SUMOylation regulates LKB1 localization and its oncogenic activity in liver cancer

BACKGROUND: Even though liver kinase B1 (LKB1) is usually described as a tumor suppressor in a wide variety of tissues, it has been shown that LKB1 aberrant expression is associated with bad prognosis in Hepatocellular Carcinoma (HCC). METHODS: Herein we have overexpressed LKB1 in human hepatoma cells and by using histidine pull-down assay we have investigated the role of the hypoxia-related post-translational modification of Small Ubiquitin-related Modifier (SUMO)ylation in the regulation of LKB1 oncogenic role. Molecular modelling between LKB1 and its interactors, involved in regulation of LKB1 nucleocytoplasmic shuttling and LKB1 activity, was performed. Finally, high affinity SUMO binding entities-based technology were used to validate our findings in a pre-clinical mouse model and in clinical HCC. FINDINGS: We found that in human hepatoma cells under hypoxic stress, LKB1 overexpression increases cell viability and aggressiveness in association with changes in LKB1 cellular localization. Moreover, by using site-directed mutagenesis, we have shown that LKB1 is SUMOylated by SUMO-2 at Lys178 hampering LKB1 nucleocytoplasmic shuttling and fueling hepatoma cell growth. Molecular modelling of SUMO modified LKB1 further confirmed steric impedance between SUMOylated LKB1 and the STe20-Related ADaptor cofactor (STRADα), involved in LKB1 export from the nucleus. Finally, we provide evidence that endogenous LKB1 is modified by SUMO in pre-clinical mouse models of HCC and clinical HCC, where LKB1 SUMOylation is higher in fast growing tumors. INTERPRETATION: Overall, SUMO-2 modification of LKB1 at Lys178 mediates LKB1 cellular localization and its oncogenic role in liver cancer. FUND: This work was supported by grants from NIH (US Department of Health and Human services)-R01AR001576-11A1 (J.M.M and M.L.M-C.), Gobierno Vasco-Departamento de Salud 2013111114 (to M.L.M.-C), ELKARTEK 2016, Departamento de Industria del Gobierno Vasco (to M.L.M.-C), MINECO: SAF2017-87301-R and SAF2014-52097-R integrado en el Plan Estatal de Investigación Cientifica y Técnica y Innovación 2013-2016 cofinanciado con Fondos FEDER (to M.L.M.-C and J.M.M., respectively), BFU2015-71017/BMC MINECO/FEDER, EU (to A.D.Q. and I.D.M.), BIOEF (Basque Foundation for Innovation and Health Research): EITB Maratoia BIO15/CA/014; Instituto de Salud Carlos III:PIE14/00031, integrado en el Plan Estatal de Investigación Cientifica y Técnica y Innovacion 2013-2016 cofinanciado con Fondos FEDER (to M.L.M.-C and J.M.M), Asociación Española contra el Cáncer (T.C.D, P·F-T and M.L.M-C), Daniel Alagille award from EASL (to T.C.D), Fundación Científica de la Asociación Española Contra el Cancer (AECC Scientific Foundation) Rare Tumor Calls 2017 (to M.L.M and M.A), La Caixa Foundation Program (to M.L.M), Programma di Ricerca Regione-Università 2007-2009 and 2011-2012, Regione Emilia-Romagna (to E.V.), Ramón Areces Foundation and the Andalusian Government (BIO-198) (A.D.Q. and I.D.M.), ayudas para apoyar grupos de investigación del sistema Universitario Vasco IT971-16 (P.A.), MINECO:SAF2015-64352-R (P.A.), Institut National du Cancer, FRANCE, INCa grant PLBIO16-251 (M.S.R.), MINECO - BFU2016-76872-R to (E.B.). Work produced with the support of a 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (M.V-R). Finally, Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III. We thank MINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644). Funding sources had no involvement in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication

Construcción de la salud sexual y análisis de su influencia en la calidad de vida y prevención de abusos sexuales en personas adultas con discapacidad intelectual

La presente tesis “Construcción de la salud sexual y análisis de su influencia en la calidad de vida y prevención de abusos sexuales en personas adultas con discapacidad intelectual.”, se va a describir en dos partes. En la primera parte, que constituye el marco teórico de la investigación, esta compuesto de tres capítulos. En el primero de ellos, que trata sobre la sexualidad en la discapacidad intelectual, se realiza una aproximación y recorrido histórico por el concepto de sexualidad, su evolución y todo lo relacionado con los mitos y las falsas creencias, así como las actitudes de las personas sin discapacidad hacia la sexualidad de las personas con DI. En el segundo capítulo, nos centraremos en la sexualidad y calidad de vida de las personas con discapacidad intelectual. Diferenciaremos entre estudios que se han llevado a cabo cuando la calidad de vida ha sido autoinformada, o por los/as profesionales que tienen atención directa con ellos/as. Finalizaremos este capítulo, haciendo una descripción de las principales barreras a las que tiene que enfrentarse una persona con DI, tanto las suyas como las sociales. En el tercer capítulo, discutiremos sobre el hecho de que no disponer de un desarrollo sexual saludable entraña riesgos más allá de los embarazos no deseados e incluso de las infecciones de transmisión sexual, convirtiendo a las personas con discapacidad intelectual en personas altamente vulnerables a sufrir o padecer algún episodio de abuso sexual a lo largo de su vida. El desconocimiento de la prevalencia real de los casos de abuso sexual, es un factor de riesgo más para este colectivo. Todo esto se ve agravado, ya que siempre que exista abuso sexual se producen secuelas de tipo físico, psicológico y sexual, que suele perdurar el resto de sus vidas. La segunda parte, hace referencia al estudio empírico. Tres objetivos y catorce hipótesis, en los que investigaremos, en primer lugar como se construye la salud sexual de las personas adultas con DI y las actitudes ante la expresión de su sexualidad suya y de la que les rodean. En segundo lugar, analizar la influencia de las vivencias de la sexualidad en la CV de las personas con DI. Por último, analizar las dimensiones e implicaciones del abuso sexual y sus posibles secuelas emocionales, físicas, psicológicas y sexuales. Dos tipos de muestra, por un lado 360 personas con discapacidad intelectual leve o moderada, con edades comprendidas entre los 18 y 55 años, y residentes en viviendas tuteladas, centros residenciales y unidad familiar. Por otro 300 personas sin discapacidad intelectual, compuesta por padres, profesionales y población general. Además entre las personas con discapacidad, 22 de estas personas nos informaban que habían padecido abusos sexuales y de 103 personas de las que teníamos constancia , a pesar de que ellos/as no lo habían reportado. De entre los resultados arrojados por nuestra investigación cabe destacar, la necesidad de educación sexual para el colectivo que tratamos, entendida como una potente herramienta que aumente el conocimiento y la precaución sobre los abusos sexuales, la satisfacción sexual como variable implicada y predictora de la calidad de vida, y la necesidad de diseñar planes específicos, que nos ayuden a adaptar el acceso a al información pues muchas de las personas que han sufrido o están sufriendo abusos sexuales no informan sobre ello, bien por desconocimiento o por miedo

Robust schedules for tardiness optimization in job shop with interval uncertainty

This paper addresses a variant of the job shop scheduling problem with total tardiness minimization where task durations and due dates are uncertain. This uncertainty is modelled with intervals. Different ranking methods for intervals are considered and embedded into a genetic algorithm. A new robustness measure is proposed to compare the different ranking methods and assess their capacity to predict ‘expected delays’ of jobs. Experimental results show that dealing with uncertainty during the optimization process yields more robust solutions. A sensitivity analysis also shows that the robustness of the solutions given by the solving method increases when the uncertainty grows.This research has been supported by the Spanish Government under research grants PID2019-106263RB-I00 and TIN2017-87600-P

Monotonicity of a profile of rankings with ties

International Conference, IPMU (17th. 2018. Cádiz

Inclusive language and queer representation in adoption applications: a contrastive English-Spanish analysis

El lenguaje inclusivo constituye una forma simbólica de definir pertenencia a una comunidad o un intento de reflejar identidades y orientaciones que van más allá de la visibilidad de la mujer. Aunque se abren camino diferentes estrategias para lograr una mayor representación de ciertos colectivos, no todas resultan igual de aceptables en lo que se refiere a la esfera administrativo-legal. Justificando la posibilidad teórica de desestabilizar el género y la responsabilidad ética de reconocer todo el espectro que abarcan las siglas LGTBIQ+, se estudia una muestra compuesta por documentos de adopción en español y en inglés, que permitirá observar hasta qué punto se logra contemplar la presencia de una comunidad que es susceptible de tener que recurrir a estos instrumentos legales. Además de comprobar la efectividad de las estrategias utilizadas en ambas lenguas con propuestas fundamentadas desde el plano de la Lingüística, como la de Grijelmo, se reflexionará acerca de qué fórmulas resultan aceptables en este contexto específico de uso, en el que, si bien es cierto que se han producido algunos avances, aún queda camino por recorrer. No obstante, ambas lenguas disponen de mecanismos propios del lenguaje administrativo-legal que no obligan a incorporar neologismos ni dobletes y están perfectamente asentadas socialmente, por lo que se defiende la necesidad de estudiarlas e incluirlas para lograr un reconocimiento que el colectivo aún lucha por conseguir.Inclusive language represents a symbolic way of defining the belonging to a community or an attempt to reflect identities and orientations beyond the visibility of women. Although some strategies are starting to be used in order to achieve a more accurate representation of some groups, not all of them are totally acceptable in administrative and legal fields. By justifying the theoretical possibility of destabilizing gender and the ethical responsibility of acknowledging the whole spectrum included in the LGBTIQ+ denomination, this paper studies a corpus of adoption applications in Spanish and English, which allows to explore to which extent the LGBTIQ+ community is represented, a social group who may experience the adoption process. Validating the effect of the particular use of inclusive language in both languages, resorting to studies from Spanish Linguistics such as Grijelmo’s, the paper will also analyse formulas which may be acceptable in this specific context of use, where some advances have been made, but deeper research is needed. However, both languages have their own mechanisms, belonging to the administrative-legal context of use, which do not force speakers to include neologisms or artificial formulas, and are socially accepted: this is why there is a need to study and use them to achieve a representation which the LGBTIQ+ members are still fighting to see

Carbon-based nanomaterials for gold (III) recovery: kinetics and loading investigations

Currently, the development of different smart technology to recover or eliminate strategic or toxic metals from liquid effluent is constant. Among the different process developed to the treatment of liquid effluents bearing these types of metallic elements, include chemical or electrochemical precipitation, membrane based technology, ion exchange and adsorption. Adsorption is a high efficiency, cost-effectiveness and easily handing method to recover pollutants or strategic metals. Nowadays a research challenge is the development of new adsorbents. Among nanomaterials, carbon nanomaterials have adequate properties to be used as metal adsorbent. On the other hand gold is one of the most precious elements in the world. The price in 2015 of this strategic metal is 1.376 $/kg. Besides its uses in jewellery it is highly used in different industries, so it is important the gold recovery from liquid effluents generated from these various industries. The adsorption method is a way to treat these types of effluents, characterized for their low gold concentration. The aim of this research was to optimize various operational parameters, and thus obtain efficient carbon nanotubes processing for gold (III)-bearing effluents. The adsorption of gold (III) by carbon nanofibers (CNF), carbon multiwalled (MWCN) and carbon multiwalled with carboxyl group (MWCN_ox) systems were investigated. The experimental parameters which may influence gold adsorption were investigated, i.e. stirring speed of the aqueous solutions, adsorbent dosage, acid concentration, temperature etc. Figure 1 shows the effect of the acid concentration on the Au(III) adsorption to the three adsorbent. It can be seen that the adsorption Au(III) decreases with the increase of HCl concentration. Probalby it is due the existence of other gold species, such as HAuCl4, at the higher hydrochloric solution against the presence of the predominant AuCl4- species in the more dilute HCl solutions which are more adsorbable than the gold-acid form. SEM studies of gold loaded carbon nanomaterials show on the surface dark particles, Figure 2. The EDS of the dark particles show two peaks for Lα(9.7 keV) and Mα (2.1 keV) characteristic of metallic gold. Probably this reduction occurs on the carbon surface, related with the metal reduction. The isotherm and kinetic studies of the carbon nanomaterial-Au(III) system show a different behavior in function of the carbon nanomaterial used as adsorbent. The experimental data obtained using the MWCNT and CNF fit better to a pseudo second order equation and an isotherm Freundlich model. The three carbon nanomaterials, appeared to be a promising material for recovery of Au(III) from this type of acid solutions in the optimal experimental for each one of them condition.Peer reviewe

Indicators of the quality of the foster care

Una de las dificultades en la selección de las familias que se acercan al acogimiento familiar está relacionado con la falta de estudios que pudieran apuntar hacia características necesarias que apoyaran un desarrollo integral y comunitario óptimo del menor acogido y a su vez, en el proceso acogedor ayudar tanto a la familia como al menor para generar y/u optimizar aquellos recursos que permitan la consecución de las mismas. En una muestra de 53 familias que a lo largo tres años acogieron a 80 menores nuestro objetivo fue identificar las características que más habían favorecido el desarrollo del menor. Los resultados subrayan la importancia del establecimiento de vínculos seguros del menor con los acogedores, la integración del menor en la familia acogedora (la aparición de un sentido de pertenencia), la existencia de hijos en el núcleo de convivencia y una percepción de satisfacción con el acogimiento, por parte de la familia acogedora.One of the difficulties in choosing the families who come to foster care is related to the lack of studies that indicate the features needed to support optimal integrated development of children in foster care and also help in the process both the family as the child to generate the necessary resources. The sample consisted of 53 families with 80 children in foster care for three years. The aim was to identify characteristics that allow promote the development of the child. The results underline the importance of establishing secure links between the child and the foster family, the integration of the child in the foster family (the emergence of a sense of belonging), the existence of children in the foster family and a sense of satisfaction with welcoming, by the foster family.peerReviewe

Structural insights into the intracellular region of the human magnesium transport mediator CNNM4

The four member family of “Cyclin and Cystathionine β-synthase (CBS) domain divalent metal cation transport mediators”, CNNMs, are the least-studied mammalian magnesium transport mediators. CNNM4 is abundant in the brain and the intestinal tract, and its abnormal activity causes Jalili Syndrome. Recent findings show that suppression of CNNM4 in mice promotes malignant progression of intestinal polyps and is linked to infertility. The association of CNNM4 with phosphatases of the regenerating liver, PRLs, abrogates its Mg2+-efflux capacity, thus resulting in an increased intracellular Mg2+ concentration that favors tumor growth. Here we present the crystal structures of the two independent intracellular domains of human CNNM4, i.e., the Bateman module and the cyclic nucleotide binding-like domain (cNMP). We also derive a model structure for the full intracellular region in the absence and presence of MgATP and the oncogenic interacting partner, PRL-1. We find that only the Bateman module interacts with ATP and Mg2+, at non-overlapping sites facilitating their positive cooperativity. Furthermore, both domains dimerize autonomously, where the cNMP domain dimer forms a rigid cleft to restrict the Mg2+ induced sliding of the inserting CBS1 motives of the Bateman module, from a twisted to a flat disk shaped dimer.Gobierno Vasco PI2010-17, IE05-147, IE07-202Diputación Foral de Vizcaya 7/13/08/2006/11, 7/13/08/2005/14Ministerio de Ciencia e Innovación BFU2010-17857, CSD2008-00005Ministerio de Economía y Competitividad BFU2013-47531-R, BES-2014-068464, BFU2016-77408-R, BES-2017-08043