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

Multiobjective Algorithms with Resampling for Portfolio Optimization

Constrained financial portfolio optimization is a challenging domain where the use of multiobjective evolutionary algorithms has been thriving over the last few years. One of the major issues related to this problem is the dependence of the results on a set of parameters. Given the nature of financial prediction, these figures are often inaccurate, which results in unreliable estimates for the efficient frontier. In this paper we introduce a resampling mechanism that deals with uncertainty in the parameters and results in efficient frontiers that are more robust. We test this idea on real data using four multiobjective optimization algorithms (NSGA-II, GDE3, SMPSO and SPEA2). The results show that resampling significantly increases the reliability of the resulting portfolios

Dimerization model of the C-terminal RNA Recognition Motif of HuR

In PressHuman antigen R (HuR) is a ubiquitous 32kDa protein comprising three RNA Recognition Motifs (RRMs), whose main function is to bind Adenylate and uridylate Rich Elements (AREs) in 3′ UnTranslated Regions (UTRs) of mRNAs. In addition to binding RNA molecules, the third domain (RRM3) is involved in HuR oligomerization and apoptotic signaling. The RRM3 monomer is able to dimerize, with its self-binding affinity being dependent on ionic strength. Here we provide a deeper structural insight into the nature of the encounter complexes leading to the formation of RRM3 dimers by using Brownian Dynamics and Molecular Dynamics. Our computational data show that the initial unspecific encounter follows a downhill pathway until reaching an optimum conformation stabilized by hydrophobic interactions.I.D.-M. wishes to thank the Andalusian Government (P07-CVI-02896, P11-CVI-07216 and BIO198) for financial support.Peer reviewe

Time-stamped resampling for robust evolutionary portfolio optimization

Traditional mean–variance financial portfolio optimization is based on two sets of parameters, estimates for the asset returns and the variance–covariance matrix. The allocations resulting from both traditional methods and heuristics are very dependent on these values. Given the unreliability of these forecasts, the expected risk and return for the portfolios in the efficient frontier often differ from the expected ones. In this work we present a resampling method based on time-stamping to control the problem. The approach, which is compatible with different evolutionary multiobjective algorithms, is tested with four different alternatives. We also introduce new metrics to assess the reliability of forecast efficient frontiers.The authors acknowledge financial support granted by the Spanish Ministry of Science under contract TIN2008-06491-C04- 03 (MSTAR), TIN2011-28336 (MOVES) and Comunidad de Madrid (CCG10-UC3M/TIC-5029).Publicad

Through the magnifying glass: ALMA acute viewing of the intricate nebular architecture of OH231.8+4.2

We present continuum and molecular line emission ALMA observations of OH 231.8+4.2, a well studied bipolar nebula around an asymptotic giant branch (AGB) star. The high angular resolution (~0.2-0.3 arcsec) and sensitivity of our ALMA maps provide the most detailed and accurate description of the overall nebular structure and kinematics of this object to date. We have identified a number of outflow components previously unknown. Species studied in this work include 12CO, 13CO, CS, SO, SO2, OCS, SiO, SiS, H3O+, Na37Cl, and CH3OH. The molecules Na37Cl and CH3OH are first detections in OH 231.8+4.2, with CH3OH being also a first detection in an AGB star. Our ALMA maps bring to light the totally unexpected position of the mass-losing AGB star (QX Pup) relative to the large-scale outflow. QX Pup is enshrouded within a compact (<60 AU) parcel of dust and gas (clump S) in expansion (V~5-7 km/s) that is displaced by 0.6arcsec to the south of the dense equatorial region (or waist) where the bipolar lobes join. Our SiO maps disclose a compact bipolar outflow that emerges from QX Pup's vicinity. This outflow is oriented similarly to the large-scale nebula but the expansion velocities are about ten times lower (~35 km/s). We deduce short kinematical ages for the SiO outflow, ranging from ~50-80 yr, in regions within ~150 AU, to ~400-500 yr at the lobe tips (~3500 AU). Adjacent to the SiO outflow, we identify a small-scale hourglass-shaped structure (mini-hourglass) that is probably made of compressed ambient material formed as the SiO outflow penetrates the dense, central regions of the nebula. The lobes and the equatorial waist of the mini-hourglass are both radially expanding with a constant velocity gradient. The mini-waist is characterized by extremely low velocities, down to ~1 km/s at ~150 AU, which tentatively suggest the presence of a stable structure. (abridged

Obtención por vía SHS-AE de compuesto cerámico αSiC-αAl2O3-CaAl4O7

El presente trabajo muestra los resultados experimentales de la obtención del compuesto cerámico SiC-Al2O3-CaAl 4O7 mediante el proceso SHS-AE (síntesis auto-sostenida de alta temperatura combinada con arco eléctrico) a partir del sistema vidrio sódico-cálcico-Al-C. Se utilizó horno de arco eléctrico con atmósfera de argón para la reducción del contenido de sílice presente en el vidrio con aluminio.La combinación de la energía de la reacción de formación del Al2O3 con la del arco eléctrico provee suficiente energía térmica para superar las barreras cinéticas asociadas con la reacción de formación de los componentes cerámicos.A partir de las relaciones estequiométricas de las materias primas, (polvos que se compactan en forma de pastilla) se efectúa la síntesis alcanzando una temperatura superior a los 2500 K formándose el compuesto SiC-Al2O3-CaAl 4O7. Las muestras obtenidas se caracterizaron por DRX y MEB-EDX confirmando la obtención simultánea de αSiC-αAl2O3-CaAl4O7

Adipose-Derived Stem Cells in Crohn's Rectovaginal Fistula

Therapeutic options for recto-vaginal fistula in the setting of Crohn's disease are limited and many data are available in the literature. The manuscript describes the history of a patient who has been the pioneer of our Clinical Trials in treating this disease in fistulizing Crohn's disease environment. We believe it is the first time that a patient with this disease has been treated by adipose-derived stem cells in allogeneic form. The conclusion of our study with Mary is that the use of mesenchymal stem cells derived from adipose tissue is secure, either in autologous or allogeneic form. Furthermore, we have proved that if we use multi-dose and multiple applications on a patient, it does not produce any adverse effect, which confirms us the safety of using these cells in patients at least in the fistulizing Crohn's disease environment

Características del crecimiento de levaduras de aceitunas de mesa a bajas temperaturas

The behaviour of Picchia anomala, Picchia membranaefaciens, Pichia minuta, Saccharomyces cerevisiae, Candida diddensii, Candida famata y Debaryomyces hansenii, isolated form olive fermentations at low temperature was studied. The response, growth rate, at increasing time intervals, was studied by means of a General Linear Model (GLM) repeated measures, paying special attention to interactions. The most vigorous yeasts in YMGP were P. anomala, C. diddensii, y Deb. hansenii, who were able to grow at 7ºC and 8% salt. In brine, in addition to the main effects, the interactions salt-yeast, time-pH, time-yeast-species were also significant. P. membranaefaciens showed greater salt tolerance in brine than in YMPG. S. cerevisiae, P. minuta and C. famata were inhibited of both pH 3,5 and pH 4 at 7ºC. A sinergistic effect of salt and pH can inhibit yeast growth at 7ºC.Se ha estudiado el comportamiento dePicchia anomala, Picchia membranaefaciens, Pichia minuta, Saccharomyces cerevisiae, Candida diddensii, Candida famata y Debaryomyces Hansenii a bajas temperaturas. La respuesta, crecimiento relativo determinado a diferentes intervalos de tiempo, se ha estudiado mediante el modelo lineal general (GLM) con medidas repetidas, prestándose especial atención a las interacciones. Las levaduras más resistentes en medio YMGP fueron P. anomala, C. diddensii, y Deb. hansenii que crecieron a 7 ºC incluso al 8% de sal. En salmueras, además de los efectos principales, fueron también significativas las interacciones, concentración de sal-especie de levadura, tiempo-pH, tiempo-especie de levadura, tiempo-sal-pH y tiempo-sal-especie de levadura. P. membranaefaciens mostró mayor tolerancia a la sal en la salmuera que en YMGP. S. cerevisiae, P. membranaefaciens y C. famata se inhibieron a 7ºC tanto a pH 3,5 como 4, con independencia de los niveles de sal. Combinaciones adecuadas de pH y sal pueden inhibir el crecimiento a 7ºC

Natural coastal risks and the Coastal Zone Integrated Management

An analysis of the main natural risk factors of the Peninsula of Hicacos, on the coast center-west of Cuba is submitted. From an exhaustive bibliographic review, first it is presented a physical-geographical and socio-economic characterization of the peninsula of Hicacos, and on this basis are identified geological, geomorphological and hydrometeorological factors that determine natural hazards in the area under study. In particular an analysis of probabilities of extreme winds in the past 200 years associated with hurricanes, and the heights and periods of waves on the coast of the peninsula to different periods of return is materialize. Also it´s includes a brief analysis of the endogenous risks, and conclude that the hurricanes, the severe local storms and the frontal systems are the main natural dangers that affect the Peninsula. Finally the value of the MIZC for the study, prevision and confrontation of the natural risk is argued, and the positive experience of the application of that approach in the beach of Varadero.Se presenta un análisis de los principales factores de riesgos naturales de la Península de Hicacos, en la costa centro-occidental de Cuba. A partir de una revisión bibliográfica exhaustiva, se presenta primero una caracterización físico-geográfica y socio-económica de la península de Hicacos y sobre esta base se identifican los factores geológicos, geomorfológicos e hidrometeorológicos que condicionan los riesgos naturales en la zona objeto de estudio. En particular se realiza un análisis de probabilidades de los vientos extremos en los últimos 200 años asociados a los huracanes, y de las alturas y periodos del oleaje en el litoral de la península para diferentes periodos de retorno. Se incluye un breve análisis de los riesgos endógenos, y se concluye que son los huracanes, las tormentas locales severas y los frentes fríos los principales peligros naturales que afectan la a Península. Finalmente, se argumenta el valor del enfoque de MIZC para el estudio, previsión y enfrentamiento de los riesgos naturales, y se expone la positiva experiencia de aplicación de tal enfoque en la playa de Varadero.Ciencias Experimentale