Regulation of sarcomere formation and function in the healthy heart requires a titin intronic enhancer.

Heterozygous truncating variants in the sarcomere protein titin (TTN) are the most common genetic cause of heart failure. To understand mechanisms that regulate abundant cardiomyocyte TTN expression we characterized highly conserved intron 1 sequences that exhibited dynamic changes in chromatin accessibility during differentiation of human cardiomyocytes from induced pluripotent stem cells (hiPSC-CMs). Homozygous deletion of these sequences in mice caused embryonic lethality while heterozygous mice demonstrated allele-specific reduction in Ttn expression.

CHD4 and SMYD1 repress common transcriptional programs in the developing heart.

Regulation of chromatin states is essential for proper temporal and spatial gene expression. Chromatin states are modulated by remodeling complexes composed of components that have enzymatic activities. CHD4 is the catalytic core of the nucleosome remodeling and deacetylase (NuRD) complex, which represses gene transcription.

The H2Bub1-deposition complex is required for human and mouse cardiogenesis.

De novo variants affecting monoubiquitylation of histone H2B (H2Bub1) are enriched in human congenital heart disease. H2Bub1 is required in stem cell differentiation, cilia function, post-natal cardiomyocyte maturation and transcriptional elongation. However, how H2Bub1 affects cardiogenesis is unknown.

Missense Mutation in Human CHD4 Causes Ventricular Noncompaction by Repressing ADAMTS1.

Background: Left ventricular noncompaction (LVNC) is a prevalent cardiomyopathy associated with excessive trabeculation and thin compact myocardium. Patients with LVNC are vulnerable to cardiac dysfunction and at high risk of sudden death. Although sporadic and inherited mutations in cardiac genes are implicated in LVNC, understanding of the mechanisms responsible for human LVNC is limited.

Cardiomyocyte infection by promotes innate immune response and glycolysis activation.

Introduction: Chagas cardiomyopathy, a disease caused by () infection, is a major contributor to heart failure in Latin America. There are significant gaps in our understanding of the mechanism for infection of human cardiomyocytes, the pathways activated during the acute phase of the disease, and the molecular changes that lead to the progression of cardiomyopathy.

Methods: To investigate the effects of on human cardiomyocytes during infection, we infected induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) with the parasite and analyzed cellular, molecular, and metabolic responses at 3 hours, 24 hours, and 48 hours post infection (hpi) using transcriptomics (RNAseq), proteomics (LC-MS), and metabolomics (GC-MS and Seahorse) analyses.

CHD4 is recruited by GATA4 and NKX2-5 to repress noncardiac gene programs in the developing heart.

The nucleosome remodeling and deacetylase (NuRD) complex is one of the central chromatin remodeling complexes that mediates gene repression. NuRD is essential for numerous developmental events, including heart development. Clinical and genetic studies have provided direct evidence for the role of chromodomain helicase DNA-binding protein 4 (CHD4), the catalytic component of NuRD, in congenital heart disease (CHD), including atrial and ventricular septal defects.

Cardiac proteomics reveals sex chromosome-dependent differences between males and females that arise prior to gonad formation.

Sex disparities in cardiac homeostasis and heart disease are well documented, with differences attributed to actions of sex hormones. However, studies have indicated sex chromosomes act outside of the gonads to function without mediation by gonadal hormones. Here, we performed transcriptional and proteomics profiling to define differences between male and female mouse hearts.

mutations in hiPSCs inform mechanisms for maldevelopment of the heart, pancreas, and diaphragm.

Damaging variants cause cardiac outflow tract defects, sometimes with pancreatic and diaphragmic malformations. To define molecular mechanisms for these diverse developmental defects, we studied transcriptional and epigenetic responses to loss of function (LoF) and missense variants during cardiomyocyte differentiation of isogenic human induced pluripotent stem cells. We show that GATA6 is a pioneer factor in cardiac development, regulating that activates and that with orchestrates outflow tract formation.

The cardiac intensive care unit and the cardiac intensivist during the COVID-19 surge in New York City.

Critical care cardiology has been impacted by the coronavirus disease-2019 (COVID-19) pandemic. COVID-19 causes severe acute respiratory distress syndrome, acute kidney injury, as well as several cardiovascular complications including myocarditis, venous thromboembolic disease, cardiogenic shock, and cardiac arrest. The cardiac intensive care unit is rapidly evolving as the need for critical care beds increases.

Genomic analyses implicate noncoding de novo variants in congenital heart disease.

A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs). To assess the contribution of noncoding DNVs to CHD, we compared genome sequences from 749 CHD probands and their parents with those from 1,611 unaffected trios. Neural network prediction of noncoding DNV transcriptional impact identified a burden of DNVs in individuals with CHD (n = 2,238 DNVs) compared to controls (n = 4,177; P = 8.

Psychological distress, coping behaviors, and preferences for support among New York healthcare workers during the COVID-19 pandemic.

Objective: The mental health toll of COVID-19 on healthcare workers (HCW) is not yet fully described. We characterized distress, coping, and preferences for support among NYC HCWs during the COVID-19 pandemic.

Methods: This was a cross-sectional web survey of physicians, advanced practice providers, residents/fellows, and nurses, conducted during a peak of inpatient admissions for COVID-19 in NYC (April 9th-April 24th 2020) at a large medical center in NYC (n = 657).

A reference map of murine cardiac transcription factor chromatin occupancy identifies dynamic and conserved enhancers.

Mapping the chromatin occupancy of transcription factors (TFs) is a key step in deciphering developmental transcriptional programs. Here we use biotinylated knockin alleles of seven key cardiac TFs (GATA4, NKX2-5, MEF2A, MEF2C, SRF, TBX5, TEAD1) to sensitively and reproducibly map their genome-wide occupancy in the fetal and adult mouse heart. These maps show that TF occupancy is dynamic between developmental stages and that multiple TFs often collaboratively occupy the same chromatin region through indirect cooperativity.

Conservation and divergence of protein pathways in the vertebrate heart.

Heart disease is the leading cause of death in the western world. Attaining a mechanistic understanding of human heart development and homeostasis and the molecular basis of associated disease states relies on the use of animal models. Here, we present the cardiac proteomes of 4 model vertebrates with dual circulatory systems: the pig (Sus scrofa), the mouse (Mus musculus), and 2 frogs (Xenopus laevis and Xenopus tropicalis).

INTACT Proteomics in .

Analysis of the molecular mechanisms driving cell specification, differentiation, and other cellular processes can be difficult due to the heterogeneity of tissues and organs. Therefore, it is critical to isolate pure cell populations in order to properly assess the function of certain cell types in the context of a tissue. This protocol describes use of the INTACT (isolation of nuclei tagged in specific cell types) method in , followed by proteomics analysis of nuclear protein complexes.

CHD4 and the NuRD complex directly control cardiac sarcomere formation.

Cardiac development relies on proper cardiomyocyte differentiation, including expression and assembly of cell-type-specific actomyosin subunits into a functional cardiac sarcomere. Control of this process involves not only promoting expression of cardiac sarcomere subunits but also repressing expression of noncardiac myofibril paralogs. This level of transcriptional control requires broadly expressed multiprotein machines that modify and remodel the chromatin landscape to restrict transcription machinery access.

CRISPR/Cas9-Mediated Fluorescent Tagging of Endogenous Proteins in Human Pluripotent Stem Cells.

Human induced pluripotent stem cells (hiPSCs) can be used to mass produce surrogates of human tissues, enabling new advances in drug screening, disease modeling, and cell therapy. Recent developments in clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing technology use homology-directed repair (HDR) to efficiently generate custom hiPSC lines harboring a variety of genomic insertions and deletions. Thus, hiPSCs that encode an endogenous protein fused to a fluorescent reporter protein can be rapidly created by employing CRISPR/Cas9 genome editing, enhancing HDR efficiency and optimizing homology arm length.

Association Between Learning Environment Interventions and Medical Student Well-being: A Systematic Review.

Importance: Concerns exist about the current quality of undergraduate medical education and its effect on students' well-being.

Objective: To identify best practices for undergraduate medical education learning environment interventions that are associated with improved emotional well-being of students.

Data Sources: Learning environment interventions were identified by searching the biomedical electronic databases Ovid MEDLINE, EMBASE, the Cochrane Library, and ERIC from database inception dates to October 2016.

Hypertension: an unstudied potential risk factor for adverse outcomes during continuous flow ventricular assist device support.

In end-stage heart failure, left ventricular assist devices (LVADs) represent an exciting new frontier in which post-device implantation survival approaches that of heart transplant. However, expansion of this technology is still limited by complications that impact morbidity and mortality. Thus, it is essential to identify and optimize modifiable predictors of poor outcomes.

Vitamin D supplementation for depressive symptoms: a systematic review and meta-analysis of randomized controlled trials.

Objective: The aim of this study was to review the effects of vitamin D supplementation on depressive symptoms in randomized controlled trials. Although low vitamin D levels have been observationally associated with depressive symptoms, the effect of vitamin D supplementation as an antidepressant remains uncertain.

Methods: MEDLINE, CINAHL, AMED, PsycINFO, Scopus, The Cochrane Library, and references of included reports (through May 2013) were searched.

A test of the diathesis-stress model in the emergency department: who develops PTSD after an acute coronary syndrome?

Most acute coronary syndrome (ACS) patients first present to the emergency department (ED). Patients who present to overcrowded EDs develop more posttraumatic stress disorder (PTSD) symptoms due to the ACS than do patients who present to less crowded EDs, but no research has indicated whether some patients may be more vulnerable to the effects of ED crowding than others. In an observational cohort study, we tested whether depressed patients developed more ACS-induced PTSD symptoms under conditions of ED overcrowding than patients who had never been depressed.

Epidemiology and Management of Depression Following Coronary Heart Disease Diagnosis in Women.

Coronary heart disease (CHD) and depression are both highly prevalent in women. Importantly, depression is associated with significantly elevated morbidity and mortality in women with CHD. There are intriguing speculations about biological mechanisms underlying this association, such as endothelial dysfunction, subclinical atherosclerosis, inflammation, and autonomic dysregulation.