miR-873-5p targets mitochondrialGNMT-Complex II interface contributing tonon-alcoholic fatty liver disease

Objective:Non-alcoholic fatty liver disease (NAFLD) is a complex pathology in which several dysfunctions, including alterations in metabolicpathways, mitochondrial functionality and unbalanced lipid import/export, lead to lipid accumulation and progression to inflammation andfibrosis.The enzyme glycine N-methyltransferase (GNMT), the most important enzyme implicated in S-adenosylmethionine catabolism in the liver, isdownregulated during NAFLD progression. We have studied the mechanism involved in GNMT downregulation by its repressor microRNA miR-873-5p and the metabolic pathways affected in NAFLD as well as the benefit of recovery GNMT expression.Methods:miR-873-5p and GNMT expression were evaluated in liver biopsies of NAFLD/NASH patients. Differentin vitroandin vivoNAFLD murinemodels were used to assess miR-873-5p/GNMT involvement in fatty liver progression through targeting of the miR-873-5p as NAFLD therapy.Results:We describe a new function of GNMT as an essential regulator of Complex II activity in the electron transport chain in the mitochondria.In NAFLD, GNMT expression is controlled by miR-873-5p in the hepatocytes, leading to disruptions in mitochondrial functionality in a preclinicalmurine non-alcoholic steatohepatitis (NASH) model. Upregulation of miR-873-5p is shown in the liver of NAFLD/NASH patients, correlating withhepatic GNMT depletion. Importantly, NASH therapies based on anti-miR-873-5p resolve lipid accumulation, inflammation andfibrosis byenhancing fatty acidb-oxidation in the mitochondria. Therefore, miR-873-5p inhibitor emerges as a potential tool for NASH treatment.Conclusion:GNMT participates in the regulation of metabolic pathways and mitochondrial functionality through the regulation of Complex II activityin the electron transport chain. In NAFLD, GNMT is repressed by miR-873-5p and its targeting arises as a valuable therapeutic option for treatment

miR-873-5p targets mitochondrial GNMT-Complex II interface contributing to non-alcoholic fatty liver disease

Objective: Non-alcoholic fatly liver disease (NAFLD) is a complex pathology in which several dysfunctions, including alterations in metabolic pathways, mitochondrial functionality and unbalanced lipid import/export, lead to lipid accumulation and progression to inflammation and fibrosis. The enzyme glycine N-methyltransferase (GNMT), the most important enzyme implicated in S-adenosylmethionine catabolism in the liver, is downregulated during NAFLD progression. We have studied the mechanism involved in GNMT downregulation by its repressor microRNA miR-873-5p and the metabolic pathways affected in NAFLD as well as the benefit of recovery GNMT expression. Methods: miR-873-5p and GNMT expression were evaluated in liver biopsies of NAFLD/NASH patients. Different in vitro and in vivo NAFLD murine models were used to assess miR-873-5p/GNMT involvement in fatty liver progression through targeting of the miR-873-5p as NAFLD therapy. Results: We describe a new function of GNMT as an essential regulator of Complex II activity in the electron transport chain in the mitochondria. In NAFLD, GNMT expression is controlled by miR-873-5p in the hepatocytes, leading to disruptions in mitochondria! functionality in a preclinical murine non-alcoholic steatohepatitis (NASH) model. Upregulation of miR-873-5p is shown in the liver of NAFLD/NASH patients, correlating with hepatic GNMT depletion. Importantly, NASH therapies based on anti-miR-873-5p resolve lipid accumulation, inflammation and fibrosis by enhancing fatty acid beta-oxidation in the mitochondria. Therefore, miR-873-5p inhibitor emerges as a potential tool for NASH treatment. Conclusion: GNMT participates in the regulation of metabolic pathways and mitochondria! functionality through the regulation of Complex II activity in the electron transport chain. In NAFLD, GNMT is repressed by miR-873-5p and its targeting arises as a valuable therapeutic option for treatment. (C) 2019 The Authors. Published by Elsevier GmbH.This work was supported by grants from NIH (US Department of Health and Human services)-R01AT001576 (to S.C.L., J.M.M., and M.L.M.-C.), Ministerio de Economia, Industria y Competitividad: SAF2017-87301-R (to M.L.M.-C.), SAF2015-64352-R (to P.A.), Gobierno Vasco-Departamento de Salud 2013111114 (to M.L.M.-C.), Gobierno Vasco-Departamento de Educacion IT-336-10 (to PA), BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD (M.L.M.-C.), ELKARTEK 2016, Departamento de Industria del Gobierno Vasco (to M.L.M.-C), Asociacion Espanola contra el Cancer (to T.C.D., P.F.-T. and M.L.M.-C.), Mitotherapeutix (to M.L.M.-C.), Daniel Alagille award from EASL (to T.C.D), Fundacion Cientifica de la Asociacion Espanola Contra el Cancer (AECC Scientific Foundation) Rare Tumor Calls 2017 (to M.L.M.-C.), La Caixa Foundation Program (to M.L.M.-C.), Ayudas Fundacion BBVA a Equipos de Investigacion Cientifica 2019 (to M.L.M.-C.). Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III. We thank this work produced with the support of a 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (to M.V.R.). This work was supported by Fonds National de la Recherche Luxembourg and the Deutsche Forschungsgemeinschaft (C12/BM/3975937, FL/997/7-1, Inter "HepmiRSTAT", to I.B. and F.L.). We thank MINECO for the Severo Ochoa Excellence Accreditation (SEV2016-0644)

Synthesis of Monochlorosilyl Derivatives of Dialkyloligothiophenes for Self-Assembling Mono layer Field-Effect Transistors

Unsymmetrical dimethylchlorosilyl-substituted α,α'-dialkylquater-, quinque-, and sexithiophenes were designed and successfully synthesized by a combination of Kumada and Suzuki cross-coupling reactions followed by hydrosilylation. Optimization possibilities of the hydrosilylation of low-soluble linear oligothiophenes by dimethylchlorosilane as well as the nonreactive byproducts formed are described. The molecular structures of the obtained dimethylchlorosilyl-functionalized oligothiophenes were proven by NMR and DCI MS techniques. These compounds were found to be stable and reactive enough, even in the presence of the nonreactive byproducts, to form semiconducting monolayers on dielectric hydroxylated SiO2 surfaces by self-assembly from solution. The semiconducting properties of these oligothiophene SAMs were as good as those of bulk oligothiophenes. This allowed the production of stable, even under ambient conditions, SAMFETs with a mobility of up to 0.04 cm2/(V s) and an on/off ratio up to 1 × 10^8.

A shape tailored gold-conductive polymer nanocomposite as a transparent electrode with extraordinary insensitivity to volatile organic compounds (VOCs)

In this study, the transparent conducting polymer of poly (3,4-ethylenendioxythiophene): poly(styrene sulphonate) (PEDOT:PSS) was nanohybridized via inclusion of gold nanofillers including nanospheres (NSs) and nanorods (NRs). Such nanocomposite thin films offer not only more optimum conductivity than the pristine polymer but also excellent resistivity against volatile organic compounds (VOCs). Interestingly, such amazing properties are achieved in the diluted regimes of the nanofillers and depend on the characteristics of the interfacial region of the polymer and nanofillers, i.e. the aspect ratio of the latter component. Accordingly, a shape dependent response is made that is more desirable in case of using the Au nanorods with a much larger aspect ratio than their nanosphere counterparts. This transparent nanocomposite thin film with an optimized conductivity and very low sensitivity to organic gases is undoubtedly a promising candidate material for the touch screen panel production industry. Considering PEDOT as a known material for integrated electrodes in energy saving applications, we believe that our strategy might be an important progress in the field.Peer reviewe

Occupational Sex Segregation and Management-Level Wages in Germany: What Role Does Firm Size Play?

The paper analyzes the gender pay gap in private-sector management positions based on German panel data and using fixed-effects models. It deals with the effect of occupational sex segregation on wages, and the extent to which wage penalties for managers in predominantly female occupations are moderated by firm size. Drawing on economic and organizational approaches and the devaluation of women's work, we find wage penalties for female occupations in management only in large firms. This indicates a pronounced devaluation of female occupations, which might be due to the longer existence, stronger formalization, or more established old-boy networks of large firms

Isolation in Globalizing Academic Fields: A Collaborative Autoethnography of Early Career Researchers

This study examines academic isolation – an involuntary perceived separation from the academic field to which one aspires to belong, associated with a perceived lack of agency in terms of one’s engagement with the field – as a key challenge for researchers in increasingly globalized academic careers. While prior research describes early career researchers’ isolation in their institutions, we theorize early career researchers’ isolation in their academic fields and reveal how they attempt to mitigate isolation to improve their career prospects. Using a collaborative autoethnographic approach, we generate and analyze a dataset focused on the experiences of ten early career researchers in a globalizing business academic field known as Consumer Culture Theory. We identify bricolage practices, polycentric governance practices, and integration mechanisms that work to enhance early career researchers’ perceptions of agency and consequently mitigate their academic isolation. Our findings extend discussions on isolation and its role in new academic careers. Early career researchers, in particular, can benefit from a deeper understanding of practices that can enable them to mitigate isolation and reclaim agency as they engage with global academic fields

Gender-Specific Occupational Segregation, Glass Ceiling Effects, and Earnings in Managerial Positions: Results of a Fixed Effects Model

The study analyses the gender pay gap in private-sector management positions based on the German Socio-Economic Panel Study (SOEP) for the years 2001-2008. It focuses on occupational gender segregation, and on the effects of this inequality on earnings levels and gender wage differentials in management positions. Our paper is, to our knowledge, the first in Germany to use time-constant unobserved heterogeneity and gender-specific promotion probabilities to estimate wages and wage differentials for persons in managerial positions. The results of the fixed-effects model show that working in a more female job, as opposed to a more male job, affects only women's wages negatively. This result remains stable after controlling for human capital endowments and other effects. Mechanisms of the devaluation of jobs not primarily held by men also negatively affect pay in management positions (evaluative discrimination) and are even more severe for women (allocative discrimination). However, the effect is non-linear; the wage penalties for women occur only in integrated (more equally male/female) jobs as opposed to typically male jobs, and not in typically female jobs. The devaluation of occupations that are not primarily held by men becomes even more evident when promotion probabilities are taken into account. An Oaxaca/Blinder decomposition of the wage differential between men and women in management positions shows that the full model explains 65 percent of the gender pay gap. In other words: Thirty-five percent remain unexplained; this portion reflects, for example, time-varying social and cultural conditions, such as discriminatory policies and practices in the labor market