Relación entre la circulación atmosférica en el Atlántico Norte y las temperaturas máximas en la cuenca del Río Segura

Ponencia presentada en: II Congreso de la Asociación Española de Climatología “El tiempo del clima”, celebrado en Valencia del 7 al 9 de junio de 2001[ES]Se ha estudiado la relación entre la presión a nivel del mar (PNM) y las temperaturas máximas mensuales en la cuenca del río Segura durante los meses invernales (Diciembre, Enero y Febrero). Se han filtrado los datos originales con un análisis de componentes principales, seguidamente se ha realizado un análisis de correlación canónica para obtener los modos de variabilidad acoplados entre la escala local y la gran escala. Los resultados obtenidos a partir de las observaciones son comparados con los proporcionados por los datos de reanálisis de NCEP y las simulaciones del modelo climático de circulación general ECHAM4-0PYC3. Los resultados indican que las relaciones entre la PNM y las temperaturas máximas se mantienen en las tres escalas analizadas.[EN]The relation between sea level pressure (SLP) and monthly maximum temperatures has been studied in the Segura river basin during winter months (December, January y February). The original data have been filtered with a principal component analysis. Subsequently canonical correlation analysis has been carried out to obtain the modes of associated variability between local scale and large scale. The results obtained from the observed data are compared with the data from the NCEP reanalysis and with the simulations of the general circulation climatic model ECHAM4-0PYC3. The results show the relations between SLP and maximum temperatures are maintained in the three analyzed scales

Transcriptome and proteome mapping in the sheep atria reveal molecular featurets of atrial fibrillation progression.

Atrial fibrillation (AF) is a progressive cardiac arrhythmia that increases the risk of hospitalization and adverse cardiovascular events. There is a clear demand for more inclusive and large-scale approaches to understand the molecular drivers responsible for AF, as well as the fundamental mechanisms governing the transition from paroxysmal to persistent and permanent forms. In this study, we aimed to create a molecular map of AF and find the distinct molecular programmes underlying cell type-specific atrial remodelling and AF progression. We used a sheep model of long-standing, tachypacing-induced AF, sampled right and left atrial tissue, and isolated cardiomyocytes (CMs) from control, intermediate (transition), and late time points during AF progression, and performed transcriptomic and proteome profiling. We have merged all these layers of information into a meaningful three-component space in which we explored the genes and proteins detected and their common patterns of expression. Our data-driven analysis points at extracellular matrix remodelling, inflammation, ion channel, myofibril structure, mitochondrial complexes, chromatin remodelling, and genes related to neural function, as well as critical regulators of cell proliferation as hallmarks of AF progression. Most important, we prove that these changes occur at early transitional stages of the disease, but not at later stages, and that the left atrium undergoes significantly more profound changes than the right atrium in its expression programme. The pattern of dynamic changes in gene and protein expression replicate the electrical and structural remodelling demonstrated previously in the sheep and in humans, and uncover novel mechanisms potentially relevant for disease treatment. Transcriptomic and proteomic analysis of AF progression in a large animal model shows that significant changes occur at early stages, and that among others involve previously undescribed increase in mitochondria, changes to the chromatin of atrial CMs, and genes related to neural function and cell proliferation.This work was supported by the Spanish government (BFU2017-84914-P to M.M.; FPI Fellowship to A.A.-F.; FPU Fellowship to R.R.), and in part by grants to J.J. from the National Heart, Lung and Blood Institute (R01 grant HL122352 NIH/NHLBI), the Leducq Foundation (Transatlantic Network of Excellence Program on Structural Alterations in the Myocardium and the Substrate for Cardiac Fibrillation), and the University of Michigan Health System–Peking University Health Science Center Joint Institute for Translational and Clinical Research (UMHS-PUHSC; project: Molecular Mechanisms of Fibrosis and the Progression from Paroxysmal to Persistent Atrial Fibrillation). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

The cis-regulatory architecture of a gene desert controlling pleiotropic Shox2 expression and cardiac pacemaker development

Trabajo presentado en Weinstein Meeting, celebrado en Marsella (Francia) del 12 al 14 de mayo de 2022

Influencia de los forzamientos externos en los tipos de circulación sobre la Península Ibérica en el último milenio

Ponencia presentada en: VIII Congreso de la Asociación Española de Climatología celebrado en Salamanca entre el 25 y el 28 de septiembre de 2012.[ES]Nuestro estudio analiza la evolución de la frecuencia de los principales TCs obtenidos para invierno y verano, mediante una simulación paleoclimática llevada a cabo para el último milenio con una versión climática del modelo MM5 sobre Europa y la Penísula Ibérica (PI). La simulación incluye tres forzamientos externos diferentes: Gases de Efecto Invernadero (período industrial), actividad volcánica (máximo entorno a 1810) y radiación solar (mínimo hacia 1700). Para la caracterización de los TCs se utilizaron datos diarios de Presión a Nivel del Mar y Geopotencial a 500 hPa sobre una ventana que cubre la PI.[EN]This study analyses the behavior in the frequency of the main CTs obtained for winter and summer from a paleosimulation performed for Europe and the Iberian Peninsula for the last millennium (1001- 1990) using a climate version of MM5. The simulation includes three kind of external forcings: Greenhouse Gases (industrial period), volcanic activity (maximun near 1810) and solar activity (minimun around 1700). For the characterization of the CTs were employed daily data of Sea Level Pressure (SLP) and Geopotential Height at 500 hPa Level of a window that covers the Iberian Peninsula (IP)

Pluripotency factors regulate the onset of Hox cluster activation in the early embryo

Pluripotent cells are a transient population of the mammalian embryo dependent on transcription factors, such as OCT4 and NANOG, which maintain pluripotency while suppressing lineage specification. However, these factors are also expressed during early phases of differentiation, and their role in the transition from pluripotency to lineage specification is largely unknown. We found that pluripotency factors play a dual role in regulating key lineage specifiers, initially repressing their expression and later being required for their proper activation. We show that Oct4 is necessary for activation of HoxB genes during differentiation of embryonic stem cells and in the embryo. In addition, we show that the HoxB cluster is coordinately regulated by OCT4 binding sites located at the 3′ end of the cluster. Our results show that core pluripotency factors are not limited to maintaining the precommitted epiblast but are also necessary for the proper deployment of subsequent developmental programs

Pluripotency factors regulate the onset of Hox cluster activation in the early embryo

Pluripotent cells are a transient population of the mammalian embryo dependent on transcription factors, such as OCT4 and NANOG, which maintain pluripotency while suppressing lineage specification. However, these factors are also expressed during early phases of differentiation, and their role in the transition from pluripotency to lineage specification is largely unknown. We found that pluripotency factors play a dual role in regulating key lineage specifiers, initially repressing their expression and later being required for their proper activation. We show that Oct4 is necessary for activation of HoxB genes during differentiation of embryonic stem cells and in the embryo. In addition, we show that the HoxB cluster is coordinately regulated by OCT4 binding sites located at the 3′ end of the cluster. Our results show that core pluripotency factors are not limited to maintaining the precommitted epiblast but are also necessary for the proper deployment of subsequent developmental programs.This work was funded by the Spanish government (grants BFU2017-84914-P and PID2020-115755GB-I00 to M.M.; BFU2016-74961-P and BFU2016-81887-REDT to J.L.G.-S.), the Andalusian government (grant BIO-396 to J.L.G.-S.), and the European Research Council (ERC; grant agreement 740041 to J.L.G.-S.). M.T. held Juan de la Cierva fellowships from the Spanish government (FJCI-2017-31791 and IJC2019-038897-I), R.R. and R.D.A. held FPU fellowships from the government, and J.V. was the recipient of a “La Caixa” fellowship. Work in the laboratory of J.L.G.-S. was supported by a María de Maetzu Unit of Excellence Grant (MDM-2016-0687) to the Department of Gene Regulation and Morphogenesis of the CABD. The CBMSO is supported by an institutional grant from the Fundación Ramon Areces, and the CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN), and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033). : With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2020-001041-S)

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Functional Genomics of Atrial Fibrillation: Understanding Intrinsic and Extrinsic Mechanisms

Atrial Fibrillation (AF) is the most common cardiac arrhythmia, affecting over 33 million people worldwide. However, its underlying molecular mechanisms and genetic networks are still poorly understood. Recently, Genome Wide Association Studies (GWAS) have identified several polymorphic variants linked to an increased risk of AF. Almost all such variants are located in non-coding regions, which led us to hypothesize that they could reside in functional elements that interact and regulate genes involved in the origin and development of AF. To test that hypothesis, we have performed in silico screening of AF associated loci toward selecting candidate regulatory elements to study the physical interactions that they establish with neighbouring regions by Circular Chromosome Conformation Capture followed by deep sequencing (4C-seq). From all selected regions, 7q31 locus contains a potential regulatory element inside intron 2 of CAV1 that through chromatin folding could establish long-range interactions with CAV1, TES, MET, and CAPZA2. Deletion of this candidate regulatory element by CRISPR/Cas9 mediated genome-editing in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) leads to a reduction of CAV1 expression. This finding could be very relevant for AF since CAV1 has a key role on the formation of caveolae, membrane invaginations with multiple roles as holding ion-channels involved in action potential generation. Moreover, we show that in the mouse Cav1 is expressed in the atrial myocardium from early stages of cardiac development up to adulthood. To further study the molecular mechanisms behind AF, we have also used a well characterized sheep model of persistent AF. This model mimics AF progression from paroxysmal episodes to persistent and long-standing persistent AF as it occurs in many patients. Transcriptome analysis of the posterior left atrial wall evidences a strong structural remodelling and suggests that during AF development there could be a remodelling of the innervation of the autonomous nervous system. Additionally, gene expression profile of isolated cardiomyocytes from the left and right atria have revealed that, during AF progression, there is a significant alteration of gene transcription regulation that can lead to cardiomyocyte dedifferentiation. Protein expression profile of those cell populations unveils an overexpression of the subunits of the respiratory chain complexes that can produce an increase in oxidative stress that could promote AF development. Furthermore, we find that changes identified in long-standing persistent sheep (one year in AF) are already present only one week of self-sustained AF. All these results contribute to a better understanding of AF progression

Functional genomics of atrial fibrillation: understanding intrinsic and extrinsic mechanisms

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímia. Fecha de lectura: 12-04-2019Esta tesis tiene embargado el acceso al texto completo hasta el 12-10-2020Atrial Fibrillation (AF) is the most common cardiac arrhythmia, affecting over 33 million people worldwide. However, its underlying molecular mechanisms and genetic networks are still poorly understood. Recently, Genome Wide Association Studies (GWAS) have identified several polymorphic variants linked to an increased risk of AF. Almost all such variants are located in non-coding regions, which led us to hypothesize that they could reside in functional elements that interact and regulate genes involved in the origin and development of AF. To test that hypothesis, we have performed in silico screening of AF associated loci toward selecting candidate regulatory elements to study the physical interactions that they establish with neighbouring regions by Circular Chromosome Conformation Capture followed by deep sequencing (4C-seq). From all selected regions, 7q31 locus contains a potential regulatory element inside intron 2 of CAV1 that through chromatin folding could establish long-range interactions with CAV1, TES, MET, and CAPZA2. Deletion of this candidate regulatory element by CRISPR/Cas9 mediated genome-editing in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) leads to a reduction of CAV1 expression. This finding could be very relevant for AF since CAV1 has a key role on the formation of caveolae, membrane invaginations with multiple roles as holding ion-channels involved in action potential generation. Moreover, we show that in the mouse Cav1 is expressed in the atrial myocardium from early stages of cardiac development up to adulthood. To further study the molecular mechanisms behind AF, we have also used a wellcharacterized sheep model of persistent AF. This model mimics AF progression from paroxysmal episodes to persistent and long-standing persistent AF as it occurs in many patients. Transcriptome analysis of the posterior left atrial wall evidences a strong structural remodelling and suggests that during AF development there could be a remodelling of the innervation of the autonomous nervous system. Additionally, gene expression profile of isolated cardiomyocytes from the left and right atria have revealed that, during AF progression, there is a significant alteration of gene transcription regulation that can lead to cardiomyocyte dedifferentiation. Protein expression profile of those cell populations unveils an overexpression of the subunits of the respiratory chain complexes that can produce an increase in oxidative stress that could promote AF development. Furthermore, we find that changes identified in long-standing persistent sheep (one year in AF) are already present only one week of self-sustained AF. All these results contribute to a better understanding of AF progression.La Fibrilación Auricular (FA) es una de las arritmias más comunes, afectando a unos 33 millones de personas en todo el mundo. A pesar de su relevancia, los mecanismos moleculares subyacentes no son muy conocidos. Recientemente, estudios de asociación del genoma completo (GWAS, por sus siglas en inglés) han identificado múltiples variantes localizadas en regiones no codificantes del genoma. De modo que, es posible que dichas variantes estén incluidas en regiones que interaccionan y regulan genes implicados en el origen y desarrollo de la FA. Para testar esta hipótesis, hemos llevado a cabo un estudio in silico de varios loci asociados a FA y tras seleccionar regiones candidatas a ser elementos reguladores hemos testado las interacciones físicas que establecen con regiones circundantes del genoma, mediante un ensayo de la conformación circular de la cromatina seguido de secuenciación masiva. De todas las regiones estudiadas, el locus 7q31 contiene un potencial elemento regulador en el intrón 2 del gen CAV1 que puede establecer interacciones con el propio gen CAV1, así como con los genes TES, MET y CAPZA. La eliminación de esta región mediante editado genético en cardiomiocitos derivados de células humanas pluripotentes produce una reducción en la expresión de CAV1. Así mismo, hemos observado en este trabajo como Cav1 se expresa en el miocardio auricular desde comienzos del desarrollo y permanece en el corazón adulto, pudiendo tener un importante papel en la FA. Para profundizar en los mecanismos moleculares que subyacen a la FA, también hemos trabajado con un modelo de FA persistente en oveja. Este modelo mimetiza la progresión de la FA desde episodios paroxísticos a episodios de FA persistente, como ocurre en muchos pacientes. El estudio transcripcional de la pared posterior de la aurícula izquierda nos muestra un remodelado de su estructura, y sugiere un posible remodelado de la inervación del sistema nervioso autónomo. Del mismo modo, el estudio de los cambios en la expresión genética de cardiomiocitos aislados de las aurículas izquierda y derecha de este modelo apunta a que durante la progresión de la FA hay una importante alteración de la regulación de la trascripción que lleva a su desdiferenciación. Por otro lado, el estudio de los cambios proteómicos nos revela que, en estas poblaciones celulares, se produce una sobrexpresión de las subunidades que componen los complejos de la cadena respiratoria mitocondrial, lo que puede producir un aumento del estrés oxidativo y promover el desarrollo de la FA. También hemos observado que cambios en la expresión detectados en ovejas con un año de desarrollo de la enfermedad, ya estaban presentes en ovejas con una semana en FA. Así, todos estos resultados contribuyen a un mejor entendimiento de esta enfermedad