Quantitative profiling of the UGT transcriptome in human drug metabolizing tissues

Alternative splicing as a mean to control gene expression and diversify function is suspected to considerably influence drug response and clearance. We report the quantitative expression profiles of the human UGT genes including alternatively spliced variants not previously annotated established by deep RNA-sequencing in tissues of pharmacological importance. We reveal a comprehensive quantification of the alternative UGT transcriptome that differ across tissues and among individuals. Alternative transcripts that comprise novel in-frame sequences associated or not with truncations of the 5’ and/or 3’ termini, significantly contribute to the total expression levels of each UGT1 and UGT2 gene averaging 21% in normal tissues, with expression of UGT2 variants surpassing those of UGT1. Quantitative data expose preferential tissue expression patterns and remodelling in favour of alternative variants upon tumorigenesis. These complex alternative splicing programs have the strong potential to contribute to interindividual variability in drug metabolism in addition to diversify the UGT proteome

Unravelling the transcriptomic landscape of the major phase II UDP-glucuronosyltransferase drug metabolizing pathway using targeted RNA sequencing

A comprehensive view of the human UDP-glucuronosyltransferase (UGT) transcriptome is a prerequisite to the establishment of an individual’s UGT metabolic glucuronidation signature. Here, we uncover the transcriptome landscape of the ten human UGT loci genes in normal and tumoral metabolic tissues by targeted RNA next generation sequencing. Alignment on the human hg19 reference genome identifies 234 novel exon-exon junctions. We recover all previously known UGT1 and UGT2 enzyme-coding transcripts and identify over 130 structurally and functionally diverse novel UGT variants. We further expose a revised genomic structure of UGT loci and provide a comprehensive repertoire of transcripts for each UGT gene. Data also uncover a remodelling of the UGT transcriptome occurring in a tissue- and tumor-specific manner. The complex alternative splicing program regulating UGT expression and protein functions is likely critical in determining detoxification capacity of an organ and stress-related responses, with significant impact on drug responses and diseases. Keywords: Alternative splicing, transcriptome, glucuronidation, RNA sequencing, drug metabolism, glucuronosyltransferase (UGT

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Variation morpho-physiologique des plants d'épinette blanche de différentes sources génétiques et implications pour la migration assistée

Les semences forestières génétiquement améliorées pourraient ne plus être adaptées aux sites où elles sont destinées à cause des changements climatiques. La migration assistée figure parmi les stratégies d'adaptation proposées pour maintenir la productivité forestière et diminuer la vulnérabilité des écosystèmes. Les réponses morpho-physiologiques des plants d’épinette blanche (Picea glauca (Moench) Voss) issus de huit vergers à graines ont été évaluées en pépinière et sur trois sites de plantation. La modélisation des courbes de croissance a montré que la hauteur des vergers méridionaux et de deuxième génération est significativement supérieure à celle des autres vergers. Un modèle à régression multiple a montré que la hauteur finale des plants était significativement corrélée aux conditions climatiques d’origine des vergers. Le verger et le site de plantation ont affecté significativement la croissance en hauteur des plants. Les résultats de la présente étude et ceux obtenus à long terme contribueront à raffiner les règles opérationnelles de transfert des semences propres à la migration assistée.Due to climate change, genetically improved trees may no longer be adapted to the sites where they are intended to be planted. Assisted migration is a potential adaptation strategy for maintaining forest productivity and reducing vulnerability in the face of a changing climate. Morpho-physiological responses of white spruce (Picea glauca (Moench) Voss) seedlings from eight seed orchards were evaluated in a nursery and at three planting sites. The modeling of growth curves showed that the height of both the southern orchards and second generation orchards was significantly higher than the other orchards. A multiple regression model showed that the final height of the plants was significantly correlated with climatic conditions of the orchards. The orchard and the planting site significantly affected height growth of seedlings. The results of this study and those obtained over the longer term should help to refine the operational rules of seed transfer for assisted migration

Enfants attendus et enfants accueillis dans le cadre de l’adoption

Expected and welcomed children in adoption. Among the main factors involved in the adoption process, followed by the child’s adaptation to his or her family, are the composition of the family, the parent’s motivation and their preference with regard to the awaited child. A study by the Institut national d’études démographiques using 1500 adoption application files emphasises the relations between the characteristics of candidates, those they wish for the children and the probability of their occurring. Insofar as integrating a child in a family depends partly on the match between the child the parents await and the child they welcome, adopting a different child is sometimes a risk. But, among adopting parents at least one in four adopts a number of children or a child who differs in age, sex or origin compared to the original adoption application which had been approved.Parmi les principaux facteurs qui interviennent dans le déroulement d’une procédure d’adoption, puis dans l’adaptation de l’enfant à sa famille, figurent la composition de la famille, la motivation des parents et les préférences pour l’enfant attendu. Une étude de l’Institut national d’études démographiques réalisée à partir de dossiers de candidats à l’adoption souligne les relations entre les caractéristiques des candidats, celles qu’ils souhaitent pour les enfants et leurs probabilités de réaliser leur projet. Dans la mesure où l’intégration d’un enfant à sa famille dépend en partie de l’adéquation entre l’enfant attendu et l’enfant accueilli, l’adoption d’un enfant différent comporte parfois un risque. Or, parmi les adoptants, au moins un sur quatre adopte un nombre d’enfants ou un enfant différent par l’âge, le sexe ou l’origine du projet avec lequel il avait obtenu un agrément.Frechon Isabelle, Villeneuve-Gokalp Catherine. Enfants attendus et enfants accueillis dans le cadre de l’adoption. In: Politiques sociales et familiales, n°95, 2009. pp. 33-42