Myostatin in the Pathophysiology of Skeletal Muscle

Myostatin is an endogenous, negative regulator of muscle growth determining both muscle fiber number and size. The myostatin pathway is conserved across diverse species ranging from zebrafish to humans. Experimental models of muscle growth and regeneration have implicated myostatin as an important mediator of catabolic pathways in muscle cells. Inhibition of this pathway has emerged as a promising therapy for muscle wasting. Here we discuss the recent developments and the controversies in myostatin research, focusing on the molecular and cellular mechanisms underlying the actions of myostatin on skeletal muscle and the potential therapeutic role of myostatin on muscle-related disorders

Diameter of orientations of graphs with given order and number of blocks

A strong orientation of a graph $G$ is an assignment of a direction to each edge such that $G$ is strongly connected. The oriented diameter of $G$ is the smallest diameter among all strong orientations of $G$. A block of $G$ is a maximal connected subgraph of $G$ that has no cut vertex. A block graph is a graph in which every block is a clique. We show that every bridgeless graph of order $n$ containing $p$ blocks has an oriented diameter of at most $n-\lfloor \frac{p}{2} \rfloor$. This bound is sharp for all $n$ and $p$ with $p \geq 2$. As a corollary, we obtain a sharp upper bound on the oriented diameter in terms of order and number of cut vertices. We also show that the oriented diameter of a bridgeless block graph of order $n$ is bounded above by $\lfloor \frac{3n}{4} \rfloor$ if $n$ is even and $\lfloor \frac{3(n+1)}{4} \rfloor$ if $n$ is odd.Comment: 15 pages, 2 figure

Tax incentives in favour of public utility in Switzerland ::an incomplete debate?

Tax incentives in favour of public utility in Switzerland, while they are subject to some debate in terms of amounts or rates, are generally not discussed as a public policy tool. This article, based on the literature on tax incentives for public purposes, would like to shed light on the issues at stake. To do this, we will first consider tax incentives for public purposes as a public policy tool, before examining the stakes of such a tool, in the light of public policy literature and political philosophy, but also from the point of view of political authorities, based on the Swiss case. We will see that, beyond these debates, many interventions - whether by interest groups, lawyers or parliamentarians - are promoting this tool. The question of reform proposals in this area will then be asked to see how far the concerns of political actors are from the reflections of economists, politicians and philosophers who have addressed these issues

Les incitations fiscales en faveur de l’utilité publique en Suisse ::un débat tronqué?

Les incitations fiscales en faveur de l’utilité publique en Suisse, si elles connaissent quelques débats en termes de montants ou de taux, restent de manière générale très peu discutées comme outil de politique publique. Cet article, revenant sur la littérature sur les incitations fiscales à la philanthropie, voudrait éclairer les enjeux de celles-ci. Pour ce faire, nous appréhenderons dans un premier temps les incitations fiscales pour buts d’utilité publique comme un outil de politique publique, avant d’examiner les enjeux d’un tel outil, au regard de la littérature de politiques publiques et de philosophie politique, mais également du point de vue des autorités politiques, à partir du cas suisse. On verra alors que, par delà ces débats, les interventions – qu’elles soient le fait de groupes d’intérêts, de juristes, ou de parlementaires, sont nombreuses à favoriser cet outil. On posera alors la question des propositions de réforme dans ce domaine pour constater la distance qui sépare les préoccupations des acteurs politiques des réflexions des économistes, politistes et philosophes qui se sont penchés sur ces questions

Institute of Making 7th Year Report

A report on the research activities of the Institute of Making covering the period from March 2019 to March 202

Simultaneous miRNA and mRNA transcriptome profiling of human myoblasts reveals a novel set of myogenic differentiation-associated miRNAs and their target genes

Background: miRNA profiling performed in myogenic cells and biopsies from skeletal muscles has previously identified miRNAs involved in myogenesis. Results: Here, we have performed miRNA transcriptome profiling in human affinity-purified CD56+ myoblasts induced to differentiate in vitro. In total, we have identified 60 miRNAs differentially expressed during myogenic differentiation. Many were not known for being differentially expressed during myogenic differentiation. Of these, 14 (miR-23b, miR-28, miR-98, miR-103, miR-107, miR-193a, miR-210, miR-324-5p, miR-324-3p, miR-331, miR-374, miR-432, miR-502, and miR-660) were upregulated and 6 (miR-31, miR-451, miR-452, miR-565, miR-594 and miR-659) were downregulated. mRNA transcriptome profiling performed in parallel resulted in identification of 6,616 genes differentially expressed during myogenic differentiation. Conclusions: This simultaneous miRNA/mRNA transcriptome profiling allowed us to predict with high accuracy target genes of myogenesis-related microRNAs and to deduce their functions

Functional muscle impairment in facioscapulohumeral muscular dystrophy is correlated with oxidative stress and mitochondrial dysfunction

International audienceFacioscapulohumeral muscular dystrophy (FSHD),the most frequent muscular dystrophy, is an autosomal dominant disease. In most individuals with FSHD, symptoms are restricted to muscles of the face, arms, legs, and trunk. FSHD is genetically linked to contractions of the D4Z4 repeat array causing activation of several genes.One of these maps in the repeat itself and expresses the DUX4 (the double homeobox 4) transcription factor causing a gene deregulation cascade. In addition, analyses of the RNA or protein expression profiles in muscle have indicated deregulations in the oxidative stress response. Since oxidative stress affects peripheral muscle function, we investigated mitochondrial function and oxidative stress in skeletal muscle biopsies and blood samples from patients with FSHD and age-matched healthy controls, and evaluated their association with physical performances.We show that specifically, oxidative stress (lipid peroxidation and protein carbonylation), oxidative damage (lipofuscin accumulation), and antioxidant enzymes (catalase, copper–zinc-dependent super- oxide dismutase, and glutathione reductase) were higher in FSHD than in control muscles. FSHD muscles also presented abnormal mitochondrial function (decreased cytochrome c oxidase activity and reduced ATP synthesis). In addition, the ratio between reduced (GSH) and oxidized glutathione (GSSG) was strongly decreased in all FSHD blood samples as a consequence of GSSG accumulation. Patients with FSHD also had reduced systemic antioxidative response molecules, such as low levels of zinc (a SOD cofactor), selenium (a GPx cofactor involved in the elimination of lipid peroxides), and vitamin C. Half of them had a low ratio of gamma/alpha tocopherol and higher ferritin concentrations. Both systemic oxidative stress and mitochondrial dysfunction were correlated with functional muscle impairment. Mitochondrial ATP production was significantly correlated with both quadriceps endurance (TLimQ) and maximal voluntary contraction (MVCQ) values (rho¼0.79, P¼0.003; rho¼0.62, P¼0.05, respectively). The plasma concentration of oxidized glutathione was negatively correlated with the TLimQ, MVCQ values, and the 2-min walk distance (MWT) values (rho¼0.60, P¼0.03; rho¼0.56, P¼0.04; rho¼0.93, Po0.0001, respectively). Our data characterized oxidative stress in patients with FSHD and demonstrated a correlation with their peripheral skeletal muscle dysfunction. They suggest that antioxidants that might modulate or delay oxidative insult maybe useful in maintaining FSHD muscle functions

A One Medicine Mission for an Effective Rabies Therapy

Despite the disease's long history, little progress has been made toward a treatment for rabies. The prognosis for patient recovery remains dire. For any prospect of survival, patients require aggressive critical care, which physicians in rabies endemic areas may be reluctant or unable to provide given the cost, clinical expertise required, and uncertain outcome. Systematic clinical research into combination therapies is further hampered by sporadic occurrence of cases. In this Perspective, we examine the case for a One Medicine approach to accelerate development of an effective therapy for rabies through the veterinary care and investigational treatment of naturally infected dogs in appropriate circumstances. We review the pathogenesis of rabies virus in humans and dogs, including recent advances in our understanding of the molecular basis for the severe neurological dysfunction. We propose that four categories of disease process need to be managed in patients: viral propagation, neuronal degeneration, inflammation and systemic compromise. Compassionate critical care and investigational treatment of naturally infected dogs receiving supportive therapy that mimics the human clinical scenario could increase opportunities to study combination therapies that address these processes, and to identify biomarkers for prognosis and therapeutic response. We discuss the safety and ethics of this approach, and introduce the Canine Rabies Treatment Initiative, a non-profit organization with the mission to apply a One Medicine approach to the investigation of diagnostic, prognostic, and therapeutic options for rabies in naturally infected dogs, to accelerate transformation of rabies into a treatable disease for all patients