy number variation) sites. The SNPs, indels (insertions/deletions), and SVs (structural variations) were mainly heterozygous, with heterozygosity rates of 87.13 %, 92.16 %, and 83.49 %, respectively. The CNVs were dominated by low copy numbers, accounting for 53.77 %. These results indicate that plasma treatment has significant effects on plant growth and genome of Medicago sativa L. [Display omitted] • The experimental material is the earliest and largest and most important forage grass cultivated in the world - Medicago sativa L. • Mutagenesis breeding uses a combination of physical and chemical mutagenesis to carry out mutagenesis. • In previous literature and research, but the use of plasma in biological mutagenesis breeding is still a new technology, and there are few relevant reports. • After mutagenesis treatment, the plant traits changed significantly. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine particular single-nucleotide polymorphisms (IL-1A-889 C/T — rs1800587, IL-1B +3953 C/T — rs 1143634) of interleukins 1A and 1B in the development and prognosis of medication-related osteonecrosis of the jaw. DentiGen Parodontitis Tests were applied for collecting samples. This test is suitable for sampling oral mucosa cells in order to detect interleukins 1A and 1B single nucleotide polymorphisms (IL-1A−889, IL-1B+3953). Genetic samples were evaluated in the Istenhegyi Genediagnostic Center using the DNA-hybridization method. Genetic samples were collected in the patient group and the control group. The role of gene polymorphisms in the development of the disease was investigated by comparing the genetic results for the patient and control groups. The investigation of gene polymorphisms in disease prognosis is based on stage improvement, recovery, and relapses following treatment. In total, 91 patients with MRONJ and 59 healthy controls were included in the study. 51 patients in the patient group and 37 controls had unfavorable allelic variants. No association (Mp = 1.42, SDp = 0.496, Mc = 1.35, SDc = 0.482, p = 0.52) was found between unfavorable polymorphisms and the development of the MRONJ. In the patient group, surgical therapy was required in 79 cases. Stage improvement was detected in 78 cases, recovery in 67 cases, and relapse in 33 cases. No stage improvement was found in one case, recovery in nine cases, or relapse in 34 cases. Of the 79 patients requiring surgical therapy, 49 had unfavorable allelic variants. No connection was found between the polymorphisms examined and stage improvement (Mp = 1.37, SDp = 0.486, Mnp = 2, SDnp = –, p = 0.800) or recovery (Mp = 1.39, SDp = 0.491, Mnp = 1.44, SDnp = 0.527, p = 0.990). However, a significant association (Mp = 1.21, SDp = 0.415, Mnp = 1.58, SDnp = 0.502, p < 0.001) was found between relapses and the presence of unfavorable allelic variants. Within the possible limitations of this study, it can be assumed that the analysis of certain single-nucleotide polymorphisms of interleukin-1 may have the potential to help define the risk stratification of MRONJ after surgical therapy. [ABSTRACT FROM AUTHOR]

Multiple genes might interact to determine the age at onset of bipolar disorder. We investigated gene-gene interactions related to age at onset of bipolar disorder in the Korean population, using genome-wide association study (GWAS) data. The study population consisted of 303 patients with bipolar disorder. First, the top 1000 significant single-nucleotide polymorphisms (SNPs) associated with age at onset of bipolar disorder were selected through single SNP analysis by simple linear regression. Subsequently, the QMDR method was used to find gene-gene interactions. The best 10 SNPs from simple regression were located in chromosome 1, 2, 3, 10, 11, 14, 19, and 21. Only five SNPs were found in several genes, such as FOXN3 , KIAA1217 , OPCML , CAMSAP2 , and PTPRS. On QMDR analyses, five pairs of SNPs showed significant interactions with a CVC exceeding 1/5 in a two-locus model. The best interaction was found for the pair of rs60830549 and rs12952733 (CVC = 1/5, P < 1E−07). In three-locus models, four combinations of SNPs showed significant associations with age at onset, with a CVC of >1/5. The best three-locus combination was rs60830549, rs12952733, and rs12952733 (CVC = 2/5, P < 1E−6). The SNPs showing significant interactions were located in the KIAA1217 , RBFOX3 , SDK2 , CYP19A1 , NTM , SMYD3 , and RBFOX1 genes. Our analysis confirmed genetic interactions influencing the age of onset for bipolar disorder and identified several potential candidate genes. Further exploration of the functions of these promising genes, which may have multiple roles within the neuronal network, is necessary. • Genetic interactions are crucial for the sub-phenotype of psychiatric disorder. • Age at onset of bipolar disorder was influenced by gene-gene interactions. • The SNPs showing significant interactions were located in the KIAA1217 , RBFOX3 , SDK2 , CYP19A1 , NTM , SMYD3 , and RBFOX1 genes. [ABSTRACT FROM AUTHOR]

To investigate the causal relationships between plasma metabolites and osteoporosis via Mendelian randomization (MR) analysis. Bidirectional MR was used to analyze pooled data from different genome-wide association studies (GWAS). The causal effect of plasma metabolites on osteoporosis was estimated using the inverse variance weighted method, intersections of statistically significant metabolites obtained from different sources of osteoporosis-related GWAS aggregated data was determined, and then sensitivity analysis was performed on these metabolites. Heterogeneity between single nucleotide polymorphisms was evaluated by Cochran's Q test. Horizontal pleiotropy was assessed through the application of the MR-Egger intercept method and the MRPRESSO method. The causal effect of osteoporosis on plasma metabolites was also evaluated using the inverse variance weighted method. Additionally, pathway analysis was conducted to identify potential metabolic pathways involved in the regulation of osteoporosis. Primary analysis and sensitivity analysis showed that 77 and 61 plasma metabolites had a causal relationship with osteoporosis from the GWAS data in the GCST90038656 and GCST90044600 datasets, respectively. Five common metabolites were identified via intersection. X-13684 levels and the glucose-to-maltose ratio were negatively associated with osteoporosis, whereas glycoursodeoxycholate levels and arachidoylcarnitine (C20) levels were positively associated with osteoporosis (all P < 0.05). The relationship between X-11299 levels and osteoporosis showed contradictory results (all P < 0.05). Pathway analysis indicated that glycine, serine, and threonine metabolism, valine, leucine, and isoleucine biosynthesis, galactose metabolism, arginine biosynthesis, and starch and sucrose metabolism pathways were participated in the development of osteoporosis. We found a causal relationship between plasma metabolites and osteoporosis. These results offer novel perspectives with important implications for targeted metabolite-focused interventions in the management of osteoporosis. [ABSTRACT FROM AUTHOR]

Although intervertebral disc degeneration (IVDD) is a critical factor in many spine-related diseases and has an extremely high prevalence in the aging population, the potential pathogenesis remains to be clarified entirely. Immune cells have been found to perform an essential function during the onset and progression of IVDD in recent years. Therefore, we explored the association between immune cell characteristics and IVDD through Mendelian randomization (MR) analysis and further delved into the mediating role of potential metabolites. Based on the MR analysis, the association of 731 immune cell phenotypes and 1400 metabolites on IVDD were assessed. Single nucleotide polymorphisms were closely associated the expression levels of immune cell characteristics and the concentrations of metabolites and have been used as instrumental variables for deducing them as risk factors or protective factors for IVDD. In addition, mediation analyses have been performed to identify potential metabolite mediators between immune cell characteristics and IVDD. MR analysis identified 27 immune cell phenotypes and 79 metabolites significantly associated with IVDD. In addition, mediation analysis was performed by selecting the immune cell phenotype that most significantly increased the risk of IVDD - CD86 on monocytes. A total of 4 metabolite-mediated mediation relationships were revealed (3 b-hydroxy-5-cholenoic acid, X-22509, N-acetyl-L-glutamine, and N2-acetyl, N6, N6-dimethyllysine). The findings of this analysis identified underlying association between immune cell phenotypes, metabolite, and IVDD that may serve as predictive and prognostic clinical biomarkers and benefit IVDD pathogenesis research. [ABSTRACT FROM AUTHOR]

To discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach. Genome-wide association study. Not applicable. A discovery cohort of adult female childhood cancer survivors from the pan-European PanCareLIFE cohort (n = 743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nervous system or total body irradiation, or stem cell transplantation. Replication was attempted in the US-based St. Jude Lifetime Cohort (n = 391; median age: 31.3 years). Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the interindividual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions, and cyclophosphamide equivalent doses were used to quantify alkylation agent exposure. Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function, and the findings were combined in a meta-analysis. Three genome-wide significant (<5.0 × 10−8) and 16 genome-wide suggestive (<5.0 × 10−6) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. On the basis of the effect allele frequency (EAF) (>0.01 if not genome-wide significant), and biologic relevance, 15 single nucleotide polymorphisms were selected for replication. None of the single nucleotide polymorphisms were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated with borderline genome-wide statistical significance (reference/effect allele: C/T; effect allele frequency: 0.04, beta (SE): −0.484 (0.091). This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment because the findings of this genome-wide association study were not statistically significant replicated in the replication cohort. Suggestive evidence for the potential importance of 1 variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. Because the population of childhood cancer survivors is increasing, large-scale and systematic research is needed to identify genetic variants that could aid predictive risk models of gonadotoxicity as well as fertility preservation options for childhood cancer survivors. [ABSTRACT FROM AUTHOR]

• Brown Planthopper is a serious threat to rice crop, posing a significant risk to food security. • To combat the damage, molecular breeding stands as an efficient approach by utilizing resistance genes. • Accordingly, a sophisticated marker assisted breeding technique was employed with SSRs and SNPs to introduce BPH genes from M229 and 10–3 donors into susceptible Telangana Sona. • Five backcross lines (BC 1 (a)−14, BC 1 (a)−19, BC 1 (b)−2, BC 1 (b)−4, BC 1 (b)−5) from both the crosses were identified as potential materials, displaying grain characteristics similar to Telangana Sona. Brown Planthopper (BPH) is one of the most destructive insect pests of rice that threatens food security. Molecular breeding through the use of resistance genes per se would be an economic and efficient way to combat the damage caused by BPH. Telangana Sona (TS) is an elite, popular and a high yielding rice variety susceptible to the infestation of BPH causing severe yield losses. In the current investigation, a marker-assisted backcross breeding approach using gene-specific Simple Sequence Repeats (SSRs) and designed Single Nucleotide Polymorphisms (SNPs) was employed to incorporate BPH resistance genes from the donor lines, M229 and 10–3 into TS. Foreground selection using gene-specific SSRs pinned down one plant (BC 1 (a)-19) from TS//TS/M229 cross with qBph-3–1 and Bph33(t) genes/QTLs, while, six plants of TS//TS/10–3 cross had Bph33(t) gene. Validation of BC 1 F 1 plants with designed SNPs altogether identified three (BC 1 (a)-14, BC 1 (a)-18, BC 1 (a)-19) from TS//TS/M229 and three lines (BC 1 (b)-2, BC 1 (b)-4, BC 1 (b)-5) from TS//TS/10–3 cross positive for snpOS00915, snpOS00922 and snpOS00923. All these lines were also found to be phenotypically resistant to BPH as screened using a modified mass tiller screening method. Altogether, foreground selection coupled with stringent phenotypic selection and agro-morphological evaluation led to the identification of two backcross lines (BC 1 (a)-14 and BC 1 (a)-19) from TS//TS/M229 and three (BC 1 (b)-2, BC 1 (b)-4, BC 1 (b)-5) from TS//TS/10–3 that had grain type characteristics similar to TS that can be potentially used as breeding material for further backcrossing and advancing for near isogenic lines development. The study demonstrates the potential efficacy of marker-assisted selection deployed with both SSRs and SNPs that can be employed in breeding for BPH-resistant varieties. [ABSTRACT FROM AUTHOR]

Anthocyanin-rich 'blue maize' is emerging as a superfood worldwide. Traditionally maize grains lack anthocyanin, thus warrant attention from the breeders. Here, full-length 4467 bp Anthocyanin1 (A1) gene was sequenced among five wild-type (A1) and five mutant (a1) maize inbreds. A set of 21 InDel-based markers was developed and used for studying allelic diversity among 28 wild-type and 20 mutant-type inbreds. The major allele frequency ranging 0.417–0.938 had polymorphism information content ranging 0.110–0.574. Phylogenetic analysis categorized 48 inbreds into two clusters and 47 haplotypes. The epimerase domain of the Nicotinamide adenine dinucleotide (NAD)-dependent epimerase family was identified as a major functional domain of 357 amino acid long dihydroflavonol-4-reductase protein. Two polymorphisms viz. , (i) G (wild-type) to T (mutant-type) single nucleotide polymorphism (SNP) in the promoter, and (ii) 712 bp or 7 bp InDel (insertion in mutant) in exon-4 differentiated the wild-type and mutant allele. Two breeder-friendly PCR-based codominant markers viz., a gene-based allele-specific Cleaved amplified polymorphic sequence (CAPS) marker (MGU-A1–1053) and a functional InDel-based marker (MGU-A1–2840), were developed and validated among 48 inbreds and four F 2 populations. These markers can be effectively utilized in genomics-assisted breeding for blue maize that holds great potential to address malnutrition through a sustainable and cost-effective approach. [Display omitted] • An SNP (G/T) & an Indel (7 bp/712 bp) differentiated wild and mutant alleles of A1. • Two breeder-friendly gene-based markers for A1 were developed. • Both the markers were validated in 48 diverse inbreds and four F 2 populations. • 21 A1 -based markers revealed 47 haplotypes among diverse maize inbreds. • The study assumes great significance in molecular breeding for blue maize hybrids. [ABSTRACT FROM AUTHOR]

After burn injury there is considerable variation in scar outcome, partially due to genetic factors. Scar vascularity is one characteristic that varies between individuals, and this study aimed to identify genetic variants contributing to different scar vascularity outcomes. An exome-wide array association study and gene pathway analysis was performed on a prospective cohort of 665 patients of European ancestry treated for burn injury, using their scar vascularity (SV) sub-score, part of the modified Vancouver Scar Scale (mVSS), as an outcome measure. DNA was genotyped using the Infinium HumanCoreExome-24 BeadChip, imputed to the Haplotype Reference Consortium panel. Associations between genetic variants (single nucleotide polymorphisms) and SV were estimated using an additive genetic model adjusting for sex, age, % total body surface area and number of surgical procedures, utilising linear and multinomial logistic regression. No individual genetic variants achieved the cut-off threshold for significance. Gene sets were also analysed using the Functional Mapping and Annotation (FUMA) platform, in which biological processes indirectly related to angiogenesis were significantly represented. This study suggests that SNPs in genes associated with angiogenesis may influence SV, but further studies with larger datasets are essential to validate these findings. [Display omitted] • 665 burn patients genotyped and imputed for an association study. • Associations made between gene variants and scar vascularity. • No individual genetic variants reached significance due to sample size. • Gene set analysis found 8 gene significant sets, some involved in angiogenesis. • Largest association study on burn cohort to date. [ABSTRACT FROM AUTHOR]

Phylogenetic analysis based on single-nucleotide polymorphism (SNP)-based through whole-genome sequencing is recognized as the standard method for probing nosocomial transmission. However, the application of WGS is constrained by the high cost of equipment and the need for diverse analysis tools, which limits its widespread use in clinical laboratory settings. In Japan, the prevalent use of PCR-based open reading frame typing (POT) for tracing methicillin-resistant Staphylococcus aureus (MRSA) transmission routes is attributed to its simplicity and ease of use. Although POT's discriminatory power is considered insufficient for nosocomial transmission analysis, conclusive data supporting this notion is lacking. This study assessed the discriminatory capabilities of SNP analysis and POT across 64 clinical MRSA strains. All 21 MRSA strains of ST5/SCC mec IIa, having more than 16 SNPs, demonstrated distinct clones. Conversely, two strains shared the same POT number and were identified as group A. Among the 12 MRSA strains of ST8/SCC mec IVl with over nine SNPs, five fell into POT group B, and five into POT group C. All four MRSA strains of ST8/SCC mec IVa were classified into POT group D, although they included strains with more than 30 SNPs. Among the 27 MRSA strains of ST1/SCC mec IVa, 14 were classified into POT group E. However, except for two clusters (each comprising two or three strains), all had SNP counts >10 (Fig. 1-D). SNP analysis of MRSA in CC1/SCCmec IV showed that several strains had the same number of SNPs in POT number (106-183-37), even among bacteria with >100 SNPs, indicating POT's limited use in detailed nosocomial transmission analysis. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) pinpointed gastric cancer (GC)-associated single-nucleotide polymorphisms (SNPs) and other gene variants not only in genes of the human host but also in genes of the bacterial pathogen Helicobacter pylori. Functional studies unraveled the underlying mechanisms by which SNPs in H. pylori virulence factors CagA and serine protease HtrA promote GC development. The 171L/S SNP in HtrA originated in Asia 60 000 to 45 000 years ago after the human migration out-of-Africa and spread to all continents except Africa; the EPIYT mutation in CagA arose before the out-of-Africa migration. Several single-nucleotide polymorphisms (SNPs) in human chromosomes are known to predispose to cancer. However, cancer-associated SNPs in bacterial pathogens were unknown until discovered in the stomach pathogen Helicobacter pylori. Those include an alanine-threonine polymorphism in the EPIYA-B phosphorylation motif of the injected effector protein CagA that affects cancer risk by modifying inflammatory responses and loss of host cell polarity. A serine-to-leucine change in serine protease HtrA is associated with boosted proteolytic cleavage of epithelial junction proteins and introduction of DNA double-strand breaks (DSBs) in host chromosomes, which co-operatively elicit malignant alterations. In addition, H. pylori genome-wide association studies (GWAS) identified several other SNPs potentially associated with increased gastric cancer (GC) risk. Here we discuss the clinical importance, evolutionary origin, and functional advantage of the H. pylori SNPs. These exciting new data highlight cancer-associated SNPs in bacteria, which should be explored in more detail in future studies. [ABSTRACT FROM AUTHOR]

Bipolar disorder is a complex and severe mental illness characterised by manic and depressive episodes that can be triggered and exacerbated by psychosocial, environmental, and biological stressors. Genetic variations are a risk factor for bipolar disorder. However, the identification of the exact gene variants and genotypes remains complex. This study, therefore, aims to identify the potential association between genotypes of analysed single nucleotide polymorphisms and the presence of a stressor in bipolar disorder patients. We analysed 114 single nucleotide polymorphisms (SNPs) from bipolar and stress-related candidate genes in 550 patients with bipolar disorders (60.36 % females and 39.64 % male). We compared SNPs of patients reporting the presence (40.73 %) or absence of stressors (59.27 %) before the first episode using the Persons Chi-square test and Bayes Factor t -test. The genotyping of 114 SNPs was done using TaqMan assays. Statistical analysis was done using Statistica 13.3 software (StatSoft Poland, Krakow, Poland), R programming, and G*Power statistics. We found significant differences in genotype distribution (p < 0.05) in 6 polymorphisms (AVPRIB /rs28536160, FKBP4 /rs2968909, ADRA2A /rs3750625, 5HTR2A /rs6311, 5HTR2A /rs6313, and GLCCI1 /rs37972) when comparing BD patient with and without stressor with a small effect of d = 0.2. Of these, two gene variants (ADRA2A /rs3750625/AC and AVPRIB /rs28536160/CT) with minor alleles formed an association with the presence of a stressor prior to the disease onset and favoured the alternative hypothesis using Bayes Factor Analysis t -test for hypothesis testing. This study presents a novel association of ADRA2A /rs3750625/AC and AVPR1B /rs28536160/CT gene variants in stress-related bipolar disorder with the AC genotype of ADRA2A /rs3750625 constituting a risk genotype and CT of AVPR1B /rs28536160 constituting a protective genotype. However, further functional analysis is required to fully understand their clinical and biological significance and interaction. [Display omitted] • This study identified novel associations between specific gene variants (ADRA2A /rs3750625/AC and AVPRIB /rs28536160/CT) with stress-related bipolar disorder. • These less commonly observed gene variants, contribute to the understanding of gene-environment interactions in bipolar disorder. • The findings underscore the need for further functional studies to understand the clinical and biological significance of these gene variants and their interaction with stress in bipolar disorder. [ABSTRACT FROM AUTHOR]

Previous observational studies have suggested that there appears to be a close association between mitochondrial function and psychiatric disorders, but whether a causal role exists remains unclear. We extracted genetic instruments for 67 mitochondrial-related proteins and 10 psychiatric disorders from publicly available genome-wide association studies, and employed five distinct MR methods and false discovery rate correction to detect causal associations between them. Additionally, we conducted a series of sensitivity tests and additional model analysis to ensure the robustness of the results. For potential causal associations, we further performed reverse MR analyses to assess the impact of reverse causality. We identified a total of 2 significant causal associations and 24 suggestive causal associations. Specifically, Phenylalanine-tRNA ligase was found to increase the risk of Alzheimer's disease, while Mitochondrial glutamate carrier 2 decreased the risk of autism spectrum disorder. Furthermore, there was no evidence of significant pleiotropy, heterogeneity, or reverse causality. This study was limited to individuals of European ancestry, and the conclusions drawn are merely revelatory. This study provides novel insights into the relationship between mitochondria and psychiatric disorders, as well as the pathogenesis and treatment strategies for psychiatric disorders. • Provided evidence for the causal association between mitochondrial function and psychiatric disorders. • Performed analyses utilizing multiple large-scale genome-wide association study databases. • Offered novel insights into the pathogenesis and therapeutic strategies for psychiatric disorders. • Emphasized the potential of genomics research. [ABSTRACT FROM AUTHOR]

We assessed the association of prescription data with clinical manifestations and polygenic risk scores (PRS) in patients with bipolar I disorder. We enrolled 1471 individuals with BID and divided them into several groups according to treatment options and clinical manifestations. BD-PRS of each patient was calculated using the Psychiatric Genomics Consortium data. Data on single nucleotide polymorphisms, clinical manifestations, and prescriptions were extracted from BiGS. Chronicity, suicidality, substance misuse, mixed symptoms, and deterioration of life functioning were significantly more severe in the group that was not prescribed any mood stabilizers (MS). Chronicity, psychotic symptoms, suicidality, and deterioration of life functioning were significantly severe in the group that received two or more antipsychotics (APs). BD-PRS between the group with AP(s) only and that with other treatment options significantly differed. BD-PRS of the group with AP(s) only was significantly lower than that with other treatment options. Our linear regression results showed that high severity of particular clinical aspects, lower BD-PRS, and prescriptions with fewer MSs or more APs were independently associated with poor life functioning. This study had a cross-sectional design, without differentiating the bipolar phase, which could influence our results. Poor life functioning in patients with BID was associated with a high severity of particular clinical aspects, BD-PRS, and prescriptions including fewer MSs or more APs. BD-PRS was significantly higher in the group receiving only AP(s) than that in the groups receiving other drugs. • Particular clinical aspects were significantly more severe in the group that was not prescribed any mood stabilizers (MS). • Particular clinical aspects were significantly severe in the group that received two or more antipsychotics (APs). • Poor life functioning was associated with a high severity of particular clinical aspects, BD-PRS, and some prescriptions. • BD-PRS was higher in the group receiving only AP(s) than that in the groups receiving other drugs. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphism (SNP), as one of the key components of the genetic factors, is important for disease detection and early screening of hereditary diseases. Current SNP genotyping methods require laboratory instruments or long operating times. To facilitate the diagnosis of hereditary diseases, we developed a new method referred to as the LwaCas13a-based SNP genotyping platform (Cas13a platform), which is useful for detecting disease-related SNPs. We report a CRISPR/Cas13a-based SNP genotyping platform that couples recombinase-aided amplification (RAA), T7 transcription, and Leptotrichia wadei Cas13a (LwaCas13a) detection for simple and fast genotyping of human disease-related SNPs. We used this Cas13a platform to identify 17 disease-related SNPs, demonstrating that position 2 in gRNA is suitable for the introduction of additional mismatches to achieve high discrimination in genotyping across a wide range of SNP targets. The discrimination specificity of 17 SNPs was improved 3.0–35.1-fold after introducing additional mismatches at position 2 from the 5′-end. We developed a method, which has a lower risk of cross-contamination and operational complexity, for genotyping SNPs using human saliva samples in an one-pot testing that delivers results within 60 min. Compared to TaqMan probe qPCR, RFLP, AS-PCR and other SNP genotyping methods, the Cas13a platform is simple, rapid and reliable, expanding the applications of the CRISPR/Cas system in nucleic acid detection and SNP genotyping. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is considerably heterogeneous in terms of comorbidities, which may hamper the disentanglement of its biological mechanism. In a previous study, we classified the lifetime trajectories of MDD-related multimorbidities into seven distinct clusters, each characterized by unique genetic and environmental risk-factor profiles. The current objective was to investigate genome-wide gene-by-environment (G × E) interactions with childhood trauma burden, within the context of these clusters. We analyzed 77,519 participants and 6,266,189 single-nucleotide polymorphisms (SNPs) of the UK Biobank database. Childhood trauma burden was assessed using the Childhood Trauma Screener (CTS). For each cluster, Plink 2.0 was used to calculate SNP × CTS interaction effects on the participants' cluster membership probabilities. We especially focused on the effects of 31 candidate genes and associated SNPs selected from previous G × E studies for childhood maltreatment's association with depression. At SNP-level, only the high-multimorbidity Cluster 6 revealed a genome-wide significant SNP rs145772219. At gene-level, MPST and PRH2 were genome-wide significant for the low-multimorbidity Clusters 1 and 3, respectively. Regarding candidate SNPs for G × E interactions, individual SNP results could be replicated for specific clusters. The candidate genes CREB1, DBH , and MTHFR (Cluster 5) as well as TPH1 (Cluster 6) survived multiple testing correction. CTS is a short retrospective self-reported measurement. Clusters could be influenced by genetics of individual disorders. The first G × E GWAS for MDD-related multimorbidity trajectories successfully replicated findings from previous G × E studies related to depression, and revealed risk clusters for the contribution of childhood trauma. • First G × E GWAS with childhood trauma for MDD-related multimorbidity trajectories. • Most G × E findings for high MDD-multimorbidity Clusters 5–6. • Significant correlation between cluster probability and CTS (high vs low risk clusters). • stronger genetic findings in the clusters with higher childhood trauma burden. • Differential effects of candidate genes in different comorbidity clusters. [ABSTRACT FROM AUTHOR]

Aging affects all organs. Arteries, in particular, are among the most affected. Vascular aging (VA) is defined as age-associated changes in function and structure of vessels. Classical VA phenotypes are carotid intima-media thickness (IMT), carotid plaque (CP), and arterial stiffness (STIFF). Individuals have different predisposition to these VA phenotypes and their associated risk of cardiovascular events. Some develop an early vascular aging (EVA), and others are protected and identified as having supernormal vascular aging (SUPERNOVA). The mechanisms leading to these phenotypes are not well understood. In the Northern Manhattan Study (NOMAS), we found genetic variants in the 7 Sirtuins (SIRT) and 5 Uncoupling Proteins (UCP) to be differently associated with risk to developing VA phenotypes. In this article, we review the results of genetic-epidemiology studies to better understand which of the single nucleotide polymorphisms (SNPs) in SIRT and UCP are responsible for both EVA and SUPERNOVA. [Display omitted] • Vascular aging (VA) is an age-associated changes in function and structure of vessels. • Individuals have different predisposition to VA phenotypes. • Some individuals develop an early vascular aging (EVA). • Some individuals are protected and identified as having supernormal vascular aging (SUPERNOVA). • Single nucleotide polymorphisms in SIRT and UCP are responsible for both EVA and SUPERNOVA. [ABSTRACT FROM AUTHOR]

The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. The objective of this study was to assess the effect of using or not using the genotypes of the parents of a cow for imputing SNPs on the estimation of genomic inbreeding coefficients of cows. Imputation (i.e., genotyped plus imputed) genotypes from 68,127 Italian Holstein dairy cows registered in the Italian National Association of Holstein, Brown, and Jersey Breeders were analyzed. Cows were genotyped with the high-density (HD) Illumina Infinium BovineHD BeadChip and GeneSeek Genomic Profiler HD-150K, and the medium-density (MD) GeneSeek Genomic Profiler 3, GeneSeek Genomic Profiler 4, GeneSeek MD, and the Labogena MD. To assess differences among estimators, genomic inbreeding coefficients were estimated with 4 PLINK v1.9 estimators (F, F hat1 ,F hat2 , andF hat3), 2 genomic relationship matrix- (grm) based estimators (F grm and F grm2 , with the latter including also pedigree information), and one estimator of runs of homozygosity (ROH; F ROH). Assuming that the correct genomic inbreeding coefficients should be those estimated from genotyped SNPs, a comparison of the genomic inbreeding coefficients estimated either with the genotyped SNPs or the SNPs after imputation was made. Information on the presence or absence of genotypic information from sire, dam, and maternal grandsire during the imputation was investigated. Genomic inbreeding coefficients estimated with genotyped SNPs or SNPs after imputation were consistent for F, F hat3 , F grm2 , and F ROH , when at least one of the parents was genotyped. Biased (mainly higher) genomic inbreeding coefficients of imputation SNPs were observed in cows that were genotyped with MD SNP panels whose SNPs were poorly represented in the selected imputation SNP dataset and also did not have their parents genotyped, when compared with what would be expected based on actual genotype data. For cows genotyped with MD the estimators F hat1 , F hat2 , and F grm provided higher genomic inbreeding coefficients of imputation SNPs even with both parents and the maternal grandsire genotyped. Overall, F ROH was the most robust estimator, followed by F and F hat3. Our findings suggest that SNPs selection, parental genotyping and estimator should be considered for designing imputation strategies in dairy cattle for estimating genomic inbreeding with imputation SNPs. For computing genomic inbreeding coefficients, it is recommendable to have at least one parent genotyped and use an ROH-based estimator. [ABSTRACT FROM AUTHOR]

Many previously unsuspected single-nucleotide polymorphisms (SNPs) can cause phenotypic variation by affecting transcript splicing and protein translation. Small RNAs are more challenging to study than protein-coding genes but are important contributors to phenotypic evolution. Structural variation (e.g., transposable element insertion, gene copy number variation, chromosomal inversion) is an extremely common source of phenotypic divergence. The sequence composition of supergenes that control complex multi-trait polymorphisms has been elucidated at an unprecedented pace by long-read sequencing. Taxon-specific genes, including non-coding RNAs, can have a profound impact on lineage-specific phenotypic diversification and adaptation. It has been well documented that mutations in coding DNA or cis -regulatory elements underlie natural phenotypic variation in many organisms. However, the development of sophisticated functional tools in recent years in a wide range of traditionally non-model systems have revealed many 'unusual suspects' in the molecular bases of phenotypic evolution, including upstream open reading frames (uORFs), cryptic splice sites, and small RNAs. Furthermore, large-scale genome sequencing, especially long-read sequencing, has identified a cornucopia of structural variation underlying phenotypic divergence and elucidated the composition of supergenes that control complex multi-trait polymorphisms. In this review article we highlight recent studies that demonstrate this great diversity of molecular mechanisms producing adaptive genetic variation and the panoply of evolutionary paths leading to the 'grandeur of life'. [ABSTRACT FROM AUTHOR]

Studies of the dark genome are providing important insights into human pain insensitivity and chronic pain conditions. Long noncoding RNAs (lncRNAs), a major portion of the dark genome, have diverse cellular functions and can dynamically regulate pain thresholds. Often dismissed as merely fine tuners of gene expression, some lncRNAs instead play a major role in chronic pain mechanisms. Precise spatial and temporal expression patterns and low expression levels make some lncRNAs viable analgesic drug targets. RNA-targeted precision therapeutics may have fewer side effects than targeting broadly and highly expressed proteins. The dark genome, the nonprotein-coding part of the genome, is replete with long noncoding RNAs (lncRNAs). These functionally versatile transcripts, with specific temporal and spatial expression patterns, are critical gene regulators that play essential roles in health and disease. In recent years, FAAH-OUT was identified as the first lncRNA associated with an inherited human pain insensitivity disorder. Several other lncRNAs have also been studied for their contribution to chronic pain and genome-wide association studies are frequently identifying single nucleotide polymorphisms that map to lncRNAs. For a long time overlooked, lncRNAs are coming out of the dark and into the light as major players in human pain pathways and as potential targets for new RNA-based analgesic medicines. [ABSTRACT FROM AUTHOR]

Antipsychotics with weight gain as side effect and vitamin D receptor dysfunction associated with single nucleotide polymorphisms (VDR SNPs) may have different effects on vitamin D status. Hence, present study aimed to investigate the relationship between vitamin D with body mass index (BMI), antipsychotics and VDR SNPs (rs2228570, rs1544410, rs7975232 and rs731236) in Malaysian patients with schizophrenia. Serum vitamin D level was measured using competitive enzyme–linked immunosorbent assay kit. VDR SNPs were analyzed using polymerase chain reaction–restriction fragment length polymorphism. We found significantly lower serum vitamin D level in patients with schizophrenia (p < 0.01), especially those taking atypical antipsychotics (p = 0.02) and combined antipsychotics (p = 0.02) and obese (BMI ≥27.5 kg/m2) patients (p = 0.04) after adjustment for covariates. For VDR SNPs, the CT genotype of rs1544410, CA genotype of rs7975232, and AA and AG genotypes of rs731236 may contribute to the significant decreased serum vitamin D level in patients (p < 0.05). Nevertheless, these relationships may differ by populations or medical conditions. The hypotheses of volumetric dilution and sequestration of vitamin D may explain the lower vitamin D level in obese patients. In addition, lifestyle factors such as poor diet and lack of physical activity with less sunlight exposure may cause reduced vitamin D level among patients. As patients in present study were prescribed with various antipsychotics, the effect of each antipsychotic on vitamin D level could not be determined. Thus, future studies should investigate the effect of different types of antipsychotics and obesity on vitamin D level in schizophrenia. • Patients with schizophrenia were having significant reduced serum vitamin D level. • Atypical and combined antipsychotics may be linked with decreased vitamin D level. • Obese patients were having lower vitamin D level after covariate adjustment. • Certain genotypes of VDR SNPs may contribute to lower vitamin D level in patients. [ABSTRACT FROM AUTHOR]

As the stress-inducible isoform of the heat-shock protein 90 (HSP90), the HSP90AA1 gene encodes HSP90α and plays an important role in heat stress (HS) response. Therefore, this study aimed to investigate the role of the HSP90AA1 gene in cellular responses during HS and to identify functional SNPs associated with thermotolerance in Holstein cattle. For the in vitro validation experiment of acute HS, cells from the Madin-Darby bovine kidney cell line were exposed to 42°C for 1 h, and various parameters were assessed, including cell apoptosis, cell autophagy, and the cellular functions of HSP90α by using its inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). Furthermore, the polymorphisms identified in the HSP90AA1 gene and their functions related to HS were validated in vitro. Acute HS exposure induced cell apoptosis, cell autophagy, and upregulated expression of the HSP90AA1 gene. Inhibition of HSP90α by 17-AAG treatment had a significant effect on the expression of the HSP90α protein and increased cell apoptosis. However, autophagy decreased in comparison to the control treatment when cells were exposed to 42°C for 1 h. Five SNPs identified in the HSP90AA1 gene were significantly associated with rectal temperature and respiration score in Holstein cows, in which the rs109256957 SNP is located in the 3′ untranslated region (3′ UTR). Furthermore, we demonstrated that the 3′ UTR of HSP90AA1 is a direct target of bta-miR-1224 by cell transfection with exogenous microRNA (miRNA) mimic and inhibitor. The luciferase assays revealed that the SNP rs109256957 affects the regulation of bta-miR-1224 binding activity and alters the expression of the HSP90AA1 gene. Heat stress–induced HSP90AA1 expression maintains cell survival by inhibiting cell apoptosis and increasing cell autophagy. The rs109256957 located in the 3′ UTR region is a functional variation and it affects the HSP90AA1 expression by altering its binding activity with bta-miR-1224, thereby associating with the physiological parameters of Holstein cows. [ABSTRACT FROM AUTHOR]

The health benefits conferred by probiotics is specific to individual probiotic strains, highlighting the importance of identifying specific strains for research and production purposes. Streptococcus thermophilus CICC 6038 and Lactobacillus delbrueckii ssp. bulgaricus CICC 6047 are exceedingly valuable for commercial use with an excellent mixed-culture fermentation. To differentiate these 2 strains from other S. thermophilus and L. delbrueckii ssp. bulgaricus , a specific, sensitive, accurate, rapid, convenient, and cost-effective method is required. In this study, we conducted a pan-genome analysis of S. thermophilus and L. delbrueckii ssp. bulgaricus to identify species-specific core genes, along with strain-specific SNPs. These genes were used to develop suitable PCR primers, and the conformity of sequence length and unique SNPs was confirmed by sequencing for qualitative identification at the strain level. The results demonstrated that SNPs analysis of PCR products derived from these primers could distinguish CICC 6038 and CICC 6047 accurately and reproducibly from the other strains of S. thermophilus and L. delbrueckii ssp. bulgaricus , respectively. The strain-specific PCR method based on SNPs herein is universally applicable for probiotics identification. It offers valuable insights into identifying probiotics at the strain level that is fit-for-purpose in quality control and compliance assessment of commercial dairy products. [ABSTRACT FROM AUTHOR]

POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/− anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival. • POLE/D1pd is associated with male sex, younger age, right-sided primary tumor, and uncommon KRAS mutations in mCRC. • A significantly higher ORR is observed for POLE/D1pd compared to dMMR/MSI-H mCRC treated with ICIs. • POLE/D1pd mCRC exposed to ICIs have a higher PFS and OS than dMMR/MSI-H. • POLE/D1pd mCRCs are enriched in single nucleotide variant while dMMR/MSI-H are enriched in frameshift mutations. • Non-responder POLEpd mCRCs have lower TMB than responders and lower intensity of the POLE signature. [ABSTRACT FROM AUTHOR]

Scholars in the medical field have described medical writing as particularly challenging and have called for instructional support for both novice writers and L2-English medical scholars. One of the main challenges is that there exist conventionalized terms that express a wide range of concepts, and any inappropriate use of such terms can lead to miscommunication with real consequences for practitioners, researchers, and the public. Therefore, the investigations of such conventionalized expressions could constitute a good starting point in addressing some of the challenges in medical writing. Thus, the present study investigates the use of multiword collocations (a type of register-specific word combinations) in medical research articles and the medical case reports, using two corpora of over a million words, representative of the two registers. The subsequent structural and functional analyses revealed that the majority of multiword collocations in both registers consisted of complex noun phrases mostly formed through noun premodifications (e.g., fine needle aspiration, fluorescence in situ hybridization, single nucleotide polymorphisms). The identified sequences served distinct discourse functions that reflect the differences in the specific communicative functions of the two registers. Some pedagogical applications are suggested in this paper. • Specialized corpora yield multiword sequences with register-specific discourse functions. • Delta P can measure the collocational strength of sequences longer than two words. • The use of multiword collocations varies across registers even within a same discipline. • Noun premodification is key in achieving conciseness in medical writing. [ABSTRACT FROM AUTHOR]

Inorganic arsenic species exist in the environment as a result of both natural sources, such as volcanic and geothermal activities, and geological formations, as well as anthropogenic activities, including smelting, exploration of fossil fuels, coal burning, mining, and the use of pesticides. These species deposit in water, rocks, soil, sediments, and the atmosphere. Arsenic-contaminated drinking water is a global public health issue because of its natural prevalence and toxicity. Therefore, chronic exposure to arsenic can have deleterious effect on humans, including cancer and other diseases. This work describes the mechanisms of environmental exposure to arsenic, molecular regulatory factors involved in its metabolism, genetic polymorphisms affecting individual susceptibility and the toxic effects of arsenic on human health (oxidative stress, DNA damage and cancer). We conclude that the role of single nucleotide variants affecting urinary excretion of arsenic metabolites are highly relevant and can be used as biomarkers of the intracellular retention rates of arsenic, showing new avenues of research in this field. • Inorganic arsenic exposure and its impact on the human health. • Genetic polymorphisms and it role on urinary excretion of arsenic metabolites. • Susceptibility and potential risk of toxic effects by ingestion of inorganic arsenic. [ABSTRACT FROM AUTHOR]

ERCC1 rs11615 and ERCC2 rs238406 single nuclear polymorphism (SNPs) are known for their association with treatment outcome, likely related to radiosensitivity of both tumor and normal tissue in patients with non-small-cell lung cancer. This study aimed to review the effect of 1) these ERCC1/2 SNPs and 2) other SNPs of DNA repair genes on radiation pneumonitis (RP) in patients with lung cancer. SNPs of our interest included ERCC1 rs11615 and ERCC2 rs238406 and other genes of DNA repair pathways that are functional and biologically active. DNA repair SNPs reported by at least two independent studies were pooled for meta-analysis. The study endpoint was radiation pneumonitis (RP) after radiotherapy. Recessive, dominant, homozygous, heterozygous, and allelic genotype models were used where appropriate. A total of 16 studies (3080 patients) were identified from the systematic review and 12 studies (2090 patients) on 11 SNPs were included in the meta-analysis. The SNPs were ATM rs189037, ATM rs373759, NEIL1 rs4462560, NEIL1 rs7402844, APE1 rs1130409, XRCC3 rs861539, ERCC1 rs11615, ERCC1 rs3212986, ERCC2 rs238406, ERCC2 rs13181, and XRCC1 rs25487. ERCC1 rs11615 (236 patients) and ERCC2 rs238406 (254 patients) were not significantly associated with RP. Using the allelic model, the G allele for NEIL1 gene was significantly associated with a reduced odds of developing symptomatic (grade ≥2) RP compared to the C allele for rs7402844 (OR 0.70, 95% CI: 0.49, 0.99, P = 0.04). Similarly, the T allele for APE1 gene was significantly associated with a reduced odds of developing symptomatic (grade ≥2) RP compared to the G allele for rs1130409 (OR 0.59, 95% CI: 0.43, 0.81, P = 0.001). Genetic variation in the DNA repair pathway genes may play a significant role in the risk of developing radiation pneumonitis in patients with lung cancer. Further studies are needed on genotypic features of DNA repair pathway genes and their association with treatment sensitivity, as such knowledge may guide personalized radiation dose prescription. • A total of 16 studies (3080 patients) were identified from the systematic review. • Genetic variation in NEIL1 rs7402844 and APE1 rs1130409 may predict RP. • Need to further elucidate relationship between ERCC1 rs11615, ERCC2 rs238406 with RP. [ABSTRACT FROM AUTHOR]

• Eleven UGT SNP loci were simultaneously assessed and a comprehensive analysis of their effects conducted, along with clinical factors, on mycophenolic acid metabolism. • Patients who carry the UGT1A9 rs2741049 TT genotype might be at a greater risk of a lower dose-adjusted MPAG C 0. • UGT2B7 rs7662029 GG genotype carriers may face a higher risk of AcMPAG C 0 after high-dose adjustment. This study aimed to evaluate the effects of UDP-glucuronosyltransferase (UGT) polymorphisms on mycophenolic acid (MPA) metabolism in renal transplant patients. A total of 11 single nucleotide polymorphisms (SNPs) of UGT1A1, UGT1A7, UGT1A8, UGT1A9, UGT1A10 , and UGT2B7 were genotyped in 79 renal transplant patients. The associations of SNPs and clinical factors with dose-adjusted MPA area under the plasma concentration-time curve (AUC/D), the dose-adjusted plasma concentration (C 0 /D) of 7-O-MPA-glucuronide (MPAG), and the dose-adjusted plasma concentration (C 0 /D) of acyl MPAG (AcMPAG) were analyzed. In the univariate analysis, UGT1A1 rs4148323, age, and anion gap were associated with MPA AUC/D. MPA AUC/D was higher in patients with the GA genotype of UGT1A1 rs4148323 compared to patients with the GG genotype. UGT1A1 rs4148323, UGT1A9 rs2741049 and clinical factors, including age, serum total bilirubin, adenosine deaminase, anion gap, urea, and creatinine, were associated with MPAG C 0 /D. UGT2B7 rs7438135, UGT2B7 rs7439366, and UGT2B7 rs7662029 also were associated with AcMPAG C 0 /D. Multiple linear regression analysis showed that UGT1A9 rs2741049 and indirect bilirubin were negatively correlated with MPAG C 0 /D (P =.001; P =.039), and UGT2B7 rs7662029 was positively correlated with AcMPAG C 0 /D (P =.008). This study demonstrates a significant influence of UGT1A9 rs2741049 and UGT2B7 rs7662029 polymorphisms on the metabolism of MPA in vivo. [ABSTRACT FROM AUTHOR]

This study aims to investigate the association between Body Mass Index (BMI) and sex hormone levels utilizing a cross-sectional study design alongside Mendelian randomization (MR) analysis. A cross-sectional study was performed based on National Health and Nutrition Examination Survey (NHANES) 2013–2016. Additionally, a two-sample MR analysis was performed, utilizing Single Nucleotide Polymorphisms (SNPs) associated with BMI identified in a genome-wide association study (GWAS) comprising 339224 individuals. Data on outcomes, including total testosterone (TT, 199569 samples), estradiol (E 2 , 17134 samples), and sex hormone binding globulin (SHBG, 185211 samples), were sourced from the United Kingdom Biobank (UKB). In cross-sectional analysis involving 4092 males, multivariable linear regression demonstrated that each unit increase in BMI was positively correlated with an elevated risk of testosterone deficiency (TD), increased E 2 levels, and a reduced TT, SHBG, free androgen index and TT/E 2. Subsequent quartile division of BMI revealed, through multivariable logistic regression, that higher BMI quartiles were associated with a greater TD risk, elevated E 2 levels, and reduced TT, SHBG, and TT/E 2 levels compared to quartile 1 (P for trend <0.001). In the MR analysis, a causal effect was established, with each unit increase in BMI being associated with decreased TT (β = −0.17; 95 % CI −0.24 to −0.09) and SHBG (β = −0.13; 95 % CI −0.21 to −0.05) levels. Our findings unveil a causal link between BMI and reduced TT and SHBG levels in males. [ABSTRACT FROM AUTHOR]

Despite the high prevalence of comorbid hypertension in patients with major depressive disorder (MDD), the relationship between the two diseases has received little attention. Previous observational studies have descripted the association between MDD and hypertension, the causality from MDD on hypertension remained unknown. The present Mendelian randomization (MR) study aimed to assess the causal effect of MDD on hypertension. A set of genetics instrument was used for analysis, derived from publicly available genetic meta-analysis data. A total of 44 single-nucleotide polymorphisms (SNPs) associated with MDD. The largest genome-wide association study (GWAS) for hypertension (54,358 cases and 408,652 controls) was used to assess the effect of MDD on hypertension. Inverse variance weighted method (IVW), weighted median method (WM), and MR-Egger regression were used for MR analyses. The MR-Egger_intercept test and Cochran's Q statistic were used to determine the pleiotropy and the heterogeneity, respectively. A total of 28 independent and effective MDD genetic instrumental variables were extracted from the hypertension GWAS summary statistics. Pleiotropy analysis suggested no significant pleiotropic variant among the 28 selected MDD genetic instrument variants in hypertension GWAS datasets. As MDD based on genetic changes increased, the risk of hypertension increased using MR-Egger (OR = 1.004436, 95%CI 0.9884666–1.020663, P = 0.5932928), WM (OR = 1.000499, 95%CI 1.0000188–1.000980, P = 0.0416871), and IVW (OR = 1.000573, 95%CI 1.0000732–1.001074, P = 0.0246392). Our results were robust, with no obvious bias based on investigating the single MDD SNP on hypertension. Our result suggested a causal associated between genetically increased MDD and increased hypertension risk in European population. [Display omitted] [ABSTRACT FROM AUTHOR]

Delirium is an acute or subacute change in mental status caused by various factors. We evaluated the causal relationship between leisure sedentary behaviors (LSBs) and delirium. A two-sample Mendelian randomization (MR) study was performed to evaluate the causal relationship between sedentary behaviors (time spent watching television, time spent using computer, and time spent driving) and delirium. Statistical information for the associations between single nucleotide polymorphisms (SNPs) and the traits of interest was obtained from independent consortia that focused on European populations. The dataset for LSBs was acquired from genome-wide association studies (GWAS) comprising a substantial sample size: 437887 samples for time spent watching television, 360,895 for time spent using computer, and 310,555 for time spent driving. A GWAS with 1269 delirium cases and 209,487 controls was used to identify genetic variation underlying the time of LSBs. We used five complementary MR methods, including inverse variance weighted method (IVW), MR-Egger, weighted median, weighted mode, and simple mode. Genetically predicted time spent watching television (odds ratio [OR]: 2.921, 95 % confidence interval [CI]: 1.381–6.179) demonstrated significant association with delirium (P = 0.005), whereas no significant associations were observed between time spent using computer (OR: 0.556, 95 % CI: 0.246–1.257, P = 0.158) and time spent driving (OR: 1.747, 95 % CI: 0.09–3. 40, P = 0.713) and delirium. Sensitivity analyses supported a causal interpretation, with limited evidence of significant bias from genetic pleiotropy. Moreover, our MR assumptions appeared to be upheld, enhancing the credibility of our conclusions. Larger sample sizes are needed to validate the findings of our study. Time spent watching television is a significant risk factor for delirium. Reducing television time may be an important intervention for those at higher risk of delirium. • There is no single drug that can prevent delirium. • A non-pharmacological approach such as monitoring risk factors is recommended. • GWAS database to study the relationship between sedentary behavior and delirium. • Watching television is closely related to delirium. • Preventing, screening, and intervening in delirium can be targeted from the perspective of sedentary behavior. [ABSTRACT FROM AUTHOR]

Symptoms of major depressive disorder (MDD) are commonly assessed using self-rating instruments like the Patient Health Questionnaire-9 (PHQ-9) (current symptoms) and the Composite International Diagnostic Interview Short-Form (CIDI-SF) (worst-episode symptoms). We performed a systematic comparison between them for their genetic architecture and utility in investigating MDD heterogeneity. Using data from the UK Biobank (n = 41,948–109,417), we assessed the single nucleotide polymorphism heritability and genetic correlation (r g) of both sets of MDD symptoms. We further compared their r g with non-MDD traits and used Mendelian randomization to assess whether either set of symptoms has more genetic sharing with non-MDD traits. We also assessed how specific each set of symptoms is to MDD using the metric polygenic risk score pleiotropy. Finally, we used genomic structural equation modeling to identify factors that explain the genetic covariance between each set of symptoms. Corresponding symptoms reported through the PHQ-9 and CIDI-SF have low to moderate genetic correlations (r g = 0.43–0.87), and this cannot be fully attributed to different severity thresholds or the use of a skip structure in the CIDI-SF. Both Mendelian randomization and polygenic risk score pleiotropy analyses showed that PHQ-9 symptoms are more associated with traits that reflect general dysphoria, whereas the skip structure in the CIDI-SF allows for the identification of heterogeneity among likely MDD cases. Finally, the 2 sets of symptoms showed different factor structures in genomic structural equation modeling, reflective of their genetic differences. MDD symptoms assessed using the PHQ-9 and CIDI-SF are not interchangeable; the former better indexes general dysphoria, while the latter is more informative about within-MDD heterogeneity. [ABSTRACT FROM AUTHOR]

To investigate whether the number of years of schooling are causally associated traumatic brain injury (TBI). We aimed to investigate whether the number of years of schooling are causally associated TBI. We investigate the prospective causal effect of years of schooling on TBI using summary statistical data. The statistical dataset comprising years of schooling (n = 293,723) from genome-wide association studies (GWASs) deposited in the UK Biobank was used for exposure. We used the following GWAS available in the FinnGen dataset: individuals with TBI (total = 13,165; control = 136,576; number of single nucleotide polymorphisms [SNPs] = 16,380,088). Seventy significant genome-wide SNPs from GWAS datasets with annotated years of schooling were selected as instrumental variables. The inverse variance weighted method results supported a causal relationship between years of schooling and TBI (odds ratio (OR), 0.78; 95 % confidence interval (CI), 0.62–0.98; P = 0.029). MR-Egger regression showed that polydirectionality was unlikely to bias the results (intercept = 0.007, SE = 0.01, P = 0.484) and demonstrated no causal relationship between years of schooling and TBI (OR, 0.52; 95%CI, 0.17–1.64; P = 0.270). The weighted median method revealed a causal relationship with TBI (OR, 0.73; 95%CI, 0.55–0.98; P = 0.047). A Cochran's Q test and funnel plot did not show heterogeneity nor asymmetry, indicating no directional pleiotropy. The current investigation yields substantiation of a causal association between years of schooling and TBI development. More years of schooling may be causally associated with a reduced risk of TBI, which has implications for clinical and public health practices and policies. • To explore the causal association between years of schooling and traumatic brain injury with Mendelian randomization. • More years of schooling results in a lower risk of traumatic brain injury. • Our data provides the evidence required to develop clinical and public health policies. [ABSTRACT FROM AUTHOR]