Papel de la alteración del proceso de splicing en la aparición de enfermedades endocrino-metabólicas y patologías tumorales

Global human health is currently threatened by highly prevalent diseases such as obesity, diabetes and cancer. A common hallmark shared by these endocrine-metabolic and tumor diseases is the consistent alteration of the normal splicing process, which leads to the presence of aberrant mRNA variants. Splicing represents an essential biological process by which the introns of an immature pre-mRNA are excised and the exons are fused to generate mature mRNAs capable to be translated into functional proteins. However, most eukaryotic genes can also undergo alternative splicing, which is a physiologic process that allows eukaryotic organisms to exponentially increase the number of transcripts generated from a given gene. During the process of alternative splicing, the coding and non-coding regions of a gene are reorganized in order to generate different mRNA variants. Unfortunately, dysregulations of this process are associated to the appearance of diverse protein isoforms that could exhibit strong pathological potential. In this sense, it should be noted that the control of the appropriate RNA expression and the generation of the correct splicing variants and their homeostasis is mainly regulated by the spliceosome, a complex cellular machinery comprised by ribozymes and associated proteins (splicing factors) that dynamically interact to catalyze the splicing process. The appropriate functioning of this cellular machinery is essential to maintain the cellular, tissue and body homeostasis and, therefore, the dysregulation of this process has been associated to different diseases, including endocrine-metabolic and tumor pathologies. For these reasons, alterations in the splicing process could represent a novel source for the identification of diagnostic, prognostic and therapeutic targets in highly prevalent and healththreatening diseases such as endocrine-metabolic pathologies (obesity and diabetes) and cancer. To explore this promising research avenue, different experimental and methodological approaches have been implemented in the present Doctoral Thesis. First, to determine the relationship between the dysregulation of the splicing machinery components and the development of type 2 diabetes mellitus (T2DM), the expression pattern of selected components of this machinery was determined in the peripheral blood mononuclear cell (PBMCs) of individuals at high risk of T2DM development, under fasting and postprandial conditions. This approach showed that the expression levels of key splicing machinery components was altered in the PBMCs from individuals that developed T2DM compared with non-T2DM controls (patients that did not develop T2DM during the 5 years of follow-up). The molecular fingerprints comprised by the fasting and the postprandial levels of certain of these splicing machinery components were capable to predict the future development of T2DM in individual patients with high precision, outperforming the capacity of classical predictors of T2DM development, such as HbA1c or FINDRISK, and could become a valuable, non-invasive, new tool for early risk assessment of T2DM. In this scenario, it has been shown that the risk of T2DM may be reduced or even reversed with healthy dietary interventions; however, the molecular mechanisms underlying this association are still to be elucidated. Since the studies derived from this Thesis have demonstrated that the expression pattern of the splicing machinery is associated with the risk of T2DM development, we aimed to further evaluate the influence of a 3-years dietary intervention in the expression pattern of the splicing machinery components in PBMCs from the same group of individuals at high risk of T2DM development. In particular, the expression pattern of the splicing machinery components was determined, after 3-years of follow-up, in PBMCs from all patients who developed T2DM (n=107) and from 108 randomly selected non-T2DM patients. These patients were randomly enrolled in two healthy dietary interventions (Mediterranean or Low-Fat Diet). The results indicated that a long-term dietary intervention, regardless of the type of diet (Mediterranean or low-fat), influences the expression levels of key components of the splicing machinery (overexpression of SPFQ, RMB45, RNU6, etc. or decrease expression of RNU2 o SRSF6). It was also noted that some of these changes in the expression levels of components of the splicing machinery were induced differentially between those patients who developed T2DM and those patients who did not develop T2DM after five years of follow-up. Therefore, this study suggest that a long-term dietary intervention could modulate the expression levels of key components of the splicing machinery in PBMCs of patients at high risk of developing T2DM, and that such changes would be clearly differential in patients who end up developing T2DM and those patients who do not develop T2DM after five years of follow-up, which could be used as a valuable tool to monitor the progression of T2DM. Due to the rising prevalence of obesity and T2DM, non-alcoholic fatty liver disease (NAFLD) is rapidly emerging as an important and growing health issue in western countries. In an attempt to determine the possible relationship between the dysregulation of the splicing machinery components and the development of NAFLD, the expression pattern of the components of the splicing machinery was measured in liver biopsies from obese patients with different degrees of liver steatosis that underwent bariatric surgery. This experimental approach shown that the liver of steatotic obese patients exhibited an overt but differential (patientdependent) alteration of the cellular machinery responsible for the regulation of the splicing process. The expression pattern of the spliceosome components and splicing factors analyzed herein was not associated with the grade of hepatic steatosis but seemed to identify three discrete molecularly defined subpopulations of steatotic obese patients characterized by the dysregulated expression of certain spliceosome components and splicing factors. Remarkably, these subpopulations presented specific clinical characteristics and also a differential response to bariatric surgery after one year of follow-up. The fact that these spliceosome alterations were not associated with the grade of hepatic steatosis suggests their role as triggers for initiating fat deposition within the liver. Indeed, an in vitro approach suggested that alterations in splicing machinery components could precede the development of hepatic steatosis. These findings shed light to the possible underlying molecular mechanisms responsible for the development of hepatic steatosis in obese patients and provide novel information to explore the development of efficient screening strategies, diagnostic, prognostic or therapeutic tools for obesity-related NAFLD. Finally, to further expand our knowledge on the pathological interplay between aberrant splicing processes and cancer, a more profound characterization of the oncogenic role of the truncated receptor SST5TMD4 on endocrine-related cancers was performed. Specifically, the functional and mechanistic consequences of the SST5TMD4-specific, splicing-derived C-terminal domain were evaluated in different cancer cells types. First, an in silico analysis revealed the existence of two putative cleavage sites for matrix metalloproteases (MMPs) in the SST5TMD4 Cterminal extracellular domain, which could be the substrate for MMP2, 9 and 14 and/or MMP16, respectively, to generate three derived peptides with 7, 10 and 17 aminoacids. These three SST5TMD4-derived peptides were capable to enhance the malignant characteristics of multiple cancer cell lines derived from diverse tumor pathologies (neuroendocrine tumor, breast, prostate and liver cancer); however, some of these actions seemed to exhibit different dynamics (i.e. proliferation rate) or, even, be cell-line dependent (i.e. migration or tumorosphere formation). In any case, this study demonstrate that the three derived peptides were able to increase tumor malignancy likely through the activation of PI3K/AKT and/or of MEK/ERK pathways and by the modulation key pro-oncogenic genes. Therefore, this study suggests that peptides derived from the spliced SST5TMD4 receptor could contribute to the strong oncogenic role of SST5TMD4 previously observed in multiple tumor pathologies, and, therefore, represent potential candidates to identify novel diagnostic, prognostic or therapeutic targets in cancer. Altogether, the results presented in this Doctoral Thesis constitute novel, valuable and germane information supporting the contention that the dysregulation of the splicing process, including the alterations in the spliceosome components, the splicing factors or the surrogate markers of the splicing process, is closely related to the instauration and/or development of several and highly prevalent pathologies such as diabetes, NAFLD or cancer.La obesidad y la diabetes, así como el cáncer representan graves problemas de salud pública en todo el mundo. Una característica común compartida por estas patologías endocrinometabólicas y tumorales es la alteración del proceso normal de splicing, lo cual podría conducir a la presencia de variantes aberrantes de ARNm. En concreto, el splicing es un proceso biológico esencial por el cual los intrones del pre-ARNm son escindidos para unir los exones y generar así ARNs maduros capaces de ser traducidos a proteínas funcionales. Concretamente, la mayoría de genes de organismos eucariotas pueden sufrir procesos de splicing alternativo, el cual constituye un proceso fisiológico que permite a estos organismos aumentar exponencialmente el número de transcritos generados a partir de un mismo gen. Durante el proceso de splicing alternativo, las regiones no codificantes y codificantes de un gen se reorganizan para generar diferentes variantes de ARNm. Desafortunadamente, las desregulaciones de este proceso están asociadas a la aparición de diversas isoformas de splicing aberrantes que pueden exhibir un fuerte potencial patológico. En este sentido, debe tenerse en cuenta que el control de la expresión del ARN y la correcta generación de variantes de splicing, así como su homeostasis, se lleva a cabo por el spliceosoma, una maquinaria celular compleja compuesta por ribozimas y proteínas asociadas (factores de splicing) que interaccionan de forma dinámica para catalizar el proceso de splicing. Por tanto, el funcionamiento apropiado de esta maquinaria celular es esencial para mantener la homeostasis celular, tisular y del organismo y, por ello, la desregulación de este proceso ha sido asociada al desarrollo de diferentes enfermedades, incluyendo las patologías endocrinometabólicas y tumorales. Por este motivo, las alteraciones en el proceso de splicing podrían representar un nuevo campo para el estudio y la identificación de marcadores diagnósticos, pronósticos y dianas terapéuticas en enfermedades tan prevalentes, como las patologías endocrino-metabólicas (obesidad y diabetes) y el cáncer. Para explorar esta prometedora vía de investigación, se han seguido diferentes enfoques experimentales y metodológicos en la presentes Tesis Doctoral. En primer lugar, para determinar la relación entre la desregulación de los componentes de la maquinaria de splicing y el desarrollo de diabetes mellitus tipo 2 (DMT2), se midieron los niveles de expresión de algunos componentes de esta maquinaria en células mononucleares de sangre periférica de pacientes en alto riesgo de desarrollar DMT2, en condiciones tanto de ayuno como postprandiales. Esta aproximación mostró que los niveles de expresión de algunos componentes clave de esta maquinaria estaban alterados en aquellos pacientes que desarrollarían DMT2 en comparación con aquellos pacientes control que no desarrollan la enfermedad durante los 5 años que duraba el estudio. Además, la huella molecular compuesta por los niveles de expresión de estos componentes en ayunas y durante el postprandio, era capaz de predecir con elevada precisión el desarrollo futuro de DMT2 en pacientes individuales, mejorando la capacidad predictora de parámetros clásicos como la hemoglobina glicosilada o el test FINDRISK, lo cual sugería que esta huella podría representar una nueva herramienta no invasiva para la detección temprana del riesgo de desarrollar DMT2. En este contexto, se ha demostrado que el riesgo de desarrollar DMT2 puede reducirse o incluso revertirse como consecuencia de la aplicación de intervenciones dietéticas saludables; sin embargo, los mecanismos moleculares que subyacen a esta asociación están aún por dilucidar. Puesto que los resultados derivados de la presente Tesis han demostrado que el patrón de expresión de la maquinaria de splicing está asociado con el riesgo de desarrollar DMT2, nos propusimos evaluar la influencia de la intervención dietética durante 3 años en el patrón de expresión de la maquinaria de splicing en las células periféricas mononucleares (PBMCs, por sus siglas en inglés) obtenidas de este mismo grupo de pacientes en alto riesgo de desarrollar DMT2. En concreto, el patrón de expresión de los componentes de la maquinaria de splicing se determinó, tras tres años de seguimiento, en las PBMCs de todos los pacientes que desarrollaron DMT2 (n=107) y 108 pacientes que no desarrollaron DMT2, seleccionados aleatoriamente. Estos pacientes fueron asignados aleatoriamente en dos grupos dietéticos saludables, dieta mediterránea o dieta baja en grasa. Los resultados indicaron que la intervención dietética, independientemente del tipo (dieta mediterránea o baja en grasa), modula los niveles de expresión de componentes clave de la maquinaria de splicing (sobreexpresión de SPFQ, RMB45, RNU6, etc. o disminución de RNU2 o SRSF6). También se observó que algunos de estos cambios en los niveles de expresión de componentes de la maquinaria de splicing fueron inducidos diferencialmente entre aquellos pacientes que desarrollaron DMT2 y aquellos acientes que no la desarrollaron tras cinco años de seguimiento. Por tanto, este estudio sugeriría que una intervención dietética a largo plazo podría modular los niveles de expresión de componentes clave de la maquinaria de splicing en células mononucleares de sangre periférica de pacientes en alto riesgo de desarrollar DMT2, y que dichos cambios serían claramente diferenciales en pacientes que terminan desarrollando DMT2 y aquellos pacientes que no la desarrollan tras cinco años de seguimiento, lo que podría utilizarse como en una herramienta valiosa para monitorizar la progresión de DMT2. Debido a la creciente prevalencia de la obesidad y la DMT2, la enfermedad de hígado graso no alcohólico (NAFLD, por sus siglas en inglés) está emergiendo rápidamente como un problema de salud grave en los países occidentales. Para determinar la posible relación entre la desregulación de la maquinaria reguladora del splicing y el desarrollo de NAFLD, se analizó el patrón de expresión de los componentes del spliceosoma y factores de splicing en biopsias de hígado de pacientes obesas con diferentes grados de esteatosis hepática que fueron sometidas a cirugía bariátrica. Los resultados de esta aproximación mostraron que el hígado de las pacientes obesas con esteatosis presentaba una alteración manifiesta pero diferencial (dependiente del paciente) de la maquinaria celular responsable de la regulación del proceso de splicing. Concretamente, el patrón de expresión de los componentes del spliceosoma y los factores de splicing analizados no se asoció con el grado de esteatosis hepática, pero identificó tres subpoblaciones de pacientes con esteatosis molecularmente definidas y caracterizadas por la expresión alterada de ciertos componentes del spliceosoma y factores de splicing. Cabe destacar, que estas subpoblaciones presentaban características clínicas específicas, así como una respuesta diferencial a la cirugía bariátrica después de un año de seguimiento. El hecho de que estas alteraciones del spliceosoma no estuvieran asociadas con el grado de esteatosis sugiere su papel como esencadenante del inicio de la acumulación de grasa en el hígado. De hecho, una aproximación in vitro indicó que las alteraciones en los componentes de la maquinaria de splicing podrían preceder al desarrollo de la esteatosis hepática. Estos resultados arrojan luz sobre los posibles mecanismos moleculares subyacentes al desarrollo de la esteatosis hepática en pacientes obesos y proporcionan información novedosa para explorar el desarrollo de estrategias de diagnóstico, pronóstico o herramientas terapéuticas eficaces para el NAFLD. Por último, para ampliar el conocimiento sobre la interacción patológica entre los procesos de splicing aberrantes y el cáncer, se realizó una caracterización del papel oncogénico del receptor truncado SST5TMD4 en patologías tumorales endocrinas. En concreto, se evaluaron las consecuencias funcionales del posible procesamiento proteolítico del dominio C-terminal de esta variante de splicing aberrante del receptor SST5 en diferentes tipos celulares representativos de estas patologías tumorales. Específicamente, un análisis in silico reveló la existencia de dos sitios de corte para metaloproteasas de matriz (MMP) en el dominio C-terminal extracelular de la variante de splicing SST5TMD4, que podrían ser utilizados por MMP2, 9 y 14 y/o MMP16, respectivamente, para generar tres péptidos con 7, 10 y 17 aminoácidos. El tratamiento con estos tres péptidos fueron capaces de aumentar parámetros funcionales de agresividad en diferentes líneas celulares derivadas de distintas patologías tumorales (tumores neuroendocrinos, cáncer de mama, próstata e hígado); sin embargo, algunas de estas acciones parecían ejercer diferentes dinámicas, como es el caso de la proliferación celular, o, incluso, ser dependiente de la línea celular, como ocurrió con la migración o la formación de tumorosferas. En cualquier caso, los tres péptidos aumentaron de forma general las características de malignidad de dichas líneas celulares tumorales, probablemente a través de la activación de las rutas PI3K/AKT y/o MEK/ERK y la modulación de genes pro-oncogénicos clave. Este estudio sugiere que los péptidos derivados del receptor truncado SST5TMD4 podrían contribuir al fuerte papel oncogénico de este receptor, observado previamente en múltiples patologías tumorales y, por lo tanto, representan posibles candidatos para identificar nuevas dianas diagnósticas, pronosticas o terapéuticas en el cáncer. En conjunto, los resultados presentados en esta Tesis Doctoral constituyen una información novedosa y valiosa que respalda la idea de que la desregulación del proceso de splicing, tanto las alteraciones en los componentes del spliceosoma y los factores de splicing, como en las variantes resultantes de dicho proceso, está estrechamente relacionada con la instauración y/o el desarrollo de diversas patologías relevantes como la diabetes, el hígado graso o el cáncer

Quantification of Total Phenolic and Carotenoid Content in Blackberries (Rubus Fructicosus L.) Using Near Infrared Spectroscopy (NIRS) and Multivariate Analysis

A rapid method to quantify the total phenolic content (TPC) and total carotenoid content (TCC) in blackberries using near infrared spectroscopy (NIRS) was carried out aiming to provide reductions in analysis time and cost for the food industry. A total of 106 samples were analysed using the Folin-Ciocalteu method for TPC and a method based on Ultraviolet-Visible Spectrometer for TCC. The average contents found for TPC and TCC were 24.27 mg·g−1 dw and 8.30 µg·g−1 dw, respectively. Modified partial least squares (MPLS) regression was used for obtaining the calibration models of these compounds. The RPD (ratio of the standard deviation of the reference data to the standard error of prediction (SEP)) values from external validation for both TPC and TCC were between 1.5 < RPDp < 2.5 and RER values (ratio of the range in the reference data to SEP) were 5.92 for TPC and 8.63 for TCC. These values showed that both equations were suitable for screening purposes. MPLS loading plots showed a high contribution of sugars, chlorophyll, lipids and cellulose in the modelling of prediction equations

Physicochemical Characterization and Biological Activities of Black and White Garlic: In Vivo and In Vitro Assays

White and three types of black garlic (13, 32, and 45 days of aging, named 0C1, 1C2, and 2C1, respectively) were selected to study possible differences in their nutraceutic potential. For this purpose, garlic were physicochemically characterized (Brix, pH, aW, L, polyphenol, and antioxidant capacity), and both in vivo and in vitro assays were carried out. Black garlic samples showed higher polyphenol content and antioxidant capacity than the white ones. The biological assays showed that none of the samples (neither raw nor black garlic) produced toxic effects in the Drosophila melanogaster animal genetic model, nor exerted protective effects against H2O2, with the exception of the 0C1 black garlic. Moreover, only white garlic was genotoxic at the highest concentration. On the other hand, 0C1 black garlic was the most antigenotoxic substance. The in vivo longevity assays showed significant extension of lifespan at some concentrations of white and 0C1and 1C2 black garlic. The in vitro experiments showed that all of the garlic samples induced a decrease in leukemia cell growth. However, no type of garlic was able to induce proapoptotic internucleosomal DNA fragmentation. Taking into account the physicochemical and biological data, black garlic could be considered a potential functional food and used in the preventive treatment of age-related diseases. In addition, our findings could be relevant for black-garlic-processing agrifood companies, as the economical and timing costs can significantly be shortened from 45 to 13 days of aging

Pre-Roman and Republican amphorae (III-I centuries b.C.) from production contexts of the Guadalquivir Basin: technical and compositional characterization

El presente trabajo aporta una investigación arqueométrica sobre piezas cerámicas de los siglos III-I a. C. halladas en contextos alfareros de la ciudad de Sevilla (Palacio Arzobispal)y Carmona (zona del Arrabal), pertenecientes en su mayoría a ánforas de tradición púnica y turdetana, o bien ya romanizadas. Entre los principales objetivos se ha pretendido su caracterización tecnológica y composicional, la comparación de las características de cada tradición productiva y la confirmación de la posible procedencia local de estas producciones. En total, han sido 13 las muestras estudiadas con análisis petrográfico de láminas delgadas, análisis químico mediante fluorescencia de rayos X y análisis mineralógico por difracción de rayos X. Los resultados químicos muestran su carácter sílicoaluminoso y cálcico, con contenidos variables de óxido de hierro, así como otros elementos minoritarios y trazas. El tratamiento estadístico ha diferenciado 3 conglomerados y una muestra que se distingue del resto. El análisis mineralógico ha identificado 8 fases cristalinas, unas ya presentes en las materias primas y otras formadas por tratamiento térmico. Destacan la illita, identificada como fase deshidroxilada, anortita, diópsido y gehlenita. En cuanto al análisis petrográfico, se han identificado tres grupos petrográficos que se corresponden composicionalmente con el contexto de origen de las muestras, diferenciando entre las pie-zas procedentes de Sevilla, las formas romanizadas de Carmona y la cerámica común y formas de imitación de este mismo enclave.The present work consists of an archaeometric investigation concerning ceramic samples, mostly unpublished, of the III-I centuries b.C. They were found in connection with kilns of the city of Sevilla (Archbishop's Palace) and the countryside (Arrabal zone, Carmona). They are identified with evolved variations of Iron Age amphorae of Punic and Turdetanian tradition, or already Roman typologies. The main objectives of this research include their technological and compositional characterization as well as the comparison of the characteristics of each manufacture tradition. An assemblage of 13 samples has been studied through petrographic analysis of thin sections, chemical analysis (X-ray fluorescence) and mineralogical analysis (X-ray diffraction). The chemical results showed the silico-aluminous and calcitic character of the samples, with variable contents of iron oxide as well as other minor elements and traces. The statistical treatment of the data by multivariant analysis has differentiated 3 conglomerates and one sample as an outsider. The mineralogical analysis has identified 8 crystalline phases, several of them already present in the raw materials and others formed by thermal treatment. It is interesting to note the illite, identified as dehydroxylated phase, anorthite, diopside and gehlenite. The petrographical analysis has identified 3 different petro-groups, which are correlated by a compositional point of view with the original context of the samples. Thus, according to these results, it has been possible to distinguish the manufactures of Sevilla from the Roman shapes, the common ware and the imitation types of Carmona. It has been discussed the possible solid-state reactions which yielded the crystalline phases identified by X-ray diffraction, besides an estimation of firing temperatures between 820-850 °C in an oxidant atmosphere. Finally, the possible sources for the raw materials used in the fabrication of these amphorae have been proposed in the Guadalquivir River valley, considering their illitic-calcitic characteristics

Detection of environmental SARS-CoV-2 RNA in a high prevalence setting in Spain.

Since March 2020, Spain (along with many other countries) has been severely affected by the ongoing coronavirus disease 19 (COVID-19) pandemic caused by the rapid spread of a new virus (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2). As part of global efforts to improve disease surveillance, we investigated how readily SARS-CoV-2 RNA could be detected in environmental samples collected from an isolated rural community in Spain with a high COVID-19 prevalence (6% of the population of 883 inhabitants). The first diagnosis of COVID-19-compatible symptoms in the village was recorded on 3 March 2020, and the last known active case resolved on 5 June 2020. By 15 May, two months after strict movement constraints were imposed ('lockdown'), and the cumulative number of symptomatic cases had increased to 53. Of those cases, 22 (41%) had been tested and confirmed by RT-PCR. On 13 May and 5 June, samples were collected from high-use surfaces and clothes in the homes of 13 confirmed cases, from surfaces in nine public service sites (e.g. supermarket and petrol station) and from the wastewater of the village sewage system. SARS-CoV-2 RNA was detected in 7 of 57 (12%) samples, including three households and three public sites. While there is not yet sufficient evidence to recommend environmental surveillance as a standard approach for COVID-19 epidemiology, environmental surveillance research may contribute to advance knowledge about COVID-19 by further elucidating virus shedding dynamics and environmental contamination, including the potential identification of animal reservoirs.S

Dietary Intervention Modulates the Expression of Splicing Machinery in Cardiovascular Patients at High Risk of Type 2 Diabetes Development: From the CORDIOPREV Study

Type-2 diabetes mellitus (T2DM) has become a major health problem worldwide. T2DM risk can be reduced with healthy dietary interventions, but the precise molecular underpinnings behind this association are still incompletely understood. We recently discovered that the expression profile of the splicing machinery is associated with the risk of T2DM development. Thus, the aim of this work was to evaluate the influence of 3-year dietary intervention in the expression pattern of the splicing machinery components in peripheral blood mononuclear cells (PBMCs) from patients within the CORDIOPREV study. Expression of splicing machinery components was determined in PBMCs, at baseline and after 3 years of follow-up, from all patients who developed T2DM (Incident-T2DM, n = 107) and 108 randomly selected non-T2DM subjects, who were randomly enrolled in two healthy dietary patterns (Mediterranean or low-fat diets). Dietary intervention modulated the expression of key splicing machinery components (i.e., up-regulation of SPFQ/RMB45/RNU6, etc., down-regulation of RNU2/SRSF6) after three years, independently of the type of healthy diet. Some of these changes (SPFQ/RMB45/SRSF6) were associated with key clinical features and were differentially induced in Incident-T2DM patients and non-T2DM subjects. This study reveals that splicing machinery can be modulated by long-term dietary intervention, and could become a valuable tool to screen the progression of T2DM

BiFiSo-CSIC: balance de una lucha multidisciplinar contra la pandemia

En marzo de 2020 se declaró el estado de emergencia en España a raíz de una pandemia causada por el virus llamado SARS-CoV-2. La enfermedad, denominada COVID-19, produce una gran letalidad en personas de edad avanzada. Estas excepcionales circunstancias dictaron medidas inéditas en nuestro país: confinamiento domiciliario, cierre de colegios y comercios no esenciales. El Consejo Superior de Investigaciones Científicas (CSIC) reaccionó de inmediato: recién iniciado el confinamiento todos los investigadores de esta institución fueron convocados para dedicar parte de su tiempo a investigar sobre la pandemia. La respuesta fue instantánea y personas de todas las áreas de investigación se brindaron a contribuir con su granito de arena. Lo que al principio iba a suponer una media del 20% del tiempo de cada investigador pasó a ocupar toda la jornada: y así hasta hoy. En este contexto surge el proyecto BiFiSo, en el cual desde la biología, la filosofía o la antropología hemos estudiado y explicado la pandemia, complementando mutuamente la visión de nuestras respectivas especialidades.Consejo Superior de Investigaciones Científicas aporta financiación como institución fundacional de The Conversation ES. Universidad de Málaga aporta financiación como institución colaboradora de The Conversation ES.Peer reviewe

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research