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)

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Global variations in diabetes mellitus based on fasting glucose and haemogloblin A1c

Fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) are both used to diagnose diabetes, but may identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening had elevated FPG, HbA1c, or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardised proportion of diabetes that was previously undiagnosed, and detected in survey screening, ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the agestandardised proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global gap in diabetes diagnosis and surveillance.peer-reviewe

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Diseño, construcción y evaluación teórico-experimental de la eficiencia de un colector solar de placa plana en Costa Rica

Proyecto de graduación (licenciatura en ingeniería mecánica)UCR::Vicerrectoría de Docencia::Ingeniería::Facultad de Ingeniería::Escuela de Ingeniería Mecánic

Nutritive value of four by-product meals as potential protein sources in diets for Octopus maya

The nutritional value of four meals made from animal by-products of squid (SBM), tuna (TBM), poultry (PBM) and pork (POBM), and their potential use in diets for Octopus maya were evaluated. Lyophilized crab-meat meal (CRM) (Callinectes sapidus) was used as a reference for the nutritional requirements of the octopus. CRM had the highest crude protein (CP) content (847.2 g kg?1) and the lowest lipid content (27.5 g kg?1). SBM and PBM had more than 700 g kg?1 CP content, while TBM and POBM had less than 600 g kg?1. Lipid content varied between 75.3 (SBM) and 127.2 (PBM) g kg?1. Energy content of CRM was 17.5 MJ kg?1, and the maximum difference with respect to the by-product meals did not exceed 3 MJ kg?1. Amino acid analysis showed that SBM and PBM had high content of Thr, Ser and Ala, which are the most important amino acids for the metabolism of O. maya. Fatty acid analysis showed that they also had a high content of PUFA. PBM showed deficiencies in EPA and DHA content, but had a high content of linoleic acid, which can be a precursor of C:20 and C:22. Based on this, SBM and PBM have nutritional qualities which could be adequate for use as primary protein sources in artificial diets for O. maya

Mg2Ni0.5Co0.5 compound obtaining by mechanical alloying and their performance on hydriding process

Este trabajo presenta la evolución microestructural del compuesto Mg2Ni0.5Co0.5obtenido mediante aleado mecánico y el estudio de sus propiedades de hidruración. Los polvos elementales de Mg, Ni y Co con una relación atómica 2:0.5:0.5 se alearon mecánicamente en un molino de alta energía Spex 8000D por 36 h (muestra amorfa) yposteriormente se realizó un tratamiento térmico a 673 K por 15 min (muestra nanocristalina). La caracterización de las muestras se realizó mediante difracción de rayos-X. El proceso de hidruración fue realizado por técnica volumétrica Sievert a 363 K y una presión de H2de 2 MPa. El proceso de desorción se evaluó por calorimetría diferencial de barrido. Basados en los resultados podemos concluir que la estructura amorfa absorbe más hidrógeno, alcanzando un máximo de 3.6% en peso de H. Los eventos presentes en el proceso de desorción depende de si la aleación es amorfa o nanocristalina.This work presents the microstructural evolution of mechanically alloyed Mg2Ni0.5Co0.5 and a study of its hydriding properties. Mg, Ni, and Co elemental powders (atomic ratios of 2:0.5:0.5, respectively) were mechanically alloyed in a Spex 8000D high-energy mill for 36 h (amorphous sample) and subsequently submitted to a thermal treatment at 673 K for 15 min (nanocrystalline sample).The characterizations of the samples were performed with X-ray diffraction. A Sievert-type volumetric hydriding process was done at 363 K and with hydrogen pressure of 2 MPa. Desorption process was evaluated through differential scanning calorimetry. Based on the obtained results, it is possible to conclude that the amorphous structure absorbs more hydrogen, reaching a maximum of 3.6 wt. % H. Desorption process events depend on amorphous or nanocrystalline states

Relación entre la composición química y el volumen atómico en soluciones sólidas Ag- x % at Zn (x <= 20)

Este trabajo tuvo como objetivo estudiar la relación existente entre la composición química y el volumen atómico en el sistema Ag � x % at Zn (x = 20). Para este fin, se fabricaron 10 soluciones sólidas mediante fundición y aleado mecánico. La caracterización microestructural se llevó a cabo utilizando difracción de rayos-X. El parámetro reticular fue calculado mediante el método de Rietveld, mientras que la composición química se determinó utilizando espectroscopia de energía dispersiva de rayos-X. En base a los resultados obtenidos se puede concluir que existe una relación lineal inversa entre el volumen atómico de la solución sólida y su contenido Zn, presentando una desviación negativa de la ley de Vegard (-2,96%). Adicionalmente, se propuso una ecuación que vincula el contenido de Zn con el volumen atómico de la solución sólida, la cual presentó un error promedio de predicción menor al 12%