La délibération éthique : de l’étude de cas à la citoyenneté responsable

Cet article se veut une contribution réflexive sur le thème de l’éthique appliquée qui vise à alimenter les pratiques professionnelles et interdisciplinaires. Les auteurs examinent la démarche de délibération éthique qui vise quatre finalités principales, soit le développement des compétences réflexives et éthiques des professionnels, l’élaboration, chez les professionnels, d’une structure réflexive « éthique » facilitant la praxis professionnelle, l’orientation et la coordination rapide de l’action ; la mise en place d’une structure de délibération collective utile afin d’orienter les décisions difficiles et les actions futures. Enfin, le processus délibératif a aussi une visée évaluative et s’avère pertinent dans les apprentissages découlant des expériences vécues par chacun des participants.This article wants to be a contribution reflecting on the theme of applied ethics aiming at nourishing professional and interdisciplinary practices. The authors examine the process of ethical deliberation which has four major ends : the development of reflective and ethical competences of professionals, the elaboration by professionals, of an ethical reflective structure facilitating professional praxis, orientation and quick coordination of action ; implementation of a structure of collective deliberation useful in the orientation of difficult decisions and future actions. Finally, this process also has an objective of evaluation and appears relevant in the apprenticeship drawn from experiences of each participant.Este artículo pretende ser una contribución reflexiva sobre el tema de la ética aplicada que busca alimentar las prácticas profesionales e interdisciplinarias. Los autores examinan la deliberación ética que tiene como objetivo cuatro finalidades principales: el desarrollo de las competencias reflexivas y éticas de los profesionales; la elaboración, por parte de los profesionales, de una estructura reflexiva “ética” que facilite la práctica profesional; la orientación y la coordinación rápida de la acción; la puesta en marcha de una estructura de deliberación colectiva útil con el fin de orientar las decisiones difíciles y las acciones futuras. Finalmente, el proceso de deliberación también tiene el objetivo de evaluar y es pertinente en los aprendizajes que se desprenden de las experiencias vividas por cada uno de los participantes.Este artigo pretende dar uma contribuição reflexiva sobre o tema da ética aplicada que visa alimentar as práticas profissionais e interdisciplinares. Os autores examinam a abordagem de deliberação ética que visa quatro finalidades principais, seja o desenvolvimento das competências reflexivas e éticas dos profissionais, a elaboração, pelos profissionais, de uma estrutura reflexiva “ética” que facilite a práxis profissional, a orientação e a coordenação rápida da ação; a criação de uma estrutura de deliberação coletiva útil a fim de orientar as decisões difíceis e as ações futuras. Finalmente, o processo deliberativo também possui um objetivo de avaliação e se mostra pertinente nas aprendizagens que decorrem das experiências vivenciadas por cada um dos participantes

Une signature du polymorphisme structural d’acides ribonucléiques non-codants permettant de comparer leurs niveaux d’activités biochimiques

Des évidences expérimentales récentes indiquent que les ARN changent de structures au fil du temps, parfois très rapidement, et que ces changements sont nécessaires à leurs activités biochimiques. La structure de ces ARN est donc dynamique. Ces mêmes évidences notent également que les structures clés impliquées sont prédites par le logiciel de prédiction de structure secondaire MC-Fold. En comparant les prédictions de structures du logiciel MC-Fold, nous avons constaté un lien clair entre les structures presque optimales (en termes de stabilité prédites par ce logiciel) et les variations d’activités biochimiques conséquentes à des changements ponctuels dans la séquence. Nous avons comparé les séquences d’ARN du point de vue de leurs structures dynamiques afin d’investiguer la similarité de leurs fonctions biologiques. Ceci a nécessité une accélération notable du logiciel MC-Fold. L’approche algorithmique est décrite au chapitre 1. Au chapitre 2 nous classons les impacts de légères variations de séquences des microARN sur la fonction naturelle de ceux-ci. Au chapitre 3 nous identifions des fenêtres dans de longs ARN dont les structures dynamiques occupent possiblement des rôles dans les désordres du spectre autistique et dans la polarisation des œufs de certains batraciens (Xenopus spp.).Recent experimental evidence indicates that RNA structure changes, sometimes very rapidly and that these changes are both required for biochemical activity and captured by the secondary structure prediction software MC-Fold. RNA structure is thus dynamic. We compared RNA sequences from the point of view of their structural dynamics so as to investigate how similar their biochemical activities were by computing a signature from the output of the structure prediction software MC-Fold. This required us to accelerate considerably the software MC-Fold. The algorithmic approach to this acceleration is described in chapter 1. In chapter 2, point mutations that disrupt the biochemical activity of microRNA are explained in terms of changes in RNA dynamics. Finally, in chapter 3 we identify dynamic structure windows in long RNA with potentially significant roles in autism spectrum disorders and separately in Xenopus ssp. (species of frogs) egg polarisation

Comprehensive Signaling Profiles Reveal Unsuspected Functional Selectivity of δ-Opioid Receptor Agonists and Allow the Identification of Ligands with the Greatest Potential for Inducing Cyclase Superactivation

Prolonged exposure to opioid receptor agonists triggers adaptations in the adenylyl cyclase (AC) pathway that lead to enhanced production of cyclic adenosine monophosphate (cAMP) upon withdrawal. This cellular phenomenon contributes to withdrawal symptoms, hyperalgesia and analgesic tolerance that interfere with clinical management of chronic pain syndromes. Since δ-opioid receptors (DOPrs) are a promising target for chronic pain management, we were interested in finding out if cell-based signaling profiles as generated for drug discovery purposes could inform us of the ligand potential to induce sensitization of the cyclase path. For this purpose, signaling of DOPr agonists was monitored at multiple effectors. The resulting signaling profiles revealed marked functional selectivity, particularly for Met-enkephalin (Met-ENK) whose signaling bias profile differed from those of synthetic ligands like SNC-80 and ARM390. Signaling diversity among ligands was systematized by clustering agonists according to similarities in Emax and Log(τ) values for the different responses. The classification process revealed that the similarity in Gα/Gβγ, but not in β-arrestin (βarr), responses was correlated with the potential of Met-ENK, deltorphin II, (d-penicillamine2,5)-enkephalin (DPDPE), ARM390, and SNC-80 to enhance cAMP production, all of which required Ca2+ mobilization to produce this response. Moreover, superactivation by Met-ENK, which was the most-effective Ca2+ mobilizing agonist, required Gαi/o activation, availability of Gβγsubunits at the membrane, and activation of Ca2+ effectors such as calmodulin and protein kinase C (PKC). In contrast, superactivation by (N-(l-tyrosyl)-(3S)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-l-phenylalanyl-l-phenylalanine (TIPP), which was set in a distinct category through clustering, required activation of Gαi/o subunits but was independent of the Gβγdimer and Ca2+ mobilization, relying instead on Src and Raf-1 to induce this cellular adaptation

Exploring use of unsupervised clustering to associate signaling profiles of GPCR ligands to clinical response.

Signaling diversity of G protein-coupled (GPCR) ligands provides novel opportunities to develop more effective, better-tolerated therapeutics. Taking advantage of these opportunities requires identifying which effectors should be specifically activated or avoided so as to promote desired clinical responses and avoid side effects. However, identifying signaling profiles that support desired clinical outcomes remains challenging. This study describes signaling diversity of mu opioid receptor (MOR) ligands in terms of logistic and operational parameters for ten different in vitro readouts. It then uses unsupervised clustering of curve parameters to: classify MOR ligands according to similarities in type and magnitude of response, associate resulting ligand categories with frequency of undesired events reported to the pharmacovigilance program of the Food and Drug Administration and associate signals to side effects. The ability of the classification method to associate specific in vitro signaling profiles to clinically relevant responses was corroborated using β2-adrenergic receptor ligands.This research was supported by a research contract from Pfizer Inc. and grants from the Natural Sciences and Engineering Research Council of Canada (Grant 311997 to G.P.) and the Canadian Institutes of Health Research MOP 324876 (to G.P.), MOP 102630 (to M.B. and O.L.) and Foundation grant (FDN-148431) to MB. MB holds a Canada Research Chair in Signal Transduction and Molecular Pharmacology. Dr Lichtarge’s research was supported by National Institutes of Health (NIH 2R01 GM066099; NIH 5R01 GM079656). B.B. was supported by a studentship from Fonds de Recherche en Santé du Québec. P.D. was supported by a MITACS fellowship

RNA G-Quadruplexes in the model plant species Arabidopsis thaliana: prevalence and possible functional roles

Tandem stretches of guanines can associate in hydrogen-bonded arrays to form G-quadruplexes, which are stabilized by K+ ions. Using computational methods, we searched for G-Quadruplex Sequence (GQS) patterns in the model plant species Arabidopsis thaliana. We found ∼1200 GQS with a G3 repeat sequence motif, most of which are located in the intergenic region. Using a Markov modeled genome, we determined that GQS are significantly underrepresented in the genome. Additionally, we found ∼43 000 GQS with a G2 repeat sequence motif; notably, 80% of these were located in genic regions, suggesting that these sequences may fold at the RNA level. Gene Ontology functional analysis revealed that GQS are overrepresented in genes encoding proteins of certain functional categories, including enzyme activity. Conversely, GQS are underrepresented in other categories of genes, notably those for non-coding RNAs such as tRNAs and rRNAs. We also find that genes that are differentially regulated by drought are significantly more likely to contain a GQS. CD-detected K+ titrations performed on representative RNAs verified formation of quadruplexes at physiological K+ concentrations. Overall, this study indicates that GQS are present at unique locations in Arabidopsis and that folding of RNA GQS may play important roles in regulating gene expression

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Predictors of positive and negative parenting behaviours: evidence from the ALSPAC cohort

Background This study aimed to establish the predictors of positive and negative parenting behaviours in a United Kingdom population. The majority of previous research has focused on specific risk factors and has used a variety of outcome measures. This study used a single assessment of parenting behaviours and started with a wide range of potential pre- and post-natal variables; such an approach might be used to identify families who might benefit from parenting interventions. Methods Using a case-control subsample of 160 subjects from the Avon Longitudinal Study of Parents and Children (ALSPAC), regression analysis was undertaken to model parenting behaviours at 12 months as measured by the Mellow Parenting Observational System. Results Positive parenting increased with maternal age at delivery, levels of education and with prenatal anxiety. More negative interactions were observed among younger mothers, mothers with male infants, with prenatal non-smokers and among mothers who perceived they had a poor support structure. Conclusions This study indicates two factors which may be important in identifying families most at risk of negative parenting: younger maternal age at delivery and lack of social support during pregnancy. Such factors could be taken into account when planning provision of services such as parenting interventions. We also established that male children were significantly more likely to be negatively parented, a novel finding which may suggest an area for future research. However the findings have to be accepted cautiously and have to be replicated, as the measures used do not have established psychometric validity and reliability data