Glutathione reductase gsr-1 is an essential gene required for Caenorhabditis elegans early embryonic development

Glutathione is the most abundant thiol in the vast majority of organisms and is maintained in its reduced form by the flavoenzyme glutathione reductase. In this work, we describe the genetic and functional analysis of the Caenorhabditis elegans gsr-1 gene that encodes the only glutathione reductase protein in this model organism. By using green fluorescent protein reporters we demonstrate that gsr-1 produces two GSR-1 isoforms, one located in the cytoplasm and one in the mitochondria. gsr-1 loss of function mutants display a fully penetrant embryonic lethal phenotype characterized by a progressive and robust cell division delay accompanied by an aberrant distribution of interphasic chromatin in the periphery of the cell nucleus. Maternally expressed GSR-1 is sufficient to support embryonic development but these animals are short-lived, sensitized to chemical stress and have increased mitochondrial fragmentation and lower mitochondrial DNA content. Furthermore, the embryonic lethality of gsr-1 worms is prevented by restoring GSR-1 activity in the cytoplasm but not in mitochondria. Given the fact that the thioredoxin redox systems are dispensable in C. elegans, our data support a prominent role of the glutathione reductase/glutathione pathway in maintaining redox homeostasis in the nematode

Role of glutathione reductase in proteostasis regulation

Trabajo presentado en la V Spanish Worm Meeting, celebrada en Salamanca el 5 y 6 de marzo de 2015.Peer Reviewe

Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation

In the presence of aggregation-prone proteins, the cytosol and endoplasmic reticulum (ER) undergo a dramatic shift in their respective redox status, with the cytosol becoming more oxidized and the ER more reducing. However, whether and how changes in the cellular redox status may affect protein aggregation is unknown. Here, we show that C. elegans loss-of-function mutants for the glutathione reductase gsr-1 gene enhance the deleterious phenotypes of heterologous human, as well as endogenous worm aggregation-prone proteins. These effects are phenocopied by the GSH-depleting agent diethyl maleate. Additionally, gsr-1 mutants abolish the nuclear translocation of HLH-30/TFEB transcription factor, a key inducer of autophagy, and strongly impair the degradation of the autophagy substrate p62/SQST-1::GFP, revealing glutathione reductase may have a role in the clearance of protein aggregates by autophagy. Blocking autophagy in gsr-1 worms expressing aggregation-prone proteins results in strong synthetic developmental phenotypes and lethality, supporting the physiological importance of glutathione reductase in the regulation of misfolded protein clearance. Furthermore, impairing redox homeostasis in both yeast and mammalian cells induces toxicity phenotypes associated with protein aggregation. Together, our data reveal that glutathione redox homeostasis may be central to proteostasis maintenance through autophagy regulation.Ministerio de Economía y Competitividad BFU2016–78265-P, BFU2016– 79313-P, MDM-2016–0687, BFU2015–64408-PInstituto de Salud Carlos III PI11/ 00072, CPII16/00004, PI14/00949, PI17/0001

Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation

In the presence of aggregation-prone proteins, the cytosol and endoplasmic reticulum (ER) undergo a dramatic shift in their respective redox status, with the cytosol becoming more oxidized and the ER more reducing. However, whether and how changes in the cellular redox status may affect protein aggregation is unknown. Here, we show that C. elegans loss-of-function mutants for the glutathione reductase gsr-1 gene enhance the deleterious phenotypes of heterologous human, as well as endogenous worm aggregation-prone proteins. These effects are phenocopied by the GSH-depleting agent diethyl maleate. Additionally, gsr-1 mutants abolish the nuclear translocation of HLH-30/TFEB transcription factor, a key inducer of autophagy, and strongly impair the degradation of the autophagy substrate p62/SQST-1::GFP, revealing glutathione reductase may have a role in the clearance of protein aggregates by autophagy. Blocking autophagy in gsr-1 worms expressing aggregation-prone proteins results in strong synthetic developmental phenotypes and lethality, supporting the physiological importance of glutathione reductase in the regulation of misfolded protein clearance. Furthermore, impairing redox homeostasis in both yeast and mammalian cells induces toxicity phenotypes associated with protein aggregation. Together, our data reveal that glutathione redox homeostasis may be central to proteostasis maintenance through autophagy regulation.. The Spanish Ministry of Economy and Competitiveness supported EF-S and VG (BFU2016–78265-P), PA (BFU2016– 79313-P and MDM-2016–0687), and AM-V (BFU2015–64408-P). AM-V was also supported by the Instituto de Salud Carlos III (PI11/ 00072) and RPV-M (CPII16/00004, PI14/00949 and PI17/00011). All projects were cofinanced by the Fondo Social Europeo (FEDER). AM-V is a member of the GENIE and EU-ROS Cost Actions of the European Union and RPV-M is a Marie Curie Fellow (CIG322034, EU)

Protective role of DNJ-27/ERdj5 in Caenorhabditis elegans models of human neurodegenerative diseases

Aims: Cells have developed quality control systems for protection against proteotoxicity. Misfolded and aggregation-prone proteins, which are behind the initiation and progression of many neurodegenerative diseases (ND), are known to challenge the proteostasis network of the cells. We aimed to explore the role of DNJ-27/ERdj5, an endoplasmic reticulum (ER)-resident thioredoxin protein required as a disulfide reductase for the degradation of misfolded proteins, in well-established Caenorhabditis elegans models of Alzheimer, Parkinson and Huntington diseases. Results: We demonstrate that DNJ-27 is an ER luminal protein and that its expression is induced upon ER stress via IRE-1/XBP-1. When dnj-27 expression is downregulated by RNA interference we find an increase in the aggregation and associated pathological phenotypes (paralysis and motility impairment) caused by human β-amyloid peptide (Aβ), α-synuclein (α-syn) and polyglutamine (polyQ) proteins. In turn, DNJ-27 overexpression ameliorates these deleterious phenotypes. Surprisingly, despite being an ER-resident protein, we show that dnj-27 downregulation alters cytoplasmic protein homeostasis and causes mitochondrial fragmentation. We further demonstrate that DNJ-27 overexpression substantially protects against the mitochondrial fragmentation caused by human Aβ and α-syn peptides in these worm models. Innovation: We identify C. elegans dnj-27 as a novel protective gene for the toxicity associated with the expression of human Aβ, α-syn and polyQ proteins, implying a protective role of ERdj5 in Alzheimer, Parkinson and Huntington diseases. Conclusion: Our data support a scenario where the levels of DNJ-27/ERdj5 in the ER impact cytoplasmic protein homeostasis and the integrity of the mitochondrial network which might underlie its protective effects in models of proteotoxicity associated to human ND

Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits

Interleukin 2 (IL-2) is a key homeostatic cytokine, with therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical use has been hampered by pleiotropic functionality and widespread receptor expression, with unexpected adverse events. Here, we developed a novel mouse strain to divert IL-2 production, allowing identification of contextual outcomes. Network analysis identified priority access for Tregs and a competitive fitness cost of IL-2 production among both Tregs and conventional CD4 T cells. CD8 T and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified Tregs, whereas IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+ Tregs and ILC2 cells, the latter driving a downstream, IL-5–mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain adverse effects observed during clinical trials. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability

Protection against Tuberculosis in Eurasian Wild Boar Vaccinated with Heat-Inactivated Mycobacterium bovis

Tuberculosis (TB) caused by Mycobacterium bovis and closely related members of the Mycobacterium tuberculosis complex continues to affect humans and animals worldwide and its control requires vaccination of wildlife reservoir species such as Eurasian wild boar (Sus scrofa). Vaccination efforts for TB control in wildlife have been based primarily on oral live BCG formulations. However, this is the first report of the use of oral inactivated vaccines for controlling TB in wildlife. In this study, four groups of 5 wild boar each were vaccinated with inactivated M. bovis by the oral and intramuscular routes, vaccinated with oral BCG or left unvaccinated as controls. All groups were later challenged with a field strain of M. bovis. The results of the IFN-gamma response, serum antibody levels, M. bovis culture, TB lesion scores, and the expression of C3 and MUT genes were compared between these four groups. The results suggested that vaccination with heat-inactivated M. bovis or BCG protect wild boar from TB. These results also encouraged testing combinations of BCG and inactivated M. bovis to vaccinate wild boar against TB. Vaccine formulations using heat-inactivated M. bovis for TB control in wildlife would have the advantage of being environmentally safe and more stable under field conditions when compared to live BCG vaccines. The antibody response and MUT expression levels can help differentiating between vaccinated and infected wild boar and as correlates of protective response in vaccinated animals. These results suggest that vaccine studies in free-living wild boar are now possible to reveal the full potential of protecting against TB using oral M. bovis inactivated and BCG vaccines

Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation

Trabajo presentado en el VII Spanish Worm Meeting (SWN), celebrado en Castelldefels (Barcelona) el 28 y 29 de marzo de 2019.Peer reviewe

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

Semilleros de Investigación 2013, n.° 28

"Unijus promueve y apoya el desarrollo e implementación de programas y proyectos de investigación que aporten al conocimiento de la realidad nacional e internacional, de las instituciones jurídicas, políticas y sociales, así como de las teorías jurídicas y políticas que contribuyan a la construcción de nuevas propuestas para la solución de las problemáticas que aquejan la sociedad. Por tal motivo, es fundamental el apoyo constante a la formación de semilleros de investigación en la Facultad de Derecho, Ciencias Políticas y Sociales de la Sede Bogotá, así como la consolidación de los semilleros ya existentes. En el año 2013, se desarrollaron las Convocatorias No. 01 y 02 de 2013 para la Selección de Semilleros de Investigación de la Facultad de Derecho, Ciencias Políticas y Sociales. Como resultado de dicho proceso fueron seleccionadas trece propuestas de investigación integradas por un total de 47 estudiantes, quienes a su vez se encontraban vinculados a 7 grupos de investigación.""Presentación Acercamiento a la reforma del Consejo de Seguridad de las Naciones Unidas: Una mirada a las propuestas de México, Argentina y Brasil Reflections on Legal Education: an Approach to the Escuela de Derecho Propio Laureano Inampués Cuatín Iliana Jineth Yepes Acuña, Simón Camilo Hernández Gaona, Paula Alejandra Poveda Cocuy, Francisco Javier Quito Córdoba, Sonia Catalina Villamizar Almeyda Grupo de investigación en Relaciones Internacionales y Asuntos Globales - RIAG Intervención en el Bronx: Análisis descriptivo de una apuesta alternativa en política pública de seguridad humana Intervention in the Bronx: Descriptive Analysis of an alternative bet on Public Policy and human security Ana María Tarazona Galvis, Carolina Cristancho Zarco, Andrés Felipe Espinosa Zuluaga, Fredy Hernando Caro y Sergio Iván González Machetá Grupo de Investigación en Seguridad y Defensa -GISDE Conflictos socioterritoriales en la región Andina Oriental de Colombia: una mirada al campesinado y a las formas contemporáneas de la lucha por la tierra y el territorio Socio-territorial Conflicts in the East Andes Region of Colombia: A glance at the Peasantry and Contemporary Ways of Struggle for Land and Territory Catherine Moore Torres, Julián Eduardo Naranjo Vasco Grupo Interdisciplinario de Estudios Políticos y Sociales - Theseus Territorios, resistencias y espacialidad en la geopolítica de la globalización Territory, Strength and Spatiality in the Geopolitics of Globalization Sindy Katherine Castro Herrera, Camila Andrea Galindo Martínez, Paula Andrea Ricaurte Ávila, Natalia Briceño Hernández, John Freddy Gómez Celi, Ángela Beatriz Torres Tamayo Grupo Interdisciplinario de Estudios Políticos y Sociales - Theseus Territorio y construcción de subjetividades en Bogotá. Transferencias entre lo rural y lo urbano en las localidades de Chapinero, Usme y Ciudad Bolívar Territory and construction of subjectivities in Bogotá. Transfers between the rural and the urban in the localities of Chapinero, Usme and Ciudad Bolívar Javier Alejandro Jiménez González, David Fernando Salamanca Paternina, Diana Paola López Bojacá Grupo de Investigación Presidencialismo y Participación Los jóvenes y la paz: la incógnita de La Habana Young People and Peace: the Unknown of Havana Sara Camila Arias Castañeda, Reina Alejandra Jiménez Díaz, Brahiam Fernando Quintana Martínez, Fernando Villada Agudelo Grupo de investigación Presidencialismo y Participación Análisis jurídico-crítico de la producción normativa en materia ambiental en el período 2003-2013 con énfasis en el Proyecto de reforma al Código Nacional de Recursos Naturales Renovables Legal-Critical Analysis of Legislation Production in Environmental Law in the Period of 2003-2013 with an Emphasis on the National Code of Renewable Natural Resources Diana Sofía Díaz Castro, Natalia Alejandra Rodríguez Vargas, Adriana María Guerrero Arias Grupo de Investigación en Derechos Colectivos y Ambientales - GIDCA Conflictividad ambiental por monocultivos de palma aceitera en Tibú, Norte de Santander Environmental Conflict for Oil Palm Plantations in Tibú, North of Santander José Agustín Labrador Forero, Carlos Eduardo Olaya Díaz Grupo de Investigación en Derechos Colectivos y Ambientales - GIDCA Campañas electorales: lo que se puede y lo que se debería comunicar Electoral Campaigns: what can be communicated and what should be communicated Daniela Alvarado Rincón, Freddy Leonardo González Araque y Augusto Federico Padilla Grupo de investigación Cultura Jurídico Política, Instituciones y Globalización Tratamiento jurídico-social de la obscenidad en Colombia: Aproximación desde la jurisprudencia de la Corte Constitucional Legal and social treatment of obscenity in Colombia: Approximation from the jurisprudence of the Constitutional Court Germán Darío Rodríguez González, Luisa Fernanda Ortiz Rodríguez, Diego Ricardo Cárdenas Nonsoque Grupo de investigación Cultura Jurídico Política, Instituciones y Globalización Mujeres indígenas y prácticas de justicia Indigenous Women and Practices of Justice Luisa María Ocaña Muñoz, Sibelys Katina Mejía Rodríguez, Viviana Patricia López Rubio, Damaris Alejandra Quintero Leyva Grupo de investigación Escuela de Justicia Comunitaria de la Universidad Nacional (EJCUN) Justicia en red: Caminando hacia el empoderamiento y la construcción de ciudadanía para Bogotá Justice in Network: towards the Empowerment and the Construction of Citizenship in Bogotá Alejandra Méndez Molano, Jenny Alejandra Tamayo Tamayo Grupo de investigación Escuela de Justicia Comunitaria de la Universidad Nacional (EJCUN) Reflexiones sobre la educación legal: Una aproximación a la Escuela de Derecho Propio Laureano Inampués Cuatín Reflections on Legal Education: an Approach to the Escuela de Derecho Propio Laureano Inampués Cuatín Krisly Tatiana Amaya Osorio, Juan Sebastián Urdaneta Forero, Miguel Ángel Salas Dorado Grupo de investigación Escuela de Justicia Comunitaria de la Universidad Nacional (EJCUN)