Increased Risk of Glaucoma in Fuchs Endothelial Corneal Dystrophy Is Independent of TCF4 Trinucleotide Repeat Expansion.

Purpose: The purpose of this study was to determine the prevalence of glaucoma and/or ocular hypertension (G/OHTN) in patients with Fuchs endothelial corneal dystrophy (FECD) and correlate with FECD severity and TCF4 cytosine-thymine-guanine18.1 (CTG18.1) trinucleotide repeat expansion genotype.

Bridging the Gap between Sequence and Structure Classifications of Proteins with AlphaFold Models.

Classification of protein domains based on homology and structural similarity serves as a fundamental tool to gain biological insights into protein function. Recent advancements in protein structure prediction, exemplified by AlphaFold, have revolutionized the availability of protein structural data. We focus on classifying about 9000 Pfam families into ECOD (Evolutionary Classification of Domains) by using predicted AlphaFold models and the DPAM (Domain Parser for AlphaFold Models) tool.

Identification of FDA-approved drugs that induce heart regeneration in mammals.

Targeting Meis1 and Hoxb13 transcriptional activity could be a viable therapeutic strategy for heart regeneration. In this study, we performd an in silico screening to identify FDA-approved drugs that can inhibit Meis1 and Hoxb13 transcriptional activity based on the resolved crystal structure of Meis1 and Hoxb13 bound to DNA. Paromomycin (Paro) and neomycin (Neo) induced proliferation of neonatal rat ventricular myocytes in vitro and displayed dose-dependent inhibition of Meis1 and Hoxb13 transcriptional activity by luciferase assay and disruption of DNA binding by electromobility shift assay.

Transcriptional regulation of the postnatal cardiac conduction system heterogeneity.

The cardiac conduction system (CCS) is a network of specialized cardiomyocytes that coordinates electrical impulse generation and propagation for synchronized heart contractions. Although the components of the CCS, including the sinoatrial node, atrioventricular node, His bundle, bundle branches, and Purkinje fibers, were anatomically discovered more than 100 years ago, their molecular constituents and regulatory mechanisms remain incompletely understood. Here, we demonstrate the transcriptomic landscape of the postnatal mouse CCS at a single-cell resolution with spatial information.

Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria.

Malaria remains a global health concern as drug resistance threatens treatment programs. We identified a piperidine carboxamide (SW042) with anti-malarial activity by phenotypic screening. Selection of SW042-resistant Plasmodium falciparum (Pf) parasites revealed point mutations in the Pf_proteasome β5 active-site (Pfβ5).

Lysozyme 1 Inflamed CCR2 Macrophages Promote Obesity-Induced Cardiac Dysfunction.

Background: Macrophages are key players in obesity-associated cardiovascular diseases, which are marked by inflammatory and immune alterations. However, the pathophysiological mechanisms underlying macrophage's role in obesity-induced cardiac inflammation are incompletely understood. Our study aimed to identify the key macrophage population involved in obesity-induced cardiac dysfunction and investigate the molecular mechanism that contributes to the inflammatory response.

Spatial transcriptomics implicates impaired BMP signaling in NF1 fracture pseudarthrosis in murine and patient tissues.

The neurofibromatosis type 1 (NF1) RASopathy is associated with persistent fibrotic nonunions (pseudarthrosis) in human and mouse skeletal tissue. Here, we performed spatial transcriptomics to define the molecular signatures occurring during normal endochondral healing following fracture in mice. Within the control fracture callus, we observed spatially restricted activation of morphogenetic pathways, such as TGF-β, WNT, and BMP.

Associations Between Cardiac Function and Brain Health in Diverse Middle-Aged Adults: The Dallas Heart Study-2.

Background: Previous studies have linked cardiovascular risk factors during midlife to cognitive function in later life. However, few studies have looked at the association between cardiac function, brain structure, and cognitive function and even less have included diverse middle-aged populations.

Objectives: The objective of this study was to determine associations between cardiac and brain structure and function in a multiethnic cohort of middle-aged adults.

Structure classification of the proteins from Salmonella enterica pangenome revealed novel potential pathogenicity islands.

Salmonella enterica is a pathogenic bacterium known for causing severe typhoid fever in humans, making it important to study due to its potential health risks and significant impact on public health. This study provides evolutionary classification of proteins from Salmonella enterica pangenome. We classified 17,238 domains from 13,147 proteins from 79,758 Salmonella enterica strains and studied in detail domains of 272 proteins from 14 characterized Salmonella pathogenicity islands (SPIs).

Computational analysis of propeptide-containing proteins and prediction of their post-cleavage conformation changes.

A propeptide is removed from a precursor protein to generate its active or mature form. Propeptides play essential roles in protein folding, transportation, and activation and are present in about 2.3% of reviewed proteins in the UniProt database.

Incident heart failure in chronic kidney disease: proteomics informs biology and risk stratification.

Background And Aims: Incident heart failure (HF) among individuals with chronic kidney disease (CKD) incurs hospitalizations that burden patients and health care systems. There are few preventative therapies, and the Pooled Cohort equations to Prevent Heart Failure (PCP-HF) perform poorly in the setting of CKD. New drug targets and better risk stratification are urgently needed.

Preclinical Milestones in MECP2 Gene Transfer for Treating Rett Syndrome.

Background: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). After gene transfer in mice, exogenous MeCP2 expression must be regulated to avoid dose-dependent toxicity.

Summary: The preclinical gene therapy literature for treating RTT illustrates a duly diligent progression that begins with proof-of-concept studies and advances toward the development of safer, regulated MECP2 viral genome designs.

Adducin Regulates Sarcomere Disassembly During Cardiomyocyte Mitosis.

Background: Recent interest in understanding cardiomyocyte cell cycle has been driven by potential therapeutic applications in cardiomyopathy. However, despite recent advances, cardiomyocyte mitosis remains a poorly understood process. For example, it is unclear how sarcomeres are disassembled during mitosis to allow the abscission of daughter cardiomyocytes.

A Novel Subtype of Acquired Generalized Lipodystrophy Associated With Subcutaneous Panniculitis-Like T-cell Lymphoma.

Acquired generalized lipodystrophy (AGL) is an extremely rare disease that is characterized by loss of body fat affecting nearly all parts of the body. It is often associated with autoimmune diseases or panniculitis, whereas in other patients the underlying etiology is unclear. We report a 52-year-old male individual who was diagnosed with subcutaneous panniculitis-like T-cell lymphoma (SPTCL) that spontaneously went into remission.

Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis.

We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism.

Viable mutations of mouse midnolin suppress B cell malignancies.

In a genetic screen, we identified two viable missense alleles of the essential gene Midnolin (Midn) that were associated with reductions in peripheral B cells. Causation was confirmed in mice with targeted deletion of four of six MIDN protein isoforms. MIDN was expressed predominantly in lymphocytes where it augmented proteasome activity.