The oncogene PDRG1 is an interaction target of methionine adenosyltransferases

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Methionine adenosyltransferases MAT I and MAT III (encoded by Mat1a) catalyze S-adenosylmethionine synthesis in normal liver. Major hepatic diseases concur with reduced levels of this essential methyl donor, which are primarily due to an expression switch from Mat1a towards Mat2a. Additional changes in the association state and even in subcellular localization of these isoenzymes are also detected. All these alterations result in a reduced content of the moderate (MAT I) and high V max (MAT III) isoenzymes, whereas the low V max (MAT II) isoenzyme increases and nuclear accumulation of MAT I is observed. These changes derive in a reduced availability of cytoplasmic S-adenosylmethionine, together with an effort to meet its needs in the nucleus of damaged cells, rendering enhanced levels of certain epigenetic modifications. In this context, the putative role of protein-protein interactions in the control of S-adenosylmethionine synthesis has been scarcely studied. Using yeast two hybrid and a rat liver library we identified PDRG1 as an interaction target for MATα1 (catalytic subunit of MAT I and MAT III), further confirmation being obtained by immunoprecipitation and pull-down assays. Nuclear MATα interacts physically and functionally with the PDRG1 oncogene, resulting in reduced DNA methylation levels. Increased Pdrg1 expression is detected in acute liver injury and hepatoma cells, together with decreased Mat1a expression and nuclear accumulation of MATα1. Silencing of Pdrg1 expression in hepatoma cells alters their steady-state expression profile on microarrays, downregulating genes associated with tumor progression according to GO pathway analysis. Altogether, the results unveil the role of PDRG1 in the control of the nuclear methylation status through methionine adenosyltransferase binding and its putative collaboration in the progression of hepatic diseases.This work was supported by grants of the Ministerio de Economía y Competitividad (BFU2005-00050, BFU2008-00666, BFU2009-08977), and the Instituto de Salud Carlos III Carlos III (RCMN C03/08 and PI05/0563

Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma

The lysyl oxidase-like protein 2 (LOXL2) contributes to tumour progression and metastasis in different tumour entities, but its role in pancreatic ductal adenocarcinoma (PDAC) has not been evaluated in immunocompetent in vivo PDAC models.Towards this end, we used PDAC patient data sets, patient-derived xenograft in vivo and in vitro models, and four conditional genetically-engineered mouse models (GEMMS) to dissect the role of LOXL2 in PDAC. For GEMM-based studies, K-Ras +/LSL-G12D;Trp53 LSL-R172H;Pdx1-Cre mice (KPC) and the K-Ras +/LSL-G12D;Pdx1-Cre mice (KC) were crossed with Loxl2 allele floxed mice (Loxl2 Exon2 fl/fl) or conditional Loxl2 overexpressing mice (R26Loxl2 KI/KI) to generate KPCL2 KO or KCL2 KO and KPCL2 KI or KCL2 KI mice, which were used to study overall survival; tumour incidence, burden and differentiation; metastases; epithelial to mesenchymal transition (EMT); stemness and extracellular collagen matrix (ECM) organisation. Using these PDAC mouse models, we show that while Loxl2 ablation had little effect on primary tumour development and growth, its loss significantly decreased metastasis and increased overall survival. We attribute this effect to non-cell autonomous factors, primarily ECM remodelling. Loxl2 overexpression, on the other hand, promoted primary and metastatic tumour growth and decreased overall survival, which could be linked to increased EMT and stemness. We also identified tumour-associated macrophage-secreted oncostatin M (OSM) as an inducer of LOXL2 expression, and show that targeting macrophages in vivo affects Osm and Loxl2 expression and collagen fibre alignment.Taken together, our findings establish novel pathophysiological roles and functions for LOXL2 in PDAC, which could be potentially exploited to treat metastatic diseaseg JCL-G received support from a ’la Caixa’ Foundation (ID 100010434) fellowship (LCF/BQ/DR21/11880011). This study was supported by ISCIII FIS grants PI18/00757 and PI21/01110 (BSJ) and PI18/00267 (LG-B), and grants from the Spanish Ministry of Economy and Innovation SAF2016-76504-R (ACan and FP), PID2019-111052RB-I00 (FP), PID2019-104644RB-I00 (GM-B), a Ramón y Cajal Merit Award RYC-2012–12104 (BSJ) and ISCIII, CIBERONC, CB16/12/00446 (ACar) and CB16/12/00295 (ACan and GM-B), all of them co-financed through Fondo Europeo de Desarrollo Regional (FEDER) ’Una manera de hacer Europa’; a Fero Foundation Grant (BSJ); a Coordinated grant (GC16173694BARB) from the Fundación Científica Asociación Española Contra el Cáncer (FC-AECC) (BSJ); a Miguel Servet award (CP16/00121) (PS); a DFG, German Research Foundation Grant—Project no: 492 436 553 (KG); and a Max Eder Fellowship of the German Cancer Aid (111746) (PCH

Voltage balancing in three-level neutral-point-clamped converters via Luenberger observer

This paper addresses the problems associated with the dc-link capacitor voltages of the three-level neutral-point-clamped power converter: the imbalance of the capacitor voltages as well as the presence of an ac-voltage low-frequency oscillation in the dc link of the converter. In order to cope with them, a mathematical analysis of the capacitor voltage difference dynamics, based on a direct average continuous model, is carried out, considering a singular perturbation approach. The analysis leads to a final expression where a sinusoidal disturbance appears explicitly. Consequently, the two problems can be handled together using the ordinary formulation of a problem of regulating the output of a system subject to sinusoidal disturbances, applying classical control theory to design the controller. In this way, the controller is designed including the disturbance estimate provided by a Luenberger observer to asymptotically cancel the disturbance, while keeping also balanced the capacitor voltages. Experiments for a synchronous three-level neutral-point-clamped converter prototype are carried out to evaluate the performance and usefulness of the converter working as a grid-connected inverter under the proposed control law.MICINN-FEDER DPI2009-09661Junta de Andalucía P07-TIC-0299

Increased bile resistance in Salmonella enterica mutants lacking Prc periplasmic protease

Prc is a periplasmic protease involved in processing of penicillin-binding protein 3 (PBP3). Lack of Prc suppressesbile sensitivity in Dam-, Wec-, PhoP-, DamX-, and SeqA- mutants of Salmonella enterica, and increases bile resistance in thewild type. Changes in the activity of penicillin binding proteins PBP3, PBP4, PBP5/6 and PBP7 are detected in a Prc-background, suggesting that peptidoglycan remodeling might contribute to bile resistance. [Int Microbiol 2013; 16(2):87-92]Keywords: Salmonella; bile; Prc protease; peptidoglycan; penicillin-binding protein

Obatoclax and Paclitaxel Synergistically Induce Apoptosis and Overcome Paclitaxel Resistance in Urothelial Cancer Cells

Paclitaxel is a treatment option for advanced or metastatic bladder cancer after the failure of first-line cisplatin and gemcitabine, although resistance limits its clinical benefits. Mcl-1 is an anti-apoptotic protein that promotes resistance to paclitaxel in different tumors. Obatoclax, a BH3 mimetic of the Bcl-2 family of proteins, antagonizes Mcl-1 and hence may reverse paclitaxel resistance in Mcl-1-overexpressing tumors. In this study, paclitaxel-sensitive 5637 and -resistant HT1197 bladder cancer cells were treated with paclitaxel, obatoclax, or combinations of both. Apoptosis, cell cycle, and autophagy were measured by Western blot, flow cytometry, and fluorescence microscopy. Moreover, Mcl-1 expression was analyzed by immunohistochemistry in bladder carcinoma tissues. Our results confirmed that paclitaxel alone induced Mcl-1 downregulation and apoptosis in 5637, but not in HT1197 cells; however, combinations of obatoclax and paclitaxel sensitized HT1197 cells to the treatment. In obatoclax-treated 5637 and obatoclax + paclitaxel-treated HT1197 cells, the blockade of the autophagic flux correlated with apoptosis and was associated with caspase-dependent cleavage of beclin-1. Obatoclax alone delayed the cell cycle in 5637, but not in HT1197 cells, whereas combinations of both retarded the cell cycle and reduced mitotic slippage. In conclusion, obatoclax sensitizes HT1197 cells to paclitaxel-induced apoptosis through the blockade of the autophagic flux and effects on the cell cycle. Furthermore, Mcl-1 is overexpressed in many invasive bladder carcinomas, and it is related to tumor progression, so Mcl-1 expression may be of predictive value in bladder cancer.España, Sistema Público Andaluz Biobanco y ISCIII-Red de Biobancos PT17/0015/004

Representaciones sociales sobre el cambio climático y sus efectos en adolescentes de instituciones oficiales y privadas de Montería– Córdoba

Se compararon las representaciones sociales de adolescentes sobre el cambio climático, causas y consecuencias de cuatro instituciones educativas de Montería, dos oficiales: Nacional José María Córdoba y Mercedes Abrego y dos privadas: Colegio La Salle y Windsor Royal School, grupo focal con edades entre los 12 y 16 años. Caracterizando sus saberes cotidianos y contrastándolos con información científica. Con un enfoque cualitativo mediante estudio de caso, se aplicaron entrevistas a profundidad analizadas mediante Atlas ti. Los resultados muestran que los adolescentes de instituciones públicas tienen concepciones erróneas sobre cambio climático, afirman no consultar sobre el tema y visitan pocos sitios de debate. Los estudiantes de instituciones privadas, muestran mayor apropiación del tema, relacionado con el acceso a información, asocian el concepto de cambio climático con cambios en el clima, sin embargo señalan erróneamente que es estacionario. Respecto a la adaptación no plantean respuestas acertadas, asocian el fenómeno a variabilidad climática y que el ser humano puede adaptarse al estar en diferentes climas, respuestas recurrentes en los adolescentes entrevistados, por tanto, se debe fortalecer un proceso crítico, reflexivo y participativo para el generar acciones individuales y colectivas de mitigación y adaptación a través de talleres pedagógicos de formación

The skill of learning to learn at University: proposal for a theoretical model.

Aprender a aprender es una de las competencias claves fijadas por la Comisión Europea (CE, 2005 y 2006) para los sistemas educativos de los países miembros. Las últimas investigaciones ponen de relieve la importancia de que los estudiantes universitarios aprendan a aprender, por lo que este estudio se ubica en la universidad. El objetivo es concretar un modelo teórico sobre dicha competencia que permita su operacionalización en los grados universitarios. Para ello se ha realizado una revisión de la literatura sobre el tema. Después de estudiar su fundamentación científica y la normativa reguladora, se analizaron múltiples modelos -especialmente provenientes de la literatura europea- y se propuso uno propio. Esta propuesta incluye cinco dimensiones, tres de las cuales (cognitiva, metacognitiva y afectivomotivacional) provienen de la psicología cognitiva y de las teorías sobre estrategias de aprendizaje y aprendizaje autorregulado. La cuarta (social/ relacional) está vinculada al enfoque sociocognitivo y la quinta (ética) es una aportación del equipo investigador, que la consideró fundamental para el desarrollo personal y social del aprendiz. La propia Comisión Europea, en su reformulación de la competencia en 2018, incluye elementos éticos dentro del aprender a aprender. Estas dimensiones se concretaron en subdimensiones, de las que se aporta su descripción. A partir de la revisión de la literatura realizada y de la reflexión del equipo investigador se propone un modelo teórico integrador con un desarrollo más pormenorizado de lo que es habitual en la literatura que se pretende sirva de referente para el trabajo de la competencia en los grados universitarios.Learning to learn is one of the key skills set by the European Commission (EC, 2005 and 2006) to be transmitted through the education systems. The latest research highlights the relevance of university students learning to learn. Our aim is to specify a theoretical model of this skill in order to allow it to become operational in university degrees. To this end, a literature review was carried out. After studying its scientific basis and regulations, several models were analyzed -specifically from European literature- and an own model was formulated. This proposal includes five dimensions, three of them (cognitive, metacognitive and affective-motivational) coming from cognitive psychology, as well as theories on learning strategies and self-regulated learning. The fourth one (social/relational) is linked to the socio-cognitive approach and the fifth one (ethical) is a contribution of the research team, which considers it is fundamental for the personal and social development of the learner. The European Commission reformulated the skill in 2018 and included ethical elements for learning to learn. The dimensions we propose were specified in subdimensions, for which a description is provided. From the review of the scientific literature and from the reflection of the research team, an integrative model is proposed. This model has a more detailed development than is usual in the literature. Our intention is to serve as a reference for this skill in the university degreesPedagogí

Estimación del grado básico de calidad en canales bovinas conforme a madurez ósea, marmoleo y predominancia fenotípica Bos indicus

In order to estimate the Basic Quality Grade of beef carcasses according to bone maturity, marbling and Bos indicus racial predominance, data from 1,417 carcasses processed in four Federal Inspection Type establishments were analyzed. The following variables were recorded: cavitary fat, rib eye area, dorsal fat thickness, hump length and height, marbling, and bone maturity. Using the variables marbling and bone maturity, the Basic Grade of Quality was estimated in accordance with the norm NOM-004-SAGARPA-2018. The hump height was used as a criterion to determine racial predominance, and four groups were generated from this information. Based on the recorded values, descriptive statistics, analysis of variance, comparison of means, and Tukey's test were determined. The hump height in each group was 7.19, 10.54, 14.38, and 20.11 cm (P<0.01), respectively. 82 % of the carcasses were predominantly Bos indicus. The hot carcass weight was 310.05 kg for group 1 vs 326.99 kg for group 4 (P<0.01). The rib eye area was 85.59 cm2 for group 1 vs 89.14 cm2 for group 2 (P<0.05). Of the total number of carcasses evaluated, 60 were classified as Supreme quality  (4.23 %),  655 as Select  quality  (46.22 %),  621 as  Standard  quality (43.82 %), and 81 as Commercial quality (5.72 %). The beef carcasses in this study have mainly a Bos indicus breed component, and their Basic Quality Grade corresponded primarily to a greater number of carcasses with grade A bone maturity, but with less marbling.Para estimar el Grado Básico de Calidad de canales bovinas conforme a madurez ósea, marmoleo y predominancia racial Bos indicus, se analizaron los datos de 1,417 canales procesadas en cuatro establecimientos Tipo Inspección Federal. Se registraron las variables: grasa cavitaria, área del ojo de costilla, espesor de la grasa dorsal, largo y altura de la giba, marmoleo y madurez ósea. Mediante las variables marmoleo y madurez ósea se estimó el Grado Básico de Calidad con base en la NOM-004-SAGARPA-2018. La altura de la giba se utilizó como criterio para determinar la predominancia racial y mediante esta información se generaron cuatro grupos. Con base en los valores registrados, se determinaron las estadísticas descriptivas, análisis de la varianza comparación de medias, análisis de frecuencias y prueba de Tukey. La altura de la giba en cada grupo fue de 7.19, 10.54, 14.38 y 20.11 cm (P<0.01), respectivamente. El 82 % de las canales mostraron predominancia racial Bos indicus. El peso de la canal caliente fue 310.05 kg para el grupo 1 vs 326.99 kg para el grupo 4 (P<0.01). El área del ojo de la costilla fue de 85.59 cm2 para el grupo 1 vs 89.14 cm2 para el 2 (P<0.05). Del total de canales evaluadas, 60 clasificaron de calidad Suprema (4.23 %), 655 de calidad Selecta (46.22 %), 621 de calidad Estándar (43.82 %) y 81 Comerciales (5.72 %). Las canales de bovino objeto del presente estudio, presentan mayormente un componente racial Bos indicus y su Grado Básico de Calidad primordialmente correspondió a la mayor cantidad de canales con madurez ósea grado A, pero con menor marmoleo

Effect of a brief intervention for alcohol and illicit drug use on trauma recidivism in a cohort of trauma patients

OBJETIVO Estime la efectividad de las intervenciones breves para reducir la reincidencia de traumas en pacientes hospitalizados que tuvieron resultados positivos en la prueba de alcohol y / o uso de drogas ilícitas. Metodos Estudio de cohorte dinámico basado en datos de registro de 1818 pacientes incluidos en un programa de detección e intervención breve para el uso de alcohol y drogas ilícitas para pacientes hospitalizados con traumatismos. Del análisis de los datos surgieron tres subcohortes: los pacientes que obtuvieron un resultado negativo, los que obtuvieron un resultado positivo y se les ofreció una intervención breve, y los que obtuvieron un resultado positivo y no se les ofreció una intervención breve. El seguimiento duró de 10 a 52 meses. Se calcularon la supervivencia libre de traumatismo, los índices de tasa de riesgo ajustados (aHRR) y los índices de tasa de incidencia ajustados (aIRR), y se utilizó un análisis de efecto causal promedio más completo (CACE). RESULTADOS Encontramos un mayor riesgo acumulativo de reincidencia de trauma en el subcohort que dio positivo. En esta subcohorte, se obtuvo un aHRR de 0,63 (IC del 95%: 0,41-0,95) para el grupo que ofreció una intervención breve en comparación con el grupo que no recibió intervención. El análisis CACE produjo una reducción estimada del 52% en la reincidencia del trauma asociada con la intervención breve. CONCLUSIÓN La breve intervención ofrecida durante la hospitalización en pacientes con trauma positivos por el uso de alcohol y / o drogas ilícitas puede reducir a la mitad la incidencia de reincidencia del trauma.OBJECTIVE Estimate the effectiveness of brief interventions in reducing trauma recidivism in hospitalized trauma patients who screened positive for alcohol and/or illicit drug use. METHODS Dynamic cohort study based on registry data from 1818 patients included in a screening and brief intervention program for alcohol and illicit drug use for hospitalized trauma patients. Three subcohorts emerged from the data analysis: patients who screened negative, those who screened positive and were offered brief intervention, and those who screened positive and were not offered brief intervention. Follow-up lasted from 10 to 52 months. Trauma-free survival, adjusted hazard rate ratios (aHRR) and adjusted incidence rate ratios (aIRR) were calculated, and complier average causal effect (CACE) analysis was used. RESULTS We found a higher cumulative risk of trauma recidivism in the subcohort who screened positive. In this subcohort, an aHRR of 0.63 (95% CI: 0.41–0.95) was obtained for the group offered brief intervention compared to the group not offered intervention. CACE analysis yielded an estimated 52% reduction in trauma recidivism associated with the brief intervention. CONCLUSION The brief intervention offered during hospitalization in trauma patients positive for alcohol and/or illicit drug use can halve the incidence of trauma recidivism.• Dirección General de Tráfico. Beca 0100DGT22389, para Enrique Fernández Mondéjar • Junta de Andalucía. Beca PI-0691-2013, para Raquel Vilar López • Ministerio de Educación, Cultura y Deportes. Beca FPU13/00669, para Juan Francisco Navas PérezpeerReviewe