Insights into the function of HDAC3 and NCoR1/NCoR2 co-repressor complex in metabolic diseases

Histone deacetylase 3 (HDAC3) and nuclear receptor co-repressor (NCoR1/2) are epigenetic regulators that play a key role in gene expression and metabolism. HDAC3 is a class I histone deacetylase that functions as a transcriptional co-repressor, modulating gene expression by removing acetyl groups from histones and non-histone proteins. NCoR1, on the other hand, is a transcriptional co-repressor that interacts with nuclear hormone receptors, including peroxisome proliferator-activated receptor gamma (PPARγ) and liver X receptor (LXR), to regulate metabolic gene expression. Recent research has revealed a functional link between HDAC3 and NCoR1 in the regulation of metabolic gene expression. Genetic deletion of HDAC3 in mouse models has been shown to improve glucose intolerance and insulin sensitivity in the liver, skeletal muscle, and adipose tissue. Similarly, genetic deletion of NCoR1 has improved insulin resistance and reduced adiposity in mouse models. Dysregulation of this interaction has been associated with the development of cardio-metabolic diseases such as cardiovascular diseases, obesity and type 2 diabetes, suggesting that targeting this pathway may hold promise for the development of novel therapeutic interventions. In this review, we summarize the current understanding of individual functions of HDAC3 and NCoR1/2 and the co-repressor complex formation (HDAC3/NCoR1/2) in different metabolic tissues. Further studies are needed to thoroughly understand the mechanisms through which HDAC3, and NCoR1/2 govern metabolic processes and the implications for treating metabolic diseases

De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis

We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk

ANALYTICAL METHOD DEVELOPMENT AND VALIDATION FOR THE SIMULTANEOUS ESTIMATION OF SOFOSBUVIR AND VELPATASVIR DRUG PRODUCT BY REVERSE PHASE HIGH PERFORMANCE LIQUID CHROMATOGRAPHY METHOD

 Objectives: The purpose of the research is to develop a simple, precise, economical, accurate, reproducible, and sensitive method for the estimation of sofosbuvir and velpatasvir drug product by rp-hplc methodMethods: New Analytical method was developed for the estimation of Velpatasvir and Sofosbuvir in drug product by liquid chromatography. The chromatographic separation was achieved on C18 column (Luna 18 150*4.6mm3.0um) at ambient temperature. The separation achieved employing a mobile phase consists of 0.1%v/v Formic acid in water: Methanol: Acetonitrile (35:40:25). The flow rate was 0.8ml/ minute and ultra violet detector at 269nm. The average retention time for Velpatasvir and Sofosbuvir found to be 2.62 min and 3.72 min.Results: The developed method was validated as per the ICH analytical method validation guidelines. All validation parameters were within the acceptable range. The assay methods were found to be linear from 80-240 µg/ml for Sofosbuvir and 20-60µg/ml for Velpatasvir. The correlation coefficient was 0.9998 and 0.9992 for velpatasvir and sofosbuvir respectively.  The mean percentage recovery for the developed method was found to be in the range of 98.4-100.4% for velpatasvir and 98.6-100.6% for sofosbuvir. The developed method was also found to be robustConclusion: The developed method was found to be suitable for the routine quantitative analysis of Velpatasvir and Sofosbuvir in bulk and pharmaceutical dosage form. It was also concluded that developed method was accurate, precise, linear, reproducible, robust, and sensitive.Â

De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.

We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk

De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis

We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk. [Display omitted] •Recurrent de novo variants identify a new high-confidence TD risk gene: CELSR3•Genes involved in cell polarity are more likely to be disrupted by de novo variants•De novo sequence variants may carry more risk in simplex families, female probands•De novo CNVs occur 2 to 3 times more often in TD probands than in matched controls Wang et al. expand their earlier exome-sequencing work in TD, adding 291 trios and conducting combined analyses suggesting de novo variants carry more risk in individuals with unaffected parents, establishing de novo structural variants as risk factors, identifying CELSR3 as a risk gene, and implicating cell polarity in pathogenesis