SUMOylation regulates LKB1 localization and its oncogenic activity in liver cancer

BACKGROUND: Even though liver kinase B1 (LKB1) is usually described as a tumor suppressor in a wide variety of tissues, it has been shown that LKB1 aberrant expression is associated with bad prognosis in Hepatocellular Carcinoma (HCC). METHODS: Herein we have overexpressed LKB1 in human hepatoma cells and by using histidine pull-down assay we have investigated the role of the hypoxia-related post-translational modification of Small Ubiquitin-related Modifier (SUMO)ylation in the regulation of LKB1 oncogenic role. Molecular modelling between LKB1 and its interactors, involved in regulation of LKB1 nucleocytoplasmic shuttling and LKB1 activity, was performed. Finally, high affinity SUMO binding entities-based technology were used to validate our findings in a pre-clinical mouse model and in clinical HCC. FINDINGS: We found that in human hepatoma cells under hypoxic stress, LKB1 overexpression increases cell viability and aggressiveness in association with changes in LKB1 cellular localization. Moreover, by using site-directed mutagenesis, we have shown that LKB1 is SUMOylated by SUMO-2 at Lys178 hampering LKB1 nucleocytoplasmic shuttling and fueling hepatoma cell growth. Molecular modelling of SUMO modified LKB1 further confirmed steric impedance between SUMOylated LKB1 and the STe20-Related ADaptor cofactor (STRADα), involved in LKB1 export from the nucleus. Finally, we provide evidence that endogenous LKB1 is modified by SUMO in pre-clinical mouse models of HCC and clinical HCC, where LKB1 SUMOylation is higher in fast growing tumors. INTERPRETATION: Overall, SUMO-2 modification of LKB1 at Lys178 mediates LKB1 cellular localization and its oncogenic role in liver cancer. FUND: This work was supported by grants from NIH (US Department of Health and Human services)-R01AR001576-11A1 (J.M.M and M.L.M-C.), Gobierno Vasco-Departamento de Salud 2013111114 (to M.L.M.-C), ELKARTEK 2016, Departamento de Industria del Gobierno Vasco (to M.L.M.-C), MINECO: SAF2017-87301-R and SAF2014-52097-R integrado en el Plan Estatal de Investigación Cientifica y Técnica y Innovación 2013-2016 cofinanciado con Fondos FEDER (to M.L.M.-C and J.M.M., respectively), BFU2015-71017/BMC MINECO/FEDER, EU (to A.D.Q. and I.D.M.), BIOEF (Basque Foundation for Innovation and Health Research): EITB Maratoia BIO15/CA/014; Instituto de Salud Carlos III:PIE14/00031, integrado en el Plan Estatal de Investigación Cientifica y Técnica y Innovacion 2013-2016 cofinanciado con Fondos FEDER (to M.L.M.-C and J.M.M), Asociación Española contra el Cáncer (T.C.D, P·F-T and M.L.M-C), Daniel Alagille award from EASL (to T.C.D), Fundación Científica de la Asociación Española Contra el Cancer (AECC Scientific Foundation) Rare Tumor Calls 2017 (to M.L.M and M.A), La Caixa Foundation Program (to M.L.M), Programma di Ricerca Regione-Università 2007-2009 and 2011-2012, Regione Emilia-Romagna (to E.V.), Ramón Areces Foundation and the Andalusian Government (BIO-198) (A.D.Q. and I.D.M.), ayudas para apoyar grupos de investigación del sistema Universitario Vasco IT971-16 (P.A.), MINECO:SAF2015-64352-R (P.A.), Institut National du Cancer, FRANCE, INCa grant PLBIO16-251 (M.S.R.), MINECO - BFU2016-76872-R to (E.B.). Work produced with the support of a 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (M.V-R). Finally, Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III. We thank MINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644). Funding sources had no involvement in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication

La actividad empresarial respetando los derechos humanos: una oportunidad para tod@s

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Cytochrome c signalosome in mitochondria

Cytochrome c delicately tilts the balance between cell life (respiration) and cell death (apoptosis). Whereas cell life is governed by transient electron transfer interactions of cytochrome c inside the mitochondria, the cytoplasmic adducts of cytochrome c that lead to cell death are amazingly stable. Interestingly, the contacts of cytochrome c with its counterparts shift from the area surrounding the heme crevice for the redox complexes to the opposite molecule side when the electron flow is not necessary. The cytochrome c signalosome shows a higher level of regulation by post-translational modifications—nitration and phosphorylation—of the hemeprotein. Understanding protein interfaces, as well as protein modifications, would puzzle the mitochondrial cytochrome c-controlled pathways out and enable the design of novel drugs to silence the action of pro-survival and pro-apoptotic partners of cytochrome c.Spanish Ministry of Science and Innovation BFU2009-07190Andalusian Government BIO198 P08-CVI-387

Research trends in occupational health and social responsibility: A bibliometric analysis

Occupational Health & Safety (OHS) and Corporate Social Responsibility (CSR) are domains of research char- acterised by a great complexity due to their interdisciplinary nature. Although the interest in Occupational Health & Safety issues in the context of Corporate Social Responsibility has recently increased, more effort is needed to address the complexity of both research areas and to understand the dynamic and implications of their relationship. This research describes and analyses the state of the art in the literature and potential areas for further research regarding OHS and CSR. In total, 289 articles published between 1995 and 2018 related to both CSR and OHS were identified in the most reliable database, Web of Science Core Collection. The publications cover 932 authors, 142 journals, 53 countries or territories and 489 institutions, which include 313 universities in the entire world. We employ bibliometric methods to describe the evolution of publication activity, the most relevant contributors, the methodologies applied as well as the content of the articles in order to examine the main topics and research trends. Moreover, we explore the mapping of bibliographic coupling, co-word analysis of keywords and clusters analysis, which provides maps of knowledge based on data of bibliographic nature. Our study allows us to identify potential avenues for future research that could be meaningful to advance in the consolidation of CSR as an integral framework to support OHS

Cytochrome c: Surfing Off of the Mitochondrial Membrane on the Tops of Complexes III and IV

The proper arrangement of protein components within the respiratory electron transport chain is nowadays a matter of intense debate, since altering it leads to cell aging and other related pathologies. Here, we discuss three current views-the so-called solid, fluid and plasticity models-which describe the organization of the main membrane-embedded mitochondrial protein complexes and the key elements that regulate and/or facilitate supercomplex assembly. The soluble electron carrier cytochrome c has recently emerged as an essential factor in the assembly and function of respiratory supercomplexes. In fact, a 'restricted diffusion pathway' mechanism for electron transfer between complexes III and IV has been proposed based on the secondary, distal binding sites for cytochrome c at its two membrane partners recently discovered. This channeling pathway facilitates the surfing of cytochrome c on both respiratory complexes, thereby tuning the efficiency of oxidative phosphorylation and diminishing the production of reactive oxygen species. The well-documented post-translational modifications of cytochrome c could further contribute to the rapid adjustment of electron flow in response to changing cellular conditions.Spanish Ministry of Economy and Competitiveness (BFU2015-71017/BMC MINECO/FEDER and PGC2018-096049-B-I00 BIO/BMC MICINN/FEDER, EU

Dimerization model of the C-terminal RNA Recognition Motif of HuR

In PressHuman antigen R (HuR) is a ubiquitous 32kDa protein comprising three RNA Recognition Motifs (RRMs), whose main function is to bind Adenylate and uridylate Rich Elements (AREs) in 3′ UnTranslated Regions (UTRs) of mRNAs. In addition to binding RNA molecules, the third domain (RRM3) is involved in HuR oligomerization and apoptotic signaling. The RRM3 monomer is able to dimerize, with its self-binding affinity being dependent on ionic strength. Here we provide a deeper structural insight into the nature of the encounter complexes leading to the formation of RRM3 dimers by using Brownian Dynamics and Molecular Dynamics. Our computational data show that the initial unspecific encounter follows a downhill pathway until reaching an optimum conformation stabilized by hydrophobic interactions.I.D.-M. wishes to thank the Andalusian Government (P07-CVI-02896, P11-CVI-07216 and BIO198) for financial support.Peer reviewe

Proyecto de Factibilidad para la apertura de una sucursal de la Cooperativa de Ahorro y Crédito Sol de Los Andes en la provincia del Cañar cantón Cañar

El tema de tesis planteado consiste en la elaboración de un Proyecto de factibilidad para la apertura de una sucursal de la Cooperativa de Ahorro y Crédito Sol de los Andes en la provincia del Cañar cantón Cañar. Se ha planteado lo siguiente: cómo influirála investigación en la economía de la cooperativa abordando de esta manera realizar el proyecto. En el trabajo investigativo se ha utilizado varias técnicas como la observación directa dentro del cantón Cañar, investigación de campo para la realización del estudio de mercado, además se revisó material bibliográfico, páginas web que sirvieron para complementar el proyecto. El mercado para la cooperativa de ahorro y crédito Sol de los Andes Ltda. En el Cañar es atractivo y se espera que día a día vaya creciendo, a medida que se dé a conocer las bondades de los productos y servicios financieros con respecto a otros de la localidad. Este proyecto lanzará al mercado del Cañar la nueva marca de productos y servicios financieros “SOL DE LOS ANDES” utilizando una estrategia agresiva de comunicación con la cual se logrará posicionarla en la mente de los socios y clientes de la localidad calidad y buen servicio. Finalmente es recomendable la Utilización de los servicios Financieros de la Cooperativa de Ahorro y crédito Sol de los Andes Ltda. Por ser una actividad amigable con el medioambiente y considerada conservacionista y de bajo impacto ambiental.This study aims the development of a feasibility Project for opening a branch office of the savings and Credit Cooperative Sol de los Andes in te province of Cañar, it belongs to Cañar canton. How can influence the research in addressing the economy of the cooperative? This way do the project. In this research several techniques have been used such as: direct observation whithin the Cañar Canton, field research to the study of market, in addition bibliography, web pages were checked to complement the Project. The marker for savings and loan Sol de los Andes Ltda. In Cañar is attractive and it is expected that daily grows, as it is given to know the benefits of financial products and services with respect to others. This Project will launch the new Brand Cañar financial products and services “SOL DE LOS ANDES” using an aggressive communication strategy which will be achieved in the mind of partners and customers in the local quality and good service. Finally we rwcommend the of financial services cooperative savings and credit Sol de los Andes Ltda. As a friendly activity with enviromental conservation and considérate and low environmental impact

ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs

Cyclin M (CNNM1-4) proteins maintain cellular and body magnesium (Mg2+) homeostasis. Using various biochemical approaches, we have identified members of the CNNM family as direct interacting partners of ADP-ribosylation factor-like GTPase 15 (ARL15), a small GTP-binding protein. ARL15 interacts with CNNMs at their carboxyl-terminal conserved cystathionine-β-synthase (CBS) domains. In silico modeling of the interaction between CNNM2 and ARL15 supports that the small GTPase specifically binds the CBS1 and CNBH domains. Immunocytochemical experiments demonstrate that CNNM2 and ARL15 co-localize in the kidney, with both proteins showing subcellular localization in the endoplasmic reticulum, Golgi apparatus and the plasma membrane. Most importantly, we found that ARL15 is required for forming complex N-glycosylation of CNNMs. Overexpression of ARL15 promotes complex N-glycosylation of CNNM3. Mg2+ uptake experiments with a stable isotope demonstrate that there is a significant increase of 25Mg2+ uptake upon knockdown of ARL15 in multiple kidney cancer cell lines. Altogether, our results establish ARL15 as a novel negative regulator of Mg2+ transport by promoting the complex N-glycosylation of CNNMs.European Joint Program for Rare Diseases (EJPRD2019-40)Spanish Ministry of Science and Innovation and Universities (PGC2018-096049-B-I00)Junta de Andalucía (BIO-198, US-1254317 and US-1257019

Effectiveness of a multiple intervention strategy for the control of the tiger mosquito (Aedes albopictus) in Spain

This study was undertaken to evaluate the effectiveness of four complementary and combined strategies to minimize the presence of the invasive mosquito Aedes albopictus, firmly established in Sant Cugat del Vallès, Catalonia, Spain. A quasi-experimental design including six neighbourhoods was performed in 2008-2009. The abundance of mosquitoes was monitored through ovitraps. The multiple intervention strategy consisted of four actions: source reduction; larvicide treatments (Bacillus thuringiensis israelensis and diflubenzuron); adulticide treatments (alfacipermetrin); and cleaning up uncontrolled landfills. The results showed the number of eggs significantly reduced in the areas with intervention. In 2008, the accumulate median of eggs was 175 and 272 in the intervention and control areas, respectively. In 2009, these medians were 884 and 1668 eggs. In total, 3104 households were visited and 683 people were interviewed. During inspections inside the houses, the cooperation of citizens in 2009 was 16% higher than that in 2008 (95% CI 13-19%). These findings suggest that the strategy was effective in reducing the number of eggs. Citizen cooperation, an essential factor for success, was observed through a high level of collaboration by the home owners, who allowed entry into their private dwellings. This study could be a model for controlling the populations of Ae. albopictus in the Mediterranean region. © 2011 Royal Society of Tropical Medicine and Hygiene.Peer Reviewe

Peculiaridades del funcionamiento no estacionario de un destilador solar

Se ensayó en laboratorio un destilador en condiciones similares a las reales, de calentamiento no estacionario, con el fin de analizar resultados aparentemente anómalos obtenidos en experiencias previas. Se empleó un destilador con calentamiento eléctrico, variando la corriente de manera de reproducir las curvas de calentamiento de agua observadas en un destilador real funcionando en un día claro de invierno. Los resultados muestran que la temperatura del agua, el coeficiente de transferencia térmica y el destilado presentan oscilaciones con frecuencias características, que sugieren un fenómeno de tipo caótico. La profundización del conocimiento de esta característica podría permitir mejorar el diseño de destiladores para optimizar la producción.Essays on a still functioning in conditions similar to real non stationary heating were performed at laboratory with the aim of analysing apparently anomalous previous results. An electrical heated still was employed, varying the electrical current trying to reproduce the heating curves observed in real stills functioning in the open air, in winter clear days. Results show that the temperature of the water, the convective heat transfer coefficient and the production shows oscillations with characteristics frequencies, that suggest a chaotic phenomenon. A deeper knowledge of this characteristic could allow a better design of stills to optimise the production.Asociación Argentina de Energías Renovables y Medio Ambiente (ASADES