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Seborrheic dermatitis (SD) is a highly prevalent dermatological condition globally. The condition demonstrates bimodal presentation with what is commonly thought to be two subtypes: adult/adolescent seborrheic dermatitis (ASD) and infantile seborrheic dermatitis (ISD). Despite the common prevalence of ASD and ISD, there remains uncertainty around the underlying pathogenetic mechanisms, risk factors, and appropriate classification of the disease(s). This narrative review summarizes the current understanding of the epidemiology, presentation, and pathogenetic factors like epidermal barrier dysfunction, lipid abnormalities, and cutaneous microbiome for ASD and ISD. Elements such as immune responsiveness, neuroendocrine factors, and genetics in these disease states are also investigated. Throughout our review, we highlight shared features and discrepancies between ASD and ISD that are present in the literature and discuss potential avenues for future research that explore these disease states. We aim to contribute to the medical discourse on ASD and ISD and increase awareness of the need for additional research around these conditions, ultimately informing better targeting of therapeutics moving forward. [ABSTRACT FROM AUTHOR]

Different membrane microdomain compositions provide unique environments that can regulate signaling receptor function. We identify microdomains on the endosome membrane of Drosophila endosomes, enriched in lipid-raft or clathrin/ESCRT-0, which are associated with Notch activation by distinct, ligand-independent mechanisms. Transfer of Notch between microdomains is regulated by Deltex and Suppressor of deltex ubiquitin ligases and is limited by a gate-keeper role for ESCRT complexes. Ubiquitination of Notch by Deltex recruits it to the clathrin/ESCRT-0 microdomain and enhances Notch activation by an ADAM10-independent/TRPML-dependent mechanism. This requirement for Deltex is bypassed by the downregulation of ESCRT-III. In contrast, while ESCRT-I depletion also activates Notch, it does so by an ADAM10-dependent/TRPML-independent mechanism and Notch is retained in the lipid raft-like microdomain. In the absence of such endosomal perturbation, different activating Notch mutations also localize to different microdomains and are activated by different mechanisms. Our findings demonstrate the interplay between Notch regulators, endosomal trafficking components, and Notch genetics, which defines membrane locations and activation mechanisms. [ABSTRACT FROM AUTHOR]

Objectives: In response to the controversy surrounding observational studies of the association between lipid profiles and the risk of insomnia, the aim of this study was to analyze lipid profiles, including triglycerides (TG), apolipoprotein A-1 (ApoA-1), apolipoprotein B (ApoB) and lipoprotein A (LPA), in a European population to further assess the causal relationship between these lipid types and insomnia. Materials and methods: This study explores the causal effect of lipid profiles on insomnia based on a genome-wide association study (GWAS)-derived public dataset using two-sample and multivariate Mendelian randomization (MVMR) analysis. The main MR analyses used inverse variance weighting (IVW) odds ratio (OR), and the sensitivity analyses included weighted median (WM) and MR‒Egger. Results: Both MR and MVMR showed that lowering ApoA-1 and LPA levels had causal effects on the risk of insomnia [MR: per 10 units, ApoA-1: OR: 0.7546, 95% CI: 0.6075–0.9372, P = 0.011; LPA: OR: 0.8392, 95% CI: 0.7202–0.9778, P = 0.025; MVMR: per 10 units, ApoA-1: OR: 0.7600, 95% CI: 0.6362–0.9079, P = 0.002; LPA, OR: 0.903, 95% CI: 0.8283–0.9845, P = 0.021]. There were no causal effects of TG or ApoB on insomnia (all P > 0.05). The MR‒Egger intercept test, funnel plot, and IVW methods all suggested an absence of strong directional pleiotropy, and leave-one-out permutation analysis did not detect any single single-nucleotide polymorphism that had a strong influence on the results. Conclusion: Elevated levels of ApoA-1 and LPA were independently and causally associated with the risk of insomnia, suggesting that elevated ApoA-1 and LPA levels may contribute to a reduced risk of insomnia. [ABSTRACT FROM AUTHOR]

Objective: Previous observational studies revealed a potential but partially controversial relation between lipid metabolism and the risk of amyotrophic lateral sclerosis (ALS), potentially prone to bias. Therefore, we aimed to study whether lipid metabolism involves genetically determined risk factors for ALS through Mendelian randomization (MR) analysis. Methods: Using genome‐wide association study summary‐level data for total cholesterol (TC) (n = 188,578), high‐density lipoprotein cholesterol (HDL‐C) (n = 403,943), low‐density lipoprotein cholesterol (LDL‐C) (n = 440,546), apolipoprotein A1 (ApoA1) (n = 391,193), apolipoprotein B (ApoB) (n = 439,214), and ALS (12,577 cases and 23,475 controls), we implemented a bidirectional MR study to evaluate a genetic relation between lipids and ALS risk. We performed a mediation analysis to assess whether LDL‐C is a potential mediator on the pathway from traits of LDL‐C‐related polyunsaturated fatty acids (PUFAs) to ALS risk. Results: We identified genetically predicted increased lipid levels to be associated with the risk of ALS, whereby elevated LDL‐C had the most potent effect (OR 1.028, 95% CI 1.008–1.049, p = 0.006). The effect of increased levels of apolipoproteins on ALS was similar to their corresponding lipoproteins. ALS did not cause any changes in lipid levels. We found no relation between LDL‐C‐modifying lifestyles and ALS. The mediation analysis revealed that LDL‐C could act as an active mediator for linoleic acid, with the mediation effect estimated to be 0.009. Conclusions: We provided high‐level genetic evidence verifying the positive link between preclinically elevated lipid and ALS risk that had been described in previous genetic and observational studies. We also demonstrated the mediating role of LDL‐C in the pathway from PUFAs to ALS. [ABSTRACT FROM AUTHOR]

Background: Dyslipidaemia is an important cardiovascular risk factor for people with severe mental illness, contributing to premature mortality. The link between antipsychotics and dyslipidaemia is well established, while evidence on antidepressants is mixed. Aims: To investigate if antidepressant/antipsychotic use was associated with lipid parameters in UK Biobank participants and if CYP2C19 and CYP2D6 genetic variation plays a role. Methods: Review of self-reported prescription medications identified participants taking antidepressants/antipsychotics. Total, low-, and high-density lipoprotein cholesterol (L/HDL-C) and triglycerides derived from blood samples. CYP2C19 and CYP2D6 metabolic phenotypes were assigned from genetic data. Linear regression investigated aims, adjusted for key covariates. Results: Of 469,739 participants, 36,043 took antidepressants (53% female, median age 58, 17% taking cholesterol-lowering medications) and 3255 took antipsychotics (58% female, median age 57, 27% taking cholesterol-lowering medications). Significant associations were found between use of each amitriptyline, fluoxetine, citalopram/escitalopram, sertraline, paroxetine and venlafaxine with higher total cholesterol, LDL-C, and triglycerides and lower HDL-C, compared to participants not taking each medication. Venlafaxine was associated with the worst lipid profile (total cholesterol, adjusted mean difference: 0.21 mmol/L, 95% confidence interval (CI): 0.17 to 0.26, p < 0.001). Antipsychotic use was significantly associated with lower HDL-C and higher triglycerides. In participants taking sertraline, CYP2C19 intermediate metabolisers had higher HDL-C (0.05 mmol/L, 95% CI: 0.01 to 0.09, p = 0.007) and lower triglycerides (−0.17 mmol/L, 95% CI: −0.29 to −0.05, p = 0.007), compared to normal metabolisers. Conclusions: Antidepressants were significantly associated with adverse lipid profiles, potentially warranting baseline and regular monitoring. Further research should investigate the mechanistic pathways underlying the protective effects of the CYP2C19 intermediate metaboliser phenotype on HDL-C and triglycerides in people taking sertraline. [ABSTRACT FROM AUTHOR]

The relationship between caffeine consumption and cardiometabolic health has been reported, however with heterogenous results. Discrepancies in study results may be due to inter‐individual variability between study participants. This systematic review aimed to identify the impact of genetics on the relationship between caffeine consumption and cardiometabolic outcomes. Electronic databases (PubMed and EMBASE) were searched for studies published until July 2021. Selected studies were of both intervention and observational design and included (1) analysis of at least one of the selected cardiometabolic outcome (type 2 diabetes, glucose/insulin levels, cardiovascular disease [CVD], blood pressure [BP] or hypertension, and blood lipid and catecholamine levels), (2) adults aged 18–65 years, and (3) genetic analysis of individuals consuming caffeine. Seventeen studies were included: four randomised controlled trials and an interventional and quasi‐experimental study, six population‐based prospective cohort studies, three cross‐sectional studies, and three case–control studies. CYP1A2 rs762551 and ADORA rs5751876 were associated with glucose response when caffeine was consumed with carbohydrates. CYP1A2 rs762551 moderated the association between coffee intake and hypertension. Moreover, ADORA2A rs5751876 and the ADRA2B I variants moderated the associations between caffeine and BP. Studies that investigated the effects of genetic variations on CVD and caffeine consumption reported equivocal findings (CYP1A2) or warrant replication (COMT, ADORA and TRIB1). Elucidating the extent to which these genes moderate the association between caffeine and cardiometabolic outcomes will enable caffeine consumption advice to be tailored to specific individuals to optimise health. [ABSTRACT FROM AUTHOR]

We investigated the prevalence and clinical metabolic characteristics of lean nonalcoholic fatty liver disease (NAFLD) in an elderly Chinese population and assessed the relevance of lipid markers and genetic variation. All 5,338 community subjects underwent detailed clinical and laboratory examinations and were divided into three groups: lean (Body mass index (BMI) < 23 kg/m2, n = 2,012), overweight (BMI = 23–24.9 kg/m2, n = 1,354), and obese (BMI ≥ 25 kg/m2, n = 1,972). Single nucleotide polymorphisms were selected based on those reported in previous NAFLD or obesity genome-wide association studies. The frequencies of alleles and genotypes were calculated and statistically analyzed with Pearson's χ2 tests. One-way ANCOVA was used to test the association between positive SNPs and metabolic parameters in lean NAFLD individuals. Our results showed that the C allele frequency of rs2279026, the G allele of rs2279028, the C allele of rs780093, and the C allele frequency of rs1260326 were higher in obese NAFLD than in lean NAFLD (P < 0.05). In addition, we observed an association between the CC of rs1421085, TT of rs3751812, AA of rs8050136, and AA of rs9939609 genotypes in the FTO gene and low-density lipoprotein levels (P < 0.05). In conclusion, our findings provide a unique perspective on the prevalence, genetic characteristics, and metabolic profile of NAFLD in older lean individuals in China. This is the first study to examine the association between genetic variants in the FTO, TFAP2B and GCKR genes and NAFLD in a cohort of lean individuals. [ABSTRACT FROM AUTHOR]

Background and purpose: We used two‐sample Mendelian randomization (MR) to examine the effects of blood lipids and lipid‐modifying drugs on intracranial aneurysm (IA). Methods: Genetic variants for the effects of high‐density lipoprotein cholesterol (HDL‐C), apolipoprotein A1, low‐density lipoprotein cholesterol (LDL‐C), apolipoprotein B, and triglycerides and targets for lipid‐modifying drugs were selected from the genome‐wide discovery analyses of the UK Biobank. Summary‐level data on IAs were obtained from the International Stroke Genetics Consortium. Univariate and multivariate MR analyses were performed. Results: Univariate MR analyses showed that the HDL‐C was negatively correlated with IA (odds ratio [OR] = 0.816, 95% confidence interval [CI] = 0.715–0.932, p = 0.003) and ruptured IA (rIA; OR = 0.775, 95% CI = 0.663–0.906, p = 0.001). The multivariate MR–inverse variance weighted analysis showed that the HDL‐C was negatively correlated with IA (OR = 0.655, 95% CI = 0.434–0.988, p = 0.043) and rIA (OR = 0.563, 95% CI = 0.347–0.913, p = 0.02), and the LDL‐C was negatively correlated with IA (OR = 0.402, 95% CI = 0.191–0.848, p = 0.017) and rIA (OR = 0.376, 95% CI = 0.160–0.883, p = 0.025). Using genetic proxies of known lipid‐modifying drugs, we found that the increased HDL‐C with cholesterol ester transfer protein proxies was associated with a decreased risk of rIA (OR = 0.852, 95% CI = 0.747–0.973, p = 0.018), and the decreased LDL‐C with 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase proxies was associated with increased risk of IA (OR = 1.772, 95% CI = 1.080–2.908, p = 0.024) and rIA (OR = 1.856, 95% CI = 1.022–3.371, p = 0.042). Conclusions: Genetically determined HDL‐C and LDL‐C reduce the risk of IA and rIA. The effects of different lipid‐modifying drugs on IA need to be further investigated. [ABSTRACT FROM AUTHOR]

Simple Summary: The newly described form of iron-dependent cell death, called ferroptosis, has emerged as a powerful strategy for eradicating cancer cells. This is of particular importance for pancreatic ductal adenocarcinoma (PDAC), which has been shown to be one of the most aggressive tumors, with a five-year overall survival of less than 8%. The aim of the present study is to identify the most potent and selective target for the induction of ferroptosis in PDAC cells. The results presented here are of great importance not only for the development of novel and more effective anti-cancer therapeutics, but also anticipate potential resistant mechanisms that cancer cells might deploy. This way, ferroptosis-based therapeutics may be a step ahead of highly adaptable cancer cells. The conceptualization of a novel type of cell death, called ferroptosis, opens new avenues for the development of more efficient anti-cancer therapeutics. In this context, a full understanding of the ferroptotic pathways, the players involved, their precise role, and dispensability is prerequisite. Here, we focused on the importance of glutathione (GSH) for ferroptosis prevention in pancreatic ductal adenocarcinoma (PDAC) cells. We genetically deleted a unique, rate-limiting enzyme for GSH biosynthesis, γ-glutamylcysteine ligase (GCL), which plays a key role in tumor cell proliferation and survival. Surprisingly, although glutathione peroxidase 4 (GPx4) has been described as a guardian of ferroptosis, depletion of its substrate (GSH) led preferentially to apoptotic cell death, while classical ferroptotic markers (lipid hydroperoxides) have not been observed. Furthermore, the sensitivity of PDAC cells to the pharmacological/genetic inhibition of GPx4 revealed GSH dispensability in this context. To the best of our knowledge, this is the first time that the complete dissection of the xCT-GSH-GPx4 axis in PDAC cells has been investigated in great detail. Collectively, our results revealed the necessary role of GSH in the overall redox homeostasis of PDAC cells, as well as the dispensability of this redox-active molecule for a specific, antioxidant branch dedicated to ferroptosis prevention. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia (FH) is the most relevant genetic cause of early cardiovascular disease (CVD). FH is suspected when low density lipoprotein cholesterol (LDL-C) levels exceed the 95th percentile of the population distribution. Different diagnostic scoring systems have been developed, as the Dutch Lipid Clinic Network (DLCN) score, used worldwide. The aim of the study is to describe the characteristics of FH patients of a large cohort of more than eight hundred genotyped subjects enrolled in an Italian Lipid Clinic, and evaluate the DLCN score performance applied retrospectively to the case study. 836 hypercholesterolemic patients with LDL-C > 4.88 mmol/L were genotyped for FH causative gene variants in the LDLR , PCSK and APOB genes. Relatives of mutated patients were also analyzed by cascade screening. Gene variant carriers were younger, presented higher LDL-C and DLCN score and lower HDL-C levels in comparison with hypercholesterolemic (HC) non-carriers and presented a five-fold higher prevalence of previous CV events. Carotid US data available in 490 subjects showed that variant carriers had an odds ratio of 3.66 (1.43–10.24) for atherosclerotic plaques in comparison with non-carriers. Scoring system were evaluated by ROC analysis in 203 subjects without missing DLCN items and with available pre-therapy LDL-C levels, and LDL-C levels (A.U.C. = 0.737) resulted to be more performing than the DLCN score (A.U.C. = 0.662), even including carotid US data (A.U.C. = 0.641) in a modified DLCN score version. the DLCN score failed to demonstrate a clear superiority in predicting FH gene variants in comparison with the measure of LDL-C levels in a retrospective case study. [Display omitted] • A cohort of 836 hypercholesterolemic subjects were genotypized in a Lipid Clinic. • Dutch Lipid Clinic Score for the diagnosis of familial hypercholesterolemia (FH) was applied retrospectively. • Dutch Lipid Clinic Network (DLCN) was not superior than low density lipoprotein cholesterol (LDL-C) levels to predict FH mutation carriers. • Mutation carriers showed increased prevalence of cardiovascular disease. • Carotid US was not helpful to increase monogenic FH prediction accuracy. [ABSTRACT FROM AUTHOR]

Background: Increased elastase activity in α1-antitrypsin deficiency may affect elasticity of the arterial walls, and thereby blood pressure and susceptibility to cardiovascular disease. We hypothesized that severe α1-antitrypsin deficiency is associated with reduced blood pressure and susceptibility to cardiovascular disease.Methods: We genotyped 91,353 adults randomly selected from the Danish general population and 187 patients from the Danish α1-Antitrypsin Deficiency Registry and recorded baseline blood pressure, baseline plasma lipids and cardiovascular events during follow-up. 185 participants carried the ZZ genotype, 207 carried the SZ genotype and 91,148 carried the MM genotype.Results: α1-Antitrypsin deficiency was associated with decreases in blood pressure of up to 5 mmHg for systolic blood pressure and up to 2 mmHg for diastolic blood pressure, in ZZ vs SZ vs MM individuals (trend test, P's ≤ 0.01). Plasma triglycerides and remnant cholesterol were reduced in ZZ individuals compared with MM individuals (t-test, P's < 0.001). α1-Antitrypsin deficiency was associated with lower risk of myocardial infarction (trend test P = 0.03), but not with ischemic heart disease, ischemic cerebrovascular disease or hypertension (trend test, P's ≥ 0.59). However, when results for ischemic heart disease were summarized in meta-analysis with results from four previous studies, individuals with versus without α1-antitrypsin deficiency had an odds ratio for ischemic heart disease of 0.66 (95% CI:0.53-0.84).Conclusions: Individuals with severe α1-antitrypsin deficiency have lower systolic and diastolic blood pressure, lower plasma triglycerides and remnant cholesterol, reduced risk of myocardial infarction, and a 34% reduced risk of ischemic heart disease. [ABSTRACT FROM AUTHOR]

Background: Dyslipoproteinemias can be classified by their distinct lipoprotein patterns, which helps determine atherosclerotic cardiovascular disease (ASCVD) risk and directs lipid management but this has required advanced laboratory testing. Objective: To develop a new algorithm for classifying lipoprotein disorders that only relies on the standard lipid panel. Methods: Lipid thresholds for defining the different lipoprotein phenotypes were derived for Non-High-Density Lipoprotein-Cholesterol (NonHDL-C) and Triglycerides (TG) to be concordant when possible with the current US Multi-Society guidelines for blood cholesterol management. Results: The new classification method categorizes patients into all the classical Fredrickson-like phenotypes except for Type III dysbetalipoproteinemia. In addition, a new hypolipidemic phenotype (Type VI) due to genetic mutations in apoB-metabolism is described. The validity of the new algorithm was confirmed by lipid analysis by NMR (N = 11,365) and by concordance with classification by agarose gel electrophoresis/beta-quantification (N = 5504). Furthermore, based on the Atherosclerosis Risk in Communities (ARIC) cohort (N = 14,742), the lipoprotein phenotypes differ in their association with ASCVD (TypeV>IIb > IVb > IIa > IVa > normolipidemic) and can be used prognostically as risk enhancer conditions in the management of patients. Conclusions: We describe a clinically useful lipoprotein phenotyping system that is only dependent upon the standard lipid panel. It, therefore, can be easily implemented for increasing compliance with current guidelines and for improving the care of patients at risk for ASCVD. Highlights: A new algorithm is described for categorizing dyslipidemic patients into Fredrickson-like lipoprotein phenotypes except for Type III. The new lipoprotein phenotypes were validated by NMR-lipoprotein analysis and by agarose gel electrophoresis/beta-quantification in a large number of subjects. The new lipoprotein phenotyping system identifies high-risk cardiovascular patients and helps direct clinical management. A major advance is that the new lipoprotein phenotypes are based on just the standard lipid panel, and thus can be automatically calculated by the clinical laboratory and widely implemented. [ABSTRACT FROM AUTHOR]

Purpose: To examine whether serum cholesterol in early middle age is associated with age‐related macular degeneration (AMD) later in life. Methods: A group of Helsinki Businessmen Study (HBS) participants (n = 209) were recruited for the study. Total cholesterol (TC), triglyceride and body mass index (BMI) were measured at the HBS baseline visit in 1964–1973. Lipid subfractions, BMI, smoking status and statin use were recorded in 2011 and fundus photographs graded for AMD in 2005–2012. The subjects were genotyped for the main AMD risk single nucleotide polymorphisms (SNPs). Results: TC measured at baseline 1964–1973 was significantly higher in subjects later developing intermediate or late AMD (6.67 mmol/l versus 6.20 mmol/l, p = 0.024) or with drusen size of ≥125 µm (6.68 mmol/l versus 6.21 mmol/l, p = 0.030) compared with the rest of the study population. TC, LDL and TG values at follow‐up 2011 were lower in subjects with AMD compared to those without, whereas HDL levels showed no difference. In multivariate analysis, baseline TC associated with intermediate or late AMD (OR 1.59, p = 0.004) and drusen size ≥ 125 µm (OR 1.57, p = 0.006) when corrected for age, BMI, AMD risk SNPs and smoking. Lipid values measured 2011 had no associations after correction. Conclusions: High systemic total cholesterol in early middle age may have a role in the initial development of AMD, especially in patients later developing large drusen. [ABSTRACT FROM AUTHOR]

Background: Genetic, lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase the risk of cardiovascular and metabolic diseases. However, how changes in individual lipid species contribute to disease risk is often unclear. Moreover, little is known about the role of lipids on cardiovascular disease in Pakistan, a population historically underrepresented in cardiovascular studies.Methods: We characterised the genetic architecture of the human blood lipidome in 5662 hospital controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS) and 13,814 healthy British blood donors from the INTERVAL study. We applied a candidate causal gene prioritisation tool to link the genetic variants associated with each lipid to the most likely causal genes, and Gaussian Graphical Modelling network analysis to identify and illustrate relationships between lipids and genetic loci.Results: We identified 253 genetic associations with 181 lipids measured using direct infusion high-resolution mass spectrometry in PROMIS, and 502 genetic associations with 244 lipids in INTERVAL. Our analyses revealed new biological insights at genetic loci associated with cardiometabolic diseases, including novel lipid associations at the LPL, MBOAT7, LIPC, APOE-C1-C2-C4, SGPP1, and SPTLC3 loci.Conclusions: Our findings, generated using a distinctive lipidomics platform in an understudied South Asian population, strengthen and expand the knowledge base of the genetic determinants of lipids and their association with cardiometabolic disease-related loci. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is associated with an increased risk of cardiovascular disease (CVD). The increased risk of CVD concerns an increased risk of venous thromboembolism (VTE), atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF), at corresponding relative risks of 2.5, 1.2 and 2.0, respectively, as compared with the general population. Especially young patients under the age of 40 years run a relatively high risk of these complications when compared with the general population. Chronic systemic inflammation causes a hypercoagulable state leading to the prothrombotic tendency characteristic of VTE, and accelerates all stages involved during atherogenesis in ASCVD. Increased awareness of VTE risk is warranted in patients with extensive colonic disease in both ulcerative colitis and Crohn's disease, as well as during hospitalization, especially when patients are scheduled for surgery. Similarly, critical periods for ASCVD events are the 3 months prior to and 3 months after an IBD-related hospital admission. The increased ASCVD risk is not fully explained by an increased prevalence of traditional risk factors and includes pro-atherogenc lipid profiles with high levels of small dense low-density lipoprotein cholesterol particles and dysfunctional high-density lipoprotein cholesterol. Risk factors associated with HF are location and extent of inflammation, female sex, and age exceeding 40 years. A dose-dependent increase of overall CVD risk has been reported for corticosteroids. Immunomodulating maintenance therapy might reduce CVD risk in IBD, not only by a direct reduction of chronic systemic inflammation but possibly also by a direct effect of IBD medication on platelet aggregation, endothelial function and lipid and glucose metabolism. More data are needed to define these effects accurately. Despite accumulating evidence on the increased CVD risk in IBD, congruent recommendations to develop preventive strategies are lacking. This literature review provides an overview of current knowledge and identifies gaps in evidence regarding CVD risk in IBD, by discussing epidemiology, pathogenesis, and clinical management. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is associated with an increased risk of cardiovascular disease (CVD). The increased risk of CVD concerns an increased risk of venous thromboembolism (VTE), atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF), at corresponding relative risks of 2.5, 1.2 and 2.0, respectively, as compared with the general population. Especially young patients under the age of 40 years run a relatively high risk of these complications when compared with the general population. Chronic systemic inflammation causes a hypercoagulable state leading to the prothrombotic tendency characteristic of VTE, and accelerates all stages involved during atherogenesis in ASCVD. Increased awareness of VTE risk is warranted in patients with extensive colonic disease in both ulcerative colitis and Crohn's disease, as well as during hospitalization, especially when patients are scheduled for surgery. Similarly, critical periods for ASCVD events are the 3 months prior to and 3 months after an IBD-related hospital admission. The increased ASCVD risk is not fully explained by an increased prevalence of traditional risk factors and includes pro-atherogenc lipid profiles with high levels of small dense low-density lipoprotein cholesterol particles and dysfunctional high-density lipoprotein cholesterol. Risk factors associated with HF are location and extent of inflammation, female sex, and age exceeding 40 years. A dose-dependent increase of overall CVD risk has been reported for corticosteroids. Immunomodulating maintenance therapy might reduce CVD risk in IBD, not only by a direct reduction of chronic systemic inflammation but possibly also by a direct effect of IBD medication on platelet aggregation, endothelial function and lipid and glucose metabolism. More data are needed to define these effects accurately. Despite accumulating evidence on the increased CVD risk in IBD, congruent recommendations to develop preventive strategies are lacking. This literature review provides an overview of current knowledge and identifies gaps in evidence regarding CVD risk in IBD, by discussing epidemiology, pathogenesis, and clinical management. [ABSTRACT FROM AUTHOR]

Mortality risk is known to be associated with many physiological or biochemical risk factors, and polygenic risk scores (PRSs) may offer an additional or alternative approach to risk stratification. We have compared the predictive value of common biochemical tests, PRSs and information on parental survival in a cohort of twins and their families. Common biochemical test results were available for up to 13,365 apparently healthy men and women, aged 17-93 years (mean 49.0, standard deviation [SD] 13.7) at blood collection. PRSs for longevity were available for 14,169 study participants and reported parental survival for 25,784 participants. A search for information on date and cause of death was conducted through the Australian National Death Index, with median follow-up of 11.3 years. Cox regression was used to evaluate associations with mortality from all causes, cancers, cardiovascular diseases and other causes. Linear relationships with all-cause mortality were strongest for C-reactive protein, gamma-glutamyl transferase, glucose and alkaline phosphatase, with hazard ratios (HRs) of 1.16 (95% CI [1.07, 1.24]), 1.15 (95% CI 1.04-1.21), 1.13 (95% CI [1.08, 1.19]) and 1.11 (95% CI [1.05, 1.88]) per SD difference, respectively. Significant nonlinear effects were found for urea, uric acid and butyrylcholinesterase. Lipid risk factors were not statistically significant for mortality in our cohort. Family history and PRS showed weaker but significant associations with survival, with HR in the range 1.05 to 1.09 per SD difference. In conclusion, biochemical tests currently predict long-term mortality more strongly than genetic scores based on genotyping or on reported parental survival. [ABSTRACT FROM AUTHOR]

Prevailing strategies in genome-wide association studies (GWAS) mostly rely on principles of medical genetics emphasizing one gene, one function, one phenotype concept. Here, we performed GWAS of blood lipids leveraging a new systemic concept emphasizing complexity of genetic predisposition to such phenotypes. We focused on total cholesterol, low- and high-density lipoprotein cholesterols, and triglycerides available for 29,902 individuals of European ancestry from seven independent studies, men and women combined. To implement the new concept, we leveraged the inherent heterogeneity in genetic predisposition to such complex phenotypes and emphasized a new counter intuitive phenomenon of antagonistic genetic heterogeneity, which is characterized by misalignment of the directions of genetic effects and the phenotype correlation. This analysis identified 37 loci associated with blood lipids but only one locus, FBXO33, was not reported in previous top GWAS. We, however, found strong effect of antagonistic heterogeneity that leaded to profound (quantitative and qualitative) changes in the associations with blood lipids in most, 25 of 37 or 68%, loci. These changes suggested new roles for some genes, which functions were considered as well established such as GCKR, SIK3 (APOA1 locus), LIPC, LIPG, among the others. The antagonistic heterogeneity highlighted a new class of genetic associations emphasizing beneficial and adverse trade-offs in predisposition to lipids. Our results argue that rigorous analyses dissecting heterogeneity in genetic predisposition to complex traits such as lipids beyond those implemented in current GWAS are required to facilitate translation of genetic discoveries into health care. [ABSTRACT FROM AUTHOR]

Background: Conventional epidemiologic studies have evaluated associations between circulating lipid levels and breast cancer risk, but results have been inconsistent. As Mendelian randomization analyses may provide evidence for causal inference, we sought to evaluate potentially unbiased associations between breast cancer risk and four genetically predicted lipid traits.Methods: Previous genome-wide association studies (GWAS) have identified 164 discrete variants associated with high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides and total cholesterol. We used 162 of these unique variants to construct weighted genetic scores (wGSs) for a total of 101 424 breast cancer cases and 80 253 controls of European ancestry from the Breast Cancer Association Consortium (BCAC). Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between per standard deviation increase in genetically predicted lipid traits and breast cancer risk. Additional Mendelian randomization analysis approaches and sensitivity analyses were conducted to assess pleiotropy and instrument validity.Results: Corresponding to approximately 15 mg/dL, one standard deviation increase in genetically predicted HDL-C was associated with a 12% increased breast cancer risk (OR: 1.12, 95% CI: 1.08-1.16). Findings were consistent after adjustment for breast cancer risk factors and were robust in several sensitivity analyses. Associations with genetically predicted triglycerides and total cholesterol were inconsistent, and no association for genetically predicted LDL-C was observed.Conclusions: This study provides strong evidence that circulating HDL-C may be associated with an increased risk of breast cancer, whereas LDL-C may not be related to breast cancer risk. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea is associated with an increased risk of hypertension, diabetes and dyslipidaemia. Both obstructive sleep apnea and its comorbidities are at least partly heritable, suggesting a common genetic background. Our aim was to analyse the heritability of the relationship between obstructive sleep apnea and its comorbidities using a twin study. Forty‐seven monozygotic and 22 dizygotic adult twin pairs recruited from the Hungarian Twin Registry (mean age 51 ± 15 years) attended an overnight diagnostic sleep study. A medical history was taken, blood pressure was measured, and blood samples were taken for fasting glucose, total cholesterol, triglyceride, high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol and lipoprotein (a). To evaluate the heritability of obstructive sleep apnea and its comorbidities bivariate analysis was performed with an adjustment for age, gender, body mass index (BMI) and smoking after false discovery rate correction and following exclusion of patients on lipid‐lowering and antidiabetic medications. There was a significant correlation between indices of obstructive sleep apnea severity, such as the apnea–hypopnea index, oxygen desaturation index and percentage of sleep time spent with oxygen saturation below 90%, as well as blood pressure, serum triglyceride, lipoprotein (a) and glucose levels (all p <.05). The bivariate analysis revealed a common genetic background for the correlations between serum triglyceride and the oxygen desaturation index (r =.63, p =.03), as well as percentage of sleep time spent with oxygen saturation below 90% (r =.58, p =.03). None of the other correlations were significantly genetically or environmentally determined. This twin study demonstrates that the co‐occurrence of obstructive sleep apnea with hypertriglyceridaemia has a genetic influence and heritable factors play an important role in the pathogenesis of dyslipidaemia in obstructive sleep apnea. [ABSTRACT FROM AUTHOR]

Background: Avocados are rich in unsaturated fat and fiber; clinical trials have investigated their effects on metabolic disease. There is high variability in individual changes following avocado consumption, which may be in part due to individual genetic differences.Objective: Secondary analyses of the Persea americana for Total Health (PATH) Study were used to examine how single nucleotide polymorphisms (SNPs) impact blood lipid changes following a daily meal containing avocado compared with control.Methods: Adults (n = 115, 37% male) aged 25-45 y with overweight and obesity were randomly assigned to receive a daily isocaloric meal with (intervention) or without (control) a standardized amount (males: 175 g; females: 140 g) of avocado for 12 wk. Control meals were higher in saturated fat (17% of energy compared with 7%) and lower in fiber (4 g compared with 16 g) than intervention meals. Whole venous blood was taken at baseline and 12 wk to determine total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, and triglyceride (TG) concentrations. Seventeen SNPs in 10 genes related to lipoprotein metabolism were genotyped. Effects of SNP, diet, and SNP-diet interactions were determined using general linear models.Results: No group-by-time effects were detected for changes in TC (P = 0.96), HDL cholesterol (P = 0.28), or TG (P = 0.06) over 12 wk. Three SNP-diet interactions were associated with final TC concentrations: ANGPTL3-rs10889337 (P = 0.01), ANGPTL4-rs2278236 (P = 0.02), and CD36-rs10499859 (P = 0.01). SNPs in GCKR and LPL were associated with TC changes (P = 0.01). The interaction between GCKR-rs1260326 and diet was such that C-homozygotes receiving avocado (n = 23) had final TC concentrations that were significantly lower than the C-homozygotes in the control group (n = 20) (P = 0.02).Conclusions: Results from these exploratory analyses indicate that avocado consumption may help manage dyslipidemia in adults with overweight and obesity; however, effectiveness may differ by genetic profile. Understanding the role of genetic variation in variability following dietary intervention can potentially inform personalized nutrition recommendations. [ABSTRACT FROM AUTHOR]

Background: Niemann-Pick disease (NPD) is a rare autosomal recessive hereditary disease characterized by deficient activity of acid sphingomyelinase. Case presentation: We present a case of NPD type B with a unique compound heterozygosity for SMPD1 (NM_000543.4:c.[84delC];[96G > A]) in which both mutations that induce an early stop codon are located before the second in-frame initiation codon. The clinical presentation of the patient is compatible with NPD type B. She was initially diagnosed of Gaucher Disease, but her altered lipid profile led to a clinical suspicion of NPD. Combined high doses of atorvastatin and ezetimibe were given to treat the severe hypercholesterolemia. Conclusions: The pharmacological management of the lipid profile in these patients is important. A unique compound mutation in SMPD1 gene is described. [ABSTRACT FROM AUTHOR]

Objectives: To describe, for the first time (to the best of our knowledge), the genetic mechanisms of vancomycin resistance in clinical isolates of Clostridioides difficile ribotype 027.Methods: Clinical isolates and laboratory mutants were analysed: genomically to identify resistance mutations; by transcriptional analysis of vanGCd, the vancomycin resistance operon encoding lipid II d-alanine-d-serine that is less bound by vancomycin than native lipid II d-alanine-d-alanine; by imaging of vancomycin binding to cell walls; and for changes in vancomycin bactericidal activity and autolysis.Results: Vancomycin-resistant laboratory mutants and clinical isolates acquired mutations to the vanSR two-component system that regulates vanGCd. The substitutions impaired VanSR's function, resulting in constitutive transcription of vanGCd. Resistance was reversed by silencing vanG, encoding d-alanine-d-serine ligase in the vanGCd operon. In resistant cells, vancomycin was less bound to the cell wall septum, the site where vancomycin interacts with lipid II. Vancomycin's bactericidal activity was reduced against clinical isolates and laboratory mutants (64 and ≥1024 mg/L, respectively) compared with WT strains (4 mg/L). Truncation of the potassium transporter TrkA occurred in laboratory mutants, which were refractory to autolysis, accounting for their survival in high drug concentrations.Conclusions: Ribotype 027 evolved first-step resistance to vancomycin by constitutively expressing vanGCd, which is otherwise silent. Experimental evolutions and bactericidal assays show that ribotype 027 can acquire mutations to drastically enhance its tolerance to vancomycin. Thus, further epidemiological studies are warranted to examine the extent to which vancomycin resistance impacts clinical outcomes and the potential for these strains to evolve higher-level resistance, which would be devastating. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia (FH) is a monogenic disease characterized by high levels of low-density lipoprotein cholesterol and premature atherosclerotic cardiovascular disease. FH is caused by loss of function mutations in genes encoding LDL receptor (LDLR), and Apolipoprotein B (APOB) or gain of function (GOF) mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9). In this study, we identified a novel variant in PCSK9 , p.(Arg499His), located in the C-terminal domain , in two unrelated FH patients from Spain and Italy. We studied familial segregation and determined variant activity in vitro. We determined PCSK9 expression, secretion and activity of the variant in transfected HEK293 cells; extracellular activity of the recombinant p.(Arg499His) PCSK9 variant in HEK 293 and HepG2 cells; PCSK9 affinity to the LDL receptor at neutral and acidic pH; the mechanism of action of the p.(Arg499His) PCSK9 variant by co-transfection with a soluble construct of the LDL receptor and by determining total PCSK9 intracellular accumulation when endosomal acidification is impaired and when an excess of soluble LDLr is present in the culture medium. Our results show high LDL-C concentrations and FH phenotype in p.(Arg499His) carriers. In vitro functional characterization shows that p.(Arg499His) PCSK9 variant causes a reduction in LDLr expression and LDL uptake. An intracellular activity for this variant is also shown when blocking the activity of secreted PCSK9 and by inhibiting endosomal acidification. We demonstrated that p.(Arg499His) PCSK9 variant causes a direct intracellular degradation of LDLr therefore causing FH by reducing LDLr availability. Image 1 • We identified a novel PCSK9 GOF variant, p.(Arg499His), in two unrelated FH patients from Spain and Italy. • p.(Arg499His) PCSK9 variant carriers show high LDL-C concentrations and FH phenotype. • In vitro assays revealed reduced LDL receptor expression at membrane surface with p.(Arg499His). • p.(Arg499His) is a GOF mutation that causes FH through an intracellular effect reducing LDLr availability. [ABSTRACT FROM AUTHOR]

Genetic divergence is impacted by many factors, including phylogenetic history, gene flow, genetic drift, and divergent selection. Rotifers are an important component of aquatic ecosystems, and genetic variation is essential to their ongoing adaptive diversification and local adaptation. In addition to coding sequence divergence, variation in gene expression may relate to variable heat tolerance, and can impose ecological barriers within species. Temperature plays a significant role in aquatic ecosystems by affecting species abundance, spatio-temporal distribution, and habitat colonization. Recently described (formerly cryptic) species of the Brachionus calyciflorus complex exhibit different temperature tolerance both in natural and in laboratory studies, and show that B. calyciflorus sensu stricto (s.s.) is a thermotolerant species. Even within B. calyciflorus s.s., there is a tendency for further temperature specializations. Comparison of expressed genes allows us to assess the impact of stressors on both expression and sequence divergence among disparate populations within a single species. Here, we have used RNA-seq to explore expressed genetic diversity in B. calyciflorus s.s. in two mitochondrial DNA lineages with different phylogenetic histories and differences in thermotolerance. We identify a suite of candidate genes that may underlie local adaptation, with a particular focus on the response to sustained high or low temperatures. We do not find adaptive divergence in established candidate genes for thermal adaptation. Rather, we detect divergent selection among our two lineages in genes related to metabolism (lipid metabolism, metabolism of xenobiotics). [ABSTRACT FROM AUTHOR]

The reduction of synthetic fungicides in agriculture is necessary to guarantee a sustainable production that protects the environment and consumers’ health. Downy mildew caused by the oomycete Plasmopara viticola is the major pathogen in viticulture worldwide and responsible for up to 60% of pesticide treatments. Alternatives to reduce fungicides are thus utterly needed to ensure sustainable vineyard-ecosystems, consumer health and public acceptance. Essential oils (EOs) are amongst the most promising natural plant protection alternatives and have shown their antibacterial, antiviral and antifungal properties on several agricultural crops. However, the efficiency of EOs highly depends on timing, application method and the molecular interactions between the host, the pathogen and EO. Despite proven EO efficiency, the underlying processes are still not understood and remain a black box. The objectives of the present study were: a) to evaluate whether a continuous fumigation of a particular EO can control downy mildew in order to circumvent the drawbacks of direct application, b) to decipher molecular mechanisms that could be triggered in the host and the pathogen by EO application and c) to try to differentiate whether essential oils directly repress the oomycete or act as plant resistance primers. To achieve this a custom-made climatic chamber was constructed that enabled a continuous fumigation of potted vines with different EOs during long-term experiments. The grapevine (Vitis vinifera) cv Chasselas was chosen in reason of its high susceptibility to Plasmopara viticola. Grapevine cuttings were infected with P. viticola and subsequently exposed to continuous fumigation of different EOs at different concentrations, during 2 application time spans (24 hours and 10 days). Experiments were stopped when infection symptoms were clearly observed on the leaves of the control plants. Plant physiology (photosynthesis and growth rate parameters) were recorded and leaves were sampled at different time points for subsequent RNA extraction and transcriptomics analysis. Strikingly, the Oregano vulgare EO vapour treatment during 24h post-infection proved to be sufficient to reduce downy mildew development by 95%. Total RNA was extracted from leaves of 24h and 10d treatments and used for whole transcriptome shotgun sequencing (RNA-seq). Sequenced reads were then mapped onto the V. vinifera and P. viticola genomes. Less than 1% of reads could be mapped onto the P. viticola genome from treated samples, whereas up to 30% reads from the controls mapped onto the P. viticola genome, thereby confirming the visual observation of P. viticola absence in the treated plants. On average, 80% of reads could be mapped onto the V. vinifera genome for differential expression analysis, which yielded 4800 modulated genes. Transcriptomic data clearly showed that the treatment triggered the plant’s innate immune system with genes involved in salicylic, jasmonic acid and ethylene synthesis and signaling, activating Pathogenesis-Related-proteins as well as phytoalexin synthesis. These results elucidate EO-host-pathogen interactions for the first time and indicate that the antifungal efficiency of EO is mainly due to the triggering of resistance pathways inside the host plants. This is of major importance for the production and research on biopesticides, plant stimulation products and for resistance-breeding strategies. [ABSTRACT FROM AUTHOR]

The severity of negative energy balance (NEB) in high-producing dairy cows has a high incidence among health diseases. The cow’s energy status during early lactation critically affects metabolic and reproductive parameters. The first objective of this study was to investigate by RNA-seq analysis and RT-qPCR the gene expression profile in white adipose tissue and by gene ontology and upstream regulation tools the relationships with energy metabolism and reproduction in two groups of primiparous dairy cows with extreme NEB statuses (NEB < -9 Mcal/day vs. NEB > -9 Mcal/day) around parturition. The second objective was to determine the potential involvement of a new adipokine identified as a candidate for the regulation of ovarian function in our RNA-seq analysis by using bovine primary granulosa culture, thymidine incorporation to determine cell proliferation and ELISA assays to measure progesterone secretion. The RNA-seq analysis revealed that 514 genes were over-expressed and 695 were under-expressed in the adipose tissue of cows with severe NEB (SNEB) and cows with moderate NEB (MNEB) during the -4 and 16 wkpp period. In addition, 491 genes were over-expressed and 705 genes were under-expressed in the adipose tissue of SNEB cows compared to MNEB cows. Among these differently expressed genes (DEGs), 298 were related to metabolic functions and 264 to reproductive traits. A set of 19 DEGs were validated by RT-qPCR, including CCL21 (C-C motif chemokine ligand 21). Moreover, CCL21, a gene known to be secreted by adipose tissue, was chosen for further analysis in plasma and ovaries. The use of next-generation sequencing technologies allowed us to characterise the transcriptome of white adipose tissue from primiparous cows with different levels of NEB during lactation. This study highlighted the alteration of the expression of genes related to lipid metabolism, including CCL21, which is released in the bloodstream and associated with the in vitro regulation of ovarian functions. [ABSTRACT FROM AUTHOR]

We identified a mouse strain, HLB444, carrying an N-ethyl-N-nitrosourea (ENU)-induced mutation in a highly conserved C2H2 zinc-finger DNA binding motif of the transcriptional regulator KLF15 that exhibits resistance to diet-induced obesity. Characterization of the HLB444 mutant model on high-fat and chow diets revealed a number of phenotypic differences compared to wild-type controls. When fed a high fat diet, HLB444 had lower body fat, resistance to hepatosteatosis, lower circulating glucose and improved insulin sensitivity compared to C57BL/6J controls. Gut microbial profiles in HLB444 generated from 16S rRNA sequencing of fecal samples differed from controls under both chow and high fat diets. HLB444 shares similar phenotypic traits with engineered full- and adipose-specific Klf15 knockout strains; however, some phenotypic differences between this mutant and the other models suggest that the Klf15 mutation in HLB444 is a hypomorphic variant. The HLB444 model will inform further annotation of transcriptional functions of KLF15, especially with respect to the role of the first zinc-finger domain. [ABSTRACT FROM AUTHOR]

A fatty acid analogue, 2-(tridec-12-yn-1-ylthio)acetic acid (1-triple TTA), was previously shown to have hypolipidemic effects in rats by targeting mitochondrial activity predominantly in liver. This study aimed to determine if 1-triple TTA could influence carbohydrate metabolism. Male Wistar rats were treated for three weeks with oral supplementation of 100 mg/kg body weight 1-triple TTA. Blood glucose and insulin levels, and liver carbohydrate metabolism gene expression and enzyme activities were determined. In addition, human myotubes and Huh7 liver cells were treated with 1-triple TTA, and glucose and fatty acid oxidation were determined. The level of plasma insulin was significantly reduced in 1-triple TTA-treated rats, resulting in a 32% reduction in the insulin/glucose ratio. The hepatic glucose and glycogen levels were lowered by 22% and 49%, respectively, compared to control. This was accompanied by lower hepatic gene expression of phosphenolpyruvate carboxykinase, the rate-limiting enzyme in gluconeogenesis, and Hnf4A, a regulator of gluconeogenesis. Gene expression of pyruvate kinase, catalysing the final step of glycolysis, was also reduced by 1-triple TTA. In addition, pyruvate dehydrogenase activity was reduced, accompanied by 10-15-fold increased gene expression of its regulator pyruvate dehydrogenase kinase 4 compared to control, suggesting reduced entry of pyruvate into the TCA cycle. Indeed, the NADPH-generating enzyme malic enzyme 1 (ME1) catalysing production of pyruvate from malate, was increased 13-fold at the gene expression level. Despite the decreased glycogen level, genes involved in glycogen synthesis were not affected in livers of 1-triple TTA treated rats. In contrast, the pentose phosphate pathway seemed to be increased as the hepatic gene expression of glucose-6-phosphate dehydrogenase (G6PD) was higher in 1-triple TTA treated rats compared to controls. In human Huh7 liver cells, but not in myotubes, 1-triple-TTA reduced glucose oxidation and induced fatty acid oxidation, in line with previous observations of increased hepatic mitochondrial palmitoyl-CoA oxidation in rats. Importantly, this work recognizes the liver as an important organ in glucose homeostasis. The mitochondrially targeted fatty acid analogue 1-triple TTA seemed to lower hepatic glucose and glycogen levels by inhibition of gluconeogenesis. This was also linked to a reduction in glucose oxidation accompanied by reduced PHD activity and stimulation of ME1 and G6PD, favouring a shift from glucose- to fatty acid oxidation. The reduced plasma insulin/glucose ratio indicate that 1-triple TTA may improve glucose tolerance in rats. [ABSTRACT FROM AUTHOR]

Background: The double-blind OMEGA-REMODEL placebo-controlled randomized trial of high-dose omega-3 fatty acids (O-3FA) post-acute myocardial infarction (AMI) reported improved cardiac remodeling and attenuation of non-infarct myocardial fibrosis. Fatty acid desaturase 2 (FADS2) gene cluster encodes key enzymes in the conversion of essential omega-3 and omega-6 fatty acids into active arachidonic (ArA) and eicosapentaenoic acids (EPA), which influence cardiovascular outcomes. Methods and results: We tested the hypothesis that the genotypic status of FADS2 (rs1535) modifies therapeutic response of O-3FA in post-AMI cardiac remodeling in 312 patients. Consistent with known genetic polymorphism of FADS2, patients in our cohort with the guanine-guanine (GG) genotype had the lowest FADS2 activity assessed by arachidonic acid/linoleic acid (ArA/LA) ratio, compared with patients with the adenine-adenine (AA) and adenine-guanine (AG) genotypes (GG:1.62±0.35 vs. AA: 2.01±0.36, p<0.0001; vs. AG: 1.76±0.35, p = 0.03). When randomized to 6-months of O-3FA treatment, GG patients demonstrated significant lowering of LV end-systolic volume index (LVESVi), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and galectin-3 levels compared to placebo (-4.4 vs. 1.2 ml/m2, -733 vs. -181 pg/mL, and -2.0 vs. 0.5 ng/mL; p = 0.006, 0.006, and 0.03, respectively). In contrast, patients with either AA or AG genotype did not demonstrate significant lowering of LVESVi, NT-proBNP, or galectin-3 levels from O-3FA treatment, compared to placebo. The odds ratios for improving LVESVi by 10% with O-3FA treatment was 7.2, 1.6, and 1.2 in patients with GG, AG, and AA genotypes, respectively. Conclusion: Genetic profiling using FADS2 genotype can predict the therapeutic benefits of O-3FA treatment against adverse cardiac remodeling during the convalescent phase of AMI. Clinical trial registration information: clinicaltrials.gov Identifier: . [ABSTRACT FROM AUTHOR]

High-throughput multi-omics studies and corresponding network analyses of multi-omic data have rapidly expanded their impact over the last 10 years. As biological features of different types (e.g. transcripts, proteins, metabolites) interact within cellular systems, the greatest amount of knowledge can be gained from networks that incorporate multiple types of -omic data. However, biological and technical sources of variation diminish the ability to detect cross-type associations, yielding networks dominated by communities comprised of nodes of the same type. We describe here network building methods that can maximize edges between nodes of different data types leading to integrated networks, networks that have a large number of edges that link nodes of different–omic types (transcripts, proteins, lipids etc). We systematically rank several network inference methods and demonstrate that, in many cases, using a random forest method, GENIE3, produces the most integrated networks. This increase in integration does not come at the cost of accuracy as GENIE3 produces networks of approximately the same quality as the other network inference methods tested here. Using GENIE3, we also infer networks representing antibody-mediated Dengue virus cell invasion and receptor-mediated Dengue virus invasion. A number of functional pathways showed centrality differences between the two networks including genes responding to both GM-CSF and IL-4, which had a higher centrality value in an antibody-mediated vs. receptor-mediated Dengue network. Because a biological system involves the interplay of many different types of molecules, incorporating multiple data types into networks will improve their use as models of biological systems. The methods explored here are some of the first to specifically highlight and address the challenges associated with how such multi-omic networks can be assembled and how the greatest number of interactions can be inferred from different data types. The resulting networks can lead to the discovery of new host response patterns and interactions during viral infection, generate new hypotheses of pathogenic mechanisms and confirm mechanisms of disease. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with multiple human malignancies. EBV drives B-cell proliferation, which contributes to the pathogenesis of multiple lymphomas. Yet, knowledge of how EBV subverts host biosynthetic pathways to transform resting lymphocytes into activated lymphoblasts remains incomplete. Using a temporal proteomic dataset of EBV primary human B-cell infection, we identified that cholesterol and fatty acid biosynthetic pathways were amongst the most highly EBV induced. Epstein-Barr nuclear antigen 2 (EBNA2), sterol response element binding protein (SREBP) and MYC each had important roles in cholesterol and fatty acid pathway induction. Unexpectedly, HMG-CoA reductase inhibitor chemical epistasis experiments revealed that mevalonate pathway production of geranylgeranyl pyrophosphate (GGPP), rather than cholesterol, was necessary for EBV-driven B-cell outgrowth, perhaps because EBV upregulated the low-density lipoprotein receptor in newly infected cells for cholesterol uptake. Chemical and CRISPR genetic analyses highlighted downstream GGPP roles in EBV-infected cell small G protein Rab activation. Rab13 was highly EBV-induced in an EBNA3-dependent manner and served as a chaperone critical for latent membrane protein (LMP) 1 and 2A trafficking and target gene activation in newly infected and in lymphoblastoid B-cells. Collectively, these studies identify highlight multiple potential therapeutic targets for prevention of EBV-transformed B-cell growth and survival. [ABSTRACT FROM AUTHOR]

Background: Lower birth weight is associated with diabetes although the underlying mechanisms are unclear. Muscle mass could be a modifiable link and hence a target of intervention. We assessed the associations of birth weight with muscle and fat mass observationally in a population with little socio-economic patterning of birth weight and using Mendelian randomization (MR) for validation. Methods: In the population-representative “Children of 1997” birth cohort (n = 8,327), we used multivariable linear regression to assess the adjusted associations of birth weight (kg) with muscle mass (kg) and body fat (%) at ~17.5 years. Genetically predicted birth weight (effect size) was applied to summary genetic associations with fat-free mass and fat mass (kg) from the UK Biobank (n = ~331,000) to obtain unconfounded estimates using inverse-variance weighting. Results: Observationally, birth weight was positively associated with muscle mass (3.29 kg per kg birth weight, 95% confidence interval (CI) 2.83 to 3.75) and body fat (1.09% per kg birth weight, 95% CI 0.54 to 1.65). Stronger associations with muscle mass were observed in boys than in girls (p for interaction 0.004). Using MR, birth weight was positively associated with fat-free mass (0.77 kg per birth weight z-score, 95% CI 0.22 to 1.33) and fat mass (0.58, 95% CI 0.01 to 1.15). No difference by sex was evident. Conclusion: Higher birth weight increasing muscle mass may be relevant to lower birth weight increasing the risk of diabetes and suggests post-natal muscle mass as a potential target of intervention. [ABSTRACT FROM AUTHOR]

Aim: It has recently been reported that the sterol regulatory element-binding transcription factors (SREBF-1c, and -2) contribute to the variation in the plasma lipids levels, which have an important role in the atherosclerotic plaque development. The aim of the present study was to evaluate whether the SREBF1c and SREBF2 gene single nucleotide polymorphisms (SNPs) are associated with plasma lipids levels and ACS susceptibility in a case-control association study. Material and methods: A case-control study was carried out in 625 patients with ACS (82% men and 18% women, with a mean age of 57.97 ± 10.5 years) and 700 healthy controls (66% men and 34% women, with a mean age of 54.37 ± 7.65 years). The sample size was calculated for a statistical power of 80%. We genotyped three SREBF1c (rs2297508, rs11656665 and rs11868035) and three SREBF2 (rs2267439, rs2267443, and rs2228314) gene polymorphisms by 5’ exonuclease TaqMan assays. The associations were evaluated by logistic regression under the co-dominant, dominant, recessive, over-dominant and additive inheritance models. The contribution of the genotypes on the plasma lipids levels was evaluated by Student’s t-test. Results: Under different models, the SREBF1c rs2297508 (OR = 1.50, pCRes = 0.03), SREBF1c rs11656665 (OR = 1.35, pCDom = 0.02 and OR = 1.26, pCAdd = 0.02) and SREBF2 rs2228314 (OR = 1.78, pCRes = 0.03, OR = 1.27, pCAdd = 0.04) SNPs were associated with higher risk of ACS. On the other hand, the SREBF1c rs11868035 SNP was associated with lower risk of ACS (OR = 0.49, pCCo-dom = 0.001, OR = 0.66, pCDom = 0.003, OR = 0.57, PRes = 0.003 and OR = 0.71, pCAdd = 0.001). There was a statistically significant association of both SREBF1c rs11656665 and rs11868035 polymorphisms with plasma triglyceride levels. Conclusions: In summary, our data suggest the association of the SREBF1c and SREBF2 SNPs with risk of developing ACS and with triglyceride levels in a Mexican population. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is characterized by demyelinated lesions in the central nervous system. Destruction of myelin and secondary damage to axons and neurons leads to significant disability, particularly in people with progressive MS. Accumulating evidence suggests that the potential for myelin repair exists in MS, although for unclear reasons this process fails. The cells responsible for producing myelin, the oligodendrocytes, and their progenitors, oligodendrocyte precursor cells (OPCs), have been identified at the site of lesions, even in adults. Their presence suggests the possibility that endogenous remyelination without transplantation of donor stem cells may be a mechanism for myelin repair in MS. Strategies to develop novel therapies have focused on induction of signaling pathways that stimulate OPCs to mature into myelin-producing oligodendrocytes that could then possibly remyelinate lesions. We have been investigating pharmacological approaches to enhance OPC differentiation, and have identified that the combination of two agents, triiodothyronine (T3) and quetiapine, leads to an additive effect on OPC differentiation and consequent myelin production via both overlapping and distinct signaling pathways. While the ultimate production of myelin requires cholesterol biosynthesis, we identified that quetiapine enhances gene expression in this pathway more potently than T3. Two blockers of cholesterol production, betulin and simvastatin, reduced OPC differentiation into myelin producing oligodendrocytes. Elucidating the nature of agents that lead to complementary and additive effects on oligodendrocyte differentiation and myelin production may pave the way for more efficient induction of remyelination in people with MS. [ABSTRACT FROM AUTHOR]

Flavodoxins are small electron transfer proteins containing flavin mononucleotide (FMN) as a prosthetic group, which play an important role during oxidative stress or iron limitation. The aims of this study were the identification and characterization of flavodoxins in the model aromatic-degrader Paraburkholderia xenovorans LB400 and the analyses of their protective effects during oxidative stress induced by paraquat and H2O2. Two genes (BxeA0278 and BxeB0391) encoding flavodoxins (hereafter referred to as fldX for avooxin from P. enovorans), were identified at the LB400 major and minor chromosome. Genomic context of the flavodoxin-encoding genes showed genes encoding membrane proteins, transporters, and proteins involved in redox processes and biosynthesis of macromolecules. A secondary structure prediction of both LB400 flavodoxins showed the characteristic flavodoxin structure of five ß-sheets intercalated with five α-helices. FldX1 contains a loop intercalated in the fifth β-strand, which indicates that it belongs to the long-chain flavodoxins, whereas FldX2 is a short-chain flavodoxin. A phylogenetic analysis of 73 flavodoxins from 43 bacterial genera revealed eight clusters (I-VIII), while FldX1 and FldX2 grouped separately within a long-chain and a short-chain flavodoxin clades. FldX1 and FldX2 were overexpressed in P. xenovorans. Interestingly, the strain overexpressing the long-chain flavodoxin FldX1 (p2-fldX1) showed a faster growth in glucose than the control strain. The recombinant strain overexpressing the long-chain flavodoxin FldX1 (p2-fldx1) exposed to paraquat (20 mM) possessed lower susceptibility to growth inhibition on plates and higher survival in liquid medium than the control strain. The strains overexpressing the flavodoxins FldX1 and FldX2 showed higher survival during exposure to 1 mM paraquat (>95%) than the control strain (68%). Compared to the control strain, strains overexpressing FldX1 and FldX2 showed lower lipid peroxidation (>20%) after exposure to 1 mM paraquat and a lower protein carbonylation (~30%) after exposure to 1 mM H2O2 was observed. During exposure to paraquat, strain p2-fldx1 downregulated the katG4, hpf, trxB1 and ohr genes (> 2-fold), whereas strain p2-fldx2 upregulated the oxyR and ahpC1 genes (> 2-fold). In conclusion, the flavodoxins FldX1 and FldX2 of P. xenovorans LB400 conferred protection to cells exposed to the oxidizing agents paraquat and H2O2. [ABSTRACT FROM AUTHOR]

Water deficit induces reactive oxygen species (ROS) overproduction, which in turn inhibits plant growth and development. High concentrations of ROS disrupt the osmotic balance in plant cells and alter membrane integrity. Chromosomes carrying structural or regulatory genes must be detected to better understand plant response mechanisms to stress. The aim of our study was to identify Triticum aestivum L. chromosomes involved in early responses to short-term water-deficit stress (1, 3 and 6 h). In the present study, intervarietal substitution lines of drought-tolerant 'Saratovskaya 29' and sensitive 'Janetzkis Probat' wheat cultivars were examined. We studied the biochemical plant response system and conducted an analysis of catalase, ascorbate peroxidase and guaiacol peroxidase activities, levels of lipid peroxidation and changes in relative water content. Our results determined that the first reaction was a significant increase in guaiacol peroxidase (GPX) activity. However, the strongest impact on plant responses was found for catalase (CAT), which caused a significant decrease in lipid peroxidation (LPO) levels. Our findings indicate that chromosomes 5A, 4B, 6B and 7D are associated with early responses to short-term osmotic stress in wheat. [ABSTRACT FROM AUTHOR]

The phenotypic, biochemical and genetic variability was studied in M2-M5 generations of ethyl methansulfonat (EMS, 0.2%) mutagenized rapeseed lines generated from canola, ‘00’, B. napus cv. Vikros. EMS mutagenesis induced extensive diversity in morphological and agronomic traits among mutant progeny resulted in selection of EMS populations of B. napus- and B. rapa-morphotypes. The seeds of the obtained mutant lines were high-protein, low in oil and stabilized in contents of main fatty acids which make them useful for feed production. Despite the increased level of various meiotic abnormalities revealed in EMS populations, comparative karyotype analysis and FISH-based visualization of 45S and 5S rDNA indicated a high level of karyotypic stability in M2-M5 plants, and therefore, the obtained mutant lines could be useful in further rapeseed improvement. The revealed structural chromosomal reorganizations in karyotypes of several plants of B. rapa-type indicate that rapeseed breeding by chemical mutagenesis can result in cytogenetic instability in the mutant progeny, and therefore, it should include the karyotype examination. Our findings demonstrate that EMS at low concentrations has great potential in rapeseed improvement. [ABSTRACT FROM AUTHOR]

Ozone is an asthma trigger. In mice, the gut microbiome contributes to ozone-induced airway hyperresponsiveness, a defining feature of asthma, but the mechanistic basis for the role of the gut microbiome has not been established. Gut bacteria can affect the function of distal organs by generating metabolites that enter the blood and circulate systemically. We hypothesized that global metabolomic profiling of serum collected from ozone exposed mice could be used to identify metabolites contributing to the role of the microbiome in ozone-induced airway hyperresponsiveness. Mice were treated for two weeks with a cocktail of antibiotics (ampicillin, neomycin, metronidazole, and vancomycin) in the drinking water or with control water and then exposed to air or ozone (2 ppm for 3 hours). Twenty four hours later, blood was harvested and serum analyzed via liquid-chromatography or gas-chromatography coupled to mass spectrometry. Antibiotic treatment significantly affected 228 of the 562 biochemicals identified, including reductions in the known bacterially-derived metabolites, equol, indole propionate, 3-indoxyl sulfate, and 3-(4-hydroxyphenyl)propionate, confirming the efficacy of the antibiotic treatment. Ozone exposure caused significant changes in 334 metabolites. Importantly, ozone-induced changes in many of these metabolites were different in control and antibiotic-treated mice. For example, most medium and long chain fatty acids declined by 20–50% with ozone exposure in antibiotic-treated but not control mice. Most taurine-conjugated bile acids increased with ozone exposure in antibiotic-treated but not control mice. Ozone also caused marked (9-fold and 5-fold) increases in the polyamines, spermine and spermidine, respectively, in control but not antibiotic-treated mice. Each of these metabolites has the capacity to alter airway responsiveness and may account for the role of the microbiome in pulmonary responses to ozone. [ABSTRACT FROM AUTHOR]

Rapeseed oil (canola, Brassica napus L.) is an important healthy vegetable oil throughout the world, the nutritional and economical value of which largely depends on its seed fatty acid composition. In this study, based on 201,187 SNP markers developed from the SLAF-seq (specific locus amplified fragment sequencing), a genome wide association study of four important fatty acid content traits (erucic acid, oleic acid, linoleic acid and linolenic acid) in a panel of 300 inbred lines of rapeseed in two environments (JXAU and JXRIS) was carried out. A total of 148 SNP loci significantly associated with these traits were detected by MLM model analysis respectively, and 30 SNP loci on A08 and C03 chromosomes were detected in three traits of erucic acid, oleic acid and linoleic acid contents simultaneously. Furthermore, 108 highly favorable alleles for increasing oleic acid and linoleic acid content, also for decreasing erucic acid content simultaneously were observed. By a basic local alignment search tool (BLAST) search with in a distance of 100 Kb around these significantly SNP-trait associations, we identified 20 orthologs of the functional candidate genes related to fatty acid biosynthesis, including the known vital fatty acid biosynthesis genes of BnaA.FAE1 and BnaC. FAE1 on the A08 and C03 chromosomes, and other potential candidate genes involving in the fatty acid biosynthesis pathway, such as the orthologs genes of FAD2, LACS09, KCS17, CER4, TT16 and ACBP5. This study lays a basis for uncovering the genetic variations and the improvement of fatty acid composition in B. napus. [ABSTRACT FROM AUTHOR]

Gene set analysis (GSA) has become the common methodology for analyzing transcriptomics data. However, self-contained GSA techniques are rarely, if ever, used for proteomics data analysis. Here we present a self-contained proteome level GSA of four consensus molecular subtypes (CMSs) previously established by transcriptome dissection of colon carcinoma specimens. Despite notable difference in structure of proteomics and transcriptomics data, many pathway-wide characteristic features of CMSs found at the mRNA level were reproduced at the protein level. In particular, CMS1 features show heavy involvement of immune system as well as the pathways related to mismatch repair, DNA replication and functioning of proteasome, while CMS4 tumors upregulate complement pathway and proteins participating in epithelial-to-mesenchymal transition (EMT). In addition, protein level GSA yielded a set of novel observations visible at the proteome, but not at the transcriptome level, including possible involvement of major histocompatibility complex II (MHC-II) antigens in the known immunogenicity of CMS1 and a connection between cholesterol trafficking and the regulation of Integrin-linked kinase (ILK) in CMS3. Overall, this study proves utility of self-contained GSA approaches as a critical tool for analyzing proteomics data in general and dissecting protein-level molecular portraits of human tumors in particular. [ABSTRACT FROM AUTHOR]

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a hepatic enzyme that regulates circulating low-density lipoprotein (LDL) cholesterol levels by binding to LDL receptors (LDLR) and promoting their degradation. Although PCSK9 inhibitors were shown to reduce the risk of cardiovascular disease, a warning was issued concerning their possible impact on cognitive functions. In Alzheimer’s disease (AD), it is believed that cognitive impairment is associated with cholesterol metabolism alterations, which could involve PCSK9. The main objective of this study is to determine if PCSK9 plays a significant role in the pre-symptomatic phase of the disease when the pathophysiological markers of AD unfolds and, later, when cognitive symptoms emerge. Methods and findings: To test if PCSK9 is associated with AD pathology, we measured its expression levels in 65 autopsy confirmed AD brains and 45 age and gender matched controls. Messenger ribonucleic acid (mRNA) were quantified using real-time polymerase chain reaction (RT-PCR) and protein levels were quantified using enzyme-linked immunosorbent assay (ELISA). PCSK9 was elevated in frontal cortices of AD subjects compared to controls, both at the mRNA and protein levels. LDLR protein levels were unchanged in AD frontal cortices, despite and upregulation at the mRNA level. To verify if PCSK9 dysregulation was observable before the onset of AD, we measured its expression in the cerebrospinal fluid (CSF) of 104 “at-risk” subjects and contrasted it with known apolipoproteins levels and specific AD biomarkers using ELISAs. Positive correlations were found between CSF PCSK9 and apolipoprotein E (APOE), apolipoprotein J (APOJ or CLU), apolipoprotein B (APOB), phospho Tau (pTau) and total Tau. To investigate if PCSK9 levels were driven by genetic variants, we conducted an expression quantitative trait loci (eQTL) study using bioinformatic tools and found two polymorphisms in strong association. Further investigation of these variants in two independent cohorts showed a female specific association with AD risk and with CSF Tau levels in cognitively impaired individuals. Conclusions: PCSK9 levels differ between control and AD brains and its protein levels correlate with those of other lipoproteins and AD biomarkers even before the onset of the disease. PCSK9 regulation seems to be under tight genetic control in females only, with specific variants that could predispose to increased AD risk. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) play pivotal roles in T-cell homeostasis and activation, and metabolic programing has been recently linked to DC development and function. However, the metabolic underpinnings corresponding to distinct DC functions remain largely unresolved. Here, we demonstrate a special metabolic–epigenetic coupling mechanism orchestrated by tuberous sclerosis complex subunit 1 (TSC1)-mechanistic target of rapamycin (mTOR) for homeostatic DC function. Specific ablation of Tsc1 in the DC compartment (Tsc1DC-KO) largely preserved DC development but led to pronounced reduction in naïve and memory–phenotype cluster of differentiation (CD)8+ T cells, a defect fully rescued by concomitant ablation of mTor or regulatory associated protein of MTOR, complex 1 (Rptor) in DCs. Moreover, Tsc1DC-KO mice were unable to launch efficient antigen-specific CD8+ T effector responses required for containing Listeria monocytogenes and B16 melanomas. Mechanistically, our data suggest that the steady-state DCs tend to tune down de novo fatty acid synthesis and divert acetyl-coenzyme A (acetyl-CoA) for histone acetylation, a process critically controlled by TSC1-mTOR. Correspondingly, TSC1 deficiency elevated acetyl-CoA carboxylase 1 (ACC1) expression and fatty acid synthesis, leading to impaired epigenetic imprinting on selective genes such as major histocompatibility complex (MHC)-I and interleukin (IL)-7. Remarkably, tempering ACC1 activity was able to divert cytosolic acetyl-CoA for histone acetylation and restore the gene expression program compromised by TSC1 deficiency. Taken together, our results uncover a crucial role for TSC1-mTOR in metabolic programing of the homeostatic DCs for T-cell homeostasis and implicate metabolic-coupled epigenetic imprinting as a paradigm for DC specification. [ABSTRACT FROM AUTHOR]

Background: Systemic arterial hypertension (SAH) is a multifactorial condition that already affects one third of the worldwide population. The identification of candidate genes for hypertension is a challenge for the next years. Nevertheless, the small contribution of each individual genetic factor to the disease brings the necessity of evaluate genes in an integrative manner and taking into consideration the physiological interaction of functions. Angiotensin I–converting enzymes, ACE and ACE2, are key regulators of blood pressure that have counterbalance roles by acting on vasoactive peptides from Renin-Angiotensin-Aldosterone System (RAAS). Insertion/deletion (I/D) polymorphism of ACE gene and single nucleotide polymorphism G8790A of ACE2 gene have been associated with susceptibility to SAH, but the literature is controversial. We proposed to evaluate these two polymorphisms jointly exploring the combined effects of ACE and ACE2 genotypes on SAH susceptibility, an approach that have not been done yet for ACE and ACE2 polymorphisms. Methods and findings: This genetic association study included 117 hypertensive (mean age 59.7 years) patients and 123 normotensive and diabetes-free controls (mean age 57.5 years). ACE and ACE2 polymorphisms were genotyped by SYBR Green real-time PCR and RFLP-PCR, respectively. Crude and adjusted odds ratio (OR) values were calculated to estimate the susceptibility to SAH development. It was obtained homogeneity regarding distribution by sex, age range, smoking, alcohol consumption and body mass index (BMI) between case and control groups. No-association was verified for each gene individually, but the combination of ACE and ACE2 polymorphisms on female gender revealed a significative association for DD/G_ carriers who had a 3-fold increased risk to SAH development (p = 0.03), with a stronger susceptibility on DD/GG carriers (7-fold increased risk, p = 0.01). The D allele of ACE showed association with altered levels of lipid profile variables on case group (VLDL-cholesterol, p = 0.01) and DD genotype in all individuals analysis (triglycerides, p = 0.01 and VLDL-cholesterol, p = 0.01). Conclusion: These findings indicate that the combination of ACE and ACE2 polymorphisms effects may play a role in SAH predisposition been the DD/G_ genotype the susceptibility profile. This result allowed us to raise the hypothesis that an increased activity of ACE (prohypertensive effects) in conjunction with reduced ACE2 activity (antihypertensive effects) could be the underlining mechanism. The association of ACE D allele with lipid alterations indicate that this can be a marker of poor prognostic on SAH evolution and contribute to CVD development. Although these preliminary findings must be confirmed by further researches with larger sample size, we could observe that the integrative analysis of ACE and ACE2 can be an informative tool in hypertension understanding that needs to be explored in new studies. [ABSTRACT FROM AUTHOR]

JMJD6 is a member of the Jumonji C domain containing enzymes that demethylate and/or hydroxylate substrate proteins. It is a multi-functional protein that has been implicated in disparate aspects of transcriptional and post-transcriptional control of gene expression, including but not limited to enhancer and promoter binding, release of paused RNA polymerase II, control of splicing, and interaction with the translation machinery. JMJD6 contributes to multiple aspects of animal development, including adipogenesis modeled in culture. We mutated proposed or characterized domains in the JMJD6 protein to better understand the requirement for JMJD6 in adipogenic differentiation. Mutation of JMJD6 amino acids that mediate binding of iron and 2-oxogluterate, which are required cofactors for enzymatic activity, had no impact on JMJD6 function, showing that catalytic activity is not required for JMJD6 contributions to adipogenic differentiation. In addition, we documented the formation of JMJD6 oligomers and showed that catalytic activity is not required for oligomerization, as has been reported previously. We also observed no effect of mutations in the sumoylation site and in the poly-serine stretch. In contrast, mutation of the AT hook-like structure, which mediates interaction with DNA and/or RNA, compromised JMJD6 function by blocking its ability to interact with chromatin at genes that express regulators of adipogenesis. The ability of JMJD6 to interact with nucleic acids may be a critical requirement for its function in adipogenic differentiation. The requirement for the AT hook-like domain and the lack of requirement for catalytic activity giving rise to the idea that co-activation of transcription by JMJD6 may be functioning as a scaffold protein that supports the interactions of other critical regulators. [ABSTRACT FROM AUTHOR]

Background: To investigate the role of microRNA (miR)-27a and miR-27b in adipogenesis in an in vitro model of Graves’ orbitopathy (GO). Methods: Orbital fat tissues were harvested from GO and non-GO participants for primary orbital fibroblast cultures. The expression levels of miR-27a and miR-27b between GO and non-GO orbital fat tissues were compared. During adipogenesis of GO orbital fibroblasts, the expression levels of miR-27a and miR-27b were determined, and the effects of mimics of miR-27a and miR-27b transfection on adipogenesis of GO orbital fibroblast were investigated. Results: Real time-polymerase chain reaction showed significantly more decreases in miR-27a and miR-27b levels in orbital fat tissues in GO participants than in non-GO participants (p < 0.05). The expression of both miR-27a and miR-27b was highest in orbital fibroblasts at day 0 and declined gradually after the induction of adipogenic differentiation. The expression levels of PPARγ, CCAAT/enhancer binding protein (C/EBP)α and C/EBPβ were decreased and Oil Red O-stained lipid droplets were lower in GO orbital fibroblasts transfected with miR-27a and miR-27b mimics than in negative controls. Conclusions: Our results indicated that miR-27a and miR-27b inhibited adipogenesis in orbital fibroblasts from GO patients. Further studies are required to examine the potential of miR-27a and miR-27b as targets for therapeutic strategies. [ABSTRACT FROM AUTHOR]

Immune response and reproductive success are two vital energy-consuming processes in living organisms. However, it is still unclear which process is prioritized when both are required. Therefore, the present study was designed to examine this question arising for one of the world’s most destructive agricultural pests, the migratory locust, Locusta migratoria. Transcripts from the ovaries and fat bodies of newly emerged locusts were analyzed, using RNA-seq based transcriptome and qualitative real-time PCR, at 4 h and 6 d after being infected with the gram-positive bacteria Micrococcus luteus. Changes in the main biological pathways involved in reproduction and immunization were analyzed using bioinformatics. After 4 h of infection, 348 and 133 transcripts were up- and down-regulated, respectively, whereas 5699 and 44 transcripts were up- and down-regulated, respectively, at 6 d after infection. Moreover, KEGG analysis indicated that vital pathways related with immunity and reproduction, such as Insulin resistance, FoxO signaling, Lysosome, mTOR signaling, and Toll-like receptor signaling pathways were up-regulated. Among the differentially expressed genes, 22 and 17 were related to immunity and reproduction, respectively. The expression levels of PPO1 and antimicrobial peptide defensin 3 were increased (log2FC = 5.93 and 6.75, respectively), whereas those of VgA and VgB were reduced (log2FC = -17.82 and -18.13, respectively). These results indicated that locust allocate energy and resources to maintain their own survival by increasing immune response when dealing with both immune and reproductive processes. The present study provides the first report of expression levels for genes related with reproduction and immunity in locusts, thereby providing a reference for future studies, as well as theoretical guidance for investigations of locust control. [ABSTRACT FROM AUTHOR]

Protein solubility is a critical prerequisite to any proteomics analysis. Combination of urea/thiourea and 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) have been routinely used to enhance protein solubilization for oil palm proteomics studies in recent years. The goals of these proteomics analysis are essentially to complement the knowledge regarding the regulation networks and mechanisms of the oil palm fatty acid biosynthesis. Through omics integration, the information is able to build a regulatory model to support efforts in improving the economic value and sustainability of palm oil in the global oil and vegetable market. Our study evaluated the utilization of sodium deoxycholate as an alternative solubilization buffer/additive to urea/thiourea and CHAPS. Efficiency of urea/thiourea/CHAPS, urea/CHAPS, urea/sodium deoxycholate and sodium deoxycholate buffers in solubilizing the oil palm (Elaeis guineensis var. Tenera) mesocarp proteins were compared. Based on the protein yields and electrophoretic profile, combination of urea/thiourea/CHAPS were shown to remain a better solubilization buffer and additive, but the differences with sodium deoxycholate buffer was insignificant. A deeper mass spectrometric and statistical analyses on the identified proteins and peptides from all the evaluated solubilization buffers revealed that sodium deoxycholate had increased the number of identified proteins from oil palm mesocarps, enriched their gene ontologies and reduced the number of carbamylated lysine residues by more than 67.0%, compared to urea/thiourea/CHAPS buffer. Although only 62.0% of the total identified proteins were shared between the urea/thiourea/CHAPS and sodium deoxycholate buffers, the importance of the remaining 38.0% proteins depends on the applications. The only observed limitations to the application of sodium deoxycholate in protein solubilization were the interference with protein quantitation and but it could be easily rectified through a 4-fold dilution. All the proteomics data are available via ProteomeXchange with identifier PXD013255. In conclusion, sodium deoxycholate is applicable in the solubilization of proteins extracted from oil palm mesocarps with higher efficiency compared to urea/thiourea/CHAPS buffer. The sodium deoxycholate buffer is more favorable for proteomics analysis due to its proven advantages over urea/thiourea/CHAPS buffer. [ABSTRACT FROM AUTHOR]

Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT) and the nuclear receptor co-repressor1 (NCoR1) are paralogs and regulate nuclear receptor (NR) function through the recruitment of a multiprotein complex that includes histone deacetylase activity. Previous genetic strategies which deleted SMRT in a specific tissue or which altered the interaction between SMRT and NRs have suggested that it may regulate adiposity and insulin sensitivity. However, the full role of SMRT in adult mice has been difficult to establish because its complete deletion during embryogenesis is lethal. To elucidate the specific roles of SMRT in mouse target tissues especially in the context of thyroid hormone (TH) signaling, we used a tamoxifen-inducible post-natal disruption strategy. We found that global SMRT deletion causes dramatic obesity even though mice were fed a standard chow diet and exhibited normal food intake. This weight gain was associated with a decrease in energy expenditure. Interestingly, the deletion of SMRT had no effect on TH action in any tissue but did regulate retinoic acid receptor (RAR) function in the liver. We also demonstrate that the deletion of SMRT leads to profound hepatic steatosis in the setting of obesity. This is unlike NCoR1 deletion, which results in hepatic steatosis due to the upregulation of lipogenic gene expression. Taken together, our data demonstrate that SMRT plays a unique and CoR specific role in the regulation of body weight and has no role in TH action. This raises the possibility that additional role of CoRs besides NCoR1 and SMRT may exist to regulate TH action. [ABSTRACT FROM AUTHOR]