Regulación de la biología de las células troncales y el corazón adulto por la variante de calcineurina CnAβ1

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 21-12-2015Esta tesis tiene embargado el acceso al texto completo hasta el 21-06-2017El splicing alternativo desempeña un papel muy importante durante la diferenciación de las células progenitoras embrionarias (ESC). Nuestros resultados muestran como Mbnl1 regula el splicing del mRNA de calcineurina A beta (CnAβ) en ESC de ratón, resultando en la expresión de la variante atípica CnAβ1 que posee un dominio C-terminal único. La inhibición de CnAβ1 provoca la inactivación de la señalización de Akt/GSK3β/β-catenina, lo que su vez se traduce en un defecto en la especificación a mesodermo. Hemos identificado un dominio específico en la segunda α-hélice de la región C-terminal que regula la activación de la vía de Akt/GSK3β/β-catenina. Tras realizar un ensayo de doble híbrido en levadura, encontramos que CnAβ1 interacciona con Cog8 en el aparato de Golgi. La inhibición de Cog8 deslocaliza CnAβ1 e interfiere con la diferenciación a mesodermo de las ESC. En resumen, hemos determinado las bases estructurales para el mecanismo de acción de CnAβ1 y su función en la diferenciación de las ESC al linaje de mesodermo. Con el fin de caracterizar mejor la función de CnAβ1 in vivo, eliminamos la región C-terminal única de CnAβ1 por la eliminación del intrón 12-13, que llamamos CnAβΔi12. Los ratones provenientes de esta construcción nacen de manera normal y no presentan ningún defecto a 2 meses de edad, pero con el tiempo desarrollan una hipertrofia cardiaca a los 15 meses. Curiosamente, la sobreexpresión de CnAβ1 en los cardiomiocitos, bajo el promotor de α-MHC, es capaz de disminuir los efectos de la hipertrofia cardiaca en un modelo de sobrecarga por presión. Estos resultados son opuestos a los descritos anteriormente para otras isoformas de calcineurina y sugieren su potencial uso para terapiasAlternative splicing plays a key role in embryonic stem cell (ESC) differentiation but the mechanisms involved remain poorly understood. Here, we show that Mbnl1 regulates the splicing of the calcineurin A gene in mouse ESCs (mESC), resulting in expression of the atypical variant CnAβ1, which has a unique C-terminal domain. CnAβ1 knockdown results in inactivation of the AKT/GSK3β/-catenin signalling pathway, leading to defective mesoderm specification. We found that a specific motif in the second alpha helix of the Cterminal domain drives CnAβ1 localisation to the Golgi apparatus, which is necessary for the activation of the AKT/GSK3β/-Catenin pathway. Following a yeast 2-hybrid screening, we found that CnAβ1 interacts with Cog8 in the Golgi apparatus. Cog8 knockdown delocalises CnAβ1 and interferes with mESC mesodermal differentiation. In summary, we unveil here the structural basis for the mechanism of action of CnAβ1 and its role in the differentiation of mESC to the mesodermal lineage. To further unveil the function of CnAβ1 in vivo we have deleted the unique C-terminal region of this isoform by deleting intron 12- 13, which we called CnAβΔi12. These mice are born normally and do not present any defect at 2 months of age, however they developed cardiac hypertrophy by 15 months of age. Interestingly, the overexpression of CnAβ1 in the cardiomyocytes under the αMHC promoter is able to reduce cardiac hypertrophy in a mouse model of pressure overload. This result is opposite to the function described for other calcineurin isoforms and suggests its potential use for therapie

Compétence en Technologie de l’Information Géographique (TIG) dans les études universitaires: réflexions et propositions participative

El objetivo de este trabajo es ofrecer una reflexión que conduzca a una asignación coherente de competencias en la enseñanza sobre Tecnologías de la Información Geográfica (Cartografía, Sistemas de Información Geográfica y Teledetección) que se imparte en la universidad. Tras analizar diversas propuestas al respecto, en España y a nivel internacional, y a través de una serie de talleres participativos, un grupo de académicos de la Universidad de Alcalá ha generado su propia propuesta sobre las competencias más importantes y necesarias a conseguir en cada nivel de la educación superior (grado, master y doctorado). La propuesta ha sido contrastada con los resultados de una encuesta realizada entre un conjunto de académicos universitarios españoles.The aim of this paper is to offer an insight on competences leading to their consistent allocation in the different courses on Geographic Information Technologies (Cartography, Geographic Information Systems - GIS and Remote Sensing) taught in universities. To do this, after analyzing the various proposals on the subject, both in Spain and internationally, and after conducting a series of participatory workshops, a group of academics from the University of Alcalá has generated its own proposal on the most important and necessary competences to acquire at each level of higher education (bachelor, master and doctorate). Furthermore, the proposal has been contrasted with the results of a survey conducted by a wide range of Spanish university academics.Le but de cet article est de proposer une réflexion conduisant à une allocation cohérente des compétences dans les différents cours sur les technologies d’information géographique (Cartographie, Système d’Information Géographique- SIG et télédétection) enseignées dans les universités. Pour ce faire, après avoir analysé les différentes propositions sur le sujet, à la fois en Espagne et à l’étranger, et après la réalisation d’une série d’ateliers participatifs, un groupe de l’Université de Alcalá a généré sa propre proposition sur les compétences les plus importants et nécessaires pour obtenir à chaque niveau de l’enseignement supérieur (licence, master et doctorat). En outre, la proposition a été contrastée avec les résultats d’une enquête menée par un large éventail d’universitaires espagnols

Gerentur: Una aplicación transversal de gamificación para la estadística en turismo y ciencias económicas

Depto. de Economía Financiera y Actuarial y EstadísticaFac. de Ciencias Económicas y EmpresarialesFALSEsubmitte

Effectiveness of a strategy that uses educational games to implement clinical practice guidelines among Spanish residents of family and community medicine (e-EDUCAGUIA project):A clinical trial by clusters

This study was funded by the Fondo de Investigaciones Sanitarias FIS Grant Number PI11/0477 ISCIII.-REDISSEC Proyecto RD12/0001/0012 AND FEDER Funding.Background: Clinical practice guidelines (CPGs) have been developed with the aim of helping health professionals, patients, and caregivers make decisions about their health care, using the best available evidence. In many cases, incorporation of these recommendations into clinical practice also implies a need for changes in routine clinical practice. Using educational games as a strategy for implementing recommendations among health professionals has been demonstrated to be effective in some studies; however, evidence is still scarce. The primary objective of this study is to assess the effectiveness of a teaching strategy for the implementation of CPGs using educational games (e-learning EDUCAGUIA) to improve knowledge and skills related to clinical decision-making by residents in family medicine. The primary objective will be evaluated at 1 and 6months after the intervention. The secondary objectives are to identify barriers and facilitators for the use of guidelines by residents of family medicine and to describe the educational strategies used by Spanish teaching units of family and community medicine to encourage implementation of CPGs. Methods/design: We propose a multicenter clinical trial with randomized allocation by clusters of family and community medicine teaching units in Spain. The sample size will be 394 residents (197 in each group), with the teaching units as the randomization unit and the residents comprising the analysis unit. For the intervention, both groups will receive an initial 1-h session on clinical practice guideline use and the usual dissemination strategy by e-mail. The intervention group (e-learning EDUCAGUIA) strategy will consist of educational games with hypothetical clinical scenarios in a virtual environment. The primary outcome will be the score obtained by the residents on evaluation questionnaires for each clinical practice guideline. Other included variables will be the sociodemographic and training variables of the residents and the teaching unit characteristics. The statistical analysis will consist of a descriptive analysis of variables and a baseline comparison of both groups. For the primary outcome analysis, an average score comparison of hypothetical scenario questionnaires between the EDUCAGUIA intervention group and the control group will be performed at 1 and 6months post-intervention, using 95% confidence intervals. A linear multilevel regression will be used to adjust the model. Discussion: The identification of effective teaching strategies will facilitate the incorporation of available knowledge into clinical practice that could eventually improve patient outcomes. The inclusion of information technologies as teaching tools permits greater learning autonomy and allows deeper instructor participation in the monitoring and supervision of residents. The long-term impact of this strategy is unknown; however, because it is aimed at professionals undergoing training and it addresses prevalent health problems, a small effect can be of great relevance. Trial registration: ClinicalTrials.gov: NCT02210442.Publisher PDFPeer reviewe

Design and performance analysis of a solar dual fluidized bed gasifier

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)The potential to conduct allothermal steam-gasification of biomass using a dual fluidized bed gasifier (DFBG) assisted by solar energy has already been conceptually proposed. In this paper the design and operation of a solar DFBG (SDFBG) device to deal with this concept is assessed by modeling, considering thermodynamic, kinetic and fluid-dynamic issues. The challenges identified in previous works, as well as the modifications required in the current state-of-the-art technologies of (no-solar) DFBG for implementing the new solution using heated particles as heat carriers, are worked out. Two SDFBGs, considering different arrangements for integrating the solids carrying the solar energy into the system, are designed. The operation of both under different solar-external heat loads, from autothermal operation (no external heat) to 3 MJ kgbio,daf−1 of external heat, is assessed and compared. This work shows how the technology can be implemented and scaled up

Measurement of char surface temperature in a fluidized bed combustor using pyrometry with digital camera

A method is presented to measure the char surface temperature during conversion in fluidized bed (FB) using a digital camera. The method applies one-color pyrometry (P1C) sequentially for the three wavelength bands (red, green, and blue) changing from one band to another automatically as a function of radiation intensity received by the sensor of the video camera. Experiments were made in a twodimensional FB combustor (0.18x0.50x0.018 m) equipped with a window for visual observation. It is shown that the new method improves the accuracy compared to two-color pyrometry (P2C), allowing the measurement of a wider range of temperature, including temperatures lower than the bed (background). The main limitation of P1C (compared to P2C) is that the char emissivity has to be known. However, a sensitivity analysis, assuming a char emissivity variation from 0.85 to 1, reveled that the relative error in temperature is lower than 1% when the surface temperature of the char is higher than that of the bed. Then an assumed value of emissivity within this range is sufficient. However, a more precise estimate of char emissivity is needed when measuring temperatures lower than the bed temperature. Furthermore, the method enables determination of details such as surface temperature gradients and size of the particle during combustion. Overall, the technique allows determination of precise data of the fuel conversion process in FB

Four-Year Incidence of Diabetic Retinopathy in a Spanish Cohort: The MADIABETES Study

<div><p>Objective</p><p>To evaluate the incidence of diabetic retinopathy in patients with Type 2 Diabetes Mellitus, to identify the risk factors associated with the incidence of retinopathy and to develop a risk table to predict four-year retinopathy risk stratification for clinical use, from a four-year cohort study.</p><p>Design</p><p>The MADIABETES Study is a prospective cohort study of 3,443 outpatients with Type 2 Diabetes Mellitus, sampled from 56 primary health care centers (131 general practitioners) in Madrid (Spain).</p><p>Results</p><p>The cumulative incidence of retinopathy at four-year follow-up was 8.07% (95% CI = 7.04–9.22) and the incidence density was 2.03 (95% CI = 1.75–2.33) cases per 1000 patient-months or 2.43 (95% CI = 2.10–2.80) cases per 100 patient-years. The highest adjusted hazard ratios of associated risk factors for incidence of diabetic retinopathy were LDL-C >190 mg/dl (HR = 7.91; 95% CI = 3.39–18.47), duration of diabetes longer than 22 years (HR = 2.00; 95% CI = 1.18–3.39), HbA1c>8% (HR = 1.90; 95% CI = 1.30–2.77), and aspirin use (HR = 1.65; 95% CI = 1.22–2.24). Microalbuminuria (HR = 1.17; 95% CI = 0.75–1.82) and being female (HR = 1.12; 95% CI = 0.84–1.49) showed a non-significant increase of diabetic retinopathy. The greatest risk is observed in females who had diabetes for more than 22 years, with microalbuminuria, HbA1c>8%, hypertension, LDL-Cholesterol >190 mg/dl and aspirin use.</p><p>Conclusions</p><p>After a four-year follow-up, the cumulative incidence of retinopathy was relatively low in comparison with other studies. Higher baseline HbA1c, aspirin use, higher LDL-Cholesterol levels, and longer duration of diabetes were the only statistically significant risk factors found for diabetic retinopathy incidence. This is the first study to demonstrate an association between aspirin use and diabetic retinopathy risk in a well-defined cohort of patients with Type 2 Diabetes Mellitus at low risk of cardiovascular events. However, further studies with patients at high cardiovascular and metabolic risk are needed to clarify this issue.</p></div

Calcineurin Abeta1 overexpression using an adeno-associated virus vector (AAV9) demonstrates decreased pathological remodelling and decreased expression of heart failure markers in ischemic and non-ischemic heart disease

Sin financiación4.187 (2016) Q1, 26/160 Biotechnology and applied microbiology, 38/167 Genetics and heredity, 24/128 Medicine, research and experimentalUE

Elaboración de un marco de desarrollo de materias no troncales : líneas de actuación para el diseño de materias comunes

Se diseñan unas estrategias para armonizar las materias no troncales entre titulaciones análogas de diferentes universidades europeas para contribuir al proceso de implantación al Sistema Europeo de Transferencia de Créditos (ECTS). Se expone el extracto de los listados de materias en vigor en el estudio de las lenguas modernas y sus literaturas en las diferentes universidades. Se realiza una planificación curricular contextualizada para la puesta en práctica de un plan razonado y articulado, considerando al profesor universitario como agente curricular que participa en el diseño de planes formativos y, miembro del equipo docente que lo lleva a cabo. El proyecto va más allá de los cambios normativos, ya que introduce prácticas que refuerzan el sistema de calidad. Los beneficiarios directos son los estudiantes, debido a las ventajas que representa para su formación e integración laboral.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; +34983411939;ES

Flow diagram of the MADIABETES cohort.

<p>Flow diagram of the MADIABETES cohort.</p