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

Enhanced Parallel Generation of Tree Structures for the Recognition of 3D Images

Segmentations of a digital object based on a connectivity criterion at n-xel or sub-n-xel level are useful tools in image topological analysis and recognition. Working with cell complex analogous of digital objects, an example of this kind of segmentation is that obtained from the combinatorial representation so called Homological Spanning Forest (HSF, for short) which, informally, classifies the cells of the complex as belonging to regions containing the maximal number of cells sharing the same homological (algebraic homology with coefficient in a field) information. We design here a parallel method for computing a HSF (using homology with coefficients in Z/2Z) of a 3D digital object. If this object is included in a 3D image of m1 × m2 × m3 voxels, its theoretical time complexity order is near O(log(m1 + m2 + m3)), under the assumption that a processing element is available for each voxel. A prototype implementation validating our results has been written and several synthetic, random and medical tridimensional images have been used for testing. The experiments allow us to assert that the number of iterations in which the homological information is found varies only to a small extent from the theoretical computational time.Ministerio de Economía y Competitividad MTM2016-81030-

The political hourglass: opportunistic behavior in local government policy decisions

The aim of this article is to determine whether there is opportunistic behavior in local government decisions related to contracting out, public-private partnership (PPP) and/or public externalization. Analysis of the results obtained from applying a fixed effects panel data model to a sample of 2,274 Spanish municipalities supports the existence of asymmetric opportunistic behavior. Specifically, there is strong evidence that in preelection years, there is less likelihood of contracting out and PPP decisions being approved, and a greater probability of public externalization taking place. In post-election years, an increase in capital spending is associated with a lower probability of contracting out and of PPP. An increase in current spending in preelection years reduces the probability of decisions being taken on contracting out and PPP. These empirical results highlight the extent of opportunistic behavior in selecting management forms for the delivery of local government services

Cost Minimization of Virtual Machine Allocation in Public Clouds Considering Multiple Applications

International Conference, GECON 2017 (14. 2017. Biarritz)This paper presents a virtual machine (VM) allocation strategy to optimize the cost of VM deployments in public clouds. It can simultaneously deal with multiple applications and it is formulated as an optimization problem that takes the level of performance to be reached by a set of applications as inputs. It considers real characteristics of infrastructure providers such as VM types, limits on the number VMs that can be deployed, and pricing schemes. As output, it generates a VM allocation to support the performance requirements of all the applications. The strategy combines short-term and long-term allocation phases in order to take advantage of VMs belonging to two different pricing categories: on-demand and reserved. A quantization technique is introduced to reduce the size of the allocation problem and, thus, significantly decrease the computational complexity. The experiments show that the strategy can optimize costs for problems that could not be solved with previous approache

A comparison of methods for the quality control of 123I-Ioflupane

Objetivos: Se pretende establecer un método sencillo, preciso y reproducible para determinar la pureza radioquímica del 123I-Ioflupano.Material y Métodos: Se utilizó la radiocromatografía con tres tipos de fases estacionarias (whatmann-17MM, Whatmann-3MM e ITLC-SG) y cinco fases móviles (Éter Dietílico, Metiletilcetona, NaCl al 0,9%, Metanol:Cloroformo(1:9), Metanol:Agua al 85%). Este procedimiento fue realizado con alícuotas de 123I-Ioflupano (DatScan®) y 123INa para estudiar el comportamiento del yoduro libre.Resultados: Se descartó el whatmann-3MM por su mala separación y el ITLC-SG con Metanol:Agua por su baja reproducibilidad. Usando Metiletilcetona como fase móvil en ITLC-SG y Whatmann-17MM no se observa la fracción libre. Únicamente se observó la fracción libre en Whatmann-17MM tanto con Metanol:Cloroformo como con Éter Dietílico y en ITLC-SG con NaCl 0,9% .Conclusiones: La mejor separación del 123I-Ioflupano del 123I- fue observada con: Whatmann-17MM/ Metanol:Cloroformo (1:9) (Rf de la fracción ligada = 0,62±0,03, Pureza Radioquímica = 91,6±2,36) , ITLC-SG/NaCl 0,9% (Rf de la fracción ligada = 0,21±0,05, Pureza Radioquímica = 90,19±3,4) y Whatmann-17MM /Éter Dietílico (Rf de la fracción ligada = 0,62±0,06, Pureza Radioquímica = 92,79±1,65).Aim: The aim of this study is to stablish an easy, reproducible, and precise method to determine the radiochemical purity of 123I-Ioflupane.Material and methods: Different systems of radiochromatography were used with three types of stationary phases (Whatmann-17MM, Whatmann-3MM and ITLC-SG) and five mobile phases (Diethylether, NaCl 0.9%, Methanol:Chloroform(1:9), Methanol:Water (85:15) and Methylethylketone). This procedure was made with samples of 123I-Ioflupane and 123I-NaI to study the behaviour of free iodide.Results: Whatmann-3MM was rejected due to an unsuccessful separation and Methanol:Water (85:15) with ITLC-SG was not reproducible. Free fraction wasn`t observed in Methylethylketone as mobile phase with ITLC-SG and Whatmann-17MM. Free fraction was just observed in Whatmann-17MM with Methanol:Cloroform and Diethylether and in ITLC-SG with NaCl 0.9%.Conclusions: Maximum separation between 123I-Ioflupane and 123I- was observed in Whatmann-17MM/Methanol:Cloroform(1:9) (Rf of bound fraction = 0.62±0.03, Radiochemical Purity =91.6±2.36%), ITLC-SG/NaCl 0,9% (Rf of bound fraction = 0.21±0.05, Radiochemical Purity =90.19±3.4%) and Whatmann-17MM/ Diethylether (Rf of bound fraction = 0.62±0.06, Radiochemical Purity =92.79±1.65%)

Implicaciones anestésicas en el Síndrome de Larsen: A propósito de un caso

Larsen Syndrome (SL) is a rare hereditary disease characterized by a defect in the formation of collagen due to mutations in the genes encoding the cytoskeletal protein filamin B. Its prevalence in Europe is approximately 1 to 250,000 live births. This implies a number of anatomical features of the airway that we must assess in children who are going under anesthesia. We present the case of an 11-year-old boy diagnosed with Larsen syndrome who underwent left ear aticotomy. In this regard, we conducted a literature review on the peculiarities of anesthetic management of these patients.  El síndrome de Larsen (SL) es una enfermedad hereditaria rara caracterizada por un defecto en la formación de colágeno debido a mutaciones en los genes que codifican la proteína citoesquelética filamina B. Su prevalencia en Europa es aproximadamente de 1/250.000 nacidos vivos. Esto implica una serie de rasgos y particularidades anatómicas de la vía aérea que debemos valorar en niños que van a ser sometidos a un acto anestésico. Se presenta el caso de un niño de 11 años diagnosticado de síndrome de Larsen que se interviene de aticotomía oído izquierdo. A este propósito, realizamos revisión bibliográfica sobre las peculiaridades del manejo anestésico de estos pacientes

The effects of spatial survey bias and habitat suitability on predicting the distribution of threatened species living in remote areas

Knowledge of a species’ potential distribution and the suitability of available habitat are fundamental for effective conservation planning and management. However, the quality of information on the distribution of species and their required habitats is highly variable in terms of accuracy and availability across taxa and regions, particularly in tropical landscapes where accessibility is especially challenging. Species distribution models (SDMs) provide predictive tools for addressing gaps for poorly surveyed species, but they rarely consider biases in geographical distribution of records and their consequences. We applied SDMs and variation partitioning analyses to investigate the relative importance of habitat characteristics, human accessibility, and their joint effects in the global distribution of the Critically Endangered Blue-throated Macaw Ara glaucogularis, a species endemic to the Amazonian flooded savannas of Bolivia. The probability of occurrence was skewed towards more accessible areas, mostly secondary roads. Variability in observed occurrence patterns was mostly accounted for by the pure effect of habitat characteristics (76.2%), indicating that bias in the geographical distribution of occurrences does not invalidate species-habitat relationships derived from niche models. However, observed spatial covariation between land-use at a landscape scale and accessibility (joint contribution: 22.3%) may confound the independent role of land-use in the species distribution. New surveys should prioritise collecting data in more remote (less accessible) areas better distributed with respect to land-use composition at a landscape scale. Our results encourage wider application of partitioning methods to quantify the extent of sampling bias in datasets used in habitat modelling for a better understanding of species-habitat relationships, and add insights into the potential distribution of our study species and opportunities for its conservation

Actualidad del Síndrome de Munchausen: su médico, su cuerpo y su dolor.

A propósito de seis casos, con probable diagnóstico de Síndrome de Munchausen, se hace una revisión bibliográfica de los tres últimos años, al mismo tiempo que mediante tests proyectivos se intenta buscar características comunes en este síndrome, así como se hace un intento de aproximación psicodinámica a dicho síndrome

UNA EXPERIENCIA SOBRE LA UTILIZACIÓN DEL DIARIO REFLEXIVO COMO INSTRUMENTO DE SEGUIMIENTO Y EVALUACIÓN DE LAS PRÁCTICAS HOSPITALARIAS DEL ALUMNADO DE ENFERMERÍA.

The European Higher Education Space outlines several changes on the perspectives both on the basic function of the nursing discipline, on the structure of the universitary curriculum and on the teaching/learning process based in the skills. This changes prompt us to a integrated organization of the clinical practices of the curriculum subject. In this way, we had promoted a Clinical Practices Project based on the skills to be acquired by the second course students of the Degree in Nursing of the University of Córdoba during the academic course 2006-07. In this Project the following subjects had participated: Medical-Surgical Nursing I, Maternal-Infantile Nursing I and Clinical Farmacology, Nutrition and Dietary. The objective of this article is to analyze the use of the Reflexive Diary as an assessment technique, i. e., has an instrument to follow and evaluate the learning results of the professional skills in the integrated clinical practices of those subjects.El Espacio Europeo de Educación Superior plantea diversos cambios tanto en la proyección de la función básica de la disciplina enfermera, como en la estructura de los currículos universitarios y en el proceso de enseñanza/aprendizaje por competencias. Estos cambios inducen a una organización de las prácticas clínicas de las diferentes asignaturas de forma integrada. A tal fin, se ha puesto en marcha un proyecto de Prácticas Integradas basadas en las competencias a adquirir por el alumnado del segundo curso de la Diplomatura de Enfermería de la Universidad de Córdoba para el curso 2006-07, en el que han participado las asignaturas: Enfermería Medico-Quirúrgica I, Enfermería Materno-Infantil I y Farmacología Clínica Nutrición y Dietética. El objeto de este artículo es analizar la utilización del Diario Reflexivo como técnica de “assessment”; es decir, como instrumento para el seguimiento y evaluación de los resultados de aprendizaje de las competencias profesionales en las prácticas clínicas integradas de esas asignaturas