Disruption of Notch1 and Gata5 in Mice Leads to Congenital Aortic Valve Disease.

Here, we describe Notch1;Gata5 compound mutant mice as a novel mouse model of highly penetrant congenital aortic valve disease displaying bicuspid aortic valve and progressive aortic valve stenosis. Further, we find downregulation of smooth muscle genes in the neonatal aortic valves in Notch1;Gata5 compound mice consistent with an immature valve phenotype. Our findings demonstrate a novel genetic interaction between Notch1 and Gata5 in mice that is critical for proper aortic valve development.

Rapidly progressive cystic lung disease in a patient with a scalp lesion.

We describe an elderly patient presenting with pneumothorax, cystic lung disease and a scalp lesion. The pneumothorax resolved after placing a chest tube and suction but recurred within a week. Progression of cystic features was also seen, and biopsies of the lung and scalp lesions were performed.

Novel pathogenic GATA6 variant associated with congenital heart disease, diabetes mellitus and necrotizing enterocolitis.

Background: Pathogenic GATA6 variants have been associated with congenital heart disease (CHD) and a spectrum of extracardiac abnormalities, including pancreatic agenesis, congenital diaphragmatic hernia, and developmental delay. However, the comprehensive genotype-phenotype correlation of pathogenic GATA6 variation in humans remains to be fully understood.

Methods: Exome sequencing was performed in a family where four members had CHD.

Single-cell RNA-sequencing analysis of aortic valve interstitial cells demonstrates the regulation of integrin signaling by nitric oxide.

Calcific aortic valve disease (CAVD) is an increasingly prevalent condition among the elderly population that is associated with significant morbidity and mortality. Insufficient understanding of the underlying disease mechanisms has hindered the development of pharmacologic therapies for CAVD. Recently, we described nitric oxide (NO) mediated S-nitrosylation as a novel mechanism for preventing the calcific process.

Single-cell transcriptomic profiling unveils dysregulation of cardiac progenitor cells and cardiomyocytes in a mouse model of maternal hyperglycemia.

Congenital heart disease (CHD) is the most prevalent birth defect, often linked to genetic variations, environmental exposures, or combination of both. Epidemiological studies reveal that maternal pregestational diabetes is associated with ~5-fold higher risk of CHD in the offspring; however, the causal mechanisms affecting cardiac gene-regulatory-network (GRN) during early embryonic development remain poorly understood. In this study, we utilize an established murine model of pregestational diabetes to uncover the transcriptional responses in key cell-types of the developing heart exposed to maternal hyperglycemia (matHG).

Inhibition of BK channels protects neonatal hearts against myocardial ischemia and reperfusion injury.

BK channels are large-conductance calcium and voltage-activated potassium channels that are heterogeneously expressed in a wide array of cells. Activation of BK channels present in mitochondria of adult ventricular cardiomyocytes is implicated in cardioprotection against ischemia-reperfusion (IR) injury. However, the BK channel's activity has never been detected in the plasma membrane of adult ventricular cardiomyocytes.

A 21-Year-Old Man With Dyspnea, Wheezing, and Cough.

A 21-year-old male college student presented for a second opinion with low alpha-1 antitrypsin (AAT) levels and complaints of episodic dyspnea with wheezing and cough. He was a never smoker with a medical history of frequent respiratory tract infections in early childhood and allergy to dander, dust mites, peanuts, and eggs. There was no travel history outside of the continental United States.

Use of machine learning to classify high-risk variants of uncertain significance in lamin A/C cardiac disease.

Background: Variation in lamin A/C results in a spectrum of clinical disease, including arrhythmias and cardiomyopathy. Benign variation is rare, and classification of LMNA missense variants via in silico prediction tools results in a high rate of variants of uncertain significance (VUSs).

Objective: The goal of this study was to use a machine learning (ML) approach for in silico prediction of LMNA pathogenic variation.

A Multi-Omics Approach Using a Mouse Model of Cardiac Malformations for Prioritization of Human Congenital Heart Disease Contributing Genes.

Congenital heart disease (CHD) is the most common type of birth defect, affecting ~1% of all live births. Malformations of the cardiac outflow tract (OFT) account for ~30% of all CHD and include a range of CHDs from bicuspid aortic valve (BAV) to tetralogy of Fallot (TOF). We hypothesized that transcriptomic profiling of a mouse model of CHD would highlight disease-contributing genes implicated in congenital cardiac malformations in humans.

Impact of maternal hyperglycemia on cardiac development: Insights from animal models.

Congenital heart disease (CHD) is the leading cause of birth defect-related death in infants and is a global pediatric health concern. While the genetic causes of CHD have become increasingly recognized with advances in genome sequencing technologies, the etiology for the majority of cases of CHD is unknown. The maternal environment during embryogenesis has a profound impact on cardiac development, and numerous environmental factors are associated with an elevated risk of CHD.

Inhaled corticosteroids do not adversely impact outcomes in COVID-19 positive patients with COPD: An analysis of Cleveland Clinic's COVID-19 registry.

Inhaled Corticosteroids (ICS) are commonly prescribed to patients with severe COPD and recurrent exacerbations. It is not known what impact ICS cause in terms of COVID-19 positivity or disease severity in COPD. This study examined 27,810 patients with COPD from the Cleveland Clinic COVID-19 registry between March 8th and September 16th, 2020.

Nitric oxide prevents aortic valve calcification by S-nitrosylation of USP9X to activate NOTCH signaling.

Calcific aortic valve disease (CAVD) is an increasingly prevalent condition, and endothelial dysfunction is implicated in its etiology. We previously identified nitric oxide (NO) as a calcification inhibitor by its activation of , which is genetically linked to human CAVD. Here, we show NO rescues calcification by an S-nitrosylation-mediated mechanism in porcine aortic valve interstitial cells and single-cell RNA-seq demonstrated NO regulates the NOTCH pathway.

A 46-Year-Old Woman With a Mediastinal Mass.

A 46-year-old otherwise healthy woman visited the ED twice over a period of 4 days for chest discomfort, midback pain, and dyspnea. The pain was localized, constant, nonpleuritic in nature, moderate in severity, and was not relieved by over-the-counter medications.

In Vivo and In Vitro Genetic Models of Congenital Heart Disease.

Congenital cardiovascular malformations represent the most common type of birth defect and encompass a spectrum of anomalies that range from mild to severe. The etiology of congenital heart disease (CHD) is becoming increasingly defined based on prior epidemiologic studies that supported the importance of genetic contributors and technological advances in human genome analysis. These have led to the discovery of a growing number of disease-contributing genetic abnormalities in individuals affected by CHD.

An analysis of the degree of concordance among international guidelines regarding alpha-1 antitrypsin deficiency.

Background: Practice guidelines (PGs) attempt to standardize practice to optimize care. For uncommon lung diseases like alpha-1 antitrypsin deficiency (AATD), a paucity of definitive studies and geographic variation in prevalence may hamper guideline generation. The current study assembled and assesses the degree of concordance among available PGs regarding AATD.

Developmental origins for semilunar valve stenosis identified in mice harboring congenital heart disease-associated mutation.

Congenital heart defects affect ∼2% of live births and often involve malformations of the semilunar (aortic and pulmonic) valves. We previously reported a highly penetrant p.Gly296Ser mutation in familial, congenital atrial septal defects and pulmonic valve stenosis and showed that mice harboring the orthologous G295S disease-causing mutation display not only atrial septal defects, but also semilunar valve stenosis.

Electronic inhaler monitoring and healthcare utilization in chronic obstructive pulmonary disease.

Introduction: The effect of electronic inhaler monitoring (EIM) on healthcare utilization in chronic obstructive pulmonary disease (COPD) has not been studied. We hypothesized that the use of EIM in conjunction with a disease management program reduces healthcare utilization in patients with COPD.

Methods: This is a retrospective pre- and post-analysis of a quality improvement project.

SGLT-2 Inhibitors and Peripheral Artery Disease: A Statistical Hoax or Reality?

Inhibitors of sodium-glucose cotransporters type-2 are the most recent addition to the armamentarium of oral antidiabetic agents. This class of drugs has shown promising results in glycemic control and most importantly to reduce cardiovascular disease (CVD) mortality risk. Despite the encouraging data, there is concern regarding their potential for causing or worsening peripheral artery disease (PAD), which may increase the risk of lower extremity amputations.

Analysis of Reverse Transcribed mRNA Using PCR and Polyacrylamide Gel Electrophoresis.

The patterns of gene expression in the fission yeast Schizosaccharomyces pombe under various experimental conditions form the basis of any transcriptomic study. We describe a method involving reverse transcription of the mRNA, Polymerase Chain Reaction (PCR), and the subsequent separation of the products onto Urea-Polyacrylamide gel that can be used to study the gene expression patterns in the fission yeast. The method described is cost effective and reproducible with satisfactory resolution of expressed transcripts in the gel.

Epigenetic mechanisms underlying maternal diabetes-associated risk of congenital heart disease.

Birth defects are the leading cause of infant mortality, and they are caused by a combination of genetic and environmental factors. Environmental risk factors may contribute to birth defects in genetically susceptible infants by altering critical molecular pathways during embryogenesis, but experimental evidence for gene-environment interactions is limited. Fetal hyperglycemia associated with maternal diabetes results in a 5-fold increased risk of congenital heart disease (CHD), but the molecular basis for this correlation is unknown.

Trs33-Containing TRAPP IV: A Novel Autophagy-Specific Ypt1 GEF.

Ypt/Rab GTPases, key regulators of intracellular trafficking pathways, are activated by guanine-nucleotide exchange factors (GEFs). Here, we identify a novel GEF complex, TRAPP IV, which regulates Ypt1-mediated autophagy. In the yeast Saccharomyces cerevisiae, Ypt1 GTPase is required for the initiation of secretion and autophagy, suggesting that it regulates these two distinct pathways.

Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract.

Background: Congenital heart disease is the most common type of birth defect, affecting ≈2% of the population. Malformations involving the cardiac outflow tract and semilunar valves account for >50% of these cases predominantly because of a bicuspid aortic valve, which has an estimated prevalence of 1% in the population. We previously reported that mutations in NOTCH1 were a cause of bicuspid aortic valve in nonsyndromic autosomal-dominant human pedigrees.

Regulation of Golgi Cisternal Progression by Ypt/Rab GTPases.

Current models entail that transport through the Golgi-the main sorting compartment of the cell-occurs via cisternal progression/maturation and that Ypt/Rab GTPases regulate this process. However, there is very limited evidence that cisternal progression is regulated, and no evidence for involvement of Ypt/Rab GTPases in such a regulation. Moreover, controversy about the placement of two of the founding members of the Ypt/Rab family, Ypt1 and Ypt31, to specific Golgi cisternae interferes with addressing this question in yeast, where cisternal progression has been extensively studied.

Gene expression profiling data of Schizosaccharomyces pombe under nitrosative stress using differential display.

Excess production of nitric oxide (NO) and reactive nitrogen intermediates (RNIs) causes nitrosative stress on cells. Schizosaccharomyces pombe was used as a model to study nitrosative stress response. In the present data article, we have used differential display to identify the differentially expressed genes in the fission yeast under nitrosative stress conditions.