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)

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

Ruta de innovación social en un grupo de estudiantes del programa de administración de empresas de la Corporación Universitaria Minuto de Dios - UNIMINUTO en el municipio de Ibagué

The article shows the implementation of the social innovation route, a methodology created by the PCIS (social innovation science park), a route that approaches problems that are trying to be solved through the participation of different actors and resources. The main objective of the research was to develop and implement the methodology for the execution of the social innovation route in the "organizational analysis and diagnosis" course of the Business Administration program (AEMD) at Uniminuto Tolima and Magdalena Medio vice-rectory (VTMM) in the city of Ibagué. The methodology used in the research was qualitative, the action research method was also used, with the participation of the teacher who guides the course and the students. As main results, it was found that the students were able to apply the knowledge studied in the course in a real environment. Likewise, they were able to generate greater organizational skills, as a result of the interaction with the shopkeepers and the operation of their stores. On the other hand, the shopkeepers of commune 6 showed some shortcomings in the development of the activities they carried out in their stores.El presente artículo muestra la implementación de la ruta de la innovación social, metodología creada por el parque científico de innovación social PCIS, ruta que, aborda problemáticas, que intentan solucionarse, mediante la participación de diferentes actores y recursos. El objetivo principal de la investigación fue desarrollar e implementar la metodología para la ejecución de la ruta de innovación social en el curso análisis y diagnóstico organizacional del programa de Administración de Empresas (AEMD) de la Vicerrectoría del Tolima y Magdaleno Medio (VTMM) Corporación Universitaria Minuto de Dios – Uniminuto en el municipio de Ibagué. La metodología utilizada en la investigación fue cualitativa, se recurrió también a el método de investigación acción contando con la participación del docente que orienta el curso y los estudiantes. Como resultados principales se encontró que los estudiantes pudieron aplicar los conocimientos vistos en el curso en un entorno real.  Asimismo, ellos lograron generar mayores habilidades organizativas, resultado de la interacción con los tenderos y el funcionamiento de sus tiendas. Por otro lado, Los tenderos de la comuna 6 evidenciaron algunas falencias en el desarrollo de las actividades que realizaban en sus tiendas

Ruta de innovación social en un grupo de estudiantes del programa de administración de empresas de la Corporación Universitaria Minuto de Dios - UNIMINUTO en el municipio de Ibagué

The article shows the implementation of the social innovation route, a methodology created by the PCIS (social innovation science park), a route that approaches problems that are trying to be solved through the participation of different actors and resources. The main objective of the research was to develop and implement the methodology for the execution of the social innovation route in the "organizational analysis and diagnosis" course of the Business Administration program (AEMD) at Uniminuto Tolima and Magdalena Medio vice-rectory (VTMM) in the city of Ibagué. The methodology used in the research was qualitative, the action research method was also used, with the participation of the teacher who guides the course and the students. As main results, it was found that the students were able to apply the knowledge studied in the course in a real environment. Likewise, they were able to generate greater organizational skills, as a result of the interaction with the shopkeepers and the operation of their stores. On the other hand, the shopkeepers of commune 6 showed some shortcomings in the development of the activities they carried out in their stores.El presente artículo muestra la implementación de la ruta de la innovación social, metodología creada por el parque científico de innovación social PCIS, ruta que, aborda problemáticas, que intentan solucionarse, mediante la participación de diferentes actores y recursos. El objetivo principal de la investigación fue desarrollar e implementar la metodología para la ejecución de la ruta de innovación social en el curso análisis y diagnóstico organizacional del programa de Administración de Empresas (AEMD) de la Vicerrectoría del Tolima y Magdaleno Medio (VTMM) Corporación Universitaria Minuto de Dios – Uniminuto en el municipio de Ibagué. La metodología utilizada en la investigación fue cualitativa, se recurrió también a el método de investigación acción contando con la participación del docente que orienta el curso y los estudiantes. Como resultados principales se encontró que los estudiantes pudieron aplicar los conocimientos vistos en el curso en un entorno real.  Asimismo, ellos lograron generar mayores habilidades organizativas, resultado de la interacción con los tenderos y el funcionamiento de sus tiendas. Por otro lado, Los tenderos de la comuna 6 evidenciaron algunas falencias en el desarrollo de las actividades que realizaban en sus tiendas

Alcance y limitaciones de la justicia internacional

El presente libro hace parte de los trabajos del grupo de justicia internacional de la Red Multidisciplinar de Investigación “Perspectiva Epistemológica Ibero-Americana sobre la Justicia” Volumen 4, coordinada desde el Instituto Ibero-Americano de la Haya para la Paz, los Derechos Humanos y la Justicia Internacional. Así mismo, se inscribe dentro de los siguientes proyectos de investigación: (i) “Principios de armonización entre la función y alcance de la Justicia Internacional y las demandas surgidas en los procesos políticos de transición”, financiado por el Fondo de Investigación de la Universidad del Rosario, Bogotá, Colombia —FIUR—; y (ii) “La función de los órganos judiciales y arbitrales internacionales en la ejecución de un eventual acuerdo de paz en Colombia fruto de la renegociación resultante del Referéndum del 2 de octubre de 2016”, financiado por la Facultad de Jurisprudencia de la Universidad del Rosario. Ambos proyectos se encuentran adscritos a la línea de investigación “Crítica al Derecho Internacional desde Fundamentos Filosóficos”, del Grupo de Investigación de Derecho Internacional de la Facultad de Jurisprudencia de la Universidad del Rosario, Bogotá, Colombia

Sars-Cov-2 Infection in Patients on Long-Term Treatment with Macrolides in Spain: A National Cross-Sectional Study

The aim of this study was to know the prevalence and severity of COVID-19 in patients treated with long-term macrolides and to describe the factors associated with worse outcomes. A cross-sectional study was conducted in Primary Care setting. Patients with macrolides dispensed continuously from 1 October 2019 to 31 March 2020, were considered. Main outcome: diagnosis of coronavirus disease-19 (COVID-19). Secondary outcomes: symptoms, severity, characteristics of patients, comorbidities, concomitant treatments. A total of 3057 patients met the inclusion criteria. Median age: 73 (64–81) years; 55% were men; 62% smokers/ex-smokers; 56% obese/overweight. Overall, 95% of patients had chronic respiratory diseases and four comorbidities as a median. Prevalence of COVID-19: 4.8%. This was in accordance with official data during the first wave of the pandemic. The most common symptoms were respiratory: shortness of breath, cough, and pneumonia. Additionally, 53% percent of patients had mild/moderate symptoms, 28% required hospital admission, and 19% died with COVID-19. The percentage of patients hospitalized and deaths were 2.6 and 5.8 times higher, respectively, in the COVID-19 group (p < 0.001). There was no evidence of a beneficial effect of long-term courses of macrolides in preventing SARS-CoV-2 infection or the progression to worse outcomes in old patients with underlying chronic respiratory diseases and a high burden of comorbidity

Subcutaneous anti-COVID-19 hyperimmune immunoglobulin for prevention of disease in asymptomatic individuals with SARS-CoV-2 infection: a double-blind, placebo-controlled, randomised clinical trialResearch in context

Summary: Background: Anti-COVID-19 hyperimmune immunoglobulin (hIG) can provide standardized and controlled antibody content. Data from controlled clinical trials using hIG for the prevention or treatment of COVID-19 outpatients have not been reported. We assessed the safety and efficacy of subcutaneous anti-COVID-19 hyperimmune immunoglobulin 20% (C19-IG20%) compared to placebo in preventing development of symptomatic COVID-19 in asymptomatic individuals with SARS-CoV-2 infection. Methods: We did a multicentre, randomized, double-blind, placebo-controlled trial, in asymptomatic unvaccinated adults (≥18 years of age) with confirmed SARS-CoV-2 infection within 5 days between April 28 and December 27, 2021. Participants were randomly assigned (1:1:1) to receive a blinded subcutaneous infusion of 10 mL with 1 g or 2 g of C19-IG20%, or an equivalent volume of saline as placebo. The primary endpoint was the proportion of participants who remained asymptomatic through day 14 after infusion. Secondary endpoints included the proportion of individuals who required oxygen supplementation, any medically attended visit, hospitalisation, or ICU, and viral load reduction and viral clearance in nasopharyngeal swabs. Safety was assessed as the proportion of patients with adverse events. The trial was terminated early due to a lack of potential benefit in the target population in a planned interim analysis conducted in December 2021. ClinicalTrials.gov registry: NCT04847141. Findings: 461 individuals (mean age 39.6 years [SD 12.8]) were randomized and received the intervention within a mean of 3.1 (SD 1.27) days from a positive SARS-CoV-2 test. In the prespecified modified intention-to-treat analysis that included only participants who received a subcutaneous infusion, the primary outcome occurred in 59.9% (91/152) of participants receiving 1 g C19-IG20%, 64.7% (99/153) receiving 2 g, and 63.5% (99/156) receiving placebo (difference in proportions 1 g C19-IG20% vs. placebo, −3.6%; 95% CI -14.6% to 7.3%, p = 0.53; 2 g C19-IG20% vs placebo, 1.1%; −9.6% to 11.9%, p = 0.85). None of the secondary clinical efficacy endpoints or virological endpoints were significantly different between study groups. Adverse event rate was similar between groups, and no severe or life-threatening adverse events related to investigational product infusion were reported. Interpretation: Our findings suggested that administration of subcutaneous human hyperimmune immunoglobulin C19-IG20% to asymptomatic individuals with SARS-CoV-2 infection was safe but did not prevent development of symptomatic COVID-19. Funding: Grifols

Identification of sixteen novel candidate genes for late onset Parkinson's disease

Altres ajuts: Italian Ministry of Health grant (RF 2019-12370224, GR2016-02362247); Italian Ministry of Economic Development (F/0009/00X26); Fondazione Umberto Veronesi.Background: Parkinson's disease (PD) is a neurodegenerative movement disorder affecting 1-5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods: The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results: Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions: Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment