Oncogenic RET Kinase domain mutations perturb the autophosphorylation trajectory by enhancing substrate presentation in trans

To decipher the molecular basis for RET kinase activation and oncogenic deregulation, we defined the temporal sequence of RET autophosphorylation by label-free quantitative mass spectrometry. Early autophosphorylation sites map to regions flanking the kinase domain core, while sites within the activation loop only form at later time points. Comparison with oncogenic RET kinase revealed that late autophosphorylation sites become phosphorylated much earlier than wild-type RET, which is due to a combination of an enhanced enzymatic activity, increased ATP affinity, and surprisingly, by providing a better intermolecular substrate. Structural analysis of oncogenic M918T and wild-type RET kinase domains reveal a cis-inhibitory mechanism involving tethering contacts between the glycine-rich loop, activation loop, and αC-helix. Tether mutations only affected substrate presentation but perturbed the autophosphorylation trajectory similar to oncogenic mutations. This study reveals an unappreciated role for oncogenic RET kinase mutations in promoting intermolecular autophosphorylation by enhancing substrate presentation

Factores de riesgo de enfermedades cardiovasculares en pacientes hospitalizados en el hospital de apoyo Víctor Ramos Guardia (Huaraz-Perú)

Determinar los factores de riesgo controlables directos y controlables indirectos de enfermedades cardiovasculares

Super star cluster feedback driving ionization, shocks and outflows in the halo of the nearby starburst ESO 338-IG04

Stellar feedback strongly affects the interstellar medium (ISM) of galaxies. Stellar feedback in the first galaxies likely plays a major role in enabling the escape of LyC photons, which contribute to the re-ionization of the Universe. Nearby starburst galaxies serve as local analogues allowing for a spatially resolved assessment of the feedback processes in these galaxies. We characterize the feedback effects from the star clusters in the local high-redshift analogue ESO 338-IG04 on the ISM and compare the results with the properties of the most massive clusters. We use high quality VLT/MUSE optical integral field data to derive the physical properties of the ISM such as ionization, density, shocks, and perform new fitting of the spectral energy distributions of the brightest clusters in ESO 338-IG04 from HST imaging. ESO 338-IG04 has a large ionized halo which we detect to a distance of 9 kpc. We identify 4 Wolf-Rayet (WR) clusters based on the blue and red WR bump. We follow previously identified ionization cones and find that the ionization of the halo increases with distance. Analysis of the galaxy kinematics shows two complex outflows driven by the numerous young clusters in the galaxy. We find a ring of shocked emission traced by an enhanced [OI]/H$\alpha$ ratio surrounding the starburst and at the end of the outflow. Finally we detect nitrogen enriched gas associated with the outflow, likely caused by the WR stars in the massive star clusters. Photo-ionization dominates the central starburst and sets the ionization structure of the entire halo, resulting in a density bounded halo, facilitating the escape of LyC photons. Outside the central starburst, shocks triggered by an expanding super bubble become important. The shocks at the end of the outflow suggest interaction between the hot outflowing material and the more quiescent halo gas.Comment: Accepted for publication in Astronomy and Astrophysics, 22 pages, 15 figure

La Inclusión del alumnado con trastorno del espectro autista en Educación Física

En el presente TFG se muestra interés en la idea de proponer situaciones de aprendizaje en la Educación Física mediante juegos de cooperación y colaboración, donde el alumnado con TEA sea integrado en el mismo entorno que los compañeros sin discapacidad. Permitiendo así a estos últimos, adquirir una educación con mayor consciencia respecto a ese concepto y con mejores conductas, esta vez positivas, hacia ese tipo de personas, ayudándoles a facilitarles el camino hacia una educación digna con las mismas oportunidades que todos, obteniendo a su vez mejoras en su desarrollo tanto psíquico como físico.El presente Trabajo Fin de Grado tiene como objetivo el estudio de los Trastornos Generalizados del Desarrollo (TGD) y la realización de una propuesta de inclusión en Educación Física para un alumnado diagnosticado con Trastorno del Espectro Autista (TEA), en una clase ordinaria de educación primaria.Número de páginas 5

Estudio de los compuestos bioactivos de la soya con beneficios a la salud

La soya es una fuente importante de proteínas y otros nutrientes con beneficios a la salud de una gran parte de la población mundial. El programa de mejoramiento de soya Embrapa-Brasil, ha desarrollado las variedades BRS 133 con bajo contenido proteico (37.36%) y BRS 258 con alto contenido proteico (42.29%). El objetivo de este estudio fue comparar las concentraciones de los compuestos bioactivos con beneficios a la salud de estas variedades de soya en relación a su contenido proteico. Las concentraciones de isoflavonas y saponinas se determinó por cromatografía líquida de alta resolución (CLAR) y las concentraciones de proteína soluble, lunasina, inhibidor Bowman Birk (BBI) y lectina se determinaron por el método ELISA (ensayo inmunoenzimático). La identificación del polipéptido bioactivo lunasina, fue determinado mediante el método Western blot y la actividad de lipoxigenasa se determinó mediante la cuantificación de la banda lipoxigenasa por electroforesis en gel

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

R-Ras2 is a transforming GTPase that shares downstream effectors with Ras subfamily proteins. However, little information exists about the function of this protein in tumorigenesis and its signalling overlap with classical Ras GTPases. Here we show, by combining loss- and gain-of-function studies in breast cancer cells, mammary epithelial cells and mouse models, that endogenous R-Ras2 has a role in both primary breast tumorigenesis and the late metastatic steps of cancer cells in the lung parenchyma. R-Ras2 drives tumorigenesis in a phosphatidylinostiol-3 kinase (PI3K)-dependent and signalling autonomous manner. By contrast, its prometastatic role requires other priming oncogenic signals and the engagement of several downstream elements. R-Ras2 function is required even in cancer cells exhibiting constitutive activation of classical Ras proteins, indicating that these GTPases are not functionally redundant. Our results also suggest that application of long-term R-Ras2 therapies will result in the development of compensatory mechanisms in breast tumoursFil: Larive, Ramon. Universidad de Salamanca; España. University of Montpellier I and II; FranciaFil: Moriggi, Giulia. Universidad de Salamanca; EspañaFil: Menacho Márquez, Mauricio Ariel. Universidad de Salamanca; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Cañamero, Marta. Centro Nacional de Investigaciones Oncológicas; EspañaFil: de Alava, Enrique. Universidad de Salamanca; España. Hospital Universitario Virgen del Rocío. Sevilla; EspañaFil: Alarcón, Balbino. Centro de Biología Molecular ‘‘Severo Ochoa’. Madrid; EspañaFil: Dosil, Mercedes. Universidad de Salamanca; EspañaFil: Bustelo, Xosé R.. Universidad de Salamanca; Españ

Longitudinal study of low and high achievers in early mathematics

Background. Longitudinal studies allow us to identify, which specific maths skills are weak in young children, and whether there is a continuing weakness in these areas throughout their school years. Aims. This 2-year study investigated whether certain socio-demographic variables affect early mathematical competency in children aged 5–7 years. Sample. A randomly selected sample of 127 students (64 female; 63 male) participated. At the start of the study, the students were approximately 5 years old (M = 5.2; SD = 0.28; range = 4.5–5.8). Method. The students were assessed using the Early Numeracy Test and then allocated to a high (n = 26), middle (n = 76), or low (n = 25) achievers group. The same children were assessed again with the Early Numeracy Test at 6 and 7 years old, respectively. Eight socio-demographic characteristics were also evaluated: family model, education of the parent(s), job of the parent(s), number of family members, birth order, number of computers at home, frequency of teacher visits, and hours watching television. Results. Early Numeracy Test scores were more consistent for the high-achievers group than for the low-achievers group. Approximately 5.5% of low achievers obtained low scores throughout the study. A link between specific socio-demographic characteristics and early achievement in mathematics was only found for number of computers at home. Conclusions. The level of mathematical ability among students aged 5–7 years remains relatively stable regardless of the initial level of achievement. However, early screening for mathematics learning disabilities could be useful in helping low-achieving students overcome learning obstacles.This material is based on work supported by the Spanish Ministry of Science & Technology grant no. SEJ2007-62420/EDUC and Junta de Andalucia grant no. P09-HUM-4918