ATPase-Dependent Control of the Mms21 SUMO Ligase during DNA Repair

Modification of proteins by SUMO is essential for the maintenance of genome integrity. During DNA replication, the Mms21-branch of the SUMO pathway counteracts recombination intermediates at damaged replication forks, thus facilitating sister chromatid disjunction. The Mms21 SUMO ligase docks to the arm region of the Smc5 protein in the Smc5/6 complex; together, they cooperate during recombinational DNA repair. Yet how the activity of the SUMO ligase is controlled remains unknown. Here we show that the SUMO ligase and the chromosome disjunction functions of Mms21 depend on its docking to an intact and active Smc5/6 complex, indicating that the Smc5/6-Mms21 complex operates as a large SUMO ligase in vivo. In spite of the physical distance separating the E3 and the nucleotide-binding domains in Smc5/6, Mms21-dependent sumoylation requires binding of ATP to Smc5, a step that is part of the ligase mechanism that assists Ubc9 function. The communication is enabled by the presence of a conserved disruption in the coiled coil domain of Smc5, pointing to potential conformational changes for SUMO ligase activation. In accordance, scanning force microscopy of the Smc5-Mms21 heterodimer shows that the molecule is physically remodeled in an ATP-dependent manner. Our results demonstrate that the ATP-binding activity of the Smc5/6 complex is coordinated with its SUMO ligase, through the coiled coil domain of Smc5 and the physical remodeling of the molecule, to promote sumoylation and chromosome disjunction during DNA repair

ADGRL3 (LPHN3) variants predict substance use disorder

Genetic factors are strongly implicated in the susceptibility to develop externalizing syndromes such as attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder, conduct disorder, and substance use disorder (SUD). Variants in the ADGRL3 (LPHN3) gene predispose to ADHD and predict ADHD severity, disruptive behaviors comorbidity, long-term outcome, and response to treatment. In this study, we investigated whether variants within ADGRL3 are associated with SUD, a disorder that is frequently co-morbid with ADHD. Using family-based, case-control, and longitudinal samples from disparate regions of the world (n = 2698), recruited either for clinical, genetic epidemiological or pharmacogenomic studies of ADHD, we assembled recursive-partitioning frameworks (classification tree analyses) with clinical, demographic, and ADGRL3 genetic information to predict SUD susceptibility. Our results indicate that SUD can be efficiently and robustly predicted in ADHD participants. The genetic models used remained highly efficient in predicting SUD in a large sample of individuals with severe SUD from a psychiatric institution that were not ascertained on the basis of ADHD diagnosis, thus identifying ADGRL3 as a risk gene for SUD. Recursive-partitioning analyses revealed that rs4860437 was the predominant predictive variant. This new methodological approach offers novel insights into higher order predictive interactions and offers a unique opportunity for translational application in the clinical assessment of patients at high risk for SUD

Repensar els estudis catalans des de la teoria queer

Catalan Studies are basically focused on national/linguistic identity, but recent debate on Catalan identity triggered by the current pro-independent process in Catalonia, may help reshape this academic field. A more diverse approach to Catalan culture should consider sexuality, which has traditionally been banished from literary analysis as a ‘private’ matter. Here, we discussed how queer theory can reframe Catalan Studies mainly by building a specific LGBT literary tradition, identifying queer episodes and characters in the canon, questioning received meanings, promoting interdisciplinary analysis of Catalan culture and exploring the role of queer subjectivity in history

Modelo para predecir mortalidad en pacientes con cáncer diferenciado de tiroides

El carcinoma diferenciado tiroideo presenta un incremento de la mortalidad por todas las causas. Pocos estudios han construido modelos predictivos de mortalidad por todas las causas con alto poder discriminante en este tipo de pacientes y permiten conocer cuáles tienen mayor probabilidad de fallecimiento. Objetivo: construir un modelo predictivo de mortalidad por todas las causas a los 5, 10, 15 y 20 años en pacientes diagnosticados y tratados quirúrgicamente de carcinoma diferenciado tiroideo e implementarlo en una aplicación para teléfono móvil. Diseño: estudio de cohortes retrospectivo con datos entre 1984 y 2013. Marco: todos los pacientes diagnosticados y operados de carcinoma diferenciado tiroideo en un hospital general universitario de una población cercana a los 200,000 habitantes en España. Participantes: 201 pacientes diagnosticados y operados de carcinoma diferenciado tiroideo (174, papilar; 27, folicular). Variables de exposición: edad, sexo, municipio, antecedentes familiares, tipo de cirugía, tipo de cáncer, subtipos histológicos, microcarcinoma, multicentricidad, TNM, estadios diagnósticos, complicaciones postcirugía permanentes, persistencia tumoral local y regional, metástasis a distancia y radioiodo. Variable principal: mortalidad por todas las causas. Métodos: se construyó un modelo de regresión de Cox multivariante para determinar qué variables al diagnóstico se asociaban a la misma. En base al modelo, se construyó una tabla de riesgo basada en la suma de puntos para estimar la probabilidad de fallecimiento y ésta fue implementada en una aplicación para teléfono móvil. Resultados: La media de seguimiento fue de 8,8±6,7 años. Mortalidad por todas las causas: 12,9% (IC 95%: 8,3-17,6%). Variables predictoras de mortalidad: mayor edad, persistencia local tumoral y metástasis a distancia. El área bajo la curva ROC del modelo predictivo fue de 0,81 (IC 95%: 0,72-0,91, p<0,001). Conclusión: este estudio aporta a la práctica clínica una herramienta que nos indica de forma sencilla y rápida (a través de una aplicación para teléfono móvil), qué pacientes diagnosticados de cáncer diferenciado de tiroides tienen riesgo de fallecer en un periodo de 5, 10, 15 y 20 años. Sin embargo, tenemos que ser cautos, ya que son necesarios estudios de validación que corroboren nuestros resultados

Scoring System for Mortality in Patients Diagnosed with and Treated Surgically for Differentiated Thyroid Carcinoma with a 20-Year Follow-Up.

Differentiated thyroid carcinoma (DTC) is associated with an increased mortality. Few studies have constructed predictive models of all-cause mortality with a high discriminating power for patients with this disease that would enable us to determine which patients are more likely to die.To construct a predictive model of all-cause mortality at 5, 10, 15 and 20 years for patients diagnosed with and treated surgically for DTC for use as a mobile application.We undertook a retrospective cohort study using data from 1984 to 2013.All patients diagnosed with and treated surgically for DTC at a general university hospital covering a population of around 200,000 inhabitants in Spain.The study involved 201 patients diagnosed with and treated surgically for DTC (174, papillary; 27, follicular).Age, gender, town, family history, type of surgery, type of cancer, histological subtype, microcarcinoma, multicentricity, TNM staging system, diagnostic stage, permanent post-operative complications, local and regional tumor persistence, distant metastasis, and radioiodine therapy.All-cause mortality.A Cox multivariate regression model was constructed to determine which variables at diagnosis were associated with mortality. Using the model a risk table was constructed based on the sum of all points to estimate the likelihood of death. This was then incorporated into a mobile application.The mean follow-up was 8.8±6.7 years. All-cause mortality was 12.9% (95% confidence interval [CI]: 8.3-17.6%). Predictive variables: older age, local tumor persistence and distant metastasis. The area under the ROC curve was 0.81 (95% CI: 0.72-0.91, p<0.001).This study provides a practical clinical tool giving a simple and rapid indication (via a mobile application) of which patients with DTC are at risk of dying in 5, 10, 15 or 20 years. Nonetheless, caution should be exercised until validation studies have corroborated our results

Area under the ROC curve of the predictive model.

<p>ROC, receiver operating characteristic; AUC, area under the curve; CI, confidence interval.</p

Survival of the different risk groups.

<p>Survival of the different risk groups.</p

Cut points of the predictive model and their indicators of validity, yield and usefulness.

<p>PPV, positive predictive value; NPV, negative predictive value; PLR, positive likelihood ratio test; NLR, negative likelihood ratio test; CI, confidence interval.</p><p>Cut points of the predictive model and their indicators of validity, yield and usefulness.</p

Desarrollo de un criterio unificado para la redacción y evaluación de los trabajos fin de grado en la titulación de ingeniería civil

La investigación se centrará en el análisis del estado actual de la asignatura del Trabajo Fin de Grado, así como de los parámetros de evaluación y redacción, dentro de la titulación de Grado en Ingeniería Civil. Asimismo, se realizará una propuesta de un modelo unificado por temáticas, tanto para la redacción como para la evaluación de los mismos, teniendo en cuenta la diversificación de trabajos en tareas de proyectos de construcción o de otra tipología de proyectos difícilmente catalogables. Además se incluye un estudio de la tasa de éxito y de eficiencia de la asignatura asociada al trabajo fin de grado, a fin de evaluar su evolución en los últimos años y como justificación de la necesidad de establecer una rúbrica de cara a facilitar las labores de estandarización en la redacción y evaluación de dicha asignatura, por parte de alumnos y los profesores. De esta forma se pretende mejorar la calidad docente en dicha titulación, al realizar un trabajo de colaboración docente entre todos los profesores colabores de la asignatura

Multivariate ordered logistic regression models: Dealing with the model-building strategy

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