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• 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]

Preimplantation genetic testing for monogenic diseases for adult-onset conditions is ethically permissible for various conditions, including when the condition is fully penetrant or confers disease predisposition. The Committee strongly recommends that a genetic counselor experienced with both preimplantation genetic testing for monogenic diseases and assisted reproductive technology therapies counsel patients considering such procedures. [ABSTRACT FROM AUTHOR]

Hereditary or familial cancer syndromes are caused by inherited pathogenic variants in cancer susceptibility genes and are associated with an increased risk of developing malignancies occurring at an earlier age. BRCA-associated Hereditary Breast and Ovarian Cancer and Lynch Syndromes are the most common conditions encountered in gynaecology. Identification presents opportunities to prevent or reduce the risk of cancer, or to detect cancers at earlier stages with improved outcomes. When cancer does occur, there may be options for personalized therapeutic approaches. Cancer prevention invariably requires risk-reducing surgical treatment, which may result in irreversible loss of fertility and premature menopause; issues which must be addressed through a personalized management approach. Regular review with adjustments to plans are required as individuals pass through different reproductive life-stages. Comprehensive management requires a multi-professional approach including specialist genetics input, prevention of cancer by education, modification of risk factors and specific interventions, in addition to psychosocial support. [ABSTRACT FROM AUTHOR]

The U.S. Preventive Services Task Force recommends screening women to identify individuals eligible for genetic counseling based on a priori hereditary breast and ovarian cancer syndrome (HBOC) risk (i.e., risk assessment). However, risk assessment has not been widely integrated into primary care. This qualitative study explored young women's views on implementing routine HBOC risk assessment with a focus on equity and patient-centeredness. We conducted group discussions with young women (aged 21–40 years) receiving care in an integrated health care system. Discussion groups occurred in two phases and used a modified deliberative approach that included a didactic component and prioritized developing consensus. Twenty women participated in one of three initial small group discussions (phase one). All 20 were invited to participate in a subsequent large group discussion (phase two), and 15 of them attended. Key themes and recommendations were as follows. Risk assessment should be accessible, contextualized, and destigmatized to encourage participation and reduce anxiety, particularly for women who do not know their family history. Providers conducting risk assessments must be equipped to address women's informational needs, relieve emotionality, and plan next steps after positive screens. Finally, to minimize differential screening uptake, health care systems must prioritize equity in program design and contribute to external educational and outreach efforts. Young women see pragmatic opportunities for health systems to optimize HBOC screening implementation. [ABSTRACT FROM AUTHOR]

La spondyloarthrite est une maladie à médiation immunitaire caractérisée par une forte héritabilité, comme en témoigne sa fréquente agrégation familiale. Les études familiales offrent donc un outil intéressant pour clarifier les bases génétiques de la spondyloarthrite. Elles ont notamment permis d'évaluer l'importance relative des facteurs génétiques et environnementaux, et d'établir le caractère polygénique de la maladie. Les analyses de liaison sont la méthode privilégiée dans les études familiales en vue d'identifier des facteurs génétiques de prédisposition. Dans la spondyloarthrite, trois études de liaison pangénomiques ont été publiées dans les années 1990, avec malheureusement des résultats peu reproductibles. Abandonnées pendant quelques années au profit des études d'association génome entier cas-témoin, les approches familiales suscitent actuellement un regain d'intérêt, notamment pour détecter des associations avec des variants rares. La présente revue récapitule la contribution des études familiales à la compréhension de la génétique des spondyloarthrites, depuis les études d'épidémiologie génétique jusqu'aux plus récentes analyses de variants rares. Elle met aussi en évidence l'intérêt potentiel de la présence d'antécédents familiaux de spondyloarthrite pour guider le diagnostic et l'identification de patients ayant un risque élevé de déclarer la maladie. Spondyloarthritis (SpA) is an immune-mediated disease characterized by a high heritability, reflected by strong familial aggregation. Therefore, family studies are a powerful tool for elucidating the genetic basis of SpA. First, they helped to assess the relative importance of genetic and environmental factors, and established the polygenic character of the disease. Family-based designs were also historically used to identify genetic factors of susceptibility through linkage analyses. In SpA, three whole genome linkage studies were published in the 1990s, unfortunately with few consistent results. After having been put aside for several years in favour of case-control GWAS, there is a renewed interest in family-based designs in particular to detect rare variant associations. This review aims at summarizing what family studies have brought to the field of SpA genetics, from genetic epidemiology studies to the most recent rare variant analyses. It also highlights the potential interest of family history of SpA to help diagnosis and detection of patients at high risk to develop the disease. [ABSTRACT FROM AUTHOR]

• 5 % of APOE2/E2 homozygotes develop familial dysbetalipoproteinemia (FD). • several gene SNPs are individual additive factors influencing FD development. • unweighted GRS2 is a clinically relevant tool that improves the prediction of FD. Familial dysbetalipoproteinemia (FD) is an autosomal recessive (rarely dominant) inherited disorder that is almost exclusively associated with the apolipoprotein E gene (APOE) variability. Nonetheless, only a small proportion of APOE2/E2 subjects develop the phenotype for mixed dyslipidemia; the context of other trigger metabolic or genetic factors remains unknown. One hundred and one patients with FD and eighty controls (all APOE2/E2 homozygotes; rs429358) were screened for 18 single-nucleotide polymorphisms (SNPs) within the genes involved in triglyceride metabolism. Two SNPs were significantly associated with the FD phenotype (rs439401 within APOE; P < 0.0005 and rs964184 within ZPR1/APOA5/A4/C3/A1 gene cluster; P < 0.0001). Unweighted genetic risk scores - from these two SNPs (GRS2), and, also, additional 13 SNPs with P-value below 0.9 (GRS15) - were created as an additional tool to improve the risk estimation of FD development in subjects with the APOE2/E2 genotype. Both GRS2 and GRS15 were significantly (P < 0.0001) increased in patients and both GRSs discriminated almost identically between the groups (P = 0.86). Subjects with an unweighted GRS2 of three or more had an almost four-fold higher risk of FD development than other individuals (odds ratio (OR) 3.58, 95% confidence interva (CI): 1.78–7.18, P < 0.0005). We identified several SNPs that are individual additive factors influencing FD development. The use of unweighted GRS2 is a simple and clinically relevant tool that further improves the prediction of FD in APOE2/E2 homozygotes with corresponding biochemical characteristics. [ABSTRACT FROM AUTHOR]

The previous lack of national UK guidance on the use of Prenatal and Pre-implantation Genetic Testing (PND and PGT-M) for Monogenic Disorders for Germline Cancer Susceptibility Gene Variants (gCSGV) has led to disparities in care across the UK, and inequitable access to reproductive options for families living with cancer susceptibility syndromes. In 2023, the UK Cancer Genetics Group and Fetal Genomics Group of the British Society of Genetic Medicine developed joint consensus guidance seeking to provide healthcare professionals with a clear counselling framework to support individuals/couples during their reproductive decision-making process. The guidance is for healthcare professionals, individuals and couples with a gCSGV and their families, policy makers and charities supporting people with cancer susceptibility syndromes. Details about the consensus group participants, the main workshop's format, and the pre- and post-workshop nationwide surveys, are available in the full document. [ABSTRACT FROM AUTHOR]

To assess changes in the susceptibility of the caudate nucleus (CN), putamen, and globus pallidus (GP) in patients with neurological and hepatic Wilson's disease (WD) by quantitative susceptibility mapping (QSM). The brain MRI images of 33 patients diagnosed with WD and 20 age-matched controls were analysed retrospectively. All participants underwent brain T1-weighted, T2-weighted, and QSM imaging using a 1.5 T magnetic resonance imaging (MRI) machine. QSM maps were evaluated with the STISuite toolbox. The quantitative susceptibility levels of the CN, putamen, and GP were analysed using region of interest analysis on QSM maps. Differences among neurological WD patients, hepatic patients, and controls were determined. Susceptibility levels were significantly higher for all examined structures (CN, putamen and GP) in patients with neurological WD compared with controls (all p< 0.05) and hepatic WD patients (all p< 0.05). No statistically significant differences were found in susceptibility levels between patients with hepatic WD and controls (all p> 0.05). The QSM technique is a valuable tool for detecting changes in brain susceptibility in WD patients, indicating abnormal metal deposition. Notably, the current findings suggest that neurological WD patients exhibit more severe susceptibility changes compared with hepatic WD patients. Therefore, QSM can be utilised as a complementary method to detect brain injury in WD patients. • Neurological WD patients showed higher brain susceptibility versus hepatic patients. • Positive correlations existed between serum copper and brain susceptibility. • QSM can be utilized as a complementary method to detect brain injury in WD patients. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) relies on myelin for proper functioning. Myelin remodeling is a risk factor for neurometabolic and endocrine malfunction, resulting in cognitive decline and heightened susceptibility to neurological diseases. The plasticity of myelin upon nutrient shifts may lead to dietary and hormonal interventions for preventing and treating neural complications. [ABSTRACT FROM AUTHOR]

Cellular lipids have an enormous diversity in their chemical structures, which affect the physicochemical properties of lipids and membranes, as well as their regulatory roles on protein functions. Here, I review additional roles of lipid structures. Multiple studies show that structural differences affect how lipids, even from the same class, are metabolically converted via distinct pathways. I propose the name "structure-guided metabolic bias" for this phenomenon, and discuss its biological relevance. This metabolic bias seems implicated in the buildup of basic cellular lipid compositions, as well as genetic predisposition to diseases. Thus, guiding metabolic biases is an important function of lipid structures, while having the characteristic of being difficult to study by in vitro biochemical reconstitutions. • Unequal amounts of distinct metabolic products are made from a single lipid. • Lipid chemical structures, such as their acyl-chains, affect this metabolic bias. • Metabolic biases explain some functions of lipid structures. • Mechanisms and tools to study structure-guided metabolic biases are presented. [ABSTRACT FROM AUTHOR]

Current national severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination policy covers children aged >12 years. Unvaccinated, uninfected children remain susceptible to SARS-CoV-2 and play a role in community transmission, as paediatric infection is mostly mild or asymptomatic. To estimate the proportion of susceptible children in a community for public health measures, there is a need to assess the extent of natural infection. We performed a cross-sectional household serosurvey of SARS-CoV-2 antibodies in unvaccinated children aged between 6 and 18 years after the second COVID-19 wave. Anti-SARS-CoV-2 immunoglobin G (IgG) testing in serum was done using chemiluminescence immunoassay. We used a logistic regression model to investigate predicted factors of seropositivity. We observed a high prevalence (weighted average: 68.3%) of anti-SARS-CoV-2 IgG in 2700 enrolled children. Logistic regression for predictors of IgG seropositivity showed lower odds in households with completely vaccinated adults (adjusted odds ratio [OR]: 0.43, 95% confidence interval [CI]: 0.26–0.71, P = 0.0011) compared with households with unvaccinated adults. Other factors for low seropositivity included frontline workers as family members (adjusted OR: 0.69, 95% CI: 0.52–0.91, P = 0.0091) and non-crowded households (adjusted OR: 0.74, 95% CI: 0.61–0.89, P = 0.0019). A high SARS-CoV-2 IgG prevalence in unvaccinated children was indicative of previous exposure to potentially infected contacts. This implies in-person academic activities for children can be continued during future community transmission. Comparatively lower seropositivity in children of completely vaccinated households or frontline workers suggests decreased transmission due to vaccination-induced immunity of family members. Vaccination will still be required in these children to maintain protective IgG levels, particularly in low seroprevalence groups. [Display omitted] [ABSTRACT FROM AUTHOR]

Aggressive periodontitis (AgP), Stage III or IV and Grade C according to the new periodontitis classification, is characterized by the rapid destruction of periodontal tissues in the systemically healthy population and often causes premature tooth loss. The presence of familial aggregation suggests the involvement of genetic factors in the pathogenesis. However, the genes associated with the onset and progression of the disease and details of its pathogenesis have not yet been fully identified. In recent years, the genome-wide approach (GWAS), a comprehensive genome analysis method using bioinformatics, has been used to search for disease-related genes, and the results have been applied in genomic medicine for various diseases, such as cancer. In this review, we discuss GWAS in the context of AgP. First, we introduce the relationship between single-nucleotide polymorphisms (SNPs) and susceptibility to diseases and how GWAS is useful for searching disease-related SNPs. Furthermore, we summarize the recent findings of disease-related genes using GWAS on AgP inside and outside Japan and a possible mechanism of the pathogenesis of AgP based on available literature and our research findings. These findings will lead to advancements in the prevention, prognosis, and treatment of AgP. [ABSTRACT FROM AUTHOR]

The extensive variation in lifespan among organisms provides a natural dataset to probe the evolutionary tradeoffs that constrain and mold this phenotype across taxa. Several key pathways repeatedly emerge as the targets of selection from comparative genomics of long-lived species. Overall, these pathways exhibit increased constraint in long-lived species and reduced constraint in short-lived species with distinct signatures of diversifying selection observed in individual taxa. Large cohort studies demonstrate that even late-acting deleterious alleles appear to be under strong purifying selection in human populations. Somatic mutation rates scale with lifespan and are significantly higher than matched germline mutation rates. Cell culture models of extreme agers are beginning to facilitate characterization of key genotype–phenotype interactions in biological aging. Aging is a nearly inescapable trait among organisms yet lifespan varies tremendously across different species and spans several orders of magnitude in vertebrates alone. This vast phenotypic diversity is driven by distinct evolutionary trajectories and tradeoffs that are reflected in patterns of diversification and constraint in organismal genomes. Age-specific impacts of selection also shape allele frequencies in populations, thus impacting disease susceptibility and environment-specific mortality risk. Further, the mutational processes that spawn this genetic diversity in both germline and somatic cells are strongly influenced by age and life history. We discuss recent advances in our understanding of the evolution of aging and lifespan at organismal, population, and cellular scales, and highlight outstanding questions that remain unanswered. [ABSTRACT FROM AUTHOR]

Early-life environmental exposures influence long-lasting immune phenotypes and disease susceptibility. Immunity comprises durable programmable components that are affected by early environmental interactions and maintained in a stable manner. Some immune components are intrinsically programmable, whereas others are influenced by critical developmental processes during early life. Non-immune factors, including microbiota, hormones, and metabolites, strongly impact immune programming. Developmental immune programming may promote adaptation to anticipated future environments, but mismatches between predicted and actual environments can lead to disease. We propose that developmental programming of the immune system is possible due to programmable components of immunity. These developmentally programmable components are established by their interaction with an early-life environment and result in persistent immune alterations and disease susceptibility. Early-life environmental exposures play a significant role in shaping long-lasting immune phenotypes and disease susceptibility. Nevertheless, comprehensive understanding of the developmental programming of immunity is limited. We propose that the vertebrate immune system contains durable programmable components established through early environmental interactions and maintained in a stable and homeostatic manner. Some immune components, such as immunological memory, are intrinsically programmable. Others are influenced by conditions during critical developmental windows in early life, including microbiota, hormones, metabolites, and environmental stress, which impact programming. Developmental immune programming can promote adaptation to an anticipated future environment. However, mismatches between predicted and actual environments can result in disease. This is relevant because understanding programming mechanisms can offer insights into the origin of inflammatory diseases, ideally enabling effective prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is the most common pathological subtype of lung cancer. Both environmental and genetic factors have been reported to impact the lung cancer susceptibility. We conducted a genome-wide association study (GWAS) of 287 NSCLC patients and 467 healthy controls in a Chinese population using the Illumina Genome-Wide Asian Screening Array Chip on 712,095 SNPs (single nucleotide polymorphisms). Using logistic regression modeling, GWAS identified 17 new noncoding region SNP loci associated with the NSCLC risk, and the top three (rs80040741, rs9568547, rs6010259) were under a stringent p-value (<3.02e-6). Notably, rs80040741 and rs6010259 were annotated from the intron regions of MUC3A and MLC1, respectively. Together with another five SNPs previously reported in Chinese NSCLC patients and another four covariates (e.g., smoking status, age, low dose CT screening, sex), a predictive model by machine learning methods can separate the NSCLC from healthy controls with an accuracy of 86%. This is the first time to apply machine learning method in predicting the NSCLC susceptibility using both genetic and clinical characteristics. Our findings will provide a promising method in NSCLC early diagnosis and improve our understanding of applying machine learning methods in precision medicine. • We identified 17 SNPs from noncoding regions associated with the NSCLC risk. • Two of the top three SNPs are from the introns of MUC3A and MLC1. • Combination of genomic variations and clinical covariates had an accuracy of 86% in predicting NSCLC. [ABSTRACT FROM AUTHOR]

Although the possible efficacy and adverse effects of paracetamol and ibuprofen on dementia are of global clinical and public health importance, to date, the relationship of the use of paracetamol and ibuprofen with incident dementia remains uncertain. We aimed to assess the prospective association of regular use of ibuprofen and paracetamol with new-onset dementia in an older population. This study included 212,968 participants from the UK Biobank, aged ≥60 years, with available data of ibuprofen, paracetamol use and without dementia at baseline. The primary outcome was new-onset all-cause dementia. The secondary outcomes included new-onset Alzheimer's disease and new-onset vascular dementia. During a median follow-up of 12.3 years, 6407 (3.0%) participants developed new-onset all-cause dementia. Participants who regularly used paracetamol had a significantly higher risk of new-onset all-cause dementia (adjusted HR, 1.18; 95%CI: 1.10–1.26), compared with non-users. However, there was no significant association between regular use of ibuprofen and new-onset all-cause dementia (users vs. non-users; adjusted HR, 1.06; 95%CI: 0.97–1.16). Furthermore, APOE ε4 dosage and genetic risk scores (GRS) of Alzheimer's disease calculated by 25 single nucleotide polymorphisms did not significantly modify the relationship of regular use of paracetamol and ibuprofen with new-onset all-cause dementia (Both P -interactions >0.05). Similar results were found in the propensity score analysis. Similar findings were also observed for new-onset Alzheimer's disease and new-onset vascular dementia. Regular use of paracetamol, but not ibuprofen, was associated with a significantly higher risk of new-onset dementia in the old population, regardless of genetic risks of dementia. [ABSTRACT FROM AUTHOR]

We aimed to evaluate the relationship of the variety and duration of different sedentary behaviors (TV-watching, driving, and nonoccupational computer use) with the risk of dementia in older participants, and examine whether inflammation and genetic susceptibility may modify the relationship. A prospective cohort study. 173,829 older participants (≥60 years) without prior dementia in the UK Biobank were enrolled. A healthy sedentary behavior score was calculated as the number of the 3 major sedentary behaviors with a duration associated with the lowest risk of dementia. The primary outcome was new-onset all-cause dementia. During a median follow-up of 12.4 years, 4965 (2.9%) participants developed new-onset dementia. There were U-shaped associations for TV-watching and driving time, and a reversed J-shaped association for nonoccupational computer use time with new-onset all-cause dementia, with the lowest dementia risk at >0-<2 hours/day for all the 3 sedentary behaviors. Moreover, a higher healthy sedentary behavior score was significantly associated with a lower risk of all-cause dementia (per 1 score increment: hazard ratio 0.78, 95% CI 0.75-0.81), with a stronger inverse association in those with higher levels of high-sensitivity C-reactive protein and monocytes (both P -interactions <.05). Genetic risks of dementia did not significantly modify the association. Similar trends were found for new-onset Alzheimer's disease and vascular dementia. The associations between the duration of different sedentary behaviors and new-onset dementia were different in the older population. Moreover, the variety of sedentary behavior was inversely associated with new-onset dementia, especially among those with higher levels of inflammation. [ABSTRACT FROM AUTHOR]

• Providing cardiovascular risk based on genetic testing further reduced LDL-C levels. • Inconsistent effects exist according to the variant status on LDL-C levels. • Beneficial effects were attenuated after 48 weeks of the intervention. Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disease characterized by high low-density lipoprotein cholesterol (LDL-C) levels. Although carrying causative FH variants is associated with coronary heart disease (CHD), it remains unclear whether disclosing its associated cardiovascular risk affects outcomes in patients with FH. We aimed to evaluate the efficacy of providing future cardiovascular risk based on genetic testing in addition to a standard FH education program. We conducted a randomized, wait-list controlled, open-label, single-center trial. In the intervention group, we reported a future cardiovascular risk based on the genetic testing adding to standard FH education at week 0. In the wait-list control group, we only disseminated standard FH education according to the guidelines at week 0; they later received a genetic testing-based cardiovascular risk assessment at week 24. The primary endpoint of this study was the plasma LDL-C level at week 24. Fifty eligible patients with clinically diagnosed FH, without a history of CHD, were allocated to the intervention group (n = 24) or the wait-list control group (n = 26). At week 24, the intervention group had a significantly greater reduction in LDL-C levels than the wait-list control group (mean changes, -13.1 mg/dL vs. 6.6 mg/dL; difference, -19.7 mg/dL; 95% confidence interval, -34 to -5.6; p = 0.009). This interventional effect was consistent with FH causative variant carriers but not with non-carriers. In addition to standard FH care, providing future cardiovascular risk based on genetic testing can further reduce plasma LDL-C levels, particularly among FH causal variant carriers. Japan Registry of Clinical Trials (jRCTs04218002). URL: https://jrct.niph.go.jp/latest-detail/jRCTs042180027 [Display omitted] [ABSTRACT FROM AUTHOR]

Neisseria meningitidis is a common human commensal which occasionally causes invasive meningococcal disease (IMD). The bacterium recruits the negative complement regulator complement factor H (CFH) to its surface by expressing factor H-binding protein (fHbp); this protects the meningococcus from the human complement system. fHbp is regulated in vivo by environmental cues (such as oxygen levels and temperature), and interactions between fHbp and CFH and other host complement proteins (encoded by the cfh locus) are central to host susceptibility to IMD. A recent bacterial genome-wide association study highlighted the role of fHbp determining whether strains harmlessly colonize an individual or cause IMD. Knowledge of fHbp structure:function is being exploited to develop next-generation vaccines against the meningococcus, and to understand why infection can result in harmless colonization or IMD in certain individuals. Neisseria meningitidis is a human-adapted pathogen that causes meningitis and sepsis worldwide. N. meningitidis factor H-binding protein (fHbp) provides a mechanism for immune evasion by binding human complement factor H (CFH) to protect it from complement-mediated killing. Here, we discuss features of fHbp which enable it to engage human CFH (hCFH), and the regulation of fHbp expression. Studies of host susceptibility and bacterial genome-wide association studies (GWAS) highlight the importance of the interaction between fHbp and CFH and other complement factors, such as CFHR3, on the development of invasive meningococcal disease (IMD). Understanding the basis of fHbp:CFH interactions has also informed the design of next-generation vaccines as fHbp is a protective antigen. Structure-informed refinement of fHbp vaccines will help to combat the threat posed by the meningococcus, and accelerate the elimination of IMD. [ABSTRACT FROM AUTHOR]

Germline pathogenic variants (PVs) in BRCA1/2 genes are associated with breast cancer (BC) risk in both women and men. Multigene panel testing is being increasingly used for BC risk assessment, allowing the identification of PVs in genes other than BRCA1/2. While data on actionable PVs in other cancer susceptibility genes are now available in female BC, reliable data are still lacking in male BC (MBC). This study aimed to provide the patterns, prevalence and risk estimates associated with PVs in non- BRCA1/2 genes for MBC in order to improve BC prevention for male patients. We performed a large case-control study in the Italian population, including 767 BRCA1/ 2-negative MBCs and 1349 male controls, all screened using a custom 50 cancer gene panel. PVs in genes other than BRCA1/2 were significantly more frequent in MBCs compared with controls (4.8% vs 1.8%, respectively) and associated with a threefold increased MBC risk (OR: 3.48, 95% CI: 1.88–6.44; p < 0.0001). PV carriers were more likely to have personal (p = 0.03) and family (p = 0.02) history of cancers, not limited to BC. PALB2 PVs were associated with a sevenfold increased MBC risk (OR: 7.28, 95% CI: 1.17–45.52; p = 0.034), and ATM PVs with a fivefold increased MBC risk (OR: 4.79, 95% CI: 1.12–20.56; p = 0.035). This study highlights the role of PALB2 and ATM PVs in MBC susceptibility and provides risk estimates at population level. These data may help in the implementation of multigene panel testing in MBC patients and inform gender-specific BC risk management and decision making for patients and their families. • About 5% of MBC cases are carriers of pathogenic variants in genes other than BRCA1/2 • PALB2 and ATM are associated with increased MBC risk • CHEK2 is not associated with MBC risk in the Italian population • Multigene panel test should be implemented in MBC patients [ABSTRACT FROM AUTHOR]

This study aimed to perform a systematic review and meta-analysis to assess the scientific evidence of the relationship between vulnerability to access to safe drinking water, sanitation, and hygiene (WASH) practices on stunting in children aged <5 years in developing countries. This is a systematic review and meta-analysis article to assess the relationship between under-five stunting and WASH vulnerability in developing countries. The systematic review with meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol methodology. The following databases were used: LILACS, MEDLINE (via PubMed), SciELO, Web of Science, ScienceDirect, SCOPUS, and Embase. All original studies identified that related WASH vulnerability to stunting in children aged <5 years in developing countries was included. Three authors performed independently the selection and extraction of data from the articles. The statistical software STATA version 11 was used. Cochran's Q test and Chi-square test (I 2) with 95% significance were used to assess the heterogeneity of the studies. The search resulted in the initial identification of 2047 articles; after reading the abstracts, followed by the full articles, 14 articles were included in the systematic review and eight articles were included in the meta-analysis. The studies selected for the systematic review were published between the years 1992 and 2021 and conducted in eight countries, namely, Ethiopia, India, Indonesia, Bangladesh, Tanzania, Peru, China, and Lesotho. The studies assessed vulnerability to access to WASH on the growth of children aged <5 years. There was a significant difference when relating WASH vulnerability to children's height. The meta-analysis of this study showed that the impact of WASH on child stunting is significant when it comes to lack of sanitation in 72% of the studies. The study found that WASH vulnerability contributes to stunting in children aged <5 years in developing countries. Based on our findings, we recommend incorporating WASH strategies, especially sanitation, into the formulation of interventions integrating with health promotion policies for healthy early childhood development. [ABSTRACT FROM AUTHOR]

The roles of gut microbiota and susceptibility genes in patients with major depression disorder (MDD) are not well understood. Examining the microbiome and host genetics might be helpful for clinical decision-making. Patients with MDD were recruited in this study and subsequently treated for eight weeks. We identified the differences between the population with a response after two weeks and those with a response after eight weeks. The factors that were significantly correlated with efficacy were used to predict the treatment response. The differences in the importance of microbiota and genetics in prediction were analyzed. Our study identified rs58010457 as a potentially key locus affecting the treatment effect. Different microbiota and enriched pathways might play different roles in the response after two and eight weeks. We found that the area under the curve (AUC) value was greater than 0.8 for both random forest models. The contribution of different components to the AUC was evaluated by removing genetic information, microbiota abundance, and pathway data. The gut microbiome was an important predictor of the response after eight weeks, while genetics was an important predictor of the response after two weeks. These results suggested a dynamic effect of interaction among genetics and gut microbes on treatment. Furthermore, these results provide new guidance for clinical decisions: in cases of inadequate treatment effects after two weeks, the composition of the intestinal flora can be improved by diet therapy, which could ultimately affect the efficacy. [ABSTRACT FROM AUTHOR]

PD-1/PD-L1 inhibitors have brought remarkable benefits but can cause profound immune-related adverse events (irAEs). The host immunogenetic background is likely to play a role in irAE susceptibility. In this study, we aimed to identify potential immunogenetic biomarkers to predict irAEs. Patients with solid tumours receiving PD-1/PD-L1 blockade were recruited and followed up. Genes considered pivotal contributors to tumour-immunity and autoimmune diseases were screened out via protein–protein interaction network and Cytoscape. Consequently, thirty-nine variants in eighteen genes were genotyped using the multiplex genotyping assay. Association analysis between genetic variants and irAEs as well as irAEs-free survival was performed. Four immunogenetic variants as predictive biomarkers of irAEs were identified. The C allele of Mitogen-Activated Protein Kinase 1 (MAPK 1) rs3810610 (odds ratio [OR] = 1.495, 95% confidence interval [CI] = 1.093–2.044, P = 0.012) was a risk predictor while the A allele of PTPRC rs6428474 (OR = 0.717, 95% CI = 0.521–0.987, P = 0.041) was a protective factor for all-grade irAEs. The A allele of ADAD1 rs17388568 (OR = 2.599, 95% CI = 1.355–4.983, P = 0.003) increased the risk while the G allele of IL6 rs1800796 (OR = 0.425, 95% CI = 0.205–0.881, P = 0.018) protected patients from high-grade irAEs. Significant immunogenetic variants reached a similar tendency in PD-1 blockade or lung cancer subgroups. In multivariate Cox regression analysis, the MAPK1 rs3810610 was an independent factor regarding all-grade irAEs-free survival (CC versus CT or TT: hazard ratio [HR] = 0.71, 95% CI = 0.52–0.99, P = 0.042). ADAD1 rs17388568 (AA versus AG or GG: HR = 0.11, 95% CI = 0.025–0.49, P = 0.004) and IL6 rs1800796 (GG or GC versus CC: HR = 3.10, 95% CI = 1.315–7.29, P = 0.01) were independent variables for high-grade irAEs-free survival. We first identified several immunogenetic polymorphisms associated with irAEs and irAEs-free survival in PD-1/PD-L1 blockade-treated tumour patients, and they may serve as potential predictive biomarkers. • MAPK1 rs3810610 and PTPRC rs6428474 possibly predict any-grade irAEs of ICIs. • ADAD1 rs17388568 and IL6 rs1800796 are likely to predict grade ≥3 irAEs of ICIs. • Significant immunogenetic variants are associated with irAEs-free survival of ICIs. • A link between four immunogenetic variants and irAEs of ICIs was first identified. [ABSTRACT FROM AUTHOR]

After several decades of therapeutic stagnation, the treatment of patients with urothelial carcinoma has met a revolutionary wave, anticipated by the advent of immune-checkpoint inhibitors (ICI) and followed by newer therapeutic options in the post-ICI setting. These achievements were made in a very short time-frame, thus making the treatment of this disease particularly susceptible to geographical health disparity due to the differences in healthcare systems and approval processes of the regulatory authorities. Furthermore, additional barriers to access innovative care are represented by a limited coverage of clinical trials availability, that is consistent in focusing on selected geographical areas, across trials and clinical settings. Here, we present the current picture of new drug approvals in urothelial carcinoma worldwide, and we also focus our considerations onto the spectrum of ongoing trial inclusion possibilities, trying to understand what are the current gaps in clinical research and routine practice, identifying a way to move forward. [ABSTRACT FROM AUTHOR]

Bile acids are important for digestion of food and antimicrobial activity. Pathogenic Vibrio parahaemolyticus senses bile acids and induce pathogenesis. The bile acid taurodeoxycholate (TDC) was shown to activate the master regulator, VtrB, of this system, whereas other bile acids such as chenodeoxycholate (CDC) do not. Previously, VtrA-VtrC was discovered to be the co-component signal transduction system that binds bile acids and induces pathogenesis. TDC binds to the periplasmic domain of the VtrA-VtrC complex, activating a DNA-binding domain in VtrA that then activates VtrB. Here, we find that CDC and TDC compete for binding to the VtrA-VtrC periplasmic heterodimer. Our crystal structure of the VtrA-VtrC heterodimer bound to CDC revealed CDC binds in the same hydrophobic pocket as TDC but differently. Using isothermal titration calorimetry, we observed that most mutants in the binding pocket of VtrA-VtrC caused a decrease in bile acid binding affinity. Notably, two mutants in VtrC bound bile acids with a similar affinity as the WT protein but were attenuated for TDC-induced type III secretion system 2 activation. Collectively, these studies provide a molecular explanation for the selective pathogenic signaling by V. parahaemolyticus and reveal insight into a host's susceptibility to disease. [ABSTRACT FROM AUTHOR]

Medication during pregnancy is widespread, but there are few reports on its fetal safety. Recent studies suggest that medication during pregnancy can affect fetal morphological and functional development through multiple pathways, multiple organs, and multiple targets. Its mechanisms involve direct ways such as oxidative stress, epigenetic modification, and metabolic activation, and it may also be indirectly caused by placental dysfunction. Further studies have found that medication during pregnancy may also indirectly lead to multi-organ developmental programming, functional homeostasis changes, and susceptibility to related diseases in offspring by inducing fetal intrauterine exposure to too high or too low levels of maternal-derived glucocorticoids. The organ developmental toxicity and programming alterations caused by medication during pregnancy may also have gender differences and multi-generational genetic effects mediated by abnormal epigenetic modification. Combined with the latest research results of our laboratory, this paper reviews the latest research progress on the developmental toxicity and functional programming alterations of multiple organs in offspring induced by medication during pregnancy, which can provide a theoretical and experimental basis for rational medication during pregnancy and effective prevention and treatment of drug-related multiple fetal-originated diseases. This review summarizes the intrauterine mechanisms, gender differences, and multi-generational genetic effects of offspring's multi-organ developmental toxicity, programming alterations and susceptibility to multiple diseases induced by medication during pregnancy. [Display omitted] [ABSTRACT FROM AUTHOR]

• EEG theta activity reflects the degree of epileptic diathesis. • Theta activity shows a common topographical pattern in generalized and focal epilepsy. • Electroencephalography is correlated with epileptic diathesis, regardless of the syndrome. Epileptic diathesis is an inherited neurophysiological trait that contributes to the development of all types of epilepsy. The amount of resting-state electroencephalography (EEG) theta activity is proportional to the degree of cortical excitability and epileptic diathesis. Our aim was to explore the amount and topographic distribution of theta activity in epilepsy groups. We hypothesized that the anatomical distribution of increased theta activity is independent of the epilepsy type. Patients with unmedicated idiopathic generalized epilepsy (IGE, n = 92) or focal epilepsy (FE, n = 149) and non-seizure patients with mild to moderate cerebral lesions (NONEP, n = 99) were compared to healthy controls (NC, n = 114). We analysed artifact-free EEG activity and defined multiple distributed sources of theta activity in the source space via low resolution electromagnetic tomography software. Age-corrected and Z-transformed theta values were compared across the groups. The rank of increased theta activity was IGE > FE > NONEP > NC. Both epilepsy groups showed significantly more theta activity than did the NC group. Maximum theta abnormality occurred in the medial-basal prefrontal and anterior temporal cortex in both epilepsy groups. We confirmed the hypothesis outlined above. The common topographical pattern of increased EEG theta activity is correlated with epileptic diathesis, regardless of the epilepsy type. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) is a highly prevalent psychiatric condition characterised by a heterogeneous clinical presentation and an estimated twin-based heritability of ~40-50 %. Different clinical MDD subtypes might partly reflect distinctive underlying genetics. This study aims to investigate if polygenic risk scores (PRSs) for different psychiatric disorders, personality traits, and substance use-related traits may be associated with different clinical subtypes of MDD (i.e., MDD with melancholic or psychotic features), higher symptom severity, or different clusters of depressive symptoms (i.e., sadness symptoms, typical neurovegetative symptoms, detachment symptoms, and negative thoughts).Methods: The target sample included 1149 patients with MDD, recruited by the European Group for the Study of Resistant Depression. PRSs for 25 psychiatric disorders and traits were computed based on the most recent publicly available summary statistics of the largest genome-wide association studies. PRSs were then used as predictors in regression models, adjusting for age, sex, population stratification, and recruitment sites.Results: Patients with MDD having higher PRS for MDD and loneliness were more likely to exhibit melancholic features of MDD (p = 0.0009 and p = 0.005, respectively). Moreover, patients with higher PRS for alcohol intake and post-traumatic stress disorder were more likely to experience greater typical neurovegetative symptoms (p = 0.0012 and p = 0.0045, respectively).Limitations: The proportion of phenotypic variance explained by the PRSs was limited.Conclusions: This study suggests that melancholic features and typical neurovegetative symptoms of MDD may show distinctive underlying genetics. Our findings provide a new contribution to the understanding of the genetic heterogeneity of MDD. [ABSTRACT FROM AUTHOR]

Background: The comorbidity of obesity and major depressive disorder (MDD) may be attributable to a bidirectional relationship and shared genetic influence. We aimed to examine the polygenic associations between obesity and MDD and to characterize their corresponding impacts on the obesity mechanism.Methods: Genome-wide genotyping was available in 106,604 unrelated individuals from Taiwan Biobank. Polygenic risk score (PRS) for body mass index (BMI) and MDD was derived to evaluate their effects on obesity-related traits. Stratified analyses were performed for the modified effect of depression on the polygenic associations.Results: The MDD PRS was positively associated with waistline (beta in per SD increase in PRS = 0.12), hipline (beta = 0.08), waist-hip ratio (WHR) (beta = 0.05), body fat rate (beta = 0.08), BMI (beta = 0.05), overweight (OR = 1.02 for BMI ≥ 25), and obesity (OR = 1.05 for BMI ≥ 30). For the synergism between depression and BMI PRS, the presence of active depression symptoms defined by the PHQ-4 (p for interaction < 0.05 for waistline, WHR, and BMI) was more salient than lifetime MDD.Limitations: Limitations include recall bias for MDD due to a retrospective self-reporting questionnaire, a low response rate of the PHQ-4 for evaluating active psychological symptoms, and limited generalizability to non-Taiwanese ancestries.Conclusions: The shared genetic etiology of obesity and depression was demonstrated. The amplified effect of BMI polygenic effect on obesity for individuals with active depressive symptoms was also characterized. The study may be helpful for designing public health interventions to reduce the disease burden caused by obesity and depression. [ABSTRACT FROM AUTHOR]

The presence of silicone particles in breast implant capsules has been observed since the 1970s. Since then, little data has been published regarding the amount of silicone that is susceptible to migrate into the capsule. Quantifying the amount of silicone migration from the implant to the capsule could inform on the level of silicone exposure a patient with breast implants may experience in the short- or long-term. The objective of this study is to present a histological quantification methodology of the number of silicone particles present in breast implant capsules. A prospective study was performed on capsule samples from patients requiring revision surgery. The slides were digitalized and analyzed with a viewer software. For each sample, we (1) manually counted each silicone particle, (2) measured the average particle size, (3) measured the capsule surface area, and (4) calculated the particle number density in each capsule sample. The average of all capsule samples' particle number densities was then compared to the total volume of the capsule to estimate the total number of silicone particles found within the capsule of each breast implant. Six capsules from six different patients were analyzed. Two capsules were from saline implants while four capsules were from silicone implants. All four silicone implant capsules contained between 352,928 and 9,002,235 silicone particles. The particle number density ranged from 20.5 to 683.5 particles per mm3 of capsule. The two saline-filled implant capsules were free of silicone particles. The average of all capsule samples' particle number densities was then compared to the total volume of the capsule to estimate the total number of silicone particles found within the capsule of each breast implant. We describe a new and reproducible methodology to quantify realistically the silicone particles in the periprosthetic capsule of breast implants. [ABSTRACT FROM AUTHOR]

Contrary to the classical cell-wall model, pectin metabolism may play a crucial role in cell-wall integrity, detection of plant pathogens, and defense response. Here we discuss the evidence and propose a new metabolic and regulatory model linking pectin to cell-wall-mediated immunity, including ripening-associated disease susceptibility in the tomato. [ABSTRACT FROM AUTHOR]

Background: Selenium is an essential trace element with both beneficial and detrimental effects on health depending on dose and chemical form. Currently, there is debate on recommendations for selenium supplementation as a public health measure to improve immune function and reduce infectious disease susceptibility. Objectives: We performed a systematic review and meta-analysis of experimental studies assessing the effect of selenium supplementation on immunity-related outcomes in healthy people. Methods: We undertook a search of published and unpublished studies in literature databases such as PubMed/MEDLINE, Embase, and clinicaltrials.gov up to 17 October, 2022, and performed a meta-analysis comparing the effects on immunity-related outcomes between Se-supplemented versus control arms. Whenever possible we assessed the nonlinear relation using a dose-response approach. Results: 9 trials were included, 5 in North America, and 4 in Europe, with a duration between 8 and 48 weeks and supplementation of both inorganic and organic selenium forms. Selenium supplementation did not substantially affect immunoglobulin or white blood cell concentrations, and the dose-response meta-analysis indicated that an increase in plasma selenium concentrations above 100 µg/L did not further increase IgA levels nor T cells. An inverted U-shaped relation emerged for NK cell count, with a lower number of these cells both below and above 120 µg/L. The only beneficial effect of selenium supplementation was the increased activity for NK lysis, but the available data did not permit dose-response analysis. Cytokine levels were substantially unaffected by selenium supplementation. Conclusions: Although some of the data suggested beneficial effects of selenium supplementation on immune function, the overall picture appears to be inconsistent and heterogeneous due to differences in trial duration and interventions, plus evidence of null and even detrimental effects. Overall, the evidence that we extracted from the literature in this systematic review does not support the need to supplement selenium beyond the recommended dietary intake to obtain beneficial effects on immune function. This trial was registered at PROSPERO (CRD42022312280). [ABSTRACT FROM AUTHOR]

Familial bladder cancer in a first degree relative was seen in 4.3% of bladder cancer patients and was not associated with age of diagnosis. Among patients suspected to have a familial cancer syndrome, one-third harbored a germline pathogenic/likely pathogenic variant. Genetic evaluation is important in patients who are younger, have a second cancer or family history of malignancies. Background: The familial aggregation of bladder cancers has been observed, but the incidence and association of familial bladder cancer with germline pathogenic and likely pathogenic (P/LP) variants is unknown. Patients and Methods: A retrospective analysis was conducted of patients with bladder cancer treated at the Dana-Farber Cancer Institute to identify those with a first-degree relative with bladder cancer. A second cohort of patients referred to DFCI for suspicion of a cancer predisposition syndrome was analyzed for candidate P/LP germline var iants. Descr iptive statistics were generated. Results: Among 885 patients with bladder cancer, 38 patients (4.3%) had a family history of bladder cancer in a first-degree relative. No significant association of age of diagnosis was observed between patients with and without a first-degree family history of bladder cancer (P = .3). In the second cohort, 27 of 80 (34%) patients with bladder cancer evaluated for cancer predisposition syndromes harbored a P/LP germline variant. P/LP variants were identified most commonly in the following genes: BRCA1 (n = 5), MSH2 (n = 5), MLH1 (n = 4), ATM (n = 3), and CHEK2 (n = 2). Of the 27 patients with identified germline P/LP variants, 20 (74%) had a family history of a tumor component syndrome in a first- or second-degree relative and 3 were subsequently diagnosed with another genetically-linked associated cancer. Conclusion: Familial bladder cancer defined as bladder cancer in the proband and a first-degree relative, was present in 4.3% of patients with bladder cancer and was not associated with age of diagnosis. Additionally, among patients suspected to have a familial cancer syndrome, one-third harbored a germline P/LP variant. Further study of germline variants in patients with familial bladder cancer including somatic testing for loss of heterozygosity may provide insights regarding disease pathogenesis and inform therapy. [ABSTRACT FROM AUTHOR]

Systematic literature searches on POT1 / POLE / BAP1 found that limited skin phenotypic characteristics have been documented in mutation carriers; 248 variants were annotated, and high-cluster variant regions associated with cutaneous melanoma were found in all three genes. Genotype–phenotype correlations can be used to identify patient disease predisposition based on mutation position and cluster regions. [ABSTRACT FROM AUTHOR]

Are there (sex-specific) differences in first-trimester embryonic growth and morphological development between two culture media used for IVF and intracytoplasmic sperm injection (ICSI) treatment? A total of 835 singleton pregnancies from a prospective hospital-based cohort study were included, of which 153 conceived after IVF/ICSI treatment with Vitrolife G-1™ PLUS culture medium, 252 after culture in SAGE 1-Step™ and 430 were naturally conceived. Longitudinal three-dimensional ultrasound examinations were performed at 7, 9 and 11 weeks of gestation for offline biometric (crown rump length, CRL), volumetric (embryonic volume) and morphological (Carnegie stage) measurements. Embryos cultured in SAGE 1-Step grew faster than those cultured in Vitrolife G-1 PLUS (beta EV 0.030 3√ml [95% CI 0.008–0.052], P = 0.007). After stratification for fetal sex, male embryos cultured in SAGE 1-Step demonstrated faster growth than those cultured in Vitrolife G-1 PLUS (beta EV 0.048 3√ml [95% CI 0.015–0.081], P = 0.005). When compared with naturally conceived embryos, those cultured in SAGE 1-Step grew faster (beta EV 0.040 3√ml [95% CI 0.012–0.069], P = 0.005). This association was most pronounced in male embryos (beta EV 0.078 3√ml [95% CI 0.035–0.120], P < 0.001). This study shows that SAGE 1-Step culture medium accelerates embryonic growth trajectories compared with Vitrolife G-1 PLUS and naturally conceived pregnancies, especially in male embryos. Further research should focus on the impact of culture media on postnatal development and the susceptibility to non-communicable diseases. [ABSTRACT FROM AUTHOR]

Background: A major bottleneck to the introduction of noninvasive presymptomatic diagnostic tests for the pharmacogenetic disorder malignant hyperthermia is the lack of functional data for associated variants.Methods: We screened 50 genes having a potential role in skeletal muscle calcium homeostasis using the HaloPlex™ (Agilent Technologies, Santa Clara, CA, USA) target enrichment system and next-generation sequencing. Twenty-one patients with a history of a clinical malignant hyperthermia reaction together with a positive in vitro contracture test were included. Eight variants in RYR1 were subsequently introduced into the cDNA for the human ryanodine receptor gene and tested in cultured human embryonic kidney (HEK293) cells for their effect on calcium release from intracellular stores in response to the ryanodine receptor-1 agonist 4-chloro-m-cresol using fura-2 as calcium indicator. Each variant was subjected to in silico curation using the European Malignant Hyperthermia Group scoring matrix and ClinGen RYR1 variant curation expert panel guidelines.Results: Potentially causative RYR1 variants were identified in 15 patients. Of these, two families carried two RYR1 variants, five variants had been previously reported as 'pathogenic', two variants had been previously reported as 'likely benign', and eight were of 'uncertain significance'. Of these eight variants, four showed hypersensitivity to 4-chloro-m-cresol. Three variants were reclassified as either 'pathogenic' or 'likely pathogenic'. Two were classified as 'benign', whilst three remained of 'uncertain significance'.Conclusions: Three (p.Tyr1711Cys, p.Val2280Ile, and p.Arg4737Gln) additional variants can be added to the list of RYR1 disease-associated variants managed by the European Malignant Hyperthermia Group. These can therefore be used diagnostically in the future. Three variants (p.Glu2348Gly, p.Asn2634Lys, and p.Arg3629Trp) that remained classified as of uncertain significance require further family studies or a different functional test to determine clinical relevance in malignant hyperthermia. [ABSTRACT FROM AUTHOR]

Human aging is characterized by a gradual decline in physiological functions and an increased susceptibility to various diseases. The complex mechanisms underlying human aging are still not fully elucidated. Single-cell sequencing (SCS) technologies have revolutionized aging research by providing unprecedented resolution and detailed insights into cellular diversity and dynamics. In this review, we discuss the application of various SCS technologies in human aging research, encompassing single-cell, genomics, transcriptomics, epigenomics, and proteomics. We also discuss the combination of multiple omics layers within single cells and the integration of SCS technologies with advanced methodologies like spatial transcriptomics and mass spectrometry. These approaches have been essential in identifying aging biomarkers, elucidating signaling pathways associated with aging, discovering novel aging cell subpopulations, uncovering tissue-specific aging characteristics, and investigating aging-related diseases. Furthermore, we provide an overview of aging-related databases that offer valuable resources for enhancing our understanding of the human aging process. • Single-cell sequencing gives insights into human aging across tissues and organs. • Combining multiple single-cell omics offers a full view of human aging. • Single-cell sequencing reveals molecular and cellular mechanisms of age-related diseases. [ABSTRACT FROM AUTHOR]

Epidemiological evidence of familial predispositions to myeloid malignancies and myeloproliferative neoplasms (MPN) has long been recognised, but recent studies have added to knowledge of specific germline variants in multiple genes that contribute to the familial risk. These variants may be common risk alleles in the general population but have low penetrance and cause sporadic MPN, such as the JAK2 46/1 haplotype, the variant most strongly associated with MPN. Association studies are increasingly identifying other MPN susceptibility genes such as TERT , MECOM , and SH2B3 , while some common variants in DDX41 and RUNX1 appear to lead to a spectrum of myeloid malignancies. RBBP6 and ATM variants have been identified in familial MPN clusters and very rare germline variants such as chromosome 14q duplication cause hereditary MPN with high penetrance. Rarely, there are hereditary non-malignant diseases with an MPN-like phenotype. Knowledge of those genes and germline genetic changes which lead to MPN or diseases that mimic MPN helps to improve accuracy of diagnosis, aids with counselling regarding familial risk, and may contribute to clinical decision-making. Large scale population exome and genome sequencing studies will improve our knowledge of both common and rare germline genetic contributions to MPN. • Familial predispositions to myeloproliferative neoplasms (MPN) exist. • Some risk alleles are common in the general population but have low penetrance and cause sporadic MPN. • Rare variants can cause familial MPN with high penetrance. • Hereditary but non-malignant diseases may present with an MPN-like phenotype. [ABSTRACT FROM AUTHOR]

Anemia may contribute significantly to the onset of Parkinson's disease (PD). Current research on the association between anemia and PD risk is inconclusive, and the relationships between anemia-related blood cell indices and PD incidence require further clarification. This study aims to investigate the relationships between anemia, blood cell indicators, and PD risk using a thorough prospective cohort study. We used data from the UK Biobank, a prospective cohort study of 502,649 participants, and ultimately, 365,982 participants were included in the analysis. Cox proportional hazards models were utilized to adjust for confounding factors, aiming to thoroughly explore the associations between anemia and blood cell indices with the risk of incident PD. The interaction between anemia and Polygenic Risk Score (PRS) for PD was also examined. Linear regression and mediation analyses assessed potential mechanisms driven by brain structures, including grey matter volume. During a median follow-up of 14.24 years, 2513 participants were diagnosed with PD. Anemia considerably increased PD risk (hazard ratio [HR] 1.98, 95 % confidence interval [CI]: 1.81–2.18, P < 0.001) after adjustments. Those with high PRS for anemia had an 83 % higher PD incidence compared to low PRS participants. Sensitivity analyses confirmed result robustness. Linear regression showed that anemia correlated with grey matter volumes and most white matter tracts. Furthermore, mediation analyses identified that the volume of grey matter in Thalamus mediates the relationship between anemia and PD risk. In summary, we consider there to be a substantial correlation between anemia and increased PD risk. • The association between anemia and Parkinson's disease (PD) development was positive in the adjusted model. • Those with high Polygenic Risk Score (PRS) for anemia had an 83 % higher PD incidence compared to low PRS participants. • Linear regression showed that anemia correlated with grey matter volumes and most white matter tracts. • Mediation analyses identified that the volume of grey matter in Thalamus mediates the relationship between anemia and PD. [ABSTRACT FROM AUTHOR]

Charcot-Marie-Tooth type 1A (CMT1A) is an inherited neuropathy with an estimated prevalence of 1/5000 in the general population. CMT1A results from abnormal dosage of the PMP22 gene, arising from non-allelic homologous recombination (NAHR) events between paralogous sequences called CMT1A-REPs, flanking the gene. While extensively documented in Caucasian individuals, CMT1A is under-reported in individuals of African genetic ancestry. We hypothesize that this is due to differences in the CMT1A-REPs between individuals of African and non-African genetic background. Our aim is to study the variability of CMT1A-REPs between populations using available genetic data and in silico analyses. Here, we have built a combined dataset from previous whole genome sequencing efforts (1KGP, HGDP and other available datasets at EGA) with a focus on capturing African genetic variation. Leveraging this data, we explore haplotypes based on both common and rare SNPs, structural variants in CMT1A-REP regions, recombination-related elements, and their potential interactions, as well as their distribution across different populations. We find that individuals of African genetic ancestry harbour distinct CMT1A-REP haplotypes with lower recombination rates and reduced sequence similarity compared to other ethnicities. This suggests potential genetic variation protective against NAHR-mediated events causing CMT1A. Additionally, recombination regulators like PRDM9 might differ between African and non-African ethnicities, hinting at distinct mechanisms at play. In conclusion, our study shows genetic differences in the CMT1A locus between African and non-African ancestries, which may account to the under-reporting of CMT1A in individuals of African genetic origin. However, further research is needed to better understand the epidemiology of inherited neuropathies and CMT1A in the African continent and how CMT1A-REP variations influence disease risk. [ABSTRACT FROM AUTHOR]

Radiation pneumonitis (RP) presents a clinical concern in breast cancer treatment, especially when radiotherapy (RT) field encompasses the internal mammary chain (IMC), increasing the potential for lung toxicity. This retrospective study evaluates the incidence and risk factors of RP in breast cancer patients with comprehensive RT including the IMC, comparing outcomes between those treated with 3D conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT). A total of 438 breast cancer patients were treated with adjuvant RT to the IMC. Between 2013-2015, 63 patients received 3D-CRT (50.4 Gy in 28 fractions), while in 2021, 375 patients underwent IMRT (43.2 Gy in 16 fractions). Patients were first followed up 3-6 months post-RT and then biannually with chest CT. RP was diagnosed by qualified radiologists and assessed using the Common Terminology Criteria for Adverse Events v5.0. The study's primary endpoint was the development of any grade of RP within one year after the end of RT. The overall incidence of RP was significantly higher in the 3D-CRT group compared to the IMRT group (74.6% vs. 17.0%, P = 0.01). Patients treated with 3D-CRT also exhibited a greater prevalence of symptomatic RP (18.5% vs. 5.6%, P = 0.02). After adjusting for confounders with inverse probability treatment weighting and employing multiple logistic regression, adjuvant T-DM1 therapy (OR 3.28, 95% CI = 1.30-30.2, P = 0.02), elevated V30(%) of ipsilateral lung (OR 1.18, 95% CI = 1.12-1.23, P = 0.01), and HER2-receptor overexpression (OR 3.28, 95% CI = 1.39-7.71, P = 0.01) emerged as significant RP predictors. However, 3D-CRT did not (OR 0.13, 95% CI = 0.00-5.76, P = 0.298). A normal tissue complication probability model further revealed higher RP susceptibility in patients with HER2 overexpression or those receiving adjuvant T-DM1 therapy. The study identifies HER2 receptor overexpression and the administration of adjuvant T-DM1 therapy, along with higher V30(%) of ipsilateral lung, as significant factors in RP risk assessment. Furthermore, this study also suggests the importance of careful dose-volume histogram parameter evaluation to mitigate RP risk, particularly when T-DM1 therapy is involved. [ABSTRACT FROM AUTHOR]

Enhanced Disease Susceptibility 1 (EDS1) is a key regulator of plant-pathogen-associated molecular pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) responses. In the Brassica napus genome, we identified six novel EDS1 genes, among which four were responsive to clubroot infection, a major rapeseed disease resistant to chemical control. Developing resistant cultivars is a potent and economically viable strategy to control clubroot infection. Bioinformatics analysis revealed conserved domains and structural uniformity in Bna-EDS1 homologs. Bna-EDS1 promoters harbored elements associated with diverse phytohormones and stress responses, highlighting their crucial roles in plant defense. A functional analysis was performed with Bna-EDS1 overexpression and RNAi transgenic lines. Bna-EDS1 overexpression boosted resistance to clubroot and upregulated defense-associated genes (PR1 , PR2 , ICS1 , and CBP60), while Bna-EDS1 RNAi increased plant susceptibility, indicating suppression of the defense signaling pathway downstream of NBS-LRRs. RNA-Seq analysis identified key transcripts associated with clubroot resistance, including phenylpropanoid biosynthesis. Activation of SA regulator NPR1 , defense signaling markers PR1 and PR2 , and upregulation of MYC-TFs suggested that EDS1-mediated clubroot resistance potentially involves the SA pathway. Our findings underscore the pivotal role of Bna-EDS1 -dependent mechanisms in resistance of B. napus to clubroot disease, and provide valuable insights for fortifying resistance against Plasmodiophora brassicae infection in rapeseed. • Enhanced Disease Susceptibility EDS1 genes in Brassica napus boost early defense responses against Plasmodiophora brassica, providing robust clubroot disease resistance. • Overexpressing Bna-EDS1 induces defense marker genes, enhances resistance, whereas suppressing heightens susceptibility. • Clubroot inoculation enriches transcripts linked to clubroot resistance pathways. [ABSTRACT FROM AUTHOR]

Recent advances in human genetics have shed light on the genetic factors contributing to inflammatory diseases, particularly Crohn's disease (CD), a prominent form of inflammatory bowel disease. Certain risk genes associated with CD directly influence cytokine biology and cell-specific communication networks. Current CD therapies primarily rely on anti-inflammatory drugs, which are inconsistently effective and lack strategies for promoting epithelial restoration and mucosal balance. To understand CD's underlying mechanisms, we investigated the link between CD and the FGFR1OP gene, which encodes a centrosome protein. FGFR1OP deletion in mouse intestinal epithelial cells disrupted crypt architecture, resulting in crypt loss, inflammation, and fatality. FGFR1OP insufficiency hindered epithelial resilience during colitis. FGFR1OP was crucial for preserving non-muscle myosin II activity, ensuring the integrity of the actomyosin cytoskeleton and crypt cell adhesion. This role of FGFR1OP suggests that its deficiency in genetically predisposed individuals may reduce epithelial renewal capacity, heightening susceptibility to inflammation and disease. [Display omitted] • GWASs have linked CD with FGFR1OP , which encodes a centrosome protein • FGFR1OP deletion in mouse intestinal epithelial cells disrupted crypts architecture • FGFR1OP promoted activation of non-muscle myosin II, ensuring crypt cell adhesion • FGFR1OP defects may heighten CD susceptibility by reducing gut epithelial renewal Trsan et al. show that deletion of the centrosomal protein FGFR1OP in mouse intestinal cells disrupts crypt architecture, impairs regeneration, and causes inflammation. FGFR1OP is crucial for non-muscle myosin II activation, cytoskeleton integrity, and cell adhesion, with FGFR1OP defects likely causing Crohn's disease susceptibility by reducing intestinal epithelial renewal capacity. [ABSTRACT FROM AUTHOR]

The Punjabi population, constituting over 45 % of the country's total population, holds the highest prevalence in Pakistan. To understand their HLA genetics, we genotyped 389 Punjabi subjects for major Class-I loci using the PCR-SSO Luminex® method. Our study identified a total of 162 alleles, including 41 different HLA-A, 72 HLA-B, and 49 HLA-C alleles. The most common alleles included A*11:01 (14.6 %), A*01:01 (11.8 %), A*24:02 (11.3 %); B*40:06 (13.3 %), B*08:01 (10.9 %), B*51:01 (8.7 %); C*15:02 (15.5 %), C*07:02 (15.3 %), and C*04:01 (10.8 %). However, only locus B showed a significant deviation from HWE. The dominant Class I haplotype was A*24:02-B*40:06-C*15:02, followed by A*11:01-B*40:06-C*15:02, while significant LD was observed between all pairs of HLA loci. A distinct genetic makeup was observed in the Pakistani Punjabis as compared to Indian Punjabis, emphasizing the impact of the Indo-Pak partition and religious choices for marriage. In comparison to country's other ethnic groups, the Pakistani population exhibited 76 different alleles at a low field-resolution, with the Punjabi population having highest polymorphism. Phylogenetic analysis revealed that the Punjabi population is most closely related to the Sindhi population, while both populations sharing ancient connections with the Burusho population. These findings have significant implications for transplantation procedures, personalized medicine, disease susceptibility, and evolutionary studies. [ABSTRACT FROM AUTHOR]

Background: Segmentation of cardiovascular magnetic resonance (CMR) images is an essential step for evaluating dimensional and functional ventricular parameters as ejection fraction (EF) but may be limited by artifacts, which represent the major challenge to automatically derive clinical information. The aim of this study is to investigate the accuracy of a deep learning (DL) approach for automatic segmentation of cardiac structures from CMR images characterized by magnetic susceptibility artifact in patient with cardiac implanted electronic devices (CIED). Methods: In this retrospective study, 230 patients (100 with CIED) who underwent clinically indicated CMR were used to developed and test a DL model. A novel convolutional neural network was proposed to extract the left ventricle (LV) and right (RV) ventricle endocardium and LV epicardium. In order to perform a successful segmentation, it is important the network learns to identify salient image regions even during local magnetic field inhomogeneities. The proposed network takes advantage from a spatial attention module to selectively process the most relevant information and focus on the structures of interest. To improve segmentation, especially for images with artifacts, multiple loss functions were minimized in unison. Segmentation results were assessed against manual tracings and commercial CMR analysis software cvi42(Circle Cardiovascular Imaging, Calgary, Alberta, Canada). An external dataset of 56 patients with CIED was used to assess model generalizability. Results: In the internal datasets, on image with artifacts, the median Dice coefficients for end-diastolic LV cavity, LV myocardium and RV cavity, were 0.93, 0.77 and 0.87 and 0.91, 0.82, and 0.83 in end-systole, respectively. The proposed method reached higher segmentation accuracy than commercial software, with performance comparable to expert inter-observer variability (bias ± 95%LoA): LVEF 1 ± 8% vs 3 ± 9%, RVEF − 2 ± 15% vs 3 ± 21%. In the external cohort, EF well correlated with manual tracing (intraclass correlation coefficient: LVEF 0.98, RVEF 0.93). The automatic approach was significant faster than manual segmentation in providing cardiac parameters (approximately 1.5 s vs 450 s). Conclusions: Experimental results show that the proposed method reached promising performance in cardiac segmentation from CMR images with susceptibility artifacts and alleviates time consuming expert physician contour segmentation. [ABSTRACT FROM AUTHOR]

Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by a selective predisposition to infections caused by intracellular pathogens, such as mycobacteria, due to impaired IFN-γ immunity. To date, 18 different genes associated with MSMD have been reported. This review describes recent discoveries, a 2020–2021 update, in MSMD through the introduction of three novel genetic disorders, namely, AR IFN-γ, T-bet, and ZNFX1 complete deficiency, as well as molecular mechanisms underlying multifocal osteomyelitis in patients with this condition. PubMed databases were searched for reports of MSMD since January 2020. Relevant articles and their references were screened. The review covers a general overview, known genes, classifications, symptoms, and treatments for MSMD. MSMD is classified into two groups: isolated MSMD and syndromic MSMD. Among the 18 genes responsible, 13 cause isolated MSMD, which is characterized by selective predisposition to one or more mycobacterial and related infections, and 8 cause syndromic MSMD, which involves the combination of the mycobacterial disease infectious phenotype with additional clinical phenotypes. Among the three genetic etiologies described herein, AR IFN-γ deficiency is classified as isolated MSMD, whereas AR T-bet and ZNFX1 deficiency are classified as syndromic MSMD. Multifocal osteomyelitis is a representative symptom of MSMD, and a high frequency of multifocal osteomyelitis is reported in MSMD patients due to impaired IFN-γ responses, such as with AD IFN-γR1, AD IFN-γR2, or AD STAT1 deficiency. Impaired inhibition of osteoclast differentiation and bone resorption owing to a poor response to IFN-γ has been shown to be in association with multifocal osteomyelitis in MSMD. Over the past decade, genetic dissection by next-generation sequencing techniques has contributed to the understanding of the molecular bases of human immunity to mycobacteria. However, genetic etiologies are lacking for half of MSMD cases. Further studies will be needed to elucidate the pathogenesis of MSMD. [ABSTRACT FROM AUTHOR]

During the past decades, studies on patients with severe viral infections have revealed rare inborn errors of immunity (IEIs) underlying these diseases. This has led to important new insights into the molecular genetics and immunological mechanisms governing susceptibility to viral infection in humans. Herein, the current knowledge on major IEIs predisposing to severe or chronic viral infections are described and discussed, and the clinical implications of these findings for individualized prophylaxis and treatment are outlined. The review is based on a broad literature search, including relevant studies primarily based on patients, supported by experimental molecular models in vitro or in mice, to characterize the pathophysiological mechanism governing these disease conditions. Current concepts and principles of genetic predisposition to viral infections in humans are described with a major focus on defects related to innate immune responses and new concepts of constitutive immune mechanisms. The topic therefore spans from seminal studies on the human genetics of herpesvirus infections in the central nervous system, severe influenza, and disease after vaccination with live attenuated viral vaccines, to genetic resistance to viral infection. Past and present studies of patients with IEIs conferring vulnerability to viral infections have taught us important lessons on protective innate and adaptive antiviral immunity in humans. Such knowledge also has important clinical implications, allowing development of prophylactic and therapeutic solutions to prevent or dampen the clinical consequences of insufficient or dysregulated antiviral immunity in patients. Collectively, such measures are likely to improve patient management at an individualized level and help societies reduce the disease burden from viral infections. [ABSTRACT FROM AUTHOR]

Introduction: The study was designed to assess the effects of hypertension (HT) susceptibility genes polymorphisms in the development of preeclampsia (PE) in Caucasians from Central Russia.Methods: PE patients (n = 452) and women control group (n = 498) were genotyped for 10 polymorphisms of HT/blood pressure (BP) susceptibility genes (according to the previously published GWAS in Caucasian populations) including AC026703.1 (rs1173771), HFE (rs1799945), BAG6 (rs805303), PLCE1 (rs932764), OBFC1 (rs4387287), ARHGAP42 (rs633185), CERS5 (rs7302981), ATP2B1 (rs2681472), TBX2 (rs8068318) and RGL3 (rs167479). A logistic regression method was applied to search for associations between SNPs and PE. The relationship between SNP-SNP interactions and PE risk was analyzed by performing MB-MDR.Results: The rs1799945 gene in HFE significantly independently increased the risk of developing PE (OR = 2.24) and rs805303 in BAG6 was associated with a reduced risk in the occurrence of PE (OR = 0.55-0.78). Among the 10 SNPs examined, nine SNPs were associated with PEs within the 10 most significant SNP-SNP interaction models. Loci rs7302981 CERS5, rs805303 BAG6 and rs932764 PLCE1 contributed to the largest number of epistatic models (50% or more).Discussion: The present study is the first to report an association between polymorphisms of HT/BP susceptibility genes important for GWAS and the risk of PE in Caucasians from Central Russia. Our pathway-based functional annotation of the PE risk variants highlights the potential regulatory function (epigenetic/eQTL/sQTL/non-synonymous) that nine genetic risk markers and their 115 highly correlated variants exert on 155 genes. The study shows that these genes may function cooperatively in key signaling pathways in PE biology. [ABSTRACT FROM AUTHOR]

A recent Chinese genome-wide association study found evidence for 58 out of the 128 schizophrenia-associated variants previously discovered in Western samples by the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC). However, the functional impact of these trans-ancestry genome-wide single-nucleotide polymorphisms (SNPs) is not clear. In the current study, we examined the roles of trans-ancestry SNPs in cognitive and neural plasticity. We first performed a behavioral study of 547 healthy volunteers, who received month-long working memory training, and working memory capability assessment both before and after the training. A separate sample of 101 subjects received the same training and received fMRI scans during a working memory task, both before and after the training. The behavioral study found a significant association between the polygenic risk score (PRS) and behavioral plasticity, with higher schizophrenia risk scores being linked to less plasticity. At the SNP level, rs36068923 showed a significant signal, with the risk allele being associated with less plasticity. The fMRI study further found that the PRS and rs36068923 polymorphism were associated with training-induced changes in striatal activation, with higher PRS and the risk allele of rs36068923 being linked to less brain plasticity. In sum, this study found that a high genetic risk for schizophrenia was associated with less plasticity at both behavioral and neural levels. These results provide new insights into the neural and cognitive mechanisms linking genes to schizophrenia. [ABSTRACT FROM AUTHOR]