328 research outputs found
Use of animal models to understand titin physiology and pathology
In recent years, increasing attention has been paid to titin (TTN) and its mutations. Heterozygous TTN truncating variants (TTNtv) increase the risk of a cardiomyopathy. At the same time, TTNtv and few missense variants have been identified in patients with mainly recessive skeletal muscle diseases. The pathogenic mechanisms underlying titin-related diseases are still partly unknown. Similarly, the titin mechanical and functional role in the muscle contraction are far from being exhaustively clarified. In the last few years, several animal models carrying variants in the titin gene have been developed and characterized to study the structural and mechanical properties of specific titin domains or to mimic patients' mutations. This review describes the main animal models so far characterized, including eight mice models and three fish models (Medaka and Zebrafish) and discusses the useful insights provided by a thorough characterization of the cell-, tissue- and organism-phenotypes in these models.Peer reviewe
Is Gene-Size an Issue for the Diagnosis of Skeletal Muscle Disorders?
Human genes have a variable length. Those having a coding sequence of extraordinary length and a high number of exons were almost impossible to sequence using the traditional Sanger-based gene-by-gene approach. High-throughput sequencing has partly overcome the size-related technical issues, enabling a straightforward, rapid and relatively inexpensive analysis of large genes. Several large genes (e.g. TTN, NEB, RYR1, DMD) are recognized as disease-causing in patients with skeletal muscle diseases. However, because of their sheer size, the clinical interpretation of variants in these genes is probably the most challenging aspect of the high-throughput genetic investigation in the field of skeletal muscle diseases. The main aim of this review is to discuss the technical and interpretative issues related to the diagnostic investigation of large genes and to reflect upon the current state of the art and the future advancements in the field. © 2020 - IOS Press and the authors. All rights reserved.Peer reviewe
A multiple case-study investigation on the intersection between sustainability and reputation: An impact-driven framework for sport teams
The concept of impact, referring to short-term effects resulting from the implementation of sustainability practices and initiatives, and its connection to the longer term perception of sustainability for the brand, is becoming increasingly pervasive in various businesses, including the sports industry, attracting attention of different stakeholders, from scholars to practitioners, institutions, sport-teams, and their fans. A significant portion of extant theory indicates a direct link between sustainable practices and positive effects on the economic, social, and reputational fronts. Through the utilization of a multiple case study methodology, we initially investigated clubs belonging to the top five European football leagues. Subsequently, we developed a theoretical framework connecting the activation of sustainable practices to the development of corporate reputation, as perceived by multiple stakeholders. Moreover, we clarified how the interplay of various factors can either reinforce or weaken these cycles, serving as basis for both managerial plans and future research avenues
Identification of an intragenic deletion in the SGCB gene through a re-evaluation of negative next generation sequencing results
A large mutation screening of 504 patients with muscular dystrophy or myopathy has been performed by next generation sequencing (NGS). Among this cohort of patients, we report a case with a severe form of muscular dystrophy with a proximal weakness in the limb-girdle muscles. Her biopsy revealed typical dystrophic features and immunohistochemistry for α- and γ-sarcoglycans showed an absent reaction, addressing the clinical diagnosis toward a sarcoglycanopathy. Considering that no causative point mutation was detected in any of the four sarcoglycan genes, we re-evaluated the NGS data by careful quantitative analysis of the specific reads mapping on the four sarcoglycan genes. A complete absence of reads from the sixth exon of the β-sarcoglycan gene was found. Subsequent array comparative genomic hybridization (CGH) analysis confirmed the result with the identification of a novel 3.3 kb intragenic deletion in the SGCB gene. This case illustrates the importance of a multidisciplinary approach involving clinicians and molecular geneticists and the need for a careful re-evaluation of NGS data
Valosin-containing protein-related myopathy and Meige syndrome : Just a coincidence or not?
Non peer reviewe
Bi-Allelic DES Gene Variants Causing Autosomal Recessive Myofibrillar Myopathies Affecting Both Skeletal Muscles and Cardiac Function
Mutations in the human desmin gene (DES) may cause both autosomal dominant and recessive cardiomyopathies leading to heart failure, arrhythmias and atrio-ventricular blocks, or progressive myopathies. Cardiac conduction disorders, arrhythmias and cardiomyopathies usually associated with progressive myopathy are the main manifestations of autosomal dominant desminopathies, due to mono-allelic pathogenic variants. The recessive forms, due to bi-allelic variants, are very rare and exhibit variable phenotypes in which premature sudden cardiac death could also occur in the first or second decade of life. We describe a further case of autosomal recessive desminopathy in an Italian boy born of consanguineous parents, who developed progressive myopathy at age 12, and dilated cardiomyopathy four years later and died of intractable heart failure at age 17. Next Generation Sequencing (NGS) analysis identified the homozygous loss-of-function variant c.634C>T; p.Arg212*, which was likely inherited from both parents. Furthermore, we performed a comparison of clinical and genetic results observed in our patient with those of cases so far reported in the literature
Sample-Efficient Safety Assurances using Conformal Prediction
When deploying machine learning models in high-stakes robotics applications,
the ability to detect unsafe situations is crucial. Early warning systems can
provide alerts when an unsafe situation is imminent (in the absence of
corrective action). To reliably improve safety, these warning systems should
have a provable false negative rate; i.e. of the situations that are unsafe,
fewer than will occur without an alert. In this work, we present a
framework that combines a statistical inference technique known as conformal
prediction with a simulator of robot/environment dynamics, in order to tune
warning systems to provably achieve an false negative rate using as
few as data points. We apply our framework to a driver warning
system and a robotic grasping application, and empirically demonstrate
guaranteed false negative rate while also observing low false detection
(positive) rate.Comment: International Journal of Robotics Research, 202
The complexity of titin splicing pattern in human adult skeletal muscles
Background: Mutations in the titin gene (TTN) cause a large spectrum of diseases affecting skeletal and/or cardiac muscle. TTN includes 363 coding exons, a repeated region with a high degree of complexity, isoform-specific elements, and metatranscript-only exons thought to be expressed only during fetal development. Although three main classes of isoforms have been described so far, alternative splicing events (ASEs) in different tissues or in different developmental and physiological states have been reported. Methods: To achieve a comprehensive view of titin ASEs in adult human skeletal muscles, we performed a RNA-Sequencing experiment on 42 human biopsies collected from 12 anatomically different skeletal muscles of 11 individuals without any skeletal-muscle disorders. Results: We confirmed that the skeletal muscle N2A isoforms are highly prevalent, but we found an elevated number of alternative splicing events, some at a very high level. These include previously unknown exon skipping events and alternative 5' and 3' splice sites. Our data suggests the partial inclusion in the TTN transcript of some metatranscript-only exons and the partial exclusion of canonical N2A exons. Conclusions: This study provides an extensive picture of the complex TTN splicing pattern in human adult skeletal muscle, which is crucial for a proper clinical interpretation of TTN variants.Peer reviewe
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