Nucleosome repositioning in cardiac reprogramming.

Early events in the reprogramming of fibroblasts to cardiac muscle cells are unclear. While various histone undergo modification and re-positioning, and these correlate with the activity of certain genes, it is unknown if these events are causal or happen in response to reprogramming. Histone modification and re-positioning would be expected to open up chromatin on lineage-specific genes and this can be ascertained by studying nucleosome architecture.

Nucleosome repositioning in cardiac reprogramming.

Early events in the reprogramming of fibroblasts to cardiac muscle cells are unclear. While various histone undergo modification and re-positioning, and these correlate with the activity of certain genes, it is unknown if these events are causal or happen in response to reprogramming. Histone modification and re-positioning would be expected to open up chromatin on lineage-specific genes and this can be ascertained by studying nucleosome architecture.

The impact of aging on cardiac repair and regeneration.

In contrast to neonates and lower organisms, the adult mammalian heart lacks any capacity to regenerate following injury. The vast majority of our understanding of cardiac regeneration is based on research in young animals. Research in aged individuals is rare.

Exome-wide association analysis identifies novel risk loci for alcohol-associated hepatitis.

Background And Aims: Alcohol-associated hepatitis (AH) is a clinically severe, acute disease that afflicts only a fraction of patients with alcohol use disorder. Genomic studies of alcohol-associated cirrhosis (AC) have identified several genes of large effect, but the genetic and environmental factors that lead to AH and AC, and their degree of genetic overlap, remain largely unknown. This study aims to identify genes and genetic variations that contribute to the development of AH.

Neural indices of heritable impulsivity: Impact of the COMT Val158Met polymorphism on frontal beta power during early motor preparation.

Studies of COMT ValMet suggest that the neural circuitry subserving inhibitory control may be modulated by this functional polymorphism altering cortical dopamine availability, thus giving rise to heritable differences in behaviors. Using an anatomically-constrained magnetoencephalography method and stratifying the sample by COMT genotype, from a larger sample of 153 subjects, we examined the spatial and temporal dynamics of beta oscillations during motor execution and inhibition in 21 healthy Met/Met (high dopamine) or 21 Val/Val (low dopamine) genotype individuals during a Go/NoGo paradigm. While task performance was unaffected, Met homozygotes demonstrated an overall increase in beta power across regions essential for inhibitory control during early motor preparation (∼100 ms latency), suggestive of a global motor "pause" on behavior.

A patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis.

Only ~20% of heavy drinkers develop alcohol cirrhosis (AC). While differences in metabolism, inflammation, signaling, microbiome signatures and genetic variations have been tied to the pathogenesis of AC, the key underlying mechanisms for this interindividual variability, remain to be fully elucidated. Induced pluripotent stem cell-derived hepatocytes (iHLCs) from patients with AC and healthy controls differ transcriptomically, bioenergetically and histologically.

Skeletal muscle differentiation induces wide-ranging nucleosome repositioning in muscle gene promoters.

In a previous report, we demonstrated that Cbx1, PurB and Sp3 inhibited cardiac muscle differentiation by increasing nucleosome density around cardiac muscle gene promoters. Since cardiac and skeletal muscle express many of the same proteins, we asked if Cbx1, PurB and Sp3 similarly regulated skeletal muscle differentiation. In a C2C12 model of skeletal muscle differentiation, Cbx1 and PurB knockdown increased myotube formation.

Sex-dependent responses to high concentration of binge ethanol in spleen of adolescent F344 rats.

Background: We previously reported that binge ethanol induces atrophy of the spleen, a key immune organ, in adolescent male F344 rats. Because there are significant sex effects in immune function, we investigated whether binge ethanol exerts sex-dependent effects on the spleen, including producing splenic atrophy.

Methods: We gave F344 rats ethanol (4.

C166 EVs potentiate miR cardiac reprogramming via miR-148a-3p.

We have demonstrated that directly reprogramming cardiac fibroblasts into new cardiomyocytes via miR combo improves cardiac function in the infarcted heart. However, major challenges exist with delivery and efficacy. During a screening based approach to improve delivery, we discovered that C166-derived EVs were effective delivery agents for miR combo both in vitro and in vivo.

Modifying miRs for effective reprogramming of fibroblasts to cardiomyocytes.

Reprogramming scar fibroblasts into cardiomyocytes has been proposed to reverse the damage associated with myocardial infarction. However, the limited improvement in cardiac function calls for enhanced strategies. We reported enhanced efficacy of our miR reprogramming cocktail miR combo (miR-1, miR-133a, miR-208a, and miR-499) via RNA-sensing receptor stimulation.

RNA Therapeutics for the Cardiovascular System.

RNA therapeutics hold significant promise in the treatment of cardiovascular diseases. RNAs are biologically diverse and functionally specific and can be used for gain- or loss-of-function purposes. The effectiveness of mRNA-based vaccines in the recent COVID-19 pandemic has undoubtedly proven the benefits of an RNA-based approach.

Precision Hypertension.

Hypertension affects >1 billion people worldwide. Complications of hypertension include stroke, renal failure, cardiac hypertrophy, myocardial infarction, and cardiac failure. Despite the development of various antihypertensive drugs, the number of people with uncontrolled hypertension continues to rise.

The mechanisms underlying alcohol-induced decreased splenic size: A network meta-analysis study.

Background: Organ weight change is widely accepted as a measure of toxicologic pathology. We and other groups have shown that excessive alcohol exposure leads to decreased spleen weight in rodents. This study explores the mechanisms underlying alcohol-induced splenic injury through a network meta-analysis.

Multi-omics analysis of alcohol effects on the liver in young and aged mice.

Excessive alcohol consumption has detrimental effects on the entire organism, especially on the liver. The toxicity is partly dependent on age, as older individuals metabolize alcohol more slowly leading to increased cellular injury. This study aimed to investigate the effects of moderate binge drinking on the liver of young and aged mice in a genome-wide multi-omics approach.

Neonatal and adult cardiac fibroblasts exhibit inherent differences in cardiac regenerative capacity.

Directly reprogramming fibroblasts into cardiomyocytes improves cardiac function in the infarcted heart. However, the low efficacy of this approach hinders clinical applications. Unlike the adult mammalian heart, the neonatal heart has an intrinsic regenerative capacity.

Methylome changes associated with functional movement/conversion disorder: Influence of biological sex and childhood abuse exposure.

Epigenetic changes, such as DNA methylation (DNAm), may represent an important mechanism implicated in the etiopathogenesis of functional movement/conversion disorder (FMD). Here, we aimed to identify methylomic variations in a case-control cohort of FMD and to uncover specific epigenetic signatures associated with female sex and childhood abuse, two key risk factors for FMD and other functional neurological disorders. Genome-wide DNAm analysis was performed from peripheral blood in 57 patients with FMD and 47 healthy controls with and without childhood abuse.

Novel method of differentiating human induced pluripotent stem cells to mature cardiomyocytes via Sfrp2.

Current methods to generate cardiomyocytes from induced pluripotent stem cells (iPSc) utilize broad-spectrum pharmacological inhibitors. These methods give rise to cardiomyocytes which are typically immature. Since we have recently demonstrated that cardiomyogenesis in vitro and in vivo requires Sfrp2, we asked if Sfrp2 would drive differentiation of human iPSc into cardiomyocytes.

Rig1 receptor plays a critical role in cardiac reprogramming via YY1 signaling.

We discovered that innate immunity plays an important role in the reprogramming of fibroblasts into cardiomyocytes. In this report, we define the role of a novel retinoic acid-inducible gene 1 Yin Yang 1 (Rig1:YY1) pathway. We found that fibroblast to cardiomyocyte reprogramming efficacy was enhanced by specific Rig1 activators.

Genetic and genomic signatures in ethanol withdrawal seizure-prone and seizure-resistant mice implicate genes involved in epilepsy and neuronal excitability.

Alcohol withdrawal is a clinically important consequence and potential driver of Alcohol Use Disorder. However, susceptibility to withdrawal symptoms, ranging from craving and anxiety to seizures and delirium, varies greatly. Selectively bred Withdrawal Seizure-Prone (WSP) and Seizure-Resistant (WSR) mice are an animal model of differential susceptibility to withdrawal and phenotypes with which withdrawal severity correlates.

Additive Effects of Stress and Alcohol Exposure on Accelerated Epigenetic Aging in Alcohol Use Disorder.

Background: Stress contributes to premature aging and susceptibility to alcohol use disorder (AUD), and AUD itself is a factor in premature aging; however, the interrelationships of stress, AUD, and premature aging are poorly understood.

Methods: We constructed a composite score of stress from 13 stress-related outcomes in a discovery cohort of 317 individuals with AUD and control subjects. We then developed a novel methylation score of stress (MS stress) as a proxy of composite score of stress comprising 211 CpGs selected using a penalized regression model.

Conservation of miR combo based direct cardiac reprogramming.

There is considerable interest in regenerating the injured heart by reprogramming resident fibroblasts into new functional cardiomyocytes. Cardiac reprogramming has been achieved via transcription factors or miRNAs. Transcription factor combinations appear to be species-specific as evidenced by the fact that combinations of transcription factors which are effective for the reprogramming of mouse fibroblasts are ineffective in pigs and humans.

A novel Cbx1, PurB, and Sp3 complex mediates long-term silencing of tissue- and lineage-specific genes.

miRNA-based cellular fate reprogramming offers an opportunity to investigate the mechanisms of long-term gene silencing. To further understand how genes are silenced in a tissue-specific manner, we leveraged our miRNA-based method of reprogramming fibroblasts into cardiomyocytes. Through screening approaches, we identified three proteins that were downregulated during reprogramming of fibroblasts into cardiomyocytes: heterochromatin protein Cbx1, transcriptional activator protein PurB, and transcription factor Sp3.