👤 Bruce M McManus

Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia. Show less

The present study describes the expression of genes in the Longissimus dorsi muscle related to meat quality of hair lambs finished in an Integration Crop-Livestock system. Twenty-eight non-castrated lambs of two breeds, Somalis Brasileira and Santa Inês, at 120 ± 15 days of age, with an average initial live weight of 18 ± 3.1 kg, were kept in a pasture-based finishing system with supplementation. Upon reaching 28 kg body weight, animals were sent for slaughter. Samples of the Longissimus dorsi and Biceps femoris muscle were harvested for analyses of gene expression and physicochemical properties. Significant differences were detected between the breeds for tissue and chemical composition, whereas the physical aspects did not differ. We observed the expression of six genes related to lipid synthesis (acetyl-CoA carboxylase [ACACA], fatty acid synthase [FAS], stearoyl-CoA desaturase [SCD], lipoprotein lipase [LPL], cell death-inducing DFFA-like effector A [CIDEA], and thyroid hormone responsive [THRSP]) and six genes related to molecular synthesis (myostatin [MSTN], growth differentiation factor 8 [GDF8], insulin-like growth factor 1 [IGF1], insulin-like growth factor 2 [IGF2], delta-like 1 homolog [DLK1], and growth hormone receptor [GHr]) in both breeds. The Santa Inês breed and the Somalis Brasileira showed similar expression patterns of genes related to lipogenesis and myogenesis of the Longissimus dorsi muscle, with the exception of the THRSP gene, in which the Somalis Brasileira have more receptors for the action of thyroid hormones, which resulted in greater thickness of fat in the carcass (subcutaneous fat) and higher lipid content in the chemical composition of the meat. Show less

Organophosphates insecticides (OPs) are common surface water contaminants in both urban and agricultural landscapes. Neurobehavioral effects on larval fish are known to occur at concentrations higher than those reported in the environment. The aim of this study was to perform a comparative analysis of neurobehavioral, molecular, and biochemical responses of four OPs (diazinon, dichlorvos, malathion, methyl-parathion) via the following endpoint measurements: distance traveled, velocity, gene expression (AChE, c-Fos, LINGO-1B, GRIN-1B), enzymatic acetylcholinesterase (AChE) activity, and carboxylesterase (CES) activity. OP exposures (5 hpf - 120 dpf) on embryo-larval zebrafish (Danio rerio) were assessed using a larval zebrafish behavior assay at concentrations: 0.01, 0.1, 10, and 100 μg/L. Individual OPs had varying degrees of neurotoxicity. Significant hypoactivity was observed in the 100 μg/L treatments for diazinon and malathion (p < 0.05) as compared to the controls. Diazinon-exposed larvae exhibited a 26% locomotor decrease, and hypoactivity was observed in malathion-exposed larvae at a reduction of 22% and 29% for distance traveled and velocity, respectively. Gene regulation and enzymatic activity changes were measured for both 0.1 and 100 μg/L exposures across OP treatments. Increased CES activity was observed for the 0.1 μg/L treatments of diazinon and methyl-parathion as well as the 100 μg/L treatment of dichlorvos; meanwhile, decreased CES activity was observed for 100 μg/L treatments of diazinon and malathion. Relative enzymatic activity of AChE was inhibited as compared to the control for the 0.1 μg/L diazinon. No other treatment group exhibited a significant effect on biochemical AChE activity; however, AChE upregulation was observed in the 0.1 μg/L exposure for diazinon, dichlorvos, and malathion. Methyl-parathion was observed to downregulate c-Fos at 0.1 μg/L exposure. Malathion upregulated LINGO-1B at 100 μg/L, a gene associated with neuronal regeneration; meanwhile, downregulation of LINGO-1B was observed for 0.1 μg/L exposure of methyl-parathion. Additional downregulation was observed for GRIN-1B in the 100 μg/L diazinon, 100 μg/L dichlorvos, and 0.1 μg/L methyl-parathion treatments. Exposure of ZF embryos to independent concentrations of 100 μg/L concentrations of diazinon and malathion resulted in hypoactivity and decreased CES activity at 5 dfp. No changes in swimming behavior were observed for either the 0.1 μg/L or 100 μg/L dichlorvos or methyl-parathion treatments. Observations from this study indicate that AChE inhibition may not be the most sensitive biomarker of OP pesticide exposure in zebrafish. Rather, the enzyme CES demonstrated higher sensitivity as a biomarker of OP toxicity. Show less

The ABC transporter ABCA1 plays a key role in the first steps of the reverse cholesterol transport pathway by mediating lipid efflux from macrophages. Previously, it was demonstrated that human ABCA1 overexpression in vivo in transgenic mice results in a mild elevation of plasma HDL levels and increased efflux of cholesterol from macrophages. In this study, we determined the effect of overexpression of ABCA1 on atherosclerosis development. Human ABCA1 transgenic mice (BAC(+)) were crossed with ApoE(-/-) mice, a strain that spontaneously develop atherosclerotic lesions. BAC(+)ApoE(-/-) mice developed dramatically smaller, less-complex lesions as compared with their ApoE(-/-) counterparts. In addition, there was increased efflux of cholesterol from macrophages isolated from the BAC(+)ApoE(-/-) mice. Although the increase in plasma HDL cholesterol levels was small, HDL particles from BAC(+)ApoE(-/-) mice were significantly better acceptors of cholesterol. Lipid analysis of HDL particles from BAC(+)ApoE(-/-) mice revealed an increase in phospholipid levels, which was correlated significantly with their ability to enhance cholesterol efflux. Show less