Substances psychoactives : politiques et responsabilité de l'État : le point de vue des Français

Our first study relates to the conditions of perceived acceptability of State policies regarding drugs: 225 randomly selected subjects judged the degree of State policy acceptability in 28 scenarios derived from the combination of three factors: information campaigns, interior drug demand, State policy (from laisser-faire to prohibition). Our second study relates to the conditions of perceived State responsibility when a death linked to substance consumption occurred: 234 subjects judged the degree of State responsibility in 80 scenarios derived from the combination of five factors: relationship between consumption/disease, amount of time since the substance toxicity is known, risk generality, consumption, State action (from State monopoly to sale interdiction). Our studies rely on a method derived from the functional theory of cognition (Anderson, 1981). The first study identifies three clusters: the regulationists (42%), who favor total regulation by the State, the radicals (32%), for who none of the policies are acceptable, and the prohibitionists (26%), who favor a total interdiction with the condition of information campaigns. The policy of the laissez faire is judged by all groups as being the most inacceptable. In the second study, three clusters are separated: centrist-dominated (44%), leftist-dominated (38%) and rightist-dominated (17%). The rightists tend to attribute less responsibility to the state and are less sensitive to scientific evidences than the leftists. A consensus between groups is that the State is freed from responsibility when sales are totally forbidden. In other cases, the State is perceived as partially responsible when a consumer’s health deteriorates.La première étude porte sur les conditions de l’acceptabilité des politiques de l’Etat face aux drogues: 225 sujets tout-venant ont jugé du degré d’acceptabilité dans 28 scénarios issus de la combinaison de trois facteurs: campagnes d’information, demande intérieure en drogue, action de l’État (du laissez-faire à l’interdiction). La seconde étude porte sur les conditions de la responsabilité de l’État dans le cas d’un décès lié à la consommation de substance: 234 sujets ont jugé du degré de responsabilité dans 80 scénarios issus de la combinaison de cinq facteurs: relation consommation/maladie, temps depuis lequel la nocivité est connue, généralité du risque, consommation, action de l’État (du monopole à l’interdiction des ventes). Nos études s’appuient sur une méthode issue de la théorie fonctionnelle de la cognition (Anderson, 1981). La première étude permet d’identifier trois clusters: les régulationnistes (42%), en faveur d’une réglementation totale par l’État, les radicaux (32%), pour qui aucune des politiques n’est acceptable, les prohibitionnistes (26%), en faveur d’une interdiction totale à condition que des campagnes soient menées. La politique du laissez-faire est jugée par tous comme étant la plus inacceptable. La seconde étude fait apparaître trois clusters: un plus au centre (44%), un plus à gauche (38%), un plus à droite (17%). Celui de droite a tendance à attribuer moins de responsabilité à l’État et est plus sensible aux preuves scientifiques. Un consensus montre que l’État se dégage de toute responsabilité seulement s’il interdit totalement les ventes. Dans les autres cas, l'État est perçu comme partiellement responsable quand la santé d'un consommateur se détériore

Toxic effect and inability of L-homoserine to be a nitrogen source for growth of Escherichia coli resolved by a combination of in vivo evolution engineering and omics analyses

L-homoserine is a pivotal intermediate in the carbon and nitrogen metabolism of E. coli. However, this non-canonical amino acid cannot be used as a nitrogen source for growth. Furthermore, growth of this bacterium in a synthetic media is potently inhibited by L-homoserine. To understand this dual effect, an adapted laboratory evolution (ALE) was applied, which allowed the isolation of a strain able to grow with L-homoserine as the nitrogen source and was, at the same time, desensitized to growth inhibition by this amino acid. Sequencing of this evolved strain identified only four genomic modifications, including a 49 bp truncation starting from the stop codon of thrL. This mutation resulted in a modified thrL locus carrying a thrL* allele encoding a polypeptide 9 amino acids longer than the thrL encoded leader peptide. Remarkably, the replacement of thrL with thrL* in the original strain MG1655 alleviated L-homoserine inhibition to the same extent as strain 4E, but did not allow growth with this amino acid as a nitrogen source. The loss of L-homoserine toxic effect could be explained by the rapid conversion of L-homoserine into threonine via the thrL*-dependent transcriptional activation of the threonine operon thrABC. On the other hand, the growth of E. coli on a mineral medium with L-homoserine required an activation of the threonine degradation pathway II and glycine cleavage system, resulting in the release of ammonium ions that were likely recaptured by NAD(P)-dependent glutamate dehydrogenase. To infer about the direct molecular targets of L-homoserine toxicity, a transcriptomic analysis of wild-type MG1655 in the presence of 10 mM L-homoserine was performed, which notably identified a potent repression of locomotion-motility-chemotaxis process and of branched-chain amino acids synthesis. Since the magnitude of these effects was lower in a ΔthrL mutant, concomitant with a twofold lower sensitivity of this mutant to L-homoserine, it could be argued that growth inhibition by L-homoserine is due to the repression of these biological processes. In addition, L-homoserine induced a strong upregulation of genes in the sulfate reductive assimilation pathway, including those encoding its transport. How this non-canonical amino acid triggers these transcriptomic changes is discussed

Genome-Wide Association Reveals Pigmentation Genes Play a Role in Skin Aging

Loss of fine skin patterning is a sign of both aging and photoaging. Studies investigating the genetic contribution to skin patterning offer an opportunity to better understand a trait that influences both physical appearance and risk of keratinocyte skin cancer. We undertook a meta-analysis of genome-wide association studies (GWAS) of a measure of skin pattern (microtopography score) damage in 1,671 twin pairs and 1,745 singletons (N = 5,087) drawn from three independent cohorts. We identified that rs185146 near SLC45A2 is associated with a skin aging trait (p = 4.1 × 10-9); to our knowledge this is previously unreported. We also confirm previously identified loci, rs12203592 near IRF4 (p = 8.8 × 10-13), and rs4268748 near MC1R (p = 1.2 × 10-15). At all three loci we highlight putative functionally relevant SNPs. There are a number of red hair/low pigmentation alleles of MC1R; we found that together these MC1R alleles explained 4.1% of variance in skin pattern damage. We also show that skin aging and reported experience of sunburns was proportional to the degree of penetrance for red hair of alleles of MC1R. Our work has uncovered genetic contributions to skin aging and confirmed previous findings, showing that pigmentation is a critical determinate of skin aging

Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants.

Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targeted arrays or enrichment methodologies preferentially covering CpG-dense regions, to characterize sufficiently large samples. To overcome this limitation, we present here a new customizable, cost-effective approach, methylC-capture sequencing (MCC-Seq), for sequencing functional methylomes, while simultaneously providing genetic variation information. To illustrate MCC-Seq, we use whole-genome bisulfite sequencing on adipose tissue (AT) samples and public databases to design AT-specific panels. We establish its efficiency for high-density interrogation of methylome variability by systematic comparisons with other approaches and demonstrate its applicability by identifying novel methylation variation within enhancers strongly correlated to plasma triglyceride and HDL-cholesterol, including at CD36. Our more comprehensive AT panel assesses tissue methylation and genotypes in parallel at ∼4 and ∼3 M sites, respectively. Our study demonstrates that MCC-Seq provides comparable accuracy to alternative approaches but enables more efficient cataloguing of functional and disease-relevant epigenetic and genetic variants for large-scale EWAS.This work was supported by a Canadian Institute of Health Research (CIHR) team grant awarded to E.G., A.T., M.C.V. and M.L. (TEC-128093) and the CIHR funded Epigeneome Mapping Centre at McGill University (EP1-120608) awarded to T.P. and M.L., and the Swedish Research Council, Knut and Alice Wallenberg Foundation and the Torsten Söderberg Foundation awarded to L.R. F.A. holds studentship from The Research Institute of the McGill University Health Center (MUHC). F.G. is a recipient of a research fellowship award from the Heart and Stroke Foundation of Canada. A.T. is the director of a Research Chair in Bariatric and Metabolic Surgery. M.C.V. is the recipient of the Canada Research Chair in Genomics Applied to Nutrition and Health (Tier 1). E.G. and T.P. are recipients of a Canada Research Chair Tier 2 award. The MuTHER Study was funded by a programme grant from the Wellcome Trust (081917/Z/07/Z) and core funding for the Wellcome Trust Centre for Human Genetics (090532). TwinsUK was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. T.D.S. is a holder of an ERC Advanced Principal Investigator award. SNP genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. Finally, we thank the NIH Roadmap Epigenomics Consortium and the Mapping Centers (http://nihroadmap.nih.gov/epigenomics/) for the production of publicly available reference epigenomes. Specifically, we thank the mapping centre at MGH/BROAD for generation of human adipose reference epigenomes used in this study.This is the final version. It was first published by NPG at http://www.nature.com/ncomms/2015/150529/ncomms8211/full/ncomms8211.html#abstrac

Comparative Analysis of Acinetobacters: Three Genomes for Three Lifestyles

Acinetobacter baumannii is the source of numerous nosocomial infections in humans and therefore deserves close attention as multidrug or even pandrug resistant strains are increasingly being identified worldwide. Here we report the comparison of two newly sequenced genomes of A. baumannii. The human isolate A. baumannii AYE is multidrug resistant whereas strain SDF, which was isolated from body lice, is antibiotic susceptible. As reference for comparison in this analysis, the genome of the soil-living bacterium A. baylyi strain ADP1 was used. The most interesting dissimilarities we observed were that i) whereas strain AYE and A. baylyi genomes harbored very few Insertion Sequence elements which could promote expression of downstream genes, strain SDF sequence contains several hundred of them that have played a crucial role in its genome reduction (gene disruptions and simple DNA loss); ii) strain SDF has low catabolic capacities compared to strain AYE. Interestingly, the latter has even higher catabolic capacities than A. baylyi which has already been reported as a very nutritionally versatile organism. This metabolic performance could explain the persistence of A. baumannii nosocomial strains in environments where nutrients are scarce; iii) several processes known to play a key role during host infection (biofilm formation, iron uptake, quorum sensing, virulence factors) were either different or absent, the best example of which is iron uptake. Indeed, strain AYE and A. baylyi use siderophore-based systems to scavenge iron from the environment whereas strain SDF uses an alternate system similar to the Haem Acquisition System (HAS). Taken together, all these observations suggest that the genome contents of the 3 Acinetobacters compared are partly shaped by life in distinct ecological niches: human (and more largely hospital environment), louse, soil

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Psychoactive substances : State policy and responsibility : the French point of view

La première étude porte sur les conditions de l’acceptabilité des politiques de l’Etat face aux drogues: 225 sujets tout-venant ont jugé du degré d’acceptabilité dans 28 scénarios issus de la combinaison de trois facteurs: campagnes d’information, demande intérieure en drogue, action de l’État (du laissez-faire à l’interdiction). La seconde étude porte sur les conditions de la responsabilité de l’État dans le cas d’un décès lié à la consommation de substance: 234 sujets ont jugé du degré de responsabilité dans 80 scénarios issus de la combinaison de cinq facteurs: relation consommation/maladie, temps depuis lequel la nocivité est connue, généralité du risque, consommation, action de l’État (du monopole à l’interdiction des ventes). Nos études s’appuient sur une méthode issue de la théorie fonctionnelle de la cognition (Anderson, 1981). La première étude permet d’identifier trois clusters: les régulationnistes (42%), en faveur d’une réglementation totale par l’État, les radicaux (32%), pour qui aucune des politiques n’est acceptable, les prohibitionnistes (26%), en faveur d’une interdiction totale à condition que des campagnes soient menées. La politique du laissez-faire est jugée par tous comme étant la plus inacceptable. La seconde étude fait apparaître trois clusters: un plus au centre (44%), un plus à gauche (38%), un plus à droite (17%). Celui de droite a tendance à attribuer moins de responsabilité à l’État et est plus sensible aux preuves scientifiques. Un consensus montre que l’État se dégage de toute responsabilité seulement s’il interdit totalement les ventes. Dans les autres cas, l'État est perçu comme partiellement responsable quand la santé d'un consommateur se détériore.Our first study relates to the conditions of perceived acceptability of State policies regarding drugs: 225 randomly selected subjects judged the degree of State policy acceptability in 28 scenarios derived from the combination of three factors: information campaigns, interior drug demand, State policy (from laisser-faire to prohibition). Our second study relates to the conditions of perceived State responsibility when a death linked to substance consumption occurred: 234 subjects judged the degree of State responsibility in 80 scenarios derived from the combination of five factors: relationship between consumption/disease, amount of time since the substance toxicity is known, risk generality, consumption, State action (from State monopoly to sale interdiction). Our studies rely on a method derived from the functional theory of cognition (Anderson, 1981). The first study identifies three clusters: the regulationists (42%), who favor total regulation by the State, the radicals (32%), for who none of the policies are acceptable, and the prohibitionists (26%), who favor a total interdiction with the condition of information campaigns. The policy of the laissez faire is judged by all groups as being the most inacceptable. In the second study, three clusters are separated: centrist-dominated (44%), leftist-dominated (38%) and rightist-dominated (17%). The rightists tend to attribute less responsibility to the state and are less sensitive to scientific evidences than the leftists. A consensus between groups is that the State is freed from responsibility when sales are totally forbidden. In other cases, the State is perceived as partially responsible when a consumer’s health deteriorates

Etude critique d'une pratique de mésusage des médicaments (le broyage des comprimés et l'ouverture des capsules)

MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF

The end of privilege? An analysis of the class pay gap in France over a quarter of a century

International audienceRecent research from Laurison and Friedman (2016, 2019) has uncovered the existence of a “class pay gap” within managerial and professional occupations – so called “high-end” occupations – in Great Britain. Based on income inequality according to social background, the concept of “class pay gap” highlights that those who climb the social ladder earn on average less than those who come from high social strata. The main research question this paper addresses is whether there exists a class pay gap in France, in particular within high-end occupations, and whether this class pay gap decreased over time in France? We also focus on the role played by education in this respect