Gut epithelial barrier dysfunction in lupus triggers a differential humoral response against gut commensals

Introduction: Systemic lupus erythematosus is an autoimmune disease with multisystemic involvement including intestinal inflammation. Lupus-associated intestinal inflammation may alter the mucosal barrier where millions of commensals have a dynamic and selective interaction with the host immune system. Here, we investigated the consequences of the intestinal inflammation in a TLR7-mediated lupus model. Methods: IgA humoral and cellular response in the gut was measured. The barrier function of the gut epithelial layer was characterised. Also, microbiota composition in the fecal matter was analysed as well as the systemic humoral response to differential commensals. Results: The lupus-associated intestinal inflammation modifies the IgA+ B cell response in the gut-associated lymphoid tissue in association with dysbiosis. Intestinal inflammation alters the tight junction protein distribution in the epithelial barrier, which correlated with increased permeability of the intestinal barrier and changes in the microbiota composition. This permeability resulted in a differential humoral response against intestinal commensals. Discussion: Lupus development can cause alterations in microbiota composition, allowing specific species to colonize only the lupus gut. Eventually, these alterations and the changes in gut permeability induced by intestinal inflammation could lead to bacterial translocationGAP 838548, the Consejerı́a de Salud y Familias, Junta de Andalucı́a grant PE-0297-2019Ministerio de Economı́a y Competitividad grant SAF2016-78631-P (MA-R),Ministerio de Ciencia e Innovación grant PID2020-113776GB-100Swedish Research Council, grant No 2022-0100

Diseño de una guía de manejo de tecnoestrés en docentes trabajadores remotos de un colegio de Bogotá durante la pandemia del Covid-19

El tecnoestrés, enmarcado en los factores y riesgos psicosociales, se ha identificado en las últimas décadas, debido al uso frecuente de las Tecnologías de la Información y las Comunicaciones (TIC) y por la sobreexposición de los trabajadores remotos a estos recursos digitales. Con ocasión de las medidas de aislamiento, establecidas por el gobierno, para evitar el contagio con el COVID 19, el número de trabajadores remotos a nivel nacional y mundial aumentó, por la necesidad de las empresas y distintas organizaciones de continuar operando, entre ellas las del sector educativo. Debido a ello, esta investigación se orienta a identificar las repercusiones del tecnoestrés en los docentes trabajadores remotos y a definir los elementos que deben constituir una guía para la mitigación de los signos de este en docentes con modalidad de trabajo remoto en un Colegio de Bogotá. Esta investigación puso en evidencia los niveles de tecnoestrés que enfrentan los docentes en la modalidad de tecno sobrecarga, así como el grado de tecno invasión en sus espacios personales y la tecno incertidumbre frente a los cambios de tecnología del Colegio. No se observó un alto grado de tecno complejidad puesto que, los docentes del estudio consideran tener las capacidades necesarias para el manejo de las tecnologías y así mismo, no consideran una amenaza para su estabilidad laboral y personal el tema de las innovaciones en la tecnología, razón por la cual no experimentan tecno inseguridad.Contenido Lista de Tablas 5 Lista de Figuras 6 Dedicatoria 8 Resumen 9 Problema de Investigación 12 Descripción del Problema 12 Formulación del Problema 15 Objetivos de la Investigación 16 Objetivo General 16 Objetivos Específicos: 16 Justificación y Delimitación 17 Justificación 17 Delimitación 18 Limitaciones 18 Marco de Referencia de la Investigación 19 Estado del Arte 19 Prevención del Tecnoestrés 26 Tecnoestrés en el Sector Educativo 30 Marco Teórico 32 Riesgo Psicosocial en Colombia 32 Consecuencias del Tecnoestrés: 35 Medición del Tecnoestrés 37 Covid-19 y Tecnoestrés 38 Marco Legal. 42 Marco Metodológico 46 Método 46 Instrumento 47 Validación del Contenido de los Ítems: 47 Formato de los Instrumentos 48 Consentimiento Informado 49 Población 50 Muestra. 50 Criterios de Inclusión 51 Criterios de Exclusión 51 Cronograma 52 Presupuesto 53 Análisis e interpretación de Resultados 57 Respuestas a las preguntas del Inventario de Tecnoestrés 60 Discusión 78 Conclusiones 82 Anexos 99EspecializaciónEspecialización en Gerencia de la Seguridad y Salud en el trabaj

CD38 Deficiency Ameliorates Chronic Graft-Versus-Host Disease Murine Lupus via a B-Cell-Dependent Mechanism

© 2021 Martínez-Blanco, Domínguez-Pantoja, Botía-Sánchez, Pérez-Cabrera, Bello-Iglesias, Carrillo-Rodríguez, Martin-Morales, Lario-Simón, Pérez-Sánchez-Cañete, Montosa-Hidalgo, Guerrero-Fernández, Longobardo-Polanco, Redondo-Sánchez, Cornet-Gomez, Torres-Sáez, Fernández-Ibáñez, Terrón-Camero, Andrés-León, O’Valle, Merino, Zubiaur and Sancho.The absence of the mouse cell surface receptor CD38 in Cd38−/− mice suggests that this receptor acts as a positive regulator of inflammatory and autoimmune responses. Here, we report that, in the context of the chronic graft-versus-host disease (cGVHD) lupus inducible model, the transfer of B6.C-H2bm12/KhEg(bm12) spleen cells into co-isogenic Cd38−/− B6 mice causes milder lupus-like autoimmunity with lower levels of anti-ssDNA autoantibodies than the transfer of bm12 spleen cells into WT B6 mice. In addition, significantly lower percentages of Tfh cells, as well as GC B cells, plasma cells, and T-bet+CD11chi B cells, were observed in Cd38−/− mice than in WT mice, while the expansion of Treg cells and Tfr cells was normal, suggesting that the ability of Cd38−/− B cells to respond to allogeneic help from bm12 CD4+ T cells is greatly diminished. The frequencies of T-bet+CD11chi B cells, which are considered the precursors of the autoantibody-secreting cells, correlate with anti-ssDNA autoantibody serum levels, IL-27, and sCD40L. Proteomics profiling of the spleens from WT cGVHD mice reflects a STAT1-driven type I IFN signature, which is absent in Cd38−/− cGVHD mice. Kidney, spleen, and liver inflammation was mild and resolved faster in Cd38−/− cGVHD mice than in WT cGVHD mice. We conclude that CD38 in B cells functions as a modulator receptor that controls autoimmune responses.S and MZ received financial support through “Proyecto del Plan Estatal”: SAF2017–89801-R. The IPBLN-CSIC Proteomics Unit belonged to ProteoRed-ISCIII (PRB2; PRB3) and was supported by grants PT13/0001/0011 (IPBLN-CSIC) and PT17/0019/0010 (CIB-CSIC; IPBLN-CSIC). RM: Project: SAF2017-82905-R. FO'V: Cátedra MIS IMPLANT-UGR. The stay of AC-G in Sancho’s lab was supported by a fellowship-contract JAE-Intro (CSIC). The stay of MD-P in Sancho’s lab was supported by a 1-year post-doctoral fellowship (Reference No. 502492) from the Consejo Nacional de Ciencia y Tecnología (CONACYT) of México. EA-L was recipient of a postdoctoral fellowship from the regional Andalusian Government

Matemáticas en contexto

El libro compila estrategias didácticas derivadas del programa de formación complementario escritas por instructores técnicos de diferentes regionales del país, describe la forma en que se incorpora el conocimiento matemático en campos específicos de diferentes áreas de formación laboral basado en las teorías didácticas y reflexiones pedagógicas de instructores.The book compiles the didactic strategies derived from the complementary training program by the technical instructors of the regional media of the country, describes the way in which mathematical knowledge is incorporated in the fields of different areas of work training based on theories didactic and pedagogical reflections of instructors.Consideraciones frente al aprendizaje de las matemáticas -- Perspectiva constructivista -- Teoría de las situaciones didácticas -- Modelación matemática -- Mediación tecnológica -- Pensamiento numérico variacional -- Pensamiento numérico -- Pensamiento variacional -- Diseño de modelo matemático con aplicación de costos de producción -- Modelo matemático del consumo de gas en un artefacto afectado por su presión de trabajo -- Planeación de la producción agrícola: Caso plan óptimo de siembra que permita alcanzar la máxima rentabilidad del cultivo -- Estudio del Álgebra de Boole -- Diseño de un modelo de inventarios para una pequeña empresa de calzado de dotación -- Estudio de la Ley de Ohm mediante herramienta interactiva -- Pensamiento métrico-geométrico -- Pensamiento geométrico -- Pensamiento métrico -- Caso de optimización de recursos en el sector industrial de la confección -- Optimización de espacios para huertas urbanas -- Optimización de los costos del espacio de almacenamiento en microempresas y pequeñas empresas de acuerdo con las normas de seguridad vigentes -- Unidad de medida métrica para confección de ropa exterior femenina -- Optimización de recursos aplicando el proceso administrativo -- Pensamiento aleatorio -- Estadística Básica para Articulación con la Media -- Evaluación del impacto de la accidentalidad en la implementación del Sistema de Gestión de Seguridad y Salud en el Trabajo (sg-sst) por medio de indicadores -- Identificar los aspectos de la declaración de renta para una persona natural no obligada a llevar contabilidad -- Fortalecimiento de la estadística: caso de las unidades productivas del Centro de Biotecnología Agropecuaria -- Estadística dinámica -- Resultados preliminaresna[270 páginas

Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

Espacio y territorios: razón, pasión e imaginarios

En este caleidoscopio de acercamientos hacia lo espacial y territorial, las visiones se mueven desde aquellas románticas y existencialistas, pasando por aquellas objetivistas y positivistas, hasta las estructuralistas y postestructuralistas. Por el espacio y el territorio se interesan con enfoques diversos numerosas disciplinas, desde la psicología, la etología o la literatura, y las ciencias naturales como la biología o la ecología, hasta las ciencias sociales y políticas, como la geografía, la antropología, la economía y la sociología. Este interés multidisciplinario demuestra la importancia y la complejidad del tema espacial y territorial, y reclama la necesidad de su estudio y comprensión interdisciplinarios, como se intenta con esta publicación

Identification of candidate Parkinson disease genes by integrating genome-wide association study, expression, and epigenetic data sets

Importance Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. Objective To investigate what genes and genomic processes underlie the risk of sporadic PD. Design and Setting This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. Main Outcomes and Measures It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. Results Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. Conclusions and Relevance Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies