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

Predictors of problematic internet and mobile phone usage in adolescents

This study uses an innovative statistical strategy to test the role of certain variables as predictors of problematic Internet and mobile phone usage among adolescents in Spain and in the United Kingdom . A paper-and-pencil questionnaire was used, with socio-demographics and patterns of technology usage as variables, and two tests were administered: the Problematic Internet Entertainment Use Scale for Adolescents (PIEUSA) and the Mobile Phone Problem Use Scale for Adolescents (MPPUSA). The overall sample size was 2228 high school students aged between 11 and 18 from Barcelona and London. PIEUSA and MPPUSA scores were transformed into normed scores, and both were then dichotomized according to three statistical criteria as cut-off points (i.e., median, 80th percentile, and extreme scores below the 25th percentile and above the 75th percentile) in order to establish the relationship between the variables above and the excessive use of the Internet or mobile phones, using a binary logistic regression. The results show that the best predictive model for both technologies includes socio-demographic variables as predictors of extreme scores for excessive Internet and mobile phone usage, with good sensitivity, specificity and classification accuracy, as well as a notable capacity for discrimination according to the receiver-operating characteristic curve. Implications of these findings are discussed

CAMBIO DE COBERTURA Y USO DEL SUELO EN LA CUENCA DEL RIO MOLOLOA, NAYARIT

Los cambios de cobertura y uso del suelo se han reconocido en muchos países como una de las principales causas de deterioro ambiental, por ello están ubicados en el centro de la investigación ambiental y representan un punto importante en diferentes ámbitos como medio para entender los mecanismos de este proceso de deterioro y guía para la toma razo- nable de decisiones sobre el uso del territorio. En el estado de Nayarit, la cuenca del río Mo- loloa ha proveído de un conjunto de bienes y servicios a las localidades que involucra; des- afortunadamente, esta relación ha repercutido en un deterioro acelerado de sus recursos na- turales. En este trabajo se analizan los cambios de cobertura y uso del suelo en la cuenca del río Mololoa, entre 1995 y 2005, a partir de la interpretación de ortofotos digitales y manejo de la información en un SIG. Los resultados muestran que el paisaje de la cuenca está dominado en 83.01% por la vegetación natural y tierras de cultivo. La dinámica de cambio está centrada en los tipos de cobertura “vegetación natural” y “construcciones”, la primera disminuye a una tasa de 41.67 ha/año, y la segunda, aumenta 74.86 ha/año. La tasa de deforestación de los bosques y selvas de la región fue de 0.1 y 0.36%, menor a las reportadas por diferentes autores a nivel nacional y estatal

Structural efficiency of percolation landscapes in flow networks

Complex networks characterized by global transport processes rely on the presence of directed paths from input to output nodes and edges, which organize in characteristic linked components. The analysis of such network-spanning structures in the framework of percolation theory, and in particular the key role of edge interfaces bridging the communication between core and periphery, allow us to shed light on the structural properties of real and theoretical flow networks, and to define criteria and quantities to characterize their efficiency at the interplay between structure and functionality. In particular, it is possible to assess that an optimal flow network should look like a "hairy ball", so to minimize bottleneck effects and the sensitivity to failures. Moreover, the thorough analysis of two real networks, the Internet customer-provider set of relationships at the autonomous system level and the nervous system of the worm Caenorhabditis elegans --that have been shaped by very different dynamics and in very different time-scales--, reveals that whereas biological evolution has selected a structure close to the optimal layout, market competition does not necessarily tend toward the most customer efficient architecture.Comment: 8 pages, 5 figure

Truncated Power Laws Reveal a Link between Low-Level Behavioral Processes and Grouping Patterns in a Colonial Bird

Background: Departures from power law group size frequency distributions have been proposed as a useful tool to link individual behavior with population patterns and dynamics, although examples are scarce for wild animal populations. Methodology/Principal Findings: We studied a population of Lesser kestrels (Falco naumanni) breeding in groups (colonies) from one to ca. 40 breeding pairs in 10,000 km 2 in NE Spain. A 3.5 fold steady population increase occurred during the eight-year study period, accompanied by a geographical expansion from an initial subpopulation which in turn remained stable in numbers. This population instability was mainly driven by first-breeders, which are less competitive at breeding sites, being relegated to breed solitarily or in small colony sizes, and disperse farther than adults. Colony size frequency distributions shifted from an initial power law to a truncated power law mirroring population increase. Thus, we hypothesized that population instability was behind the truncation of the power law. Accordingly, we found a power law distribution through years in the initial subpopulation, and a match between the power law breakpoint (at ca. ten pairs) and those colony sizes from which the despotic behavior of colony owners started to impair the settlement of newcomers. Moreover, the instability hypothesis was further supported by snapshot data from another population of Lesser kestrels in SW Spain suffering a population decline. Conclusions/Significance: Appropriate analysis of the scaling properties of grouping patterns has unraveled the lin

Simulation of the evolution of floor covering ceramic tiles during the firing

In the context of the firing of ceramic tiles the problem of simulating the final shape of the body is relevant because several defects can occur and the tile can be rejected if the conditions of the firing are inadequate for the geometry and materials of the tile -- The existing literature on this problem indicates that previous works present limitations in aspects such as not using a model characteristic of ceramics at high temperatures and oversimplifying the problem -- As a response to such shortcomings, this article presents a simulation with a 3-dimensional Norton’s model, which overcomes the difficulties because it is characteristic of ceramics at high temperatures -- The results of our simulated experiments show advantages with respect to the identification of the mechanisms that contribute to the final shape of the body -- Our work is able to divide the history of temperatures in stages where the evolution of the thermal, elastic and creep deformations is simplified and meaningful -- That is achieved because our work found that curvature is the most descriptive parameter of the simulation, the most important contribution of this article -- Future work is to be realized in the creation of a model that takes into account that the shrinkage is dependent on the history of temperatures -- The main shortcoming of the paper is the lack of physical experiments to corroborate the simulation

Galectin-3 shapes toxic alpha-synuclein strains in Parkinson's disease.

Parkinson's Disease (PD) is a neurodegenerative and progressive disorder characterised by intracytoplasmic inclusions called Lewy bodies (LB) and degeneration of dopaminergic neurons in the substantia nigra (SN). Aggregated α-synuclein (αSYN) is known to be the main component of the LB. It has also been reported to interact with several proteins and organelles. Galectin-3 (GAL3) is known to have a detrimental function in neurodegenerative diseases. It is a galactose-binding protein without known catalytic activity and is expressed mainly by activated microglial cells in the central nervous system (CNS). GAL3 has been previously found in the outer layer of the LB in post-mortem brains. However, the role of GAL3 in PD is yet to be elucidated. In post-mortem samples, we identified an association between GAL3 and LB in all the PD subjects studied. GAL3 was linked to less αSYN in the LB outer layer and other αSYN deposits, including pale bodies. GAL3 was also associated with disrupted lysosomes. In vitro studies demonstrate that exogenous recombinant Gal3 is internalised by neuronal cell lines and primary neurons where it interacts with endogenous αSyn fibrils. In addition, aggregation experiments show that Gal3 affects spatial propagation and the stability of pre-formed αSyn fibrils resulting in short, amorphous toxic strains. To further investigate these observations in vivo, we take advantage of WT and Gal3KO mice subjected to intranigral injection of adenovirus overexpressing human αSyn as a PD model. In line with our in vitro studies, under these conditions, genetic deletion of GAL3 leads to increased intracellular αSyn accumulation within dopaminergic neurons and remarkably preserved dopaminergic integrity and motor function. Overall, our data suggest a prominent role for GAL3 in the aggregation process of αSYN and LB formation, leading to the production of short species to the detriment of larger strains which triggers neuronal degeneration in a mouse model of PD

pH control of conductance in a pyrazolyl Langmuir–Blodgett monolayer

In this contribution pyrazole is identified as an excellent anchor group that forms high quality films under pH controlled conditions, allowing the modulation of the electrical properties with a more efficient electronic coupling in basic conditions.</p