Inference and design of antibody specificity: From experiments to models and back.

Exquisite binding specificity is essential for many protein functions but is difficult to engineer. Many biotechnological or biomedical applications require the discrimination of very similar ligands, which poses the challenge of designing protein sequences with highly specific binding profiles. Experimental methods for generating specific binders rely on in vitro selection, which is limited in terms of library size and control over specificity profiles.

Involvement of , , and genes in breast cancer and muscle cell development.

Patients with breast cancer show altered expression of genes within the pectoralis major skeletal muscle cells of the breast. Through analyses of The Cancer Genome Atlas (TCGA)-breast cancer (BRCA), we identified three previously uncharacterized putative novel tumor suppressor genes expressed in normal muscle cells, whose expression was downregulated in breast tumors. We found that NEDD4 binding protein 2-like 1 (), pleckstrin homology domain-containing family A member 4 (), and brain-enriched guanylate kinase-associated protein () that are normally highly expressed in breast myoepithelial cells and smooth muscle cells were significantly downregulated in breast tumor tissues of a cohort of 50 patients with this cancer.

Gut microbiota depletion delays somatic peripheral nerve development and impairs neuromuscular junction maturation.

Gut microbiota is responsible for essential functions in human health. Several communication axes between gut microbiota and other organs via neural, endocrine, and immune pathways have been described, and perturbation of gut microbiota composition has been implicated in the onset and progression of an emerging number of diseases. Here, we analyzed peripheral nerves, dorsal root ganglia (DRG), and skeletal muscles of neonatal and young adult mice with the following gut microbiota status: a) germ-free (GF), b) gnotobiotic, selectively colonized with 12 specific gut bacterial strains (Oligo-Mouse-Microbiota, OMM12), or c) natural complex gut microbiota (CGM).

Tissue memory relies on stem cell priming in distal undamaged areas.

Epithelial cells that participated in wound repair elicit a more efficient response to future injuries, which is believed to be locally restricted. Here we show that cell adaptation resulting from a localized tissue damage has a wide spatial impact at a scale not previously appreciated. We demonstrate that a specific stem cell population, distant from the original injury, originates long-lasting wound memory progenitors residing in their own niche.

DNMT3B supports meso-endoderm differentiation from mouse embryonic stem cells.

The correct establishment of DNA methylation patterns during mouse early development is essential for cell fate specification. However, the molecular targets as well as the mechanisms that determine the specificity of the de novo methylation machinery during differentiation are not completely elucidated. Here we show that the DNMT3B-dependent DNA methylation of key developmental regulatory regions at epiblast-like cells (EpiLCs) provides an epigenetic priming that ensures flawless commitment at later stages.

FOXA1 regulates alternative splicing in prostate cancer.

Dysregulation of alternative splicing in prostate cancer is linked to transcriptional programs activated by AR, ERG, FOXA1, and MYC. Here, we show that FOXA1 functions as the primary orchestrator of alternative splicing dysregulation across 500 primary and metastatic prostate cancer transcriptomes. We demonstrate that FOXA1 binds to the regulatory regions of splicing-related genes, including HNRNPK and SRSF1.

The acetyltransferase p300 is recruited in trans to multiple enhancer sites by lncSmad7.

The histone acetyltransferase p300 (also known as KAT3B) is a general transcriptional coactivator that introduces the H3K27ac mark on enhancers triggering their activation and gene transcription. Genome-wide screenings demonstrated that a large fraction of long non-coding RNAs (lncRNAs) plays a role in cellular processes and organ development although the underlying molecular mechanisms remain largely unclear (1,2). We found 122 lncRNAs that interacts directly with p300.

Genome-Wide Analysis of Smad7-Mediated Transcription in Mouse Embryonic Stem Cells.

Smad7 has been identified as a negative regulator of the transforming growth factor TGF-β pathway by direct interaction with the TGF-β type I receptor (TβR-I). Although Smad7 has also been shown to play TGF-β unrelated functions in the cytoplasm and in the nucleus, a comprehensive analysis of its nuclear function has not yet been performed. Here, we show that in ESCs Smad7 is mainly nuclear and acts as a general transcription factor regulating several genes unrelated to the TGF-β pathway.

[Cardiopulmonary exercise testing: an essential tool for a tailored exercise prescription in patients with cardiac disease].

Cardiovascular diseases are the leading cause of death in high-income countries. Exercise prescription is an effective tool for primary and secondary cardiovascular prevention and the cardiovascular benefits of physical activity are well established, ranging from improving the quality of life to reducing mortality. A tailored approach based on patient's personal and clinical characteristics represents a cornerstone for the benefits of exercise prescription.

The importance of ventilatory thresholds to define aerobic exercise intensity in cardiac patients and healthy subjects.

Background: Although structured exercise training is strongly recommended in cardiac patients, uncertainties exist about the methods for determining exercise intensity (EI) and their correspondence with effective EI obtained by ventilatory thresholds. We aimed to determine the first (VT ) and second ventilatory thresholds (VT ) in cardiac patients, sedentary subjects, and athletes comparing VT and VT with EI defined by recommendations.

Methods: We prospectively enrolled 350 subjects (mean age: 50.

Diagnostic and prognostic value of low QRS voltages in cardiomyopathies: old but gold.

The interpretation of 12-lead resting electrocardiogram (ECG) in patients with a definitive diagnosis or with the suspicion of a cardiomyopathy represents a cornerstone for the diagnostic work up and management of patients. Although low electrocardiographic QRS voltages (LQRSV) detected by 12-lead resting ECG have historically been acknowledged by physicians, in view of recent evidence on the demonstration of myocardial scar by cardiac magnetic resonance and its relevance as a cause of sudden cardiac death even in young individuals, a new interest has been raised about the utility of LQRSV in the clinical practice. Beyond their diagnostic value, LQRSV have also demonstrated a prognostic role in different cardiomyopathies.

Genome-scale deconvolution of RNA structure ensembles.

RNA structure heterogeneity is a major challenge when querying RNA structures with chemical probing. We introduce DRACO, an algorithm for the deconvolution of coexisting RNA conformations from mutational profiling experiments. Analysis of the SARS-CoV-2 genome using dimethyl sulfate mutational profiling with sequencing (DMS-MaPseq) and DRACO, identifies multiple regions that fold into two mutually exclusive conformations, including a conserved structural switch in the 3' untranslated region.

Left ventricular hypertrophy in athletes: How to differentiate between hypertensive heart disease and athlete's heart.

Athlete's heart is typically accompanied by a remodelling of the cardiac chambers induced by exercise. However, although competitive athletes are commonly considered healthy, they can be affected by cardiac disorders characterised by an increase in left ventricular mass and wall thickness, such as hypertension. Unfortunately, training-induced increase in left ventricular mass, wall thickness, and atrial and ventricular dilatation observed in competitive athletes may mimic the pathological remodelling of pathological hypertrophy.

Clinical management of young competitive athletes with premature ventricular beats: A prospective cohort study.

Background: Premature ventricular beats (PVBs) are not an unusual finding and their interpretation is sometimes challenging. Unfortunately, few data on the characteristics of PVBs that correlate with the risk of an underlying heart disease are available in athletes.

Objectives: The aim of this prospective study was to investigate the diagnostic and prognostic value of PVBs characteristics in competitive athletes.

The acute effects of an ultramarathon on biventricular function and ventricular arrhythmias in master athletes.

Aims: Endurance sports practice has significantly increased over the last decades, with a growing proportion of participants older than 40 years. Although the benefits of moderate regular exercise are well known, concerns exist regarding the potential negative effects induced by extreme endurance sport. The aim of this study was to analyse the acute effects of an ultramarathon race on the electrocardiogram (ECG), biventricular function, and ventricular arrhythmias in a population of master athletes.

[Clinical pathway for cardiogenic shock. A proposal from ANMCO Tuscany].

Cardiogenic shock is a clinical syndrome characterized by hypotension and hypoperfusion due to the inability of the heart to provide adequate cardiac output. It is an infrequent clinical condition still burdened by high mortality rates. In patients with cardiogenic shock rapid diagnosis, multiparameter monitoring and timely therapeutic strategies with pharmacological agents or mechanical circulatory support are necessary to provide adequate peripheral tissue perfusion and to improve outcome.

The determinants of positivization of anterior T-wave inversion in children.

Background: Anterior T-wave inversion (aTWI) can be a common electrical sign in cardiomyopathies but also a benign feature regressing with age in healthy children. Unfortunately, little is known about the age of positivization of aTWI and its determinants in children and longitudinal data are not available. The aim of this longitudinal study was to identify the age and determinants of positivization of aTWI in healthy children.

Bicuspid aortic valve and sports: From the echocardiographic evaluation to the eligibility for sports competition.

Bicuspid aortic valve (BAV) is the most common congenital heart defect in adults. Although a BAV may remain without clinical consequences for a lifetime, it can deteriorate in aortic valve stenosis and regurgitation and aortic dilatation. Unfortunately, the impact of regular training on patients with BAV and its natural course is not fully understood, although preliminary evidence suggests that the progression of valvular disease occurs primarily in an independent manner from sports practice.

Electromechanical delay by speckle-tracking echocardiography: A novel tool to distinguish between Brugada syndrome and isolated right bundle branch block.

Background: The electrocardiographic (ECG) definition of Brugada syndrome (BS) can be challenging because benign ECG abnormalities, such as right bundle branch block (RBBB), may mimic pathological ECG characteristics of BrS. However, although myocardial delay and deformation can be quantified by advanced imaging, it has not yet been used to differentiate between BrS and RBBB. The aim of this study was to characterize the electro-mechanical behavior of the heart of patients with type-1 BrS and isolated complete RBBB in order to differentiate these conditions.

Interpretation of T-wave inversion in physiological and pathological conditions: Current state and future perspectives.

The presence of T-wave inversion (TWI) at 12-lead electrocardiogram (ECG) in competitive athletes is one of the major diagnostic challenges for sports physicians and consulting cardiologists. Indeed, while the presence of TWI may be associated with some benign conditions and it may be occasionally seen in healthy athletes presenting signs of cardiac remodeling, it may also represent an early sign of an underlying, concealed structural heart disease or life-threatening arrhythmogenic cardiomyopathies, which may be responsible for exercise-related sudden cardiac death (SCD). The interpretation of TWI in athletes is complex and the inherent implications for the clinical practice represent a conundrum for physicians.

The acute impact of an ultramarathon on right heart: A 12-lead ECG study.

Background: Some concerns exist about possible detrimental effects on cardiac function of ultra-endurance competitions. The aim of this study was to evaluate the acute effects of an ultramarathon by comparing pre- and post-race 12-lead ECG features.

Methods: A total of 301 competitive athletes (mean age: 48 ± 9 years) running a 50-km ultramarathon were analyzed.

HaTSPiL: A modular pipeline for high-throughput sequencing data analysis.

Background: Next generation sequencing methods are widely adopted for a large amount of scientific purposes, from pure research to health-related studies. The decreasing costs per analysis led to big amounts of generated data and to the subsequent improvement of software for the respective analyses. As a consequence, many approaches have been developed to chain different software in order to obtain reliable and reproducible workflows.