Remotely acting SMCHD1 gene regulatory elements: in silico prediction and identification of potential regulatory variants in patients with FSHD

Background: Facioscapulohumeral dystrophy (FSHD) is commonly associated with contraction of the D4Z4 macro-satellite repeat on chromosome 4q35 (FSHD1) or mutations in the SMCHD1 gene (FSHD2). Recent studies have shown that the clinical manifestation of FSHD1 can be modified by mutations in the SMCHD1 gene within a given family. The absence of either D4Z4 contraction or SMCHD1 mutations in a small cohort of patients suggests that the disease could also be due to disruption of gene regulation. In this study, we postulated that mutations responsible for exerting a modifier effect on FSHD might reside within remotely acting regulatory elements that have the potential to interact at a distance with their cognate gene promoter via chromatin looping. To explore this postulate, genome-wide Hi-C data were used to identify genomic fragments displaying the strongest interaction with the SMCHD1 gene. These fragments were then narrowed down to shorter regions using ENCODE and FANTOM data on transcription factor binding sites and epigenetic marks characteristic of promoters, enhancers and silencers

Justice and Corporate Governance: New Insights from Rawlsian Social Contract and Sen’s Capabilities Approach

By considering what we identify as a problem inherent in the ‘nature of the firm’—the risk of abuse of authority—we propound the conception of a social contract theory of the firm which is truly Rawlsian in its inspiration. Hence, we link the social contract theory of the firm (justice at firm’s level) with the general theory of justice (justice at society’s level). Through this path, we enter the debate about whether firms can be part of Rawlsian theory of justice showing that corporate governance principles enter the “basic structure.” Finally, we concur with Sen’s aim to broaden the realm of social justice beyond what he calls the ‘transcendental institutional perfectionism’ of Rawls’ theory. We maintain the contractarian approach to justice but introduce Sen’s capability concept as an element of the constitutional and post-constitutional contract model of institutions with special reference to corporate governance. Accordingly, rights over primary goods and capabilities are (constitutionally) granted by the basic institutions of society, but many capabilities have to be turned into the functionings of many stakeholders through the operation of firms understood as post-constitutional institutional domains. The constitutional contract on the distribution of primary goods and capabilities should then shape the principles of corporate governance so that at post-constitutional level anyone may achieve her/his functionings in the corporate domain by exercising such capabilities. In the absence of such a condition, post-constitutional contracts would distort the process that descends from constitutional rights and capabilities toward social outcomes

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD

MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

High-performance flexible perovskite solar cells exploiting Zn2SnO4 prepared in solution below 100 degrees C

Fabricating inorganic-organic hybrid perovskite solar cells (PSCs) on plastic substrates broadens their scope for implementation in real systems by imparting portability, conformability and allowing high-throughput production, which is necessary for lowering costs. Here we report a new route to prepare highly dispersed Zn2SnO4 (ZSO) nanoparticles at low-temperature (<100 degrees C) for the development of high-performance flexible PSCs. The introduction of the ZSO film significantly improves transmittance of flexible polyethylene naphthalate/indium-doped tin oxide (PEN/ITO)-coated substrate from similar to 75 to similar to 90% over the entire range of wavelengths. The best performing flexible PSC, based on the ZSO and CH3NH3PbI3 layer, exhibits steady-state power conversion efficiency (PCE) of 14.85% under AM 1.5G 100 mW . cm(-2) illumination. This renders ZSO a promising candidate as electron-conducting electrode for the highly efficient flexible PSC applications.ope

Promoting the use of Motor Function Measure (MFM) as outcome measure in patients with Duchenne Muscular Dystrophy (DMD) treated by corticosteroids

ObjectivesAssessing muscle function is a key step in measuring changes and evaluating the outcomes of therapeutic interventions in Duchenne Muscular Dystrophy (DMD). Regarding the large use of corticosteroids (CS) in this population to delay the loss of function, our goal was to monitor the evolution of motor function in patients with DMD treated by corticosteroids (CS) and to study the responsiveness of Motor Function Measure (MFM) in this population in order to provide an estimation of the number of subject needed for a clinical trial.MethodA total of 76 patients with DMD, aged 5.9 to 11.8 years, with at least 6 months of follow-up and 2 MFM were enrolled, 30 in the CS treated group (8±1.62 y) and 46 in the untreated group (7.91±1.50 y).ResultsThe relationship between MFM scores and age was studied in CS treated patients and untreated patients. The evolution of these scores was compared between groups, on a 6-, 12- and 24-month period by calculating slopes of change and standardized response mean. At 6, 12 and 24 months, significant differences in the mean score change were found, for all MFM scores, between CS treated patients and untreated patients. For D1 subscore specifically, at 6 months, the increase is significant in the treated group (11.3±14%/y; SRM 0.8) while a decrease is observed in the untreated group (–17.8±17.7%/y; SRM 1). At 12 and 24 months, D1 subscore stabilized for treated patients but declined significantly for untreated boys (–15.5±15.1%/y; SRM 1 at 12 mo and–18.8±7.1%/y; SRM 2.6 at 24 mo). 21 patients lost the ability to walk during the study: 6 in the CS treated group (25% at 24 months, mean age: 10.74±1.28 y) and 15 in the untreated group (64.71% at 24 months, mean age: 9.20±1.78 y).Discussion and conclusionPatients with DMD treated by CS present a different course of the disease described in this paper using the MFM. Based on these results, an estimation of the number of patients needed for clinical trial could be done

Photoresponsive Polymer-Based Biomimetic Contractile Units as Building Block for Artificial Muscles

Loss of muscular mechanical function occurs in several diseases affecting millions of people worldwide, including heart failure, stroke, and neuromuscular disorders. To date, no medical or surgical treatments can restore muscular contractility, and the development of artificial muscles is of extreme interest. Mimicking biological muscles, which are optimized systems displaying quick reaction times, is not trivial; only few examples are reported, mainly focused on the use of biomimetic smart materials. Among them, liquid crystalline elastomers (LCEs) can be biocompatible, show contraction parameters comparable to those of native striated muscles, and are able to effectively potentiate cardiac contraction in vitro. To go further and develop in vivo implantable devices, the integration of the stimulation system with the LCE material represents an essential step. Here, a light-stimulated biomimetic contractile unit (BCU), combining ultra-thin photoresponsive LCE films and mini-LED (mLED) matrixes is described. BCU performance (in terms of extent and kinetics of contractile force and shortening) can be fine-tuned by modulating both mLED light power and spatial stimulation patterns, allowing to reproduce mechanical dynamics of native muscles. These results pave the way for the development of novel LCE-based contraction assist devices for cardiac, skeletal, or smooth muscle support by assembling multiple BCUs

CSR and related terms in SME owner-managers' mental models in six European countries: national context matters

As a contribution to the emerging field of corporate social responsibility (CSR) cognition, this article reports on the findings of an exploratory study that compares SME owner–managers’ mental models with regard to CSR and related concepts across six European countries (Belgium, Italy, Norway, France, UK, Spain). Utilising Repertory Grid Technique, we found that the SME owner–managers’ mental models show a few commonalities as well as a number of differences across the different country samples. We interpret those differences by linking individual cognition to macro-environmental variables, such as language, national traditions and dissemination mechanisms. The results of our exploratory study show that nationality matters but that classifications of countries as found in the comparative capitalism literature do not exactly mirror national differences in CSR cognition and that these classifications need further differentiation. The findings from our study raise questions on the universality of cognition of academic management concepts and warn that promotion of responsible business practice should not rely on the use of unmediated US American management terminology

Clinical trial readiness to solve barriers to drug development in FSHD (ReSolve): protocol of a large, international, multi-center prospective study

Background Facioscapulohumeral muscular dystrophy (FSHD) is a dominantly-inherited progressive muscular dystrophy caused by de-repression of the DUX4 gene, which causes disease by a toxic-gain-of-function. As molecularly targeted drugs move from preclinical testing into human trials, it is essential that we validate clinical trial tools and methodology to facilitate the drug development process. Methods/design The primary goal of this study is to hasten drug development for FSHD by validating two novel clinical outcome assessments (COAs) and refining clinical trial strategies. We will perform an 18-month longitudinal study in 220 genetically confirmed and clinically affected participants using our FSHD Clinical Trial Research Network, comprised of 8 sites in the United States, and 3 collaborating sites in Europe. Visits occur at baseline and months 3, 12, and 18. At each visit we will collect: 1) a novel FSHD functional composite COA made up of 18 evaluator-administered motor tasks in the domains of shoulder/arm, hand, core/abdominal, leg, and balance function; and 2) electrical impedance myography as a novel muscle quality biomarker (US sites). Other COAs include 1) Domain 1 of the Motor Function Measure; 2) Reachable workspace; 3) orofacial strength using the Iowa Oral Performance Instrument; 4) lean muscle mass using dual-energy X-ray absorptiometry (DEXA); 5) strength as measured by quantitative myometry and manual muscle testing; and 6) the FSHD Health Index and other patient-reported outcomes. Plasma, DNA, RNA, and serum will be collected for future biomarker studies. We will use an industry standard multi-site training plan. We will evaluate the test-retest reliability, validity, and sensitivity to disease progression, and minimal clinically important changes of our new COAs. We will assess associations between demographic and genetic factors and the rate of disease progression to inform refinement of eligibility criteria for future clinical trials. Discussion To the best of our knowledge, this is the largest collaborative study of patients with FSHD performed in the US and Europe. The results of this study will enable more efficient clinical trial design. During the conduct of the study, relevant data will be made available for investigators or companies pursuing novel FSHD therapeutics