How to deal with weak interactions in noncovalent complexes analyzed by electrospray mass spectrometry: Cyclopeptidic inhibitors of the nuclear receptor coactivator 1-STAT6

Mass spectrometry, and especially electrospray ionization, is now an efficient tool to study noncovalent interactions between proteins and inhibitors. It is used here to study the interaction of some weak inhibitors with the NCoA-1/STAT6 protein with K D values in the µM range. High signal intensities corresponding to some nonspecific electrostatic interactions between NCoA-1 and the oppositely charged inhibitors were observed by nanoelectrospray mass spectrometry, due to the use of high ligand concentrations. Diverse strategies have already been developed to deal with nonspecific interactions, such as controlled dissociation in the gas phase, mathematical modeling, or the use of a reference protein to monitor the appearance of nonspecific complexes. We demonstrate here that this last methodology, validated only in the case of neutral sugar-protein interactions, i.e., where dipole-dipole interactions are crucial, is not relevant in the case of strong electrostatic interactions. Thus, we developed a novel strategy based on half-maximal inhibitory concentration (IC50) measurements in a competitive assay with readout by nanoelectrospray mass spectrometry. IC50 values determined by MS were finally converted into dissociation constants that showed very good agreement with values determined in the liquid phase using a fluorescence polarization assa

How to Deal with Weak Interactions in Noncovalent Complexes Analyzed by Electrospray Mass Spectrometry: Cyclopeptidic Inhibitors of the Nuclear Receptor Coactivator 1-STAT6

Mass spectrometry, and especially electrospray ionization, is now an efficient tool to study noncovalent interactions between proteins and inhibitors. It is used here to study the interaction of some weak inhibitors with the NCoA-1/STAT6 protein with KD values in the μM range. High signal intensities corresponding to some nonspecific electrostatic interactions between NCoA-1 and the oppositely charged inhibitors were observed by nanoelectrospray mass spectrometry, due to the use of high ligand concentrations. Diverse strategies have already been developed to deal with nonspecific interactions, such as controlled dissociation in the gas phase, mathematical modeling, or the use of a reference protein to monitor the appearance of nonspecific complexes. We demonstrate here that this last methodology, validated only in the case of neutral sugar–protein interactions, i.e., where dipole–dipole interactions are crucial, is not relevant in the case of strong electrostatic interactions. Thus, we developed a novel strategy based on half-maximal inhibitory concentration (IC50) measurements in a competitive assay with readout by nanoelectrospray mass spectrometry. IC50 values determined by MS were finally converted into dissociation constants that showed very good agreement with values determined in the liquid phase using a fluorescence polarization assay

Stereoselective synthesis of chiral β2,3-disubstituted-β-amino acid derivatives using Pd/In transmetallation cascade processes

A new, highly efficient synthesis of chiral β2,3-disubstituted-β-amino acid derivatives has been developed, based on an allylation procedure employing allene and a catalytic Pd/In bimetallic process

2- and 3-substituted imidazo [1,2-a] pyrazines as inhibitors of bacterial type IV secretion

A novel series of 8-amino imidazo[1,2-a]pyrazine derivatives has been developed as inhibitors of the VirB11 ATPase HP0525, a key component of the bacterial type IV secretion system. A flexible synthetic route to both 2- and 3-aryl substituted regioisomers has been developed. The resulting series of imidazo[1,2-a]pyrazines has been used to probe the structure–activity relationships of these inhibitors, which show potential as antibacterial agents

An implicit theory perspective on emotion regulation

Despite evidence for the important relationship between emotion regulation (ER) and psychological functioning, still little is known about why some people habitually regulate their emotions in ways that are more, or less, adaptive than others. This dissertation applies an implicit theory perspective to address this question, proposing that individual differences in ER converge on the core belief one holds regarding the fundamental controllability of emotion (i.e., implicit theory of emotion). Specifically, this dissertation draws from previous research on beliefs about controllability in other self-regulation domains (e.g., learning and academic achievement) to hypothesize that: (a) implicit theories of emotion are associated with multiple dimensions of ER that, in turn, are associated with psychological functioning; (b) by guiding individuals to adopt different goals for ER, implicit theories of emotion are linked to more, or less, adaptive patterns of cognitive ER in the face of negative life events, and (c) implicit theories of emotion and goals for ER develop in relation to the emotion-related feedback received from important socialization figures during childhood. Hypotheses were tested in three manuscripts using self-report data obtained from a sample of young adult university students (n = 483; female = 81%; Mage = 20.20). Manuscript 1 examines relations between implicit theories of emotion and six dimensions of ER. Lower emotion controllability beliefs were associated with greater difficulties in emotional acceptance and clarity, poorer perceived access to effective ER strategies, lower impulse control, and more problems maintaining goal-directed behaviour when experiencing emotional distress. Among these dimensions, parallel multiple mediation analyses indicated that perceived access to effective ER strategies most strongly mediated the relationship between implicit theories of emotion and psychological functioning (i.e., stress and well-being). Manuscript 2 investigates relations between implicit theories of emotion, (learning and performance) goals for ER, and profiles of cognitive ER in response to negative life events. Higher emotion controllability beliefs were associated with lower performance-avoidance and higher performance-approach goals for ER, but were unrelated to learning goals for ER. A parallel multiple mediation analysis indicated that only lower performance-avoidance goals uniquely mediated the positive relationship between higher emotion controllability beliefs and an increased likelihood of endorsing an adaptive (vs. maladaptive) ER profile. Manuscript 3 investigates relations between implicit theories of emotion, learning and performance goals for ER, and retrospective reports of emotion-related feedback received from parents during childhood. Results indicated that higher perceived parental emotion coaching during childhood was associated with greater learning goals for ER in young adulthood, whereas higher perceived parental emotion dismissing was associated with greater performance (avoidance and approach) goals for ER. Consistent with the implicit theory framework, results support the notions that emotion controllability beliefs are associated with significant differences in how individuals regulate their emotions, and that goals for ER (particularly performance-avoidance goals) may have an important role in mediating this link. Moreover, findings point to the possibility that the adaptive or maladaptive approach one takes towards their own emotional difficulties in young adulthood may be linked to different types of emotion-related feedback received during childhood. Directions for continued research on ER from an implicit theory perspective, as well as practical implications for mental health professionals, are discussed.Bien que la relation entre la régulation émotionnelle (RE) et la santé mentale soit bien établie, les raisons expliquant pourquoi certaines personnes sont en mesure de réguler leurs émotions sainement demeurent inconnues. L'objectif de cette dissertation est d'élucider cette question en se basant sur une théorie implicite des émotions. Précisément, cette dissertation s'appuie sur des recherches antérieures portants sur d'autres domaines de régulation (ex., la réussite scolaire) afin de formuler les hypothèses suivantes: (a) les théories implicites des émotions (TIE) sont associées à divers aspects de la régulation émotionnelle, lesquels sont liés à la santé mentale; (b) en guidant les individus à adopter des objectifs différents par rapport à la régulation émotionnelle, les TIE sont liées aux réponses cognitives plus ou moins adaptives; et (c) les TIE et les objectifs de RE se développent en fonction des réactions émotionnelles des agents de socialisation durant l'enfance. Ces hypothèses ont été vérifiées dans trois manuscrits utilisant des données fournies par un échantillon d'étudiants universitaires (n = 483; femmes = 81%; âge moyen = 20.20). Manuscrit 1 examine les relations entre les TIE et six aspects de la RE. La faible perception de contrôle sur les émotions était liée aux difficultés d'acceptation émotionnelle, à un accès plus restreint aux stratégies de RE, à une baisse dans le contrôle des pulsions, et à des difficultés à maintenir des comportements axés sur l'objectif en présence de détresse psychologique. Parmi ces aspects de la RE, les analyses de médiation parallèle suggèrent que la relation entre les TIE et la santé mentale est principalement expliquée par l'accès aux stratégies de RE. Manuscrit 2 explore les relations entre les TIE, les objectifs de RE, et la régulation cognitive des émotions. La forte perception de contrôle sur les émotions était associée à une baisse d'objectifs de performance-évitement et une hausse d'objectifs de performance-approche pour la RE. Cependant, la forte perception de contrôle sur les émotions n'était pas liée aux objectifs d'apprentissage pour la RE. Les résultats d'analyse de médiation parallèle indiquent que la relation positive entre la forte perception de contrôle sur les émotions et l'augmentation de RE adaptées était expliquée principalement par une baisse au niveau des objectifs de performance-évitement. Manuscrit 3 examine les relations entre les TIE, les objectifs pour la RE, et les souvenirs des jeunes adultes par rapport aux réactions émotionnelles perçues par leur parents durant l'enfance. Les résultats de cette étude ont révélé que le « coaching » émotionnelle par les parents durant l'enfance était associé à une hausse d'objectifs d'apprentissage pour la RE à l'âge adulte. En revanche, le « dismissing » émotionnelle des parents était associée à une hausse d'objectifs performance pour la RE à l'âge adulte. En accord avec le modèle théorique implicite, les résultats de cette recherche montrent que la perception de contrôle émotionnel contribue aux différences individuelles au niveau des stratégies utilisées pour réguler les émotions. De plus, les objectifs de RE (particulièrement les objectifs de performance-évitement) ont possiblement un rôle important dans cette association. Finalement, les résultats montrent que la capacité des jeunes adultes à comprendre et à approcher les difficultés émotionnelles est influencée par les réactions émotionnelles de leurs parents au cours de l'enfance. Des pistes de recherche sur la RE dans le cadre de la théorie implicite et des implications pratiques pour les professionnels en santé mentale sont discutées dans cette dissertation

Cognitive and behavioural emotion regulation and risky behaviours in adolescence: gender differences

The present study examines gender differences in adolescent self-reported use of adaptive and maladaptive cognitive and behavioural emotion regulation strategies, as well as gender differences in the relationship between adolescent emotion regulation and engagement in broad-based risky behaviours. Fifty male and fifty female adolescents from eight Montreal high schools completed the Risky Behavior Questionnaire for Adolescents (RBQ-A; Auerbach, & Abela, 2008), the Cognitive Emotion Regulation Questionnaire (CERQ; Garnefski, Kraaij, & Spinhoven, 2002), and the Regulation of Emotions Questionnaire (REQ; Phillips & Power, 2007). Gender differences were found in adolescent use of emotion regulation strategies, whereby females reported significantly greater use of the cognitive emotion regulation strategies of rumination, acceptance, and putting into perspective, and males reported significantly greater use of maladaptive behavioural strategies. Furthermore, gender differences were found in the relationship between adolescent use of cognitive and behavioural emotion regulation strategies, and engagement in risky behaviours. Specifically, onlymaladaptive behavioural emotion regulation significantly predicted risky behaviour engagement for males, and only maladaptive cognitive emotion regulation significantly predicted risky behaviour engagement for females. Future directions for research and clinical implications for the gender differences found in the relationship between emotion regulation and risky behaviours in adolescence are discussed.Cette étude examine les différences entre les stratégies cognitives et comportementales fonctionnelles et dysfonctionnelles des adolescents en fonction de leur sexe. De plus, les différences entre les garçons et les filles au niveau de la relation entre la régularisation d'émotions et l'adoption de comportements à risque sont explorées. Cinquante adolescents et 50 adolescentes provenant de huit écoles secondaires de la région de Montréal ont rempli le Risky Behavior Questionnaire (RBQ-A; Auerbach, & Abela, 2008), le Cognitive Emotion Regulation Questionnaire (CERQ; Garnefski, Kraaij, & Spinhoven, 2002) et le Regulation of Emotions Questionnaire (REQ-2; Phillips & Power, 2007). Des différences entre les sexes ont été notées au niveau des stratégies de régularisation d'émotions, indiquant que les adolescentes sont plus portées à utiliser des stratégies cognitives, telles que ruminer, accepter et mettre en perspective, alors que les adolescents utilisent davantage des stratégies comportementales. De plus, la relation entre la régularisation d'émotions et l'adoption de comportements à risque diffère entre les garçons et les filles. Plus précisément, seules les stratégies comportementales dysfonctionnelles de régularisation d'émotions ont prédit les comportements à risque chez les adolescents, alors que seules les stratégies cognitives dysfonctionnelles de régularisation d'émotions ont prédit les comportements à risque chez les adolescentes. Les implications cliniques en ce qui a trait à la différente relation entre la régularisation d'émotions et les comportements à risque chez les garçons et les filles sont abordées

Développement d' une nouvelle voie de synthèse d' acides b2[Bêta 2]-amines et application industrielle

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF