Identification and functional characterization of LNCRNAS Associated with TYPE 1 Diabetes.

216 p.Estudios de asociación de genoma completo han detectado polimorfismos asociados con el riesgo a padecer diabetes de tipo 1 (DM1) en ARN largos no codificantes (lncRNAs). Sin embargo, todavía se desconocen los mecanismos moleculares por los que la mayoría de estos lncRNAs contribuyen al desarrollo de la DM1.Los estudios recogidos en esta tesis doctoral confirman la presencia de lncRNAs implicados en el desarrollo de DM1. Así mismo, se ha realizado la caracterización funcional de 2 de estos lncRNAs; llamados Lnc13 y ARGI. Gracias a estos estudios se demuestra la importancia de estas moléculas no sólo en el funcionamiento celular (en esta tesis centrada en el estudio de las células ß pancreáticas), sino también en el desarrollo de diversas enfermedades como son la diabetes

The Role of lncRNAs in Gene Expression Regulation through mRNA Stabilization

mRNA stability influences gene expression and translation in almost all living organisms, and the levels of mRNA molecules in the cell are determined by a balance between production and decay. Maintaining an accurate balance is crucial for the correct function of a wide variety of biological processes and to maintain an appropriate cellular homeostasis. Long non-coding RNAs (lncRNAs) have been shown to participate in the regulation of gene expression through different molecular mechanisms, including mRNA stabilization. In this review we provide an overview on the molecular mechanisms by which lncRNAs modulate mRNA stability and decay. We focus on how lncRNAs interact with RNA binding proteins and microRNAs to avoid mRNA degradation, and also on how lncRNAs modulate epitranscriptomic marks that directly impact on mRNA stability.LncRNA work in author’s laboratory is supported by European Foundation for the Study of Diabetes (EFSD)-EFSD/JDRF/Lilly Programme on Type 1 Diabetes Research and the Spanish Ministry of Science, Innovation and Universities (PID2019-104475GA-I00) to I.S; and Spanish Ministry of Science, Innovation and Universities (SAF2017-91873-EXP and PGC2018-097573-A-I00) to ACR. M.S.D. and I.G.M. are supported by a Predoctoral Fellowship Grant from the UPV/EHU (Universidad del País Vasco/Euskal Herriko Unibertsitatea) and A.O.G. is supported by a Predoctoral Fellowship Grant from the Education Department of Basque Government

A Multi-Species Analysis Defines Anaplerotic Enzymes and Amides as Metabolic Markers for Ammonium Nutrition

Nitrate and ammonium are the main nitrogen sources in agricultural soils. In the last decade, ammonium (NH4+), a double-sided metabolite, has attracted considerable attention by researchers. Its ubiquitous presence in plant metabolism and its metabolic energy economy for being assimilated contrast with its toxicity when present in high amounts in the external medium. Plant species can adopt different strategies to maintain NH4+ homeostasis, as the maximization of its compartmentalization and assimilation in organic compounds, primarily as amino acids and proteins. In the present study, we report an integrative metabolic response to ammonium nutrition of seven plant species, belonging to four different families: Gramineae (ryegrass, wheat, Brachypodium distachyon), Leguminosae (clover), Solanaceae (tomato), and Brassicaceae (oilseed rape, Arabidopsis thaliana). We use principal component analysis (PCA) and correlations among metabolic and biochemical data from 40 experimental conditions to understand the whole-plant response. The nature of main amino acids is analyzed among species, under the hypothesis that those Asn-accumulating species will show a better response to ammonium nutrition. Given the provision of carbon (C) skeletons is crucial for promotion of the nitrogen assimilation, the role of different anaplerotic enzymes is discussed in relation to ammonium nutrition at a whole-plant level. Among these enzymes, isocitrate dehydrogenase (ICDH) shows to be a good candidate to increase nitrogen assimilation in plants. Overall, metabolic adaptation of different carbon anaplerotic activities is linked with the preference to synthesize Asn or Gln in their organs. Lastly, glutamate dehydrogenase (GDH) reveals as an important enzyme to surpass C limitation during ammonium assimilation in roots, with a disparate collaboration of glutamine synthetase (GS).The design of the study, analysis, and interpretation of data and writing of the manuscript was supported by the Basque Government [IT932-16] or GIC15/179, the Spanish Ministry of Economy and Competitiveness [AGL2015-64582-C3-2-R] and [BIO2017-84035-R]. IVM held a postdoctoral grant from the Basque Government (conv. 2018) and MDLP held a PhD grant by COLCIENCIAS (conv. 672)

Implication of m6A mRNA Methylation in Susceptibility to Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract that develops due to the interaction between genetic and environmental factors. More than 160 loci have been associated with IBD, but the functional implication of many of the associated genes remains unclear. N6-Methyladenosine (m6A) is the most abundant internal modification in mRNA. m6A methylation regulates many aspects of mRNA metabolism, playing important roles in the development of several pathologies. Interestingly, SNPs located near or within m6A motifs have been proposed as possible contributors to disease pathogenesis. We hypothesized that certain IBD-associated SNPs could regulate the function of genes involved in IBD development via m6A-dependent mechanisms. We used online available GWAS, m6A and transcriptome data to find differentially expressed genes that harbored m6A-SNPs associated with IBD. Our analysis resulted in five candidate genes corresponding to two of the major IBD subtypes: UBE2L3 and SLC22A4 for Crohn’s Disease and TCF19, C6orf47 and SNAPC4 for Ulcerative Colitis. Further analysis using in silico predictions and co-expression analyses in combination with in vitro functional studies showed that our candidate genes seem to be regulated by m6A-dependent mechanisms. These findings provide the first indication of the implication of RNA methylation events in IBD pathogenesis.This work was supported by Spanish Ministry of Science, Innovation and Universities (grant PGC2018-097573-A-I00) to A.C.-R. I.S. was funded by research project grant 2015111068 of the Basque Department of Health and a Research Grant from the European Foundation for the Study of Diabetes. M.S.-d. and I.G.-M. are predoctoral fellows funded by grants from the University of Basque Country and A.O.-G. is a predoctoral fellow funded by Basque Department of Education, Universities and Research

A long non-coding RNA that harbors a SNP associated with type 2 diabetes regulates the expression of TGM2 gene in pancreatic beta cells

IntroductionMost of the disease-associated single nucleotide polymorphisms (SNPs) lie in non- coding regions of the human genome. Many of these variants have been predicted to impact the expression and function of long non-coding RNAs (lncRNA), but the contribution of these molecules to the development of complex diseases remains to be clarified. MethodsHere, we performed a genetic association study between a SNP located in a lncRNA known as LncTGM2 and the risk of developing type 2 diabetes (T2D), and analyzed its implication in disease pathogenesis at pancreatic beta cell level. Genetic association study was performed on human samples linking the rs2076380 polymorphism with T2D and glycemic traits. The pancreatic beta cell line EndoC-bH1 was employed for functional studies based on LncTGM2 silencing and overexpression experiments. Human pancreatic islets were used for eQTL analysis. ResultsWe have identified a genetic association between LncTGM2 and T2D risk. Functional characterization of the LncTGM2 revealed its implication in the transcriptional regulation of TGM2, coding for a transglutaminase. The T2Dassociated risk allele in LncTGM2 disrupts the secondary structure of this lncRNA, affecting its stability and the expression of TGM2 in pancreatic beta cells. Diminished LncTGM2 in human beta cells impairs glucose-stimulated insulin release. ConclusionsThese findings provide novel information on the molecular mechanisms by which T2D-associated SNPs in lncRNAs may contribute to disease, paving the way for the development of new therapies based on the modulation of lncRNAs.This work was supported by grants from the Ministerio de Ciencia, Innovación y Universidades (PID2019-104475GA-I00 to I.S, and PGC2018-097573-A-I00 to AC-R) and the European Foundation for the Study of Diabetes (EFSD) - EFSD/JDRF/Lilly Programme on Type 1 Diabetes Research to IS. FO (MS19/00109) is recipient of the Miguel Servet scheme, and AL (FI19/00045) was supported by the Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia, Innovación y Universidades, Gobierno de España (ES). HR-M (PRE2019-089350) is supported by predoctoral grant from the Ministerio de Ciencia, Innovacion y Universidades, Gobierno de España (ES) IG-M, MS-C, JM-S and AO-G were supported by Predoctoral Fellowship Grants from the UPV/EHU (Universidad del Pais Vasco/EuskalHerrikoUnibertsitatea) and the Basque Department of Education. MC is supported by the Fonds National de la RechercheScientifique (FNRS), the Francophone Foundation for Diabetes Research (sponsored by the French Diabetes Federation, Abbott, Eli Lilly, Merck Sharp & Dohme, and Novo Nordisk) and FF and MC by the EFSD/BoehringerIngelheim European Research Programme on Multi-System Challenges in Diabetes. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication

Leer en comunidad: Creación y desarrollo de clubes de lectura dentro y fuera de la Universidad

Depto. de Lengua Española y Teoría de la LiteraturaFac. de FilologíaFALSEsubmitte

Leer en comunidad: creación de clubes de lectura de literatura escrita por mujeres en la universidad

Depto. de Lengua Española y Teoría de la LiteraturaFac. de FilologíaFALSEUniversidad Complutense de Madridsubmitte

LncRNA ARGI Contributes to Virus‐Induced Pancreatic β Cell Inflammation Through Transcriptional Activation of IFN‐Stimulated Genes

Abstract Type 1 diabetes (T1D) is a complex autoimmune disease that develops in genetically susceptible individuals. Most T1D‐associated single nucleotide polymorphisms (SNPs) are located in non‐coding regions of the human genome. Interestingly, SNPs in long non‐coding RNAs (lncRNAs) may result in the disruption of their secondary structure, affecting their function, and in turn, the expression of potentially pathogenic pathways. In the present work, the function of a virus‐induced T1D‐associated lncRNA named ARGI (Antiviral Response Gene Inducer) is characterized. Upon a viral insult, ARGI is upregulated in the nuclei of pancreatic β cells and binds to CTCF to interact with the promoter and enhancer regions of IFNβ and interferon‐stimulated genes, promoting their transcriptional activation in an allele‐specific manner. The presence of the T1D risk allele in ARGI induces a change in its secondary structure. Interestingly, the T1D risk genotype induces hyperactivation of type I IFN response in pancreatic β cells, an expression signature that is present in the pancreas of T1D patients. These data shed light on the molecular mechanisms by which T1D‐related SNPs in lncRNAs influence pathogenesis at the pancreatic β cell level and opens the door for the development of therapeutic strategies based on lncRNA modulation to delay or avoid pancreatic β cell inflammation in T1D

La pizarra digital : motor de renovación pedagógica

Se desarrolla un proyecto de innovación educativa que pretende impulsar la innovación pedagógica y la motivación en el aula mediante el uso adecuado de las Nuevas Tecnologías, lo que supone una renovación de la metodología docente y de los procesos de enseñanza y aprendizaje. Se trata de familiarizar al profesorado con el uso de la Nuevas Tecnologías y de Internet como herramientas educativas útiles en la atención a la diversidad en el alumnado. Se conocen e intercambian experiencias con otros centros y profesorado que utilicen las nuevas Tecnologías en la práctica docente. El proyecto consigue que el alumnado elabore materiales obtenidos de Internet o de otros medios, resuelvan problemas, y realicen la presentación de los mismos a sus compañeros. El proyecto se desarrolla en tres fases: la primera se centra en la formación inicial en la que se realiza una formación técnica del funcionamiento de los nuevos elementos de la pizarra digital y una formación didáctica para que el profesorado realice propuestas didácticas de su materia y se lleve a la práctica; en la segunda fase se desarrolla el proyecto en el aula con el alumnado, cada profesor o profesora realiza las actividades programadas utilizando la pizarra digital y se realiza una encuesta para valorar los resultados de dichas actividades; en la tercera etapa se realiza la recogida de materiales elaborados, se evalúan y se realiza una memoria final en la que se aportan los resultados obtenidos tras la aplicación del proyecto de innovación. La experiencia ha favorecido el aprendizaje del alumnado y ha potenciado el uso por parte de los docentes de metodologías innovadoras que favorezcan los procesos de enseñanza aprendizaje.Castilla y LeónConsejería de Educación. Dirección General de Universidades e Investigación; Monasterio de Nuestra Señora de Prado, Autovía Puente Colgante s. n.; 47071 Valladolid; +34983411881; +34983411939ES

Cost Effectiveness of the 13-Valent Pneumococcal Conjugate Vaccination Program in Chronic Obstructive Pulmonary Disease Patients Aged 50+ Years in Spain

Background: Patients with chronic obstructive pulmonary disease (COPD) are at elevated risk of pneumococcal infection. A 13-valent pneumococcal conjugate vaccine (PCV13) was approved for protection against invasive disease and pneumonia caused by Streptococcus pneumoniae in adults. This study estimated the incremental cost-effectiveness ratio (ICER) of vaccinating COPD patients 50 years old with PCV13 compared with current vaccination policy (CVP) with 23-valent pneumococcal polysaccharide vaccine. Methods: A Markov model accounting for the risks and costs for all-cause non-bacteremic pneumonia (NBP) and invasive pneumococcal disease (IPD) was developed. All parameters, such as disease incidence and costs (; 2015 values), were based on published data. The perspective of the analysis was that of the Spanish National Healthcare System, and the horizon of evaluation was lifetime in the base case. Vaccine effectiveness considered waning effect over time. Outcomes and costs were both discounted by 3 % annually. Results: Over a lifetime horizon and for a 629,747 COPD total population, PCV13 would prevent 2224 cases of inpatient NBP, 3134 cases of outpatient NBP, and 210 IPD extra cases in comparison with CVP. Additionally, 398 related deaths would be averted. The ICER was 1518 per quality-adjusted life-year (QALY) gained for PCV13 versus CVP. PCV13 was found to be cost effective versus CVP from a 5-year modelling horizon (1302 inpatient NBP and 1835 outpatient NBP cases together with 182 deaths would be prevented [ICER 25,573/QALY]). Univariate and probabilistic sensitivity analyses confirmed the robustness of the model. Conclusions: At the commonly accepted willingness-to-pay threshold of 30,000/QALY gained, PCV13 vaccination in COPD patients aged 50 years was a cost-effective strategy compared with CVP from 5 years to lifetime horizon in Spain. © 2015 The Author(s