The cargo protein MAP17 (PDZK1IP1) regulates the cancer stem cell pool activating the Notch pathway by abducting NUMB

Purpose: Cancer stem cells (CSC) are self-renewing tumor cells, with the ability to generate diverse differentiated tumor cell subpopulations. They differ from normal stem cells in the deregulation of the mechanisms that normally control stem cell physiology. CSCs are the origin of metastasis and highly resistant to therapy. Therefore, the understanding of the CSC origin and deregulated pathways is important for tumor control. Experimental Design: We have included experiments in vitro, in cell lines and tumors of different origins. We have used patient-derived xenografts (PDX) and public transcriptomic databases of human tumors. Results: MAP17 (PDZKIP1), a small cargo protein overexpressed in tumors, interacts with NUMB through the PDZ-binding domain activating the Notch pathway, leading to an increase in stem cell factors and cancer-initiating–like cells. Identical behavior was mimicked by inhibiting NUMB. Conversely, MAP17 downregulation in a tumor cell line constitutively expressing this gene led to Notch pathway inactivation and a marked reduction of stemness. In PDX models, MAP17 levels directly correlated with tumorsphere formation capability. Finally, in human colon, breast, or lung there is a strong correlation of MAP17 expression with a signature of Notch and stem cell genes. Conclusions: MAP17 overexpression activates Notch pathway by sequestering NUMB. High levels of MAP17 correlated with tumorsphere formation and Notch and Stem gene transcription. Its direct modification causes direct alteration of tumorsphere number and Notch and Stem pathway transcription. This defines a new mechanism of Notch pathway activation and Stem cell pool increase that may be active in a large percentage of tumors.Ministerio de Economía y Competitividad PI15/00045, CTS-1848Junta de Andalucía PI-00-96-2014, PI-0306-201

The Footprint Database and Web Services of the Herschel Space Observatory

Data from the Herschel Space Observatory is freely available to the public but no uniformly processed catalogue of the observations has been published so far. To date, the Herschel Science Archive does not contain the exact sky coverage (footprint) of individual observations and supports search for measurements based on bounding circles only. Drawing on previous experience in implementing footprint databases, we built the Herschel Footprint Database and Web Services for the Herschel Space Observatory to provide efficient search capabilities for typical astronomical queries. The database was designed with the following main goals in mind: (a) provide a unified data model for meta-data of all instruments and observational modes, (b) quickly find observations covering a selected object and its neighbourhood, (c) quickly find every observation in a larger area of the sky, (d) allow for finding solar system objects crossing observation fields. As a first step, we developed a unified data model of observations of all three Herschel instruments for all pointing and instrument modes. Then, using telescope pointing information and observational meta-data, we compiled a database of footprints. As opposed to methods using pixellation of the sphere, we represent sky coverage in an exact geometric form allowing for precise area calculations. For easier handling of Herschel observation footprints with rather complex shapes, two algorithms were implemented to reduce the outline. Furthermore, a new visualisation tool to plot footprints with various spherical projections was developed. Indexing of the footprints using Hierarchical Triangular Mesh makes it possible to quickly find observations based on sky coverage, time and meta-data. The database is accessible via a web site (http://herschel.vo.elte.hu) and also as a set of REST web service functions.Comment: Accepted for publication in Experimental Astronom

Estudio de la relevancia de la interacción entre SPN Y PP1 en tumorigénesis

El gen SPN es un supresor de tumores importante en la progresión y malignidad tumoral en muchos tipos de tumores, entre ellos el cáncer de mama. Esta característica parece ser dependiente, al menos parcialmente, de su asociación a la fosfatasa PP1 y de la capacidad de esta holoenzima de desfosforilar a pRB. Mediante un análisis mutagénico se han descrito 122 mutaciones en la proteína SPN en tumores humanos, con una frecuencia aproximada del 0,2%. Estas mutaciones se encuentran a lo largo de toda la secuencia de la proteína, siendo de especial interés aquellas que pudieran afectar a la interacción de SPN con PP1 y pRB. Hemos caracterizado 4 mutaciones de SPN en dicha región y hemos comprobado que las mutaciones de SPN afectan de distinta manera a la interacción con PP1, tanto con la isoforma PP1α como con la isoforma PP1γ. Sin embargo, ni SPN endógena ni las proteínas SPN mutantes interaccionan con PP1β. Hemos observado que la holoenzima PP1-SPN interacciona con todas las proteínas de la familia de pRB (pRB, p107 y p130), al menos en sus formas fosforiladas, y que las mutaciones de SPN no afectan a esta interacción pero sí a la capacidad de dicha holoenzima de desfosforilar a las proteínas de la familia de pRB. Además, las mutaciones de SPN parecen afectar a la localización celular de la holoenzima, colocalizando con PP1 en el citoplasma. El efecto de cada una de las mutaciones en las líneas celulares de cáncer de mama T47D y MDA-MB-468 es diferente y solo A566V ha demostrado un aumento claro en las propiedades tumorales de las células y en el fenotipo de célula madre tumoral en ambas líneas celulares. De hecho, esta mutación aparece en distintos tipos de tumores humanos y ha sido encontrada en dos análisis mutacionales independientes. Las células que sobreexpresan la mutación A566V de SPN tienen mayores niveles de pRB y p107 fosforilada durante la transición G0/G1, así como mayores niveles de pRB fosforilada y, parcialmente, de p130 fosforilada al final de G1, probablemente debido a una deficiente desfosforilación por parte de la holoenzima PP1α/γ-SPN. Esto haría que la fase G1 sea más corta y que, por tanto, las células proliferen más rápido. Por tanto, la holoenzima PP1α/γ-SPN parece estar implicada en la regulación de la desfosforilación de las proteínas de la familia de pRB en la transición G0/G1 y, parcialmente, al final de G1, pero no a la salida de mitosis, fase en la que PP1β tiene un papel más relevante. Además, las células con la sobreexpresión de la mutación SPN-A566V presentan mayores niveles de expresión de genes relacionados con la pluripotencia de las células madre, como OCT4 y SOX2, por lo que podría existir una conexión entre la autorrenovación de las células y el ciclo celular a través de las proteínas de la familia de pRB y la holoenzima PP1-SPN. El efecto de las distintas mutaciones en las propiedades tumorales de las células parece depender del contexto molecular, ya que es más claro y consistente en la línea T47D que en la línea MDA-MB-468. Esto puede deberse a que la línea MDA-MB-468 no expresa pRB, dado que las mutaciones de SPN afectan a la interacción con PP1 y pRB y aunque esta línea sí exprese p107 y p130, sus funciones no son totalmente redundantes a las de pRB. Adicionalmente, se ha analizando el efecto de la mutación SPN-A566V en una línea inmortalizada no tumorigénica, MCF10A, que expresa p53 silvestre. Hemos comprobado que solo las células que sobreexpresaban tanto la mutación SPN-A566V como la mutación de p53 vieron aumentadas las propiedades tumorales de las células, así como las propiedades relacionadas con el fenotipo de célula madre tumoral. Por tanto, esto parecía indicar que la mutación A566V de SPN sería un evento que promueve la progresión tumoral una vez que esta se ha iniciado, principalmente a causa de mutaciones en p53. Al igual que otras mutaciones oncogénicas, la actividad de las mutaciones de SPN depende del contexto molecular en el que se produzcan, favoreciéndose la actividad protumoral cuando también se produce la inactivación de genes esenciales como p53. Estos datos confirman previas observaciones in vivo en ratones knock-out de Spn, en las que la ausencia de Spn por sí sola producía un aumento en la proliferación celular de algunos tejidos, necesitando también de la ausencia de p53 para permitir el desarrollo de tumores

Hubble Space Telescope STIS spectrum of RW Aurigae A: Evidence for an ionized beltlike structure and mass ejection in timescales of a few hours

Profiles of the UV semiforbidden lines of C III](1908) and Si III](1892) of RW Aur have been obtained with the Hubble Space Telescope (HST) STIS. The C III](1908) profile shows two high-velocity components at upsilon = +/-170 km s(-1) and a central one. The Si III](1892) profile is very broad (FWHM = 293 km s(-1)), and the high-velocity components are unresolved. The high-velocity components are most probably produced in a rotating belt similar to that detected in other sources of bipolar outflows. A radius between 2.7 R-* and the corotation radius (6.1 R-*) is derived, and a log T-e(K) similar or equal to 4.7 and log n(e)(cm(-3)) = 11.6 are estimated. The belt is clumpy, and the most likely source of heating is local X-ray radiation, probably associated with the release of magnetic energy. In addition, profiles of the optical lines of He I, Fe II, and Halpha retrieved from the HST archive have been analyzed. The spectra were obtained by shifting the STIS slit between exposures in the transverse direction to the flow. Two features vary from one exposure to another: a blueshifted emission feature (detected in the Fe II and He I lines) and a redshifted absorption feature (detected in Halpha), which are observed at the velocity of the blueshifted and redshifted components of the jet, respectively. There is a clear-cut correlation between the equivalent widths of these two components. These components are not associated with the flaring activity of the source, since they remain stable timescales of similar or equal to40 minutes. They are most likely associated with variations in the stellar/circumstellar environment in timescales of a few (similar or equal to5) hours, consistent with reports by other authors for variations of the veiling and the appearance of shell signatures in the optical spectrum

Development of a support needs assessment scale for children and adolescents with intellectual disabilities

RESUMEN: El artículo presentado está orientado al desarrollo de una escala de evaluación de necesidades apoyos para niños y adolescentes (5-16 años) con discapacidad intelectual. Esta herramienta es coherente con la concepción más reciente de discapacidad intelectual y se desarrolla en castellano a partir de una propuesta internacional iniciada desde la Asociación Americana de Discapacidades Intelectuales y del Desarrollo (AAIDD). El foco principal de este estudio es analizar las características psicométricas de la escala en el contexto español. El instrumento ha sido aplicado a una muestra piloto de 143 niños y adolescentes con discapacidad intelectual y analizado bajo los supuestos de la Teoría de Respuesta a los Ítems (TRI); concretamente, se han asumido los supuestos del Modelo de Escalas de Clasificación. Los resultados alcanzados muestran evidencias iniciales de la fiabilidad y validez de la escala, así como el adecuado ajuste de los datos al modelo propuesto.ABSTRACT: The paper presented is focused on the development of a scale for assessing support needs for children and adolescents with intellectual disabilities. This tool adheres to the most recent conception of intellectual disability and it is being developed in Spanish following the international proposal initiated by the American Association of Intellectual and Developmental Disabilities (AAIDD). The main focus of the research is to analyze, the psychometric characteristics of the scale within the Spanish context. The tool has been used so far with a pilot sample of 143 people (both children and adolescents) with intellectual disabilities and it has also been according to the framework of Item Response Theory (IRT), specifically the assumptions of the Rating Scale Model (RSM) have been taken into account. The results achieved so far show preliminary evidence of the reliability and validity of the scale, as well as the adequate adjustment of the data to the proposed model.Este artículo se ha escrito en el marco del proyecto de investigación I+D PSI2012-36278 financiado por el Ministerio de Economía y Competitividad

Evidence for stellar driven outflows from the Classical T Tauri star RY Tau

RY Tau is a rapidly rotating Classical T Tauri star observed close to edge-on. The combination of new HST/STIS observations obtained in 2001 with HST/GHRS Archive data from 1993 has allowed us to get, for the first time, information on the thermal structure and the velocity law of the wind. The repeated observations of the Si III] and C III] lines show a lack of changes with time in the blue side of the profile(dominated by the wind contribution). Very high temperature plasma (log Te = 4.8) is detected at densities of 9.5<log ne(cm3)< 10.2 associated with the wind. The emitting volumes are about (0.35Ro)^3 suggesting a stellar origin. The wind kinematics derived from the profiles (Si III], C III] and [O II]) does not satisfy the theoretical predictions of MHD centrifugally driven disk winds. The profiles' asymmetry, large velocity dispersions and small variability as well as the small emitting volumes are best explained if the wind is produced by the contribution of several outflows from atmospheric open field structures as those observed in the Sun.Comment: 11pages, 3 figure

Confirmatory factor analysis of the supports intensity scale for children

Abstract: Support needs assessment instruments and recent research related to this construct have been more focused on adults with intellectual disability than on children. However, the design and implementation of Individualized Support Plans (ISP) must start at an early age. Currently, a project for the translation, adaptation and validation of the supports intensity scale for children (SIS-C) is being conducted in Spain. In this study, the internal structure of the scale was analyzed to shed light on the nature of this construct when evaluated in childhood. A total of 814 children with intellectual disability between 5 and 16 years of age participated in the study. Their support need level was assessed by the SIS-C, and a confirmatory factor analysis (CFA), including different hypotheses, was carried out to identify the optimal factorial structure of this scale. The CFA results indicated that a unidimensional model is not sufficient to explain our data structure. On the other hand, goodness-of-fit indices showed that both correlated first-order factors and higher-order factor models of the construct could explain the data obtained from the scale. Specifically, a better fit of our data with the correlated first-order factors model was found. These findings are similar to those identified in previous analyses performed with adults. Implications and directions for further research are discussed.Work on this research was funded by the Spanish Ministry of the Economy and Competitiveness (R&D Projects, PSI2012-36278), and the Autonomous Community of Castile and Leon (R&D Projects, SA120U13)

Teaching Sport Management through case study and its protagonist

Desde sus inicios la asignatura de Organización y Gestión de Empresas Deportivas viene utilizando la presencia de conferenciantes en sus clases, así como otras actividades con el objetivo de dotar al alumno no sólo de contenidos sino de competencias y habilidades necesarias para la gestión de negocios (deportivos). La importancia de afrontar la docencia de este modo en esta asignatura es más importante si cabe, en tanto en cuanto, el perfil habitual del alumnado de estos estudios está tremendamente “sesgado” hacia aspectos meramente educativos y no tanto de gestión de negocios. Por tanto, consideramos de un enorme valor desarrollar iniciativas, proyectos y actividades que impacten fuertemente en el alumnado, de manera que los mismos puedan darse cuenta de que la gestión de negocios deportivos puede ser una salida profesional perfectamente contemplable y asumible. En esta experiencia, aportamos dos aspectos fundamentales a la hora del estudio de casos: primero, aumentar e incentivar la implicación y la participación del alumno y, segundo, la necesaria actualidad y/o contemporaneidad que se exige a los estudios de casos para no ser confundidos con otras técnicas como el análisis de crónicas; y para el logro de ambos aspectos hemos apostado por la utilización de protagonistas de los casos en las fases de discusión.The Sport Management subject has been inviting case protagonist into class in order to find out how the problem finally was solved. The aim is to provide to students not just competences and skills for handling sport firms. The important to plan the teaching in that way fills up the gap between education contents and management contents. Thus, we consider very valuable developing initiatives, projects and activities in order to impact strongly on sport management students. Hence, students can realize that sport management cab be a professional option perfectly. In this teaching experience, we provide two main issues for teaching case studies: (1) improving and fostering students’ participation and involvement and, (2) contributing to the updating of teaching case studies. In order to achieve it, we bet for case protagonist attending to cases discussion stage

Numb-like (NumbL) downregulation increases tumorigenicity, cancer stem cell-like properties and resistance to chemotherapy

NumbL, or Numb-like, is a close homologue of Numb, and is part of an evolutionary conserved protein family implicated in some important cellular processes. Numb is a protein involved in cell development, in cell adhesion and migration, in asymmetric cell division, and in targeting proteins for endocytosis and ubiquitination. NumbL exhibits some overlapping functions with Numb, but its role in tumorigenesis is not fully known. Here we showed that the downregulation of NumbL alone is sufficient to increase NICD nuclear translocation and induce Notch pathway activation. Furthermore, NumbL downregulation increases epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-related gene transcripts and CSC-like phenotypes, including an increase in the CSC-like pool. These data suggest that NumbL can act independently as a tumor suppressor gene. Furthermore, an absence of NumbL induces chemoresistance in tumor cells. An analysis of human tumors indicates that NumbL is downregulated in a variable percentage of human tumors, with lower levels of this gene correlated with worse prognosis in colon, breast and lung tumors. Therefore, NumbL can act as an independent tumor suppressor inhibiting the Notch pathway and regulating the cancer stem cell pool.España, Ministerio de Economía y Competitividad PI12/00137, PI15/00045España, Consejería de Ciencia e Innovación CTS-6844España, Consejería de Ciencia e Innovación CTS-1848España, Junta de Andalucía, Consejería de Salud PI-0306-2012España, Junta de Andalucía, Consejería de Salud PI-0096-201

Understanding A-type supergiants - I. Ultraviolet and visible spectral atlas of A-type supergiants

This paper is the first of a series whose aim is to perform a systematic study of A-type supergiant atmospheres and winds. Here we present a spectral atlas of 41 A-supergiants observed by us in high and medium resolution in the visible asd ultraviolet. The atlas consists of profiles of the H alpha, H beta, H gamma, H delta, H epsilon, Ca II (H and K), Na I (D1 and D2), Mg II4481, Mg II [uv1] and Fe II [uv1, uv2; uv3, uv62, uv63, uv161] lines for 41 stars with spectral types ranging from B9 to A9 and luminosity classes Ia, Iab and Ib, and provides the basic data for a thoughtful study of these stars. The overall characteristics of the sample as well as the data reduction procedures are described. We also present some examples of spectral variability