RNA-PROTEIN INTERACTION MECHANISM UNDERLYING LIQUID-LIQUID PHASE SEPARATION

Fused in Sacoma (FUS) is a nuclear RNA-binding protein which undergoes liquid-liquid phase separation (LLPS), and its cytoplasmic aggregation is a pathogenic signature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It remains unknown how the FUS-RNA interactions contribute to LLPS and whether its phase behavior is affected by ALS-linked mutations. By employing combination of single molecule, biophysical, biochemical and meso-scale tools, we discovered that wild-type FUS binds single-stranded RNA stoichiometrically in a length-dependent manner and that multimers induce highly dynamic interactions with RNA, giving rise to small and fluid condensates. Monomer FUS interacts with the RNA in a well-defined two-step mode initiated by its RNA binding domain (RBD), more specifically the RNA recognition motive (RRM) to form a proper FUS-RNA complex. This proper complex formation dictates the properties of multimer FUS-RNA interaction and phase separation. In contrast to the wild-type, ALS-linked FUS mutations in arginine display a severely altered and static binding to RNA, and formation of large condensates, signifying the role of arginine in driving proper RNA interaction. Glycine mutations undergo rapid loss of fluidity, emphasizing the role of glycine in promoting fluidity. Strikingly, the nuclear import receptor, Karyopherin-β2 reverses the mutant defects and recovers the wild-type FUS behavior. We reveal two distinct classes of ALS-linked FUS mutants underpinning potentially disparate pathogenic mechanism

The effect of circuit resistance training with different intensities on the agouti-related protein, insulin and glucose plasma levels in young men

Background: Agouti-related protein (AgRP) is a signaling peptide that affects feeding behavior, energy homeostasis, and the stimulation of the hypothalamic–pituitary–adrenal axis. The aim of the present study was to investigate the effect of a 6-week circuit-resistance training course (10 exercises at 20, 40, 60, and 80 of 1RM) at different intensities on the levels of plasma AgRP, plasma insulin, and glucose. Materials and Methods: The participants in this experimental study included 45 dormitory male students, aged 20-24 years, with the mean weight of 70.61±3.76 kg, mean age of 21.55±0.17 years, and mean height of 174.84±1.15 cm. They were randomly divided into five groups, each with nine members (i.e., one control group and four experimental groups at 20, 40, 60, and 80 of 1RM). The experimental groups performed the circuit-resistance training exercises at the specified intensities; in contrast, the control group performed no regular training during the course of the study. The blood samples were collected from the venous vein 48 hours before and after the training session (three hours after normal breakfast). Results: The results showed no significant differences between the groups in terms of the AgRP (P=0.399) and glucose levels (P=0.270); however, the difference related to the insulin levels was observed to be significant (P=0.013). Conclusion: According to the results of this study, a larger reduction in the AgRP levels is associated with high intensities of resistance training (i.e., at 80 of 1RM). Therefore, training intensity could be regarded as an influential factor in reducing the appetite and controlling obesity among young men

Effects of exercise on reverse cholesterol transport: A systemized narrative review of animal studies

Reverse Cholesterol Transport (RCTr) is the mechanism by which excess cholesterol from peripheral tissues is transported to the liver for hepatobiliary excretion, thereby inhibiting foam cell formation and the development of atherosclerosis. Exercise affects RCTr, by influencing high-density lipoprotein cholesterol (HDL) through remodeling and by promoting hepatobiliary sterol excretion. The objectives of this systematized review of animal studies is to summarize the literature and provide an overview of the effects of chronic exercise (at least two weeks) on apolipoproteins (Apo A-I, Apo-E), Paraoxonase-1 (PON1), ATP-binding cassette transporters (ABCA1, ABCG1, ABCG4, ABCG5, ABCG8), scavenger receptor class B type I (SR-BI), cholesteryl ester transfer protein (CETP), low-density lipoprotein receptor (LDLr) and cholesterol 7 alpha-hydroxylase (CYP7A1) and Niemann-Pick C1-like 1 (NPC1L1). Three electronic databases (PubMed, Science Direct and Google Scholar) were searched for eligible studies conducted from the earliest available date to August 2018. Most of studies investigate the effects of low to moderate intensity aerobic training on RCTr elements. The majority were on exercised rats undertaking moderate intensity aerobic training. This review highlights that moderate intensity and longer-term training has a greater effect on RCTr elements than low intensity training. There a few studies examining high intensity training which warrants further investigation. [Abstract copyright: Copyright © 2019. Published by Elsevier Inc.

The Effect of Ramadan Fasting and Weight-Lifting Training on Plasma Volume, Glucose and Lipids Profile of Male Weight-Lifters

Objective(s)The purpose of the present study was to evaluate the effect of Ramadan fasting and weight-lifting training on plasma volume, glucose, and lipids profile of male weight-lifter.Materials and MethodsForty male weight-lifters were recruited and divided into 4 groups (n=10 each) and as the following groups: control (C), fasting (F), training (T) and fasting-training (F-T). The T and F-T groups performed weight-lifting technique trainings and hypertrophy body building (3 sessions/week, 90 min/session). All subjects were asked to complete a medical examination as well as a medical questionnaire to ensure that they were not taking any medication, were free of cardiac, respiratory, renal, and metabolic diseases, and were not using steroids. Blood samples were taken at 24 hr before and 24 hr after one month of fasting and weight-lifting exercise. The plasma volume, fasting blood sugar (FBS), lipid profiles, and lipoproteins were analyzed in blood samples. ResultsBody weight and plasma volume showed significant (P< 0.05) decrease and increase in the F group (P< 0.05) respectively. Also, a significant reduction was observed in F-T group body weight (P< 0.01). A significant increase was found in FBS level of F group (P< 0.05). The lipid profiles and lipoproteins didn’t change significantly in C, F, T and the F-T groups.ConclusionThe effect of Ramadan fasting on body weight and plasma volumes may be closely related to the nutritional diet or biochemical response to fasting

Combined Effects of High-Intensity Aerobic Exercise Training and Ziziphus jujuba Extract on Tissue Nesfatin-1 in Rats

Nesfatin-1 is involved in metabolic/feeding regulation and prevention of cardiovascular disease. Previous studies have shown that exercise and herb supplementation can influence nesfatin-1 concentration. The present study investigated the effects of high-intensity training (HIT) and Ziziphus jujuba (ZJ) extract on tissue nesfatin-1 in rats. Twenty-eight female rats were randomly assigned to one of four groups i.e. 1) Saline-Control (SC), 2) Saline-High Intensity Training (ST), 3) Ziziphus jujuba-Control (ZJC), and 4) Ziziphus jujuba-High Intensity Training (ZJT). Rats performed exercise on a treadmill and/or administered supplements intragastrically for 6 weeks, depending on group category. Seventy-two hours after the last training session, rats were anesthetized. Blood, hypothafi 2lamus tissue, heart and gastrocnemius muscles were sent to the laboratory for analyses. Significantly higher nesfatin-1 gene expression and concentration and ATP concentration were found in trained rat. HIT increased plasma High Density Lipoprotein (HDL) and insulin concentration and reduced plasma Triglyceride (TG) and cortisol. ZJ increased tissue nesftain-1 gene expression and concentration while only increasing heart ATP. The combination of exercise and ZJ showed an additive effect compared to each intervention alone on hypothalamus, heart and gastrocnemius NUCB2 gene expression, heart and gastrocnemius nesfatin-1 concentration, plasma HDL and cortisol concentration. The authors recommend both interventions as a means to improve cardiovascular health in rats with further work needed to confirm similar findings in homo sapiens

The Effect of Ramadan Fasting and Weight-Lifting Training on Plasma Volume, Glucose and Lipids Profile of Male Weight-Lifters

Abstract Objective(s) The purpose of the present study was to evaluate the effect of Ramadan fasting and weight-lifting training on plasma volume, glucose, and lipids profile of male weight-lifter. Materials and Methods Forty male weight-lifters were recruited and divided into 4 groups (n=10 each) and as the following groups: control (C), fasting (F), training (T) and fasting-training (F-T). The T and F-T groups performed weightlifting technique trainings and hypertrophy body building (3 sessions/week, 90 min/session). All subjects were asked to complete a medical examination as well as a medical questionnaire to ensure that they were not taking any medication, were free of cardiac, respiratory, renal, and metabolic diseases, and were not using steroids. Blood samples were taken at 24 hr before and 24 hr after one month of fasting and weightlifting exercise. The plasma volume, fasting blood sugar (FBS), lipid profiles, and lipoproteins were analyzed in blood samples. Results Body weight and plasma volume showed significant (P&lt; 0.05) decrease and increase in the F group (P&lt; 0.05) respectively. Also, a significant reduction was observed in F-T group body weight (P&lt; 0.01). A significant increase was found in FBS level of F group (P&lt; 0.05). The lipid profiles and lipoproteins didn&apos;t change significantly in C, F, T and the F-T groups. Conclusion The effect of Ramadan fasting on body weight and plasma volumes may be closely related to the nutritional diet or biochemical response to fasting

mRNA structure determines specificity of a polyQ-driven phase separation

Author Posting. © The Author(s), 2018. This is the author's version of the work. It is posted here by permission of American Association for the Advancement of Science for personal use, not for redistribution. The definitive version was published in American Association for the Advancement of Science 360 (2018): 922-927, doi:10.1126/science.aar7432.RNA promotes liquid-liquid phase separation (LLPS) to build membrane-less compartments in cells. How distinct molecular compositions are established and maintained in these liquid compartments is unknown. Here we report that secondary structure allows mRNAs to self-associate and determines if an mRNA is recruited to or excluded from liquid compartments. The polyQ-protein Whi3 induces conformational changes in RNA structure and generates distinct molecular fluctuations depending on the RNA sequence. These data support a model in which structure-based, RNA-RNA interactions promote assembly of distinct droplets and protein-driven, conformational dynamics of the RNA maintain this identity. Thus, the shape of RNA can promote the formation and coexistence of the diverse array of RNA-rich liquid compartments found in a single cell.This work was supported by NIH GM R01- GM081506, the HHMI Faculty Scholars program, R35 GM122532, ACS 130845-RSG-17-114- 01-RMC, NIH 1DP2 GM105453, and NIH R01 GM115631

Obestatin as a key regulator of metabolism and cardiovascular function with emerging therapeutic potential for diabetes

Obestatin is a 23‐amino acid C‐terminally amidated gastrointestinal peptide derived from preproghrelin and which forms an α helix. Although obestatin has a short biological half‐life and is rapidly degraded, it is proposed to exert wide‐ranging pathophysiological actions. Whilst the precise nature of many of its effects is unclear, accumulating evidence supports positive actions on both metabolism and cardiovascular function. For example, obestatin has been reported to inhibit food and water intake, body weight gain and gastrointestinal motility and also to mediate promotion of cell survival and prevention of apoptosis. Obestatin‐induced increases in beta cell mass, enhanced adipogenesis and improved lipid metabolism have been noted along with up‐regulation of genes associated with beta cell regeneration, insulin production and adipogenesis. Furthermore, human circulating obestatin levels generally demonstrate an inverse association with obesity and diabetes, whilst the peptide has been shown to confer protective metabolic effects in experimental diabetes, suggesting that it may hold therapeutic potential in this setting. Obestatin also appears to be involved in blood pressure regulation and to exert beneficial effects on endothelial function, with experimental studies indicating that it may also promote cardioprotective actions against, for example, ischaemia–reperfusion injury. This review will present a critical appraisal of the expanding obestatin research area and discuss the emerging therapeutic potential of this peptide for both metabolic and cardiovascular complications of diabetes