CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; CD152) is of pivotal importance for self-tolerance, with deficiency or unfavorable polymorphisms leading to autoimmune disease. Tolerance to self-antigens is achieved through thymic deletion of highly autoreactive conventional T (Tconv) cells and generation of FoxP3(+) regulatory T (Treg) cells. The main costimulatory molecule, CD28, augments the negative selection of Tconv cells and promotes the generation of FoxP3(+) Treg cells. The role of its antagonistic homolog CTLA-4, however, remains a topic of debate. To address this topic, we investigated the thymic development of T cells in the presence and absence of CTLA-4 in a T-cell receptor (TCR) transgenic mouse model specific for the myelin basic protein peptide Ac1-9. We reveal that CTLA-4 is expressed in the corticomedullary region of the thymus. Its absence alters the response of CD4(+)CD8(-) thymocytes to self-antigen recognition, which affects the quantity of the Treg cells generated and broadens the repertoire of peripheral Tconv cells. T-cell repertoire alteration after deletion of CTLA-4 results from changes in TCR Vα and Jα segment selection as well as CDR3α composition in Tconv and Treg cells. CTLA-4, therefore, regulates the early development of self-reactive T cells in the thymus and plays a key role in central tolerance.

A productivity map of cognitive pretest methos for improving survey questions

Interest in cognitive pretest methods for evaluating survey questionnaires has been increasing for the last three decades. However, analysing the features of the scientific output in the field can be difficult due to its prevalence in public and private institutes whose main mission is not scientific research. The aim of this research is to characterize the current state of scientific output in the field by means of two bibliometric studies for the period from 1980 to 2007. Study 1 analysed documents obtained from the more commonly used bibliographic databases. Study 2 supplemented the body of documents from Study 1 with documents from non-indexed journals, conference papers, etc. Results show a constant growth in the number of publications. The wide dispersion of publication sources, together with the highlighted role of the public and private institutions as centres of production, can also be identified as relevant characteristics of the scientific output in this field.

Self construction, cognitive conflicts and polarization in bulimia nervosa

This study explores the cognitive structures, understood as construct systems, of patients suffering from bulimia nervosa (BN). Previous studies investigated the construct systems of disordered eaters suggesting that they had a higher distance between their construction of the self and the «ideal self», and also more rigidity. In addition to these aspects, this study explored the presence of implicative dilemmas (ID). Thirty two women who met criteria for BN and were treated in a specialized center were compared to a non clinical group composed by 32 women matched by age. All participants were assessed using Repertory Grid Technique (RGT). In BN patients it was more common (71.9%) to find IDs than in controls (18.8%). They also showed higher polarization and higher self-ideal discrepancies (even more for those with a long history of BN). The measures provided by the RGT can be useful for the assessment of self-construction and cognitive conflicts in BN patients and to appreciate their role in this disorder. In addition, this technique could be helpful for clinicians to explore the patient"s constructs system, and specially to identify IDs that could be maintaining the symptoms or hindering change in order to focus on them to facilitate improvement.

Cognitive behavioural therapy for obesity and binge eating associated to antipsychotic drugs

Background and Aims: Overweight, obesity and binge eating disorder are commonly reported in persons with severe mental disorders. Particularly, antipsychotic drugs (AP) induce weight gain in up to half of the patients. The aim of the present study is to confirm a previous study results on a larger sample of patients, to assess the impact of the interventions on other relevant dimensions of eating and weight related cognitions as well as to assess potential clinical indicators of outcomes such as AP drug, concomitant treatment with lithium or carbamazepine, psychiatric diagnostic, binge eating and severity of cognitive distortions. Method: A controlled study (12-week CBT vs. B N E) was carried out on 99 patients treated with an AP and who have gained weight following this treatment. Binge eating symptomatology, eating and weight-related cognitions, as well as weight and body mass index were assessed before treatment, at 12 weeks and at 24 weeks. Results: The findings confirms usefulness and effectiveness of the proposed CBT program on the treatment of binge symptomatology, cognitive distortions and obesity in patients treated with AP. Reduction of binge symptoms and maladapted cognitions appeared early, whereas the effect on weight appeared later during the follow up observation. No differences on outcomes were found across pharmacotherapy characteristics, diagnostic categories, binge eating nor severity of cognitive distortions. Conclusion: The proposed CBT treatment is useful for patients suffering from weight gain associated with AP treatments indeed when a concomitant treatment with lithium or valproate was given.

Receptor activator for NF-κB ligand in acute myeloid leukemia: expression, function, and modulation of NK cell immunosurveillance.

The TNF family member receptor activator for NF-κB ligand (RANKL) and its receptors RANK and osteoprotegerin are key regulators of bone remodeling but also influence cellular functions of tumor and immune effector cells. In this work, we studied the involvement of RANK-RANKL interaction in NK cell-mediated immunosurveillance of acute myeloid leukemia (AML). Substantial levels of RANKL were found to be expressed on leukemia cells in 53 of 78 (68%) investigated patients. Signaling via RANKL into the leukemia cells stimulated their metabolic activity and induced the release of cytokines involved in AML pathophysiology. In addition, the immunomodulatory factors released by AML cells upon RANKL signaling impaired the anti-leukemia reactivity of NK cells and induced RANK expression, and NK cells of AML patients displayed significantly upregulated RANK expression compared with healthy controls. Treatment of AML cells with the clinically available RANKL Ab Denosumab resulted in enhanced NK cell anti-leukemia reactivity. This was due to both blockade of the release of NK-inhibitory factors by AML cells and prevention of RANK signaling into NK cells. The latter was found to directly impair NK anti-leukemia reactivity with a more pronounced effect on IFN-γ production compared with cytotoxicity. Together, our data unravel a previously unknown function of the RANK-RANKL molecule system in AML pathophysiology as well as NK cell function and suggest that neutralization of RANKL with therapeutic Abs may serve to reinforce NK cell reactivity in leukemia patients.

The relationship between cognitive errors and interpersonal patterns in depressed women.

Individuals with depression process information in an overly negative or biased way (e.g., Henriques & Leitenberg, 2002) and demonstrate significant interpersonal dysfunction (e.g., Zlotnick, Kohn, Keitner, & Della Grotta, 2000). This study examined the relationship between cognitive errors (CEs) and interpersonal interactions in early psychotherapy sessions of 25 female patients with major depression. Transcripts were rated for CEs using the Cognitive Error Rating Scale (Drapeau, Perry, & Dunkley, 2008). Interpersonal patterns were assessed using the Structural Analysis of Social Behavior (Benjamin, 1974). Significant associations were found between CEs and markers of interpersonal functioning in selected contexts. The implications of these findings in bridging the gap between research and practice, enhancing treatment outcome, and improving therapist training are discussed. (PsycINFO Database Record (c) 2012 APA, all rights reserved).

New strategies in the modulation of fatty acid oxidation as a treatment for obesity

Strategies that enhance fat degradation or reduce caloricfood intake could be considered therapeutic interventions to reduce notonly obesity, but also its associated disorders. The enzyme carnitinepalmitoyltransferase 1 (CPT1) is the critical rate-determining regulatorof fatty acid oxidation (FAO) and might play a key role in increasingenergy expenditure and controlling food intake. Our group has shownthat mice overexpressing CPT1 in liver are protected from weight gain,the development of obesity and insulin resistance. Regarding foodintake control, we observed that the pharmacological inhibition ofCPT1 in rat hypothalamus decreased food intake and body weight.This suggests that modulation of CPT1 activity and the oxidation offatty acids in various tissues can be crucial for the potential treatmentof obesity and associated pathologies.

Novel action of a wake-promoting neuropeptide in hippocampus : inhibition of nmda receptor function at excitatory synapses through orexin-a

One of the most intriguing functions of the brain is the ability to learn and memorize. The mechanism through which memory and learning are expressed requires the activation of NMDA receptors (NMDARs). These molecular entities are placed at the postsynaptic density of excitatory synapses and their function is tightly controlled by the actions of several modulators at the extracellular, intracellular and pore sites. A large part of the intracellular modulation comes from the action of G-protein coupled receptors (GPCRs). Through intracellular cascades typically involving kinases and phosphatases, GPCRs potentiate or inhibit NMDARs, controlling the conductive state but also the trafficking within the synapse. The GPCRs are involved in the modulation of a variety of brain functions. Many of them control cognition, memory and learning performance, therefore, their effects on NMDARs are extensively studied. The orexinergic system signals through GPCRs and it is well known for the regulation of waking, feeding, reward and autonomic functions. Moreover, it is involved in potentiating hippocampus-related cognitive tasks. Orexin receptors and fibers are present within the hippocampus, but whether these directly modulate hippocampal cells and synapses has not yet been determined. During my thesis, I studied orexinergic actions on excitatory synaptic transmission via whole-cell patch-clamp recordings in rat acute hippocampal slices. I observed that exogenously applied orexin-A (ox-A) exerted a strong inhibitory action on NMDAR-mediated synaptic potentials at mossy fiber (MF)-CA3 synapses, by postsynaptically activating orexin-2 receptors, a minor inhibition at Schaffer collateral-CAl synapses and did not affect other synapses with the CA3 area. Moreover, I demonstrated that the susceptibility of NMDARs to ox- A depends on the tone of endogenous orexin known to fluctuate during the day-night cycle. In fact, in slices prepared during the active period of the rats, when endogenous orexin levels are high, NMDAR-currents were not affected by exogenously applied ox-A. The inhibitory effect of ox-A was, however, reverted when interfering with the orexinergic system through intraperitoneal injections of almorexant, a dual orexin receptor antagonist, during the active phase prior to slice preparation. This thesis work suggests that the orexinergic system regulates NMDAR-dependent information flow through select hippocampal pathways depending on the time-of-day. The specific orexinergic modulation of NMDARs at MFs dampens the excitability of the hippocampal circuit and could impede the mechanisms related to memory formation, possibly also following extended periods of waking. -- La capacité d'apprentissage et de mémorisation est une des fonctions les plus intrigantes de notre cerveau. Il a été montré qu'elles requièrent l'activation des récepteurs NMDA (NMDARs). Ces entités moléculaires sont présentes au niveau de la densité post-synaptique des synapses excitatrices et leur fonction est étroitement contrôlée par l'action de nombreux modulateurs au niveau extracellulaire, intracellulaire et membranaire de ces récepteurs. Une grande partie de la modulation intracellulaire s'effectue via l'action de récepteurs couplés aux protéines G (GPCRs). Grace à leurs cascades intracellulaires typiquement impliquant des kinases et des phosphatases, les GPCRs favorisent l'activation ou l'inhibition des NMDARs, contrôlant ainsi leur perméabilité mais aussi leur mouvement à la synapse. Les GPCRs sont impliquées dans de nombreuses fonctions cérébrales telles que la cognition, la mémoire ainsi que la capacité d'apprentissage c'est pour cela que leurs effets sur les NMDARs sont très étudiés. Le système orexinergique fait intervenir ces GPCRs et est connu par son rôle dans la régulation de fonctions physiologiques telles que l'éveil, la prise alimentaire, la récompense ainsi que d'autres fonctions du système nerveux autonome. De plus, ce système est impliqué dans la régulation de tâches cognitives liées à l'hippocampe. Bien que les fibres et les récepteurs à l'orexine soient présents dans l'hippocampe, leur mécanisme d'action sur les cellules et les synapses de l'hippocampe n'a pas encore été élucidé. Durant ma thèse, je me suis intéressée aux effets de l'orexine sur la transmission synaptique excitatrice en utilisant la méthode d'enregistrement en patch-clamp en configuration cellule entière sur des tranches aiguës d'hippocampes de rats. J'ai observé que l'application exogène d'orexine A d'une part inhibe fortement les courants synaptiques dépendants de l'activation des NMDARs au niveau de la synapse entre les fibres moussues et CA3 via l'activation post-synaptique des orexine récepteurs 2 mais d'autre part n'inhibe que de façon mineure la synapse entre les collatérales de Schaffer et CAI et n'affecte pas les autres synapses impliquant CA3. J'ai également démontré que la sensibilité des NMDARs à l'orexine A dépend de sa concentration endogène qui fluctue durant le cycle éveil-sommeil. En effet, lorsque les coupes d'hippocampes sont préparées durant la période active de l'animal correspondant à un niveau endogène d'orexine élevé, l'application exogène d'orexine A n'a aucun effet sur les courants dépendants de l'activation des NMDARs. Cependant, l'injection dans le péritoine, durant la phase active de l'animal, d'un antagoniste des orexine récepteurs, l'almorexant, va supprimer l'effet inhibiteur de l'orexine A. Les résultats de ma thèse suggèrent donc que le système orexinergique module les informations véhiculées par les NMDARs via des voies de signalisation sélectives de l'hippocampe en fonction du moment de la journée. La modulation orexinergique des NMDARs au niveau des fibres moussues diminue ainsi l'excitabilité du circuit hippocampal et pourrait entraver les mécanismes liés à la formation de la mémoire, potentiellement après de longues périodes d'éveil.

On the relationship between performance-approach goals and cognitive performance : when the desire to outperform others becomes interfering

Cette thèse explore dans quelle mesure la poursuite d'un but de performance-approche (i.e., le désir de surpasser autrui et de démontrer ses compétences) favorise, ou au contraire endommage, la réussite et l'apprentissage-une question toujours largement débattue dans la littérature. Quatre études menées en laboratoire ont confirmé cette hypothèse et démontré que la poursuite du but de performance-approche amène les individus à diviser leur attention entre d'une part la réalisation de la tâche évaluée, et d'autre part la gestion de préoccupations liées à l'atteinte du but-ceci empêchant une concentration efficace sur les processus de résolution de la tâche. Dans une deuxième ligne de recherche, nous avons ensuite démontré que cette distraction est exacerbée chez les individus les plus performants et ayant le plus l'habitude de réussir, ceci dérivant d'une pression supplémentaire liée au souhait de maintenir le statut positif de « bon élève ». Enfin, notre troisième ligne de recherche a cherché à réconcilier ces résultats-pointant l'aspect distractif du but de performance-approche-avec le profil se dégageant des études longitudinales rapportées dans la littérature-associant ce but avec la réussite académique. Ainsi, nous avons mené une étude longitudinale testant si l'adoption du but de performance-approche en classe pourrait augmenter la mise en oeuvre de stratégies d'étude tactiquement dirigées vers la performance-favorisant une réussite optimale aux tests. Nos résultats ont apporté des éléments en faveur de cette hypothèse, mais uniquement chez les élèves de bas niveau. Ainsi, l'ensemble de nos résultats permet de mettre en lumière les processus cognitifs à l'oeuvre lors de la poursuite du but de performance-approche, ainsi que d'alimenter le débat concernant leur aspect bénéfique ou nuisible en contexte éducatif. -- In this dissertation, we propose to investigate whether the pursuit of performance-approach goals (i.e., the desire to outperform others and appear talented) facilitates or rather endangers achievement and learning-an issue that is still widely discussed in the achievement goal literature. Four experiments carried out in a laboratory setting have provided evidence that performance- approach goals create a divided-attention situation that leads cognitive resources to be divided between task processing and the activation of goal-attainment concerns-which jeopardizes full cognitive immersion in the task. Then, in a second research line, we found evidence that high- achievers (i.e., those individuals who are the most used to succeed) experience, under evaluative contexts, heightened pressure to excel at the task, deriving from concerns associated with the preservation of their "high-achiever" status. Finally, a third research line was designed to try to reconcile results stemming from our laboratory studies with the overall profile emerging from longitudinal research-which have consistently found performance-approach goals to be a positive predictor of students' test scores. We thus set up a longitudinal study so as to test whether students' adoption of performance-approach goals in a long-term classroom setting enhances the implementation of strategic study behaviors tactically directed toward goal-attainment, hence favoring test performance. Our findings brought support for this hypothesis, but only for low-achieving students. Taken together, our findings shed new light on the cognitive processes at play during the pursuit of performance-approach goals, and are likely to fuel the debate regarding whether performance-approach goals should be encouraged or not in educational settings.