α-Synuclein induces the GSK-3-mediated phosphorylation and degradation of NURR1 and loss of dopaminergic hallmarks

In Parkinson’s disease, the dysfunction of the dopaminergic nigrostriatal tract involves the loss of function of dopaminergic neurons of the substantia nigra pars compacta followed by death of these neurons. The functional recovery of these neurons requires a deep knowledge of the molecules that maintain the dopaminergic phenotype during adulthood and the mechanisms that subvert their activity. Previous studies have shown that transcription factor NURR1, involved in differentiation and maintenance of the dopaminergic phenotype, is downregulated by α-synuclein (α-SYN). In this study, we provide a mechanistic explanation to this finding by connecting α-SYN-induced activation of glycogen synthase kinase-3 (GSK-3) with NURR1 phosphorylation followed by proteasomal degradation. The use of sequential deletion mutants and single point mutants of NURR1 allowed the identification of a domain comprising amino acids 123-PSSPPTPSTPS-134 that is targeted by GSK-3 and leads to subsequent ubiquitination and proteasome degradation. This study provides a detailed analysis of the regulation of NURR1 stability by phosphorylation in synucleinopathies such as Parkinson’s diseaseThis study was funded by the Spanish Ministry of Economy and Competitiveness (MINECO) (grant PID2019-110061RB-I00 for A.C and PID2019-105600RB-I00 for I.L.B.) and The Autonomous Community of Madrid (grant B2017/ BMD-3827 for A.C. and B2017/BMD-3813 for I.L.B.

A detailed chemistry model for transient hydrogen and carbon monoxide catalytic recombination on parallel flat Pt surfaces implemented in an integral code

A detailed chemistry model has been adapted and developed for surface chemistry, heat and mass transfer between H2/CO/air/steam/CO2 mixtures and vertical parallel Pt-coated surfaces. This model is based onto a simplified Deutschmann reaction scheme for methane surface combustion and the analysis by Elenbaas for buoyancy-induced heat transfer between parallel plates. Mass transfer is treated by the heat and mass transfer analogy. The proposed model is able to simulate the H2/CO recombination phenomena characteristic of parallel-plate Passive Autocatalytic Recombiners (PARs), which have been proposed and implemented as a promising hydrogen-control strategy in the safety of nuclear power stations or other industries. The transient model is able to approach the warm-up phase of the PAR and its shut-down as well as the dynamic changes within the surrounding atmosphere. The model has been implemented within the MELCOR code and assessed against results of the Battelle Model Containment tests of the Zx series. Results show accurate predictions and a better performance than traditional methods in integral codes, i.e., empirical correlations, which are also much case-specific. Influence of CO present in the mixture on the PAR performance is also addressed in this paper

Transcriptomic analysis of Streptomyces coelicolor differentiation in solid sporulating cultures: first compartmentalized and second multinucleated mycelia have different and distinctive transcriptomes

[EN] Streptomycetes are very important industrial bacteria, which produce two thirds of all clinically relevant secondary metabolites. They have a complex developmental-cycle in which an early compartmentalized mycelium (MI) differentiates to a multinucleated mycelium (MII) that grows inside the culture medium (substrate mycelium) until it starts to growth into the air (aerial mycelium) and ends up forming spores. Streptomyces developmental studies have focused mainly on the later stages of MII differentiation (aerial mycelium and sporulation), with regulation of pre-sporulation stages (MI/MII transition) essentially unknown. This work represents the first study of the Streptomyces MI transcriptome, analyzing how it differs from the MII transcriptome. We have used a very conservative experimental approach to fractionate MI from MII and quantify gene expressions. The expression of well characterized key developmental/metabolic genes involved in bioactive compound production (actinorhodin, undecylprodigiosin, calcium-dependent antibiotic, cpk, geosmin) or hydrophobic cover formation-sporulation (bld, whi, wbl, rdl, chp, ram) was correlated with MII differentiation. Additionally, 122 genes conserved in the Streptomyces genus, whose biological function had not been previously characterized, were found to be differentially expressed (more than 4-fold) in MI or MII. These genes encoded for putative regulatory proteins (transcriptional regulators, kinases), as well as hypothetical proteins. Knowledge about differences between the MI (vegetative) and MII (reproductive) transcriptomes represents a huge advance in Streptomyces biology that will make future experiments possible aimed at characterizing the biochemical pathways controlling pre-sporulation developmental stages and activation of secondary metabolism in StreptomycesSIThis research was funded by grant BIO2010-16303 from the Subdirección General de Proyectos de Investigación, (DGI), Ministry of Science and Innovation (MICINN), Spain; and by an ERC Starting Grant (Strp-differentiation 280304). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

M.A.B. Revestimientos vítreos con propiedades bactericidas y fungicidas

This report describes the mosaic M.A.B. (bactericide and fungicide) produced by Togama S.A. belonging to the group Fluidra S.A., which has been awarded with the Silver Alfa Award by the Spanish Society of Ceramics and Glass at the International Fair Cevisama 2012. This award recognizes the R & D efforts developed by Togama, SA, already started with participation in the Alpha Awards 2009 and 201

Tuning melatonin receptor subtype selectivity in oxadiazolone-based analogues: Discovery of QR2 ligands and NRF2 activators with neurogenic properties

New multi-target indole and naphthalene derivatives containing the oxadiazolone scaffold as a bioisostere of the melatonin acetamido group have been developed. The novel compounds were characterized at melatonin receptors MT1R and MT2R, quinone reductase 2 (QR2), lipoxygenase-5 (LOX-5), and monoamine oxidases (MAO-A and MAO-B), and also as radical scavengers. We found that selectivity within the oxadiazolone series can be modulated by modifying the side chain functionality and coplanarity with the indole or naphthalene ring. In phenotypic assays, several oxadiazolone-based derivatives induced signalling mediated by the transcription factor NRF2 and promoted the maturation of neural stem-cells into a neuronal phenotype. Activation of NRF2 could be due to the binding of indole derivatives to KEAP1, as deduced from surface plasmon resonance (SPR) experiments. Molecular modelling studies using the crystal structures of QR2 and the KEAP1 Kelch-domain, as well as the recently described X-ray free-electron laser (XFEL) structures of chimeric MT1R and MT2R, provided a rationale for the experimental data and afforded valuable insights for future drug design endeavoursThe authors gratefully acknowledge the following financial supports: Spanish Ministry of Science, Innovation and Universities; Spanish Research Agency; and European Regional Development Funds (grants RTI2018-093955-B-C21 and SAF2015-64948-C2-1-R to M.I.R.-F.; RTI2018-095793-B-I00 to M.G.L., SAF2015-64629-C2- 2-R to F.G.), General Council for Research and Innovation of the Community of Madrid and European Structural Funds (grant B2017/BMD-3827 e NRF24ADCM), Health Institute Carlos III (Miguel Servet II ProgramCP16/00014 and grant PI17/01700 to R.L.). CH-A and P.M. thank their PhD fellowships from Spanish Ministry of Education (MEC, PhD grant FPU16/01704 and mobility grant FPUEST17/00233 to CH-A and FPU13/03737 to P.M.)

V Congreso de Innovación Docente en Ingeniería Química - CIDIQ

Innovación EducativaDeterminadas asignaturas del Grado en Ingeniería Química de la Universidad de Valladolid tienen incluida en la memoria VERIFICA del Grado el desarrollo de la competencia general de capacidad de trabajar en equipo de forma eficaz (CG9). Hasta el momento, en las asignaturas implicadas, se ha hecho un esfuerzo importante en el diseño de actividades concretas que permitan desarrollar esta competencia transversal y se han elaborado determinados instrumentos basados en la utilización de rúbricas para su correcta evaluación. Sin embargo, no se ha prestado demasiada atención en enseñar a los estudiantes a construir auténticos equipos de trabajo. En este sentido, el panel Team Canvas, es una herramienta gratuita disponible para que el profesor pueda alinear a los miembros de un equipo, resolver conflictos y construir una cultura de trabajo en equipo ágil y productiva. El panel consta de cuatro partes: 1) Funciones y objetivos (personales y comunes); 2) Propósito y valores; 3) Fortalezas, Debilidades y Necesidades; 4) Normas y Actividades. Este panel lo pueden emplear los profesores implicados en la dirección de tareas grupales cuando necesiten clarificar las metas de un equipo, averiguar sus motivaciones, ayudarles a ser más productivos y conseguir que estén alineados con los objetivos. Se puede utilizar cuando el profesor crea un nuevo equipo de trabajo, cuando se detectan problemas en el funcionamiento del equipo, cuando se incorpora un nuevo miembro o para realizar una revisión del trabajo realizado hasta la fecha. Para aplicar esta plantilla Team Canvas el profesor debe de disponer de un tiempo de 90-120 minutos y explicarles a los estudiantes el objetivo de esa sesión. Los estudiantes deben de completar los distintos campos de la plantilla mediante el uso de post-its. Cada miembro del equipo se debe expresar libremente, aunque en ciertos apartados necesitarán de un consenso entre sus miembros. De esta forma irán completando los diferentes apartados: Personas y roles (5 minutos), Objetivos comunes (10 minutos), Metas personales (5 minutos), Fortalezas y activos (15 minutos), Debilidades y áreas de desarrollo (15 minutos), Necesidades y expectativas (10 minutos), Reglas y actividades (10 minutos), Valores (10 minutos). Como cierre de la sesión se pide al equipo que escriba en un post-it una frase que defina el objetivo común del equipo y si es posible que le asigne un nombre al equipo. La propuesta de crear equipos de trabajo basada en la plantilla Team Canvas se va a aplicar en las asignaturas de Tecnología Ambiental y de Procesos (obligatoria de 1er curso de los Grados en Ingenierías Industriales de la Universidad de Valladolid, 6 ECTS) y en Introducción en Ingeniería Química (obligatoria de 3er curso, 6ECTS del Grado en Ingeniería Química). Los resultados previsibles de aplicación de esta nueva metodología de trabajo serán una mejora en el desarrollo por parte de los estudiantes de la competencia de trabajo en equipo. Los estudiantes se sentirán parte del equipo de trabajo, compartirán objetivos comunes y responsabilidades y aprenderán a utilizar el mejor potencial de cada integrante del equipo. Desde el punto de vista del profesor esta metodología Team Canvas permitirá mejorar la capacidad de gestión de los conflictos de los equipos y lograr una mayor comunicación estudiante-profesor

Experiencias de Innovación docente en los Estudios Jurídicos: una visión práctica

Esta publicación se enmarca dentro de las actividades del Grupo de Investigación de la Universidad de Extremadura Fiscalitas & Iuris.Este trabajo surge con el objetivo principal de dar visibilidad y publicidad a las nuevas técnicas docentes en el seno de la Facultad de Derecho de la UEx. Como se sabe, se ha producido un innegable y significativo avance en el uso de nuevas técnicas docentes y también de las TICs aplicadas a la docencia en la Facultad de Derecho, no obstante, aún es necesario profundizar en el uso de las mismas y extenderlas entre todos los miembros del claustro de profesores, y fundamentalmente entre aquellos que llevan más años ejerciendo la docencia a través de la colaboración y la coordinación con los profesores noveles, que son quienes principalmente se sirven en mayor medida de tales instrumentos docentes. De otra parte, también era necesario que los docentes más experimentados pudieran encontrar un foro en el que transmitir y compartir con los noveles cuales son las técnicas e instrumentos docentes que ellos han venido utilizando durante el ejercicio de su magisterio, de modo que, en el marco de una relación sinalagmática, se produjera una interacción entre uno u otro grupo de docentes, a fin de fomentar el necesario debate y el intercambio de experiencias e instrumentos docentes, y en su caso el desarrollo y perfeccionamiento de los mismos; algo que hemos pretendido realizar con este trabajo, y que en buena medida hemos logrado. Las finalidades y objetivos concretos que perseguíamos, en atención a la situación expuesta eran fundamentalmente tres: • En primer lugar, la implementación de un proyecto de innovación docente integrado por una diversidad de actividades coordinadas, cada uno de ellas bajo la directa coordinación de un profesor o profesora de la UEx, aplicado a una o varias asignaturas impartidas en la Facultad de Derecho. • En segundo lugar, el establecimiento en la Facultad de Derecho de un foro de coordinación e intercambio de buenas prácticas docentes sobre la base de cada uno de las actividades coordinadas, en el que pudieran participar profesores noveles y veteranos. Para ello se desarrolló espacio virtual de innovación docente en estudios jurídicos, a través del Campus Virtual de la UEx, en el que los Profesores noveles y veteranos pudieron y puede compartir recursos e informaciones sobre prácticas de innovación. • Y, en tercer lugar, la difusión y consolidación de instrumentos de innovación docente directamente aplicadas a la docencia de los estudios jurídicos, mediante la transferencia de los resultados y la publicación de los mismos; a fin de que esta transferencia sirva de base a futuras profundizaciones en el campo de la innovación docente en los estudios jurídicos.Proyecto “Desarrollo, profundización e intercambio de buenas prácticas de innovación docente en la Facultad de Derecho” (UEx 2015-2016

Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Spain: Clinical and Genetic Characterization

Simple Summary Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancer (RCC), with no data on its prevalence worldwide. No genotype-phenotype associations have been described. The aim of our study was to describe the genotypic and phenotypic features of the largest series of patients with HLRCC from Spain reported to date. Of 27 FH germline pathogenic variants, 12 were not previously reported in databases. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants. The frequency of RCCs (10.9%) was lower than those reported in the previously published series. Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancers (RCCs). We aimed to describe the genetics, clinical features and potential genotype-phenotype associations in the largest cohort of fumarate hydratase enzyme mutation carriers known from Spain using a multicentre, retrospective study of individuals with a genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records, analysed genetic variants and looked for genotype-phenotype associations. Analyses were performed using R 3.6.0. software. We included 197 individuals: 74 index cases and 123 relatives. CLMs were diagnosed in 65% of patients, ULMs in 90% of women, RCys in 37% and RCC in 10.9%. Twenty-seven different pathogenic variants were detected, 12 (44%) of them not reported previously. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants (p = 0.0380, p = 0.0015 and p = 0.024, respectively). This is the first report of patients with HLRCC from Spain. The frequency of RCCs was lower than those reported in the previously published series. Individuals with missense pathogenic variants had higher frequencies of CLMs, ULMs and RCys

Endoscopic Submucosal Dissection. Sociedad Española de Endoscopia Digestiva (SEED) clinical guideline

The reason to write this guideline is to familiarize Spanish endoscopists and gastroenterologists not only with the general indications of the procedure and possible complications but also the dedicated tools

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio