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

Group-Wise Principal Component Analysis for Exploratory Intrusion Detection

Intrusion detection is a relevant layer of cybersecurity to prevent hacking and illegal activities from happening on the assets of corporations. Anomaly-based Intrusion Detection Systems perform an unsupervised analysis on data collected from the network and end systems, in order to identify singular events. While this approach may produce many false alarms, it is also capable of identifying new (zeroday) security threats. In this context, the use of multivariate approaches such as Principal Component Analysis (PCA) provided promising results in the past. PCA can be used in exploratory mode or in learning mode. Here, we propose an exploratory intrusion detection that replaces PCA with Group-wise PCA (GPCA), a recently proposed data analysis technique with additional exploratory characteristics. A main advantage of GPCA over PCA is that the former yields simple models, easy to understand by security professionals not trained in multivariate tools. Besides, the workflow in the intrusion detection with GPCA is more coherent with dominant strategies in intrusion detection. We illustrate the application of GPCA in two case studies.This work was supported in part by the Spanish Government-MINECO (Ministerio de Economía y Competitividad), using the Fondo Europeo de Desarrollo Regional (FEDER), under Projects TIN2014-60346-R and Project TIN2017-83494-R

QVANDOQVE BONVS DORMITAT HOMERVS. ERRORES Y FALSEDAD EN ALGUNOS AUTORES GRIEGOS

In the works of certain Greek authors one may find, more or less visible, mistakes, negligences and incoherences. In some other occasions, what those authors intend to express and what they really offer seem to be contradictory; both faults, either being willing or not, attempt against the beauty of the works and against the credibility of their content. The aim of this essay is both to offer examples of this kind, and to proceed to a critical analysis, an appraisal and an explanation of the issue

Parodias de situaciones y versos homéricos en Aristófanes

Aristophanes often integrates in his comedies situations, complete lines, hemistichs or single words from the epic. The πάθος of such expressions powerfully contrasts with the linguistic and expressive context of his plays, and he thereafter obtains a strong comic effect. The use of verses different from the hexameter and, on the other hand, the authors' own interests acts against the litterality of the quotations. Moreover Aristophanes seems to consider Homer as the author of every epic word and, interesting enough, the presence of Homer in his comedies is more frequent than in other authors, like tragic or lyric poets, where this presence would be a priori more expectable. So Aristophanes frequently is the only witness of some Homeric expressions and topics in the litterature of the VIII-V b.C. centuriesNo disponible

Jorge Bergua Cavero, Pronunciación y prosodia del griego antiguo. Guía práctica para la lectura de sus textos, Madrid, Ediciones Clásicas, 2015, 122 pp. ISBN 978-8-47-882744-2

Review: Jorge Bergua Cavero, Pronunciación y prosodia del griego antiguo. Guía práctica para la lectura de sus textos, Madrid, Ediciones Clásicas, 2015, 122 pp. ISBN 978-8-47-882744-2Reseña de Jorge Bergua Cavero, Pronunciación y prosodia del griego antiguo. Guía práctica para la lectura de sus textos, Madrid, Ediciones Clásicas, 2015, 122 pp. ISBN 978-8-47-882744-

Extension of the SIESTA MHD equilibrium code to free-plasma-boundary problems

is a recently developed MHD equilibrium code designed to perform fast and accurate calculations of ideal MHD equilibria for three-dimensional magnetic configurations. Since SIESTA does not assume closed magnetic surfaces, the solution can exhibit magnetic islands and stochastic regions. In its original implementation SIESTA addressed only fixed-boundary problems. That is, the shape of the plasma edge, assumed to be a magnetic surface, was kept fixed as the solution iteratively converges to equilibrium. This condition somewhat restricts the possible applications of SIESTA. In this paper, we discuss an extension that will enable SIESTA to address free-plasma-boundary problems, opening up the possibility of investigating problems in which the plasma boundary is perturbed either externally or internally. As an illustration, SIESTA is applied to a configuration of the W7-X stellarator.This research was funded in part by the Ministerio de Economía, Industria y Competitividad of Spain, Grant No. ENE2015-68265. This research was carried out in part at the Max-Planck-Institute for Plasma Physics in Greifswald (Germany), whose hospitality is gratefully acknowledged. This research was supported in part by the U.S. Department of Energy, Office of Fusion Energy Sciences under Award DE-AC05-00OR22725. SIESTA runs have been carred out in Uranus, a supercomputer cluster located at Universidad Carlos III de Madrid and funded jointly by the European Regional Development Funds (EU-FEDER) Project No. UNC313-4E-2361, and by the Ministerio de Economía, Industria y Competitividad via the National Project Nos. ENE2009-12213-C03-03, ENE2012-33219, and ENE2012-31753

Constituents of Quercus eduardii leaf infusion: Their interaction with gut microbiota communities and therapeutic role in colorectal cancer.

The infusion of Q. eduardii leaves has been used ancestrally for medicinal purposes. We investigated the effect of Q. eduardii infusion intake on inflammatory and oncogenic biomarkers in animals induced to have colorectal cancer with DMH. We also investigated its influence on the microbiota, establishing the main microbial metabolites in the intestinal content of the experimental animals. The microbial metabolites associated with greater anti-inflammatory and anticarcinogenic activity were 3́-hydroxyphenylacetic acid (3HPA) and €-3-(3,4,5-trimethoxyphenyl) prop-2-enoic acid (TMCA). Finally, the intake of the Q. eduardii infusion significantly increased the abundance of the Erysipelotrichaceae and Lachnospiraceae families, that seems to have a great influence on the antitumor responses detected in the study.post-print4648 K

Insights on biodiversity drivers to predict species richness in tropical forests at the local scale

Disentangling the relative importance of different biodiversity drivers (i.e., climate, edaphic, historical factors, or human impact) to predict plant species richness at the local scale is one of the most important challenges in ecology. Biodiversity modelling is a key tool for the integration of these drivers and the predictions generated are essential, for example, for climate change forecast and conservation planning. However, the reliability of biodiversity models at the local scale remains poorly understood, especially in tropical species-rich areas, where they are required. We inventoried all woody plants with stems ≥ 2.5 cm in 397 plots across the Andes-Amazon gradient. We generated and mapped 19 uncorrelated biodiversity drivers at 90 m resolution, grouped into four categories: microclimatic, microtopographic, anthropic, and edaphic. In order to evaluate the importance of the different categories, we grouped biodiversity drivers into four different clusters by categories. For each of the four clusters of biodiversity drivers, we modelled the observed species richness using two statistical techniques (random forest and Bayesian inference) and two modelling procedures (including or excluding a spatial component). All the biodiversity models produced were evaluated by cross-validation. Species richness was accurately predicted by random forest (Spearman correlation up to 0.85 and explained variance up to 67%). The results suggest that precipitation and temperature are important driving forces of species richness in the region. Nonetheless, a spatial component should be considered to properly predict biodiversity. This could reflect macroevolutionary underlying forces not considered here, such as colonization time, dispersal capacities, or speciation rates. However, the proposed biodiversity modelling approach can predict accurately species richness at the local scale and detailed resolution (90 m) in tropical areas, something that previous works had found extremely challenging. The innovative methodology presented here could be employed in other areas with conservation needsWe thank the Consejería de Educacion (Comunidad de Madrid, Spain), National Geographic Society (8047-06, 7754-04), National Science Foundation (DEB#0101775, DEB#0743457, DEB#1557094), Spanish Ministry of Economy and Competitiveness (CGL2016-75414-P), Centro de Estudios de América Latina (Universidad Autonoma de Madrid – Banco Santander), Consejería de Educacion, Cultura y Deportes (Junta de Comunidades de Castilla-La Mancha, SBPLY/21/180501/000241), Spanish Ministry of Economy and Competitiveness (PID2019-106341GB-I00) for funding our research. The full dataset can be requested from the Madidi Project (https://madidiproject.weebly.com/