LMNA R482L mutation causes impairments in C2C12 myoblasts subpopulations, alterations in metabolic reprogramming during differentiation, and oxidative stress.

LMNA mutations causing classical familial partial lipodystrophy of Dunnigan type (FPLD2) usually affect residue R482. FPLD is a severe metabolic disorder that often leads to cardiovascular and skeletal muscle complications. How LMNA mutations affect the functional properties of skeletal muscles is still not well understood.

A computational approach to predict the effects of missense mutations on protein amyloidogenicity: A case study in hereditary transthyretin cardiomyopathy.

With many amyloidosis-associated missense mutations still unidentified and early diagnostic methods largely unavailable, there is an urgent need for a reliable computational approach to predict hereditary amyloidoses from gene sequencing data. Progress has been made in predicting amyloidosis-triggering sequences within intrinsically disordered regions. However, some diseases are caused by mutations in amyloidogenic regions within structured domains that must unfold for amyloid formation.

Charge Reversal of the Uppermost Arginine in Sliding Helix S4-I Affects Gating of Cardiac Sodium Channel.

Several mutations of the uppermost arginine, R219, in the voltage-sensing sliding helix S4 of cardiac sodium channel Nav1.5 are reported in the ClinVar databases, but the clinical significance of the respective variants is unknown (VUSs). AlphaFold 3 models predicted a significant downshift of S4 in the R219C VUS.

Cushing's Disease Manifestation in -Mutated Corticotropinoma May Be Mediated by Interactions Between WNT Signaling and SST Trafficking.

In the current work, we aimed to evaluate the association of clinical data of Cushing's disease (CD) patients with mutation status and to study USP8-related molecular mechanisms connected to the regulation of corticotropinoma growth and activity. 35 CD patients were enrolled; the sequencing of exon 14 in revealed variants in eighteen adenomas, two of which were described for the first time in CD. variants were more common in women (94% vs.

Mutations Associated with Cushing's Disease Alter Protein Structure Dynamics.

The adenomas in Cushing's disease frequently exhibit mutations in exon 14, within a binding motif for the regulatory protein 14-3-3 located between the catalytic domain (DUB), responsible for ubiquitin hydrolysis, and the WW-like domain that mediates autoinhibition, resulting in constantly active USP8. The exact molecular mechanism of deubiquitinase activity disruption in Cushing's disease remains unclear. To address this, Sanger sequencing of was performed to identify mutations in corticotropinomas.

Fibro-adipogenic progenitor cells in skeletal muscle unloading: metabolic and functional impairments.

Background: Skeletal muscle resident fibro-adipogenic progenitor cells (FAPs) control skeletal muscle regeneration providing a supportive role for muscle stem cells. Altered FAPs characteristics have been shown for a number of pathological conditions, but the influence of temporary functional unloading of healthy skeletal muscle on FAPs remains poorly studied. This work is aimed to investigate how skeletal muscle disuse affects the functionality and metabolism of FAPs.

Differences in Plasma Extracellular Vesicles of Different Origin in On-Pump Versus Off-Pump Cardiac Surgery.

Coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB) causes a systemic inflammatory response that can worsen patient outcomes. Off-pump surgery has been associated with a reduced inflammatory response. The precise mechanisms and the role of extracellular vesicles (EVs) in this context are not fully understood.

The Role of NOTCH Pathway Genes in the Inherited Susceptibility to Aortic Stenosis.

The NOTCH-signaling pathway is responsible for intercellular interactions and cell fate commitment. Recently, NOTCH pathway genes were demonstrated to play an important role in aortic valve development, leading to an increased calcified aortic valve disease (CAVD) later in life. Here, we further investigate the association between genetic variants in the NOTCH pathway genes and aortic stenosis in a case-control study of 90 CAVD cases and 4723 controls using target panel sequencing of full-length 20 genes from a NOTCH-related pathway (, , , , , , , , , , , , , , , , , , , ).

Complex trait susceptibilities and population diversity in a sample of 4,145 Russians.

The population of Russia consists of more than 150 local ethnicities. The ethnic diversity and geographic origins, which extend from eastern Europe to Asia, make the population uniquely positioned to investigate the shared properties of inherited disease risks between European and Asian ancestries. We present the analysis of genetic and phenotypic data from a cohort of 4,145 individuals collected in three metro areas in western Russia.

Fine-needle aspiration technique under endoscopic ultrasound guidance: A technical approach for RNA profiling of pancreatic neoplasms.

Background: Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) has been a longstanding challenge. The prognosis of patients with PDAC depends on the stage at diagnosis. It is necessary to identify biomarkers for the detection and differentiation of pancreatic tumors and optimize PDAC sample preparation procedures for DNA and RNA analysis.

gene variants in term newborns with congenital heart defects and necrotizing enterocolitis.

Background: Necrotizing enterocolitis (NEC) is a common gastrointestinal emergency among neonates which is characterized by acute intestinal inflammation and necrosis. The main risk factors for NEC are prematurity, low birth weight, and some preexisting health conditions such as congenital heart defects (CHDs). Investigation of the potential genetic predisposition to NEC is a promising approach that might provide new insights into its pathogenesis.

Biophysical mechanisms of myocardium sodium channelopathies.

Genetic variants of gene SCN5A encoding the alpha-subunit of cardiac voltage-gated sodium channel Na1.5 are associated with various diseases, including long QT syndrome (LQT3), Brugada syndrome (BrS1), and progressive cardiac conduction disease (PCCD). In the last decades, the great progress in understanding molecular and biophysical mechanisms of these diseases has been achieved.

Topographic Distribution of miRNAs (miR-30a, miR-223, miR-let-7a, miR-let-7f, miR-451, and miR-486) in the Plasma Extracellular Vesicles.

There are many articles on the quantitative analysis of miRNAs contained in a population of EVs of different sizes under various physiological and pathological conditions. For such analysis, it is important to correctly quantify the miRNA contents of EVs. It should be considered that quantification is skewed depending on the isolation protocol, and different miRNAs are degraded by nucleases with different efficiencies.

Molecular effects of cardiac contractility modulation in patients with heart failure of ischemic aetiology uncovered by transcriptome analysis.

Cardiac contractility modulation (CCM) is based on electrical stimulation of the heart without alteration of action potential and mechanical activation, the data on its fundamental molecular mechanisms are limited. Here we demonstrate clinical and physiological effect of 12 months CCM in 29 patients along with transcriptomic molecular data. Based on the CCM effect the patients were divided into two groups: responders ( = 13) and non-responders ( = 16).

In silico analysis of TRPM4 variants of unknown clinical significance.

Background: TRPM4 is a calcium-activated channel that selectively permeates monovalent cations. Genetic variants of the channel in cardiomyocytes are associated with various heart disorders, such as progressive familial heart block and Brugada syndrome. About97% of all known TRPM4 missense variants are classified as variants of unknown clinical significance (VUSs).

Analysis of Prevalence and Clinical Features of Aortic Stenosis in Patients with and without Bicuspid Aortic Valve Using Machine Learning Methods.

Aortic stenosis (AS) is the most commonly diagnosed valvular heart disease, and its prevalence increases with the aging of the general population. However, AS is often diagnosed at a severe stage, necessitating surgical treatment, due to its long asymptomatic period. The objective of this study was to analyze the frequency of AS in a population of cardiovascular patients using echocardiography (ECHO) and to identify clinical factors and features associated with these patient groups.

The phenotypic and genetic features of arrhythmogenic cardiomyopathy in the pediatric population.

Introduction: The present study aimed to describe the phenotypic features and genetic spectrum of arrhythmogenic cardiomyopathy (ACM) presented in childhood and test the validity of different diagnostic approaches using Task Force Criteria 2010 (TFC) and recently proposed Padua criteria.

Patients And Methods: Thirteen patients (mean age at diagnosis 13.6 ± 3.

Transgenerational and intergenerational effects of early childhood famine exposure in the cohort of offspring of Leningrad Siege survivors.

Famine exposure during early life development can affect disease risk in late-life period, yet, transmission of phenotypic features from famine-exposed individuals to the next generations has not been well characterized. The purpose of our case-control study was to investigate the association of parental starvation in the perinatal period and the period of early childhood with the phenotypic features observed in two generations of descendants of Leningrad siege survivors. We examined 54 children and 30 grandchildren of 58 besieged Leningrad residents who suffered from starvation in early childhood and prenatal age during the Second World War.

Desmin mutations impact the autophagy flux in C2C12 cell in mutation-specific manner.

Desmin is the main intermediate filament of striated and smooth muscle cells and plays a crucial role in maintaining the stability of muscle fiber during contraction and relaxation cycles. Being a component of Z-disk area, desmin integrates autophagic pathways, and the disturbance of Z-disk proteins' structure negatively affects chaperone-assisted selective autophagy (CASA). In the present study, we focused on alteration of autophagy flux in myoblasts expressing various Des mutations.

Assaying Mitochondrial Respiration as an Indicator of Cellular Metabolism and Fitness.

Mitochondrial respiration is an essential component of cellular metabolism. It is a process of energy conversion through enzymatically mediated reactions, the energy of taken-up substrates transformed to the ATP production. Seahorse equipment allows to measure oxygen consumption in living cells and estimate key parameters of mitochondrial respiration in real-time mode.