LMTK2 switches on canonical TGF-β1 signaling in human bronchial epithelial cells.

Transforming growth factor (TGF-β1) is a critical profibrotic mediator in chronic lung disease, and there are no specific strategies to mitigate its adverse effects. Activation of TGF-β1 signaling is a multipart process involving ligands, transmembrane receptors, and transcription factors. In addition, an intricate network of adaptor proteins fine-tunes the signaling strength, duration, and activity.

Changes in Metabolic and Inflammatory Markers after a Combined Exercise Program in Workers: A Randomized Controlled Trial.

Purpose: We investigated the effects of a 16-wk combined exercise training on body composition, and metabolic and inflammatory markers in sedentary middle-aged workers. We also assessed whether alterations in metabolic markers were associated with changes in health-related outcomes.

Methods: This randomized controlled trial involved 46 participants randomly allocated into control and exercise groups.

Cell type-specific regulation of CFTR trafficking-on the verge of progress.

Trafficking of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein is a complex process that starts with its biosynthesis and folding in the endoplasmic reticulum. Exit from the endoplasmic reticulum (ER) is coupled with the acquisition of a compact structure that can be processed and traffic through the secretory pathway. Once reaching its final destination-the plasma membrane, CFTR stability is regulated through interaction with multiple protein partners that are involved in its post-translation modification, connecting the channel to several signaling pathways.

The Effects of Combined Aquatic Exercise on Physical Performance and Metabolic Indices in Overweight Healthy Older Adults.

Addressing overweight and obesity to promote healthy aging is essential. Exercise is an outstanding approach to manage metabolic and physical dysfunction. Aquatic exercise has been recommended for older individuals due to reduced weight pressure on joints.

Use of adenine base editing and homology-independent targeted integration strategies to correct the cystic fibrosis causing variant, W1282X.

Small molecule drugs known as modulators can treat ~90% of people with cystic fibrosis (CF), but do not work for premature termination codon variants such as W1282X (c.3846G>A). Here we evaluated two gene editing strategies, Adenine Base Editing (ABE) to correct W1282X, and Homology-Independent Targeted Integration (HITI) of a CFTR superexon comprising exons 23-27 (SE23-27) to enable expression of a CFTR mRNA without W1282X.

Personalized medicine: Function of CFTR variant p.Arg334Trp is rescued by currently available CFTR modulators.

Most of the 2,100 CFTR gene variants reported to date are still unknown in terms of their disease liability in Cystic Fibrosis (CF) and their molecular and cellular mechanism that leads to CFTR dysfunction. Since some rare variants may respond to currently approved modulators, characterizing their defect and response to these drugs is essential for effective treatment of people with CF (pwCF) not eligible for the current treatment. Here, we assessed how the rare variant, p.

Rescue of Rare CFTR Trafficking Mutants Highlights a Structural Location-Dependent Pattern for Correction.

Cystic Fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Currently, more than 2100 variants have been identified in the gene, with a large number being very rare. The approval of modulators that act on mutant CFTR protein, correcting its molecular defect and thus alleviating the burden of the disease, revolutionized the field of CF.

Mutation-class dependent signatures outweigh disease-associated processes in cystic fibrosis cells.

Background: The phenotypic heterogeneity observed in Cystic Fibrosis (CF) patients suggests the involvement of other genes, besides CFTR. Here, we combined transcriptome and proteome analysis to understand the global gene expression patterns associated with five prototypical CFTR mutations.

Results: Evaluation of differentially expressed genes and proteins unveiled common and mutation-specific changes revealing functional signatures that are much more associated with the specific molecular defects associated with each mutation than to the CFTR loss-of-function phenotype.

Fundamental and translational research in Cystic Fibrosis - why we still need it.

Clinical treatments for cystic fibrosis (CF) underwent significant changes in the last decade as therapies targeting the basic defect in the CFTR protein were approved. Significant scientific progress has also been made in several other areas that may lead in the future to novel therapeutic approaches that can help fight CF in all individuals living with this disease. Thus, focusing on fundamental research in the CF field has and will continue to be of great importance.

Effects of combined training during the COVID-19 pandemic on metabolic health and quality of life in sedentary workers: A randomized controlled study.

This study aimed to analyze the effects of a combined training (CT) program performed during the first national lockdown due to the COVID-19 pandemic on body composition, metabolic profile, quality of life and stress in sedentary workers, and examines whether changes in the metabolic profile are associated with changes in health-related outcomes which are modifiable by exercise. We evaluated 31 sedentary workers (48.26 ± 7.

The impact of aquatic exercise programs on the systemic hematological and inflammatory markers of community dwelling elderly: A randomized controlled trial.

Evidence shows that physical exercise is important in maintaining an efficient immune system during ageing. However, there are few studies that test the impact of aquatic exercise programs on the immune system. This study aims to analyze the impact of different physical exercise programs in aquatic environment on the systemic hematological and inflammatory markers of community dwelling elderly.

Absence of EPAC1 Signaling to Stabilize CFTR in Intestinal Organoids.

The plasma membrane (PM) stability of the cystic fibrosis transmembrane conductance regulator (CFTR), the protein which when mutated causes Cystic Fibrosis (CF), relies on multiple interaction partners that connect CFTR to signaling pathways, including cAMP signaling. It was previously shown that activation of exchange protein directly activated by cAMP 1 (EPAC1) by cAMP promotes an increase in CFTR PM levels in airway epithelial cells. However, the relevance of this pathway in other tissues, particularly the intestinal tissue, remains uncharacterized.

Molecular mechanisms of cystic fibrosis - how mutations lead to misfunction and guide therapy.

Cystic fibrosis, the most common autosomal recessive disorder in Caucasians, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a cAMP-activated chloride and bicarbonate channel that regulates ion and water transport in secretory epithelia. Although all mutations lead to the lack or reduction in channel function, the mechanisms through which this occurs are diverse - ranging from lack of full-length mRNA, reduced mRNA levels, impaired folding and trafficking, targeting to degradation, decreased gating or conductance, and reduced protein levels to decreased half-life at the plasma membrane. Here, we review the different molecular mechanisms that cause cystic fibrosis and detail how these differences identify theratypes that can inform the use of directed therapies aiming at correcting the basic defect.

Severity of the S1251N allele in cystic fibrosis is affected by the presence of the F508C variant in cis.

Background: In cystic fibrosis (CF), genotype-phenotype correlation is complicated by the large number of CFTR variants, the influence of modifier genes, environmental effects, and the existence of complex alleles. We document the importance of complex alleles, in particular the F508C variant present in cis with the S1251N disease-causing variant, by detailed analysis of a patient with CF, with the [S1251N;F508]/G542X genotype and a very mild phenotype, contrasting it to that of four subjects with the [S1251N;F508C]/F508del genotype and classical CF presentation.

Methods: Genetic differences were identified by Sanger sequencing and CFTR function was quantified using rectal organoids in rectal organoid morphology analysis (ROMA) and forskolin-induced swelling (FIS) assays.

The Impact of Aquatic Exercise Programs on the Intima-Media thickness of the Carotid Arteries, Hemodynamic Parameters, Lipid Profile and Chemokines of Community-Dwelling Older Persons: A Randomized Controlled Trial.

Scientific evidence has shown that physical exercise is an effective way of improving several cardiovascular disease markers. However, few studies have tested its effectiveness when performed in aquatic environments. The purpose of this study was to test the impact of different aquatic exercise programs on the intima-media thickness of carotid arteries (IMT) and hemodynamic and biochemical markers of cardiovascular diseases in community-dwelling older persons.

Rescue of Mutant CFTR Trafficking Defect by the Investigational Compound MCG1516A.

Although some therapeutic progress has been achieved in developing small molecules that correct F508del-CFTR defects, the mechanism of action (MoA) of these compounds remain poorly elucidated. Here, we investigated the effects and MoA of MCG1516A, a newly developed F508del-CFTR corrector. MCG1516A effects on wild-type (WT) and F508del-CFTR were assessed by immunofluorescence microscopy, and biochemical and functional assays both in cell lines and in intestinal organoids.

Rare Trafficking CFTR Mutations Involve Distinct Cellular Retention Machineries and Require Different Rescuing Strategies.

Most of the ~2100 CFTR variants so far reported are very rare and still uncharacterized regarding their cystic fibrosis (CF) disease liability. Since some may respond to currently approved modulators, characterizing their defect and response to these drugs is essential. Here we aimed characterizing the defect associated with four rare missense (likely Class II) CFTR variants and assess their rescue by corrector drugs.

Revisiting CFTR Interactions: Old Partners and New Players.

Remarkable progress in CFTR research has led to the therapeutic development of modulators that rescue the basic defect in cystic fibrosis. There is continuous interest in studying CFTR molecular disease mechanisms as not all cystic fibrosis patients have a therapeutic option available. Addressing the basis of the problem by comprehensively understanding the critical molecular associations of CFTR interactions remains key.

Integrity and Stability of PTC Bearing CFTR mRNA and Relevance to Future Modulator Therapies in Cystic Fibrosis.

Major advances have recently been made in the development and application of CFTR (cystic fibrosis transmembrane conductance regulator) mutation class-specific modulator therapies, but to date, there are no approved modulators for Class I mutations, i.e., those introducing a premature termination codon (PTC) into the CFTR mRNA.

CyFi-MAP: an interactive pathway-based resource for cystic fibrosis.

Cystic fibrosis (CF) is a life-threatening autosomal recessive disease caused by more than 2100 mutations in the CF transmembrane conductance regulator (CFTR) gene, generating variability in disease severity among individuals with CF sharing the same CFTR genotype. Systems biology can assist in the collection and visualization of CF data to extract additional biological significance and find novel therapeutic targets. Here, we present the CyFi-MAP-a disease map repository of CFTR molecular mechanisms and pathways involved in CF.

Impact of Different Aquatic Exercise Programs on Body Composition, Functional Fitness and Cognitive Function of Non-Institutionalized Elderly Adults: A Randomized Controlled Trial.

Aquatic physical exercise programs have become progressively more popular among elderly people. Some of the major physical exercise program disadvantages on land are minimized due to the specific properties of the aquatic environment. The purpose of the present randomized controlled study is to verify the effects of different aquatic physical exercise programs on body composition, functional fitness and cognitive function in non-institutionalized elderly people.

Comparison of Cas9 and Cas12a CRISPR editing methods to correct the W1282X-CFTR mutation.

Background: W1282X-CFTR variant (c.3846G>A) is the second most common nonsense cystic fibrosis (CF)-causing mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Even though remarkable breakthroughs have been done towards CF treatment with the approval of four CFTR protein modulators, none of these are approved for patients with nonsense mutations.

Differential Gene Expression Analysis Reveals Global LMTK2 Regulatory Network and Its Role in TGF-β1 Signaling.

Lemur tyrosine kinase 2 (LMTK2) is a transmembrane Ser/Thr kinase whose role has been increasingly recognized; however, when compared to other kinases, understanding of the LMTK2 networks and biological functions is still limited. Recent data have shown that transforming growth factor (TGF)-β1 plays a role in modulating LMTK2 function by controlling its endocytic trafficking in human bronchial epithelial cells. Here, we aimed to unveil the LMTK2 regulatory network and elucidate how it affects cellular functions and disease pathways in either TGF-β1 dependent or independent manner.

Impact of Aquatic-Based Physical Exercise Programs on Risk Markers of Cardiometabolic Diseases in Older People: A Study Protocol for Randomized-Controlled Trials.

Cardiometabolic diseases are one of the primary causes of mortality and morbidity worldwide and sedentary lifestyles are contributing factors to these pathologies. Physical exercise has been recognized as an important tool in the prevention and treatment of these diseases. However, there are still some doubts about the efficacy of certain type of physical exercise programs for older participants.