Les neurones pyramidaux sont constamment bombardés par une activité GABAergique spontanée qui régule le comportement de la décharge neuronale. Des résultats récents ont montré que cette activité spontanée GABAergique pouvait moduler l'excitabilité mais aussi la fidélité temporelle de décharge d'un neurone définie comme sa capacité à reproduire à l'identique un patron de décharge lors de la présentation répétée d'un même stimulus. D'autre part, de nombreuses études ont caractérisé l'existence d'une plasticité à court-terme de l'activité GABAergique médiée par les endocannabinoïdes. Ce phénomène, connu sous le nom de DSI (Depolarization-induced Suppression of Inhibition) a été décrit dans de nombreuses structures comme le cervelet, le cortex ou encore l'hippocampe.Au cours de ma thèse, j'ai étudié quelles pouvaient être les conséquences fonctionnelles de la production d'endocannabinoïdes sur l'activité neuronale et en particulier sur la fidélité temporelle de la décharge. Dans un premier temps nous avons montré que le profil de décharge in vivo des cellules de lieu de l'hippocampe pouvait induire, quand il était rejoué in vitro, le phénomène de DSI. Nous avons observé ensuite que cette diminution transitoire de la transmission GABAergique était associée à une amélioration de la fidélité temporelle de la décharge.En conclusion, nos travaux suggèrent que l'activité des cellules de lieu de la région CA1 de l'hippocampe peut provoquer, par la synthèse et la libération rétrograde d'endocannabinoïdes, une diminution à court-terme de l'activité GABAergique reçue par ces cellules avec pour conséquence des modifications de la précision temporelle de la décharge neuronale. / Pyramidal neurons are constantly bombarded by spontaneous GABAergic activity that regulates their firing behaviour. Recent results have shown that this spontaneous GABAergic activity can modulate both the excitability and the temporal fidelity of action potential discharge (Caillard, 2011). Many studies have characterized the existence of short-term plasticity of GABAergic activity mediated by endocannabinoids. This phenomenon, known as DSI (Depolarization-induced Suppression of Inhibition) has been described in many brain structures such as the cerebellum, cortex or hippocampus (for review see Freund et al., 2003; Kano et al. 2009).During my PhD thesis, I have evaluated the functional consequences of the endocannabinoid production on neuronal activity and in particular on the spike-time precision of the CA1 pyramidal neurons. As a first step we have shown that the in vivo firing pattern of place cells could induce, when replayed in vitro, a decrease in spontaneous GABA release by the endocannabinoid signalling pathway. We then observed that this transient depression of GABAergic transmission improved spike-time precision of CA1 pyramidal neurons.In conclusion, our work suggests that, in the hippocampus, CA1 place cell firing can induce, following the synthesis and retrograde release of endocannabinoids, a short-term decrease in the GABAergic activity received by these cells that consequently affects their spike-time precision.

La Liver Kinase B1 (LKB1) est une protéine pléiotrope, impliquée dans divers processus biologiques. Dans le foie, LKB1 est notamment connue pour être un régulateur clé du métabolisme et de la polarité cellulaire. Au cours de notre étude, nous avons investigué l’implication de LKB1 dans le contrôle de la prolifération des hépatocytes au cours du processus de régénération hépatique physiologique (hépatectomie partielle des 2/3). Nous avons démontré que la perte de Lkb1, spécifiquement dans les hépatocytes, favorise la récupération de la masse hépatique après hépatectomie partielle, en induisant une augmentation drastique de la réponse proliférative hépatocytaire, indépendamment de la balance métabolique/énergétique. Ainsi, LKB1 agit comme un senseur négatif de la prolifération et régule la transition G0/G1, en particulier en contrôlant la signalisation de l’EGFR (Epidermal Growth Factor Receptor). Par ailleurs, plus tard pendant la régénération, LKB1 garantit également l’intégrité mitotique. En effet, la suppression de Lkb1 entraîne des altérations majeures de la formation du fuseau mitotique. Nos résultats établissent également que LKB1 contrôle la polarité de la division cellulaire, indépendamment de l'activité de l’AMPK (AMP-activated protein kinase), une cible clé de LKB1. Par conséquent, la perte de LKB1 conduit à une altération majeure du profil de ploïdie, au stade tardif du processus de régénération. L’ensemble de notre étude souligne le double rôle de LKB1, au cours de la régénération hépatique, en tant que gardien de la prolifération hépatocytaire et de l'intégrité génomique. / Liver Kinase B1 (LKB1) is involved in pleiotropic biological processes and known to be a key regulator of hepatic metabolism and polarity. Here, we investigated the contribution of LKB1 in hepatocyte proliferation and liver regeneration process. We demonstrated that loss of hepatic Lkb1 promotes liver mass recovery, through an increase of hepatocytes proliferation, independently on metabolic/energetic balance. LKB1 regulates G0/G1 progression, specifically by controlling Epidermal Growth Factor Receptor (EGFR) signaling. In addition, later during regeneration, LKB1 controls mitotic fidelity. Deletion of Lkb1 results in major alterations of mitotic spindle formation, along the polarity axis, independently of AMP- activated protein kinase (AMPK) activity, a key target of LKB1. Consequently, LKB1 deficiency leads to an alteration of ploidy profile, at late stage of regenerative process. Overall our study highlights the dual role of LKB1, during liver regeneration, as a guardian of hepatocyte proliferation and genomic integrity.

Behavior during transitions in classrooms is an area in need of additional supports in order for teachers to effectively manage classrooms. Extended transition durations, particularly transition periods between one activity and another are related to problem behavior among children in educational settings. This study evaluated the use of acoustical feedback aimed to improve transition behaviors of elementary school students, using a multiple-baseline design across participants. Teachers were trained to implement the acoustical feedback procedure. Data on teacher treatment fidelity, student transition behavior (transition duration and problem behavior), generalization probes, and social validity were collected to examine the feasibility and potential efficacy of acoustical feedback. The results indicated that the participating teachers successfully implemented the acoustical feedback procedures with high levels or moderately high levels of fidelity and their implementation of the intervention was successful in reducing problem behavior and transition duration for all three participating children. Support for generalization was strong for two teachers and their students and minimal for one teacher and her student.

Pain management in hospitalized infants in the Neonatal Intensive Care Unit continues to be substandard despite the development and availability of evidence-based guidelines. The Evidence-based Practice Identification and Change (Lee et al., 2009) strategy is a multifaceted tailored intervention that has been used to promote evidence-based practice. However, the process of delivering the components of the intervention is not well understood and no valid measure for evaluating the fidelity of intervention implementation exists. The overall objective was to develop and determine the face validity, content validity, construct validity, feasibility, and clinical utility of the Process Evaluation Checklist. Three prospective studies were conducted. In Study 1, the face and content validity of the Process Evaluation Checklist was determined. In Study 2, the construct validity of the Process Evaluation Checklist was examined by assessing the fidelity of implementing the Evidence-based Practice Identification and Change intervention in a clinical setting. In Study 3, the feasibility and clinical utility of the Process Evaluation Checklist was determined. Overall, the face and content validity of the Process Evaluation Checklist was achieved. The intervention was implemented with high fidelity, supporting the construct validity of the measure. A Research Practice Council, with assistance from an external facilitator and internal facilitators, implemented multifaceted knowledge translation strategies in the form of constant reminders to improve sucrose administration practices. Post intervention admission orders were significantly more likely to include sucrose, and odds of being administered sucrose were 13 times greater compared to baseline. Beginning support was provided for the content and construct validity, feasibility, and clinical utility of the Process Evaluation Checklist for use with complex interventions. Using this measure to monitor intervention fidelity in different contexts and with different users over longer periods of time will provide additional support to the validity of the Process Evaluation Checklist.

Pain management in hospitalized infants in the Neonatal Intensive Care Unit continues to be substandard despite the development and availability of evidence-based guidelines. The Evidence-based Practice Identification and Change (Lee et al., 2009) strategy is a multifaceted tailored intervention that has been used to promote evidence-based practice. However, the process of delivering the components of the intervention is not well understood and no valid measure for evaluating the fidelity of intervention implementation exists. The overall objective was to develop and determine the face validity, content validity, construct validity, feasibility, and clinical utility of the Process Evaluation Checklist. Three prospective studies were conducted. In Study 1, the face and content validity of the Process Evaluation Checklist was determined. In Study 2, the construct validity of the Process Evaluation Checklist was examined by assessing the fidelity of implementing the Evidence-based Practice Identification and Change intervention in a clinical setting. In Study 3, the feasibility and clinical utility of the Process Evaluation Checklist was determined. Overall, the face and content validity of the Process Evaluation Checklist was achieved. The intervention was implemented with high fidelity, supporting the construct validity of the measure. A Research Practice Council, with assistance from an external facilitator and internal facilitators, implemented multifaceted knowledge translation strategies in the form of constant reminders to improve sucrose administration practices. Post intervention admission orders were significantly more likely to include sucrose, and odds of being administered sucrose were 13 times greater compared to baseline. Beginning support was provided for the content and construct validity, feasibility, and clinical utility of the Process Evaluation Checklist for use with complex interventions. Using this measure to monitor intervention fidelity in different contexts and with different users over longer periods of time will provide additional support to the validity of the Process Evaluation Checklist.

To decrease the computational cost of genetic algorithm optimizations, surrogate models are used during optimization. Online update of surrogate models and repeated exchange of surrogate models with exact model during genetic optimization converts static optimization problems to dynamic ones. However, genetic algorithms fail to converge to the global optimum in dynamic optimization problems. To address these problems, a multiploid genetic algorithm optimization method is proposed. Multi-fidelity surrogate models are assigned to corresponding levels of fitness values to sustain the static optimization problem. Low fidelity fitness values are used to decrease the computational cost. The exact/highest-fidelity model fitness value is used for converging to the global optimum. The algorithm is applied to single and multi-objective turbine blade aerodynamic optimization problems. The design objectives are selected as maximizing the adiabatic efficiency and torque so as to reduce the weight, size and the cost of the gas turbine engine. A 3-D steady Reynolds-Averaged Navier-Stokes solver is coupled with an automated unstructured grid generation tool. The solver is validated by using two well known test cases. Blade geometry is modelled by 37 design variables. Fine and coarse grid solutions are respected as high and low fidelity surrogate models, respectively. One of the test cases is selected as the baseline and is modified in the design process. The effects of input parameters on the performance of the multiploid genetic algorithm are studied. It is demonstrated that the proposed algorithm accelerates the optimization cycle while providing convergence to the global optimum for single and multi-objective problems.

<p>This thesis describes the evaluation of a prototype (Illustrator) for future simulator training of Within Visual Range - combat in the Swedish Air Force. The main focus was to collect and transform user acceptance data (expert opinions) to useful guidelines for continued development. Thirteen active fighter pilots participated in the study. The aim was to use expert opinion to study a) the psychological user acceptance, and b) the technical user acceptance, of the Illustrator together with c) gathering opinions for future improvement. Three psychological aspects were rated before and after the sessions to measure psychological user acceptance. For technical user acceptance, seven fidelity levels of the Illustrator were evaluated regarding realism, limitation of performance and importance of realism after the sessions. The sessions consisted of WVR-scenarios. Four different questionnaires were used for data collection. Two fidelity levels showed to diverge from the others in many ways, and were identified as major problems by the participants. No change of the psychological aspects was found between measurements. According to the results of the evaluation, suggestions and guidelines for future development are presented. Finally, issues of interest for future research are proposed.</p>

There is much research conducted on training teachers to use the evidence-based teaching strategies known as system of least prompts. However, there is little research conducted on using a modified system of least prompt. This study examined the fidelity of implementation by two early childhood teachers using a modified system of least prompts with preschool aged children. A multiple-probe design across participants was used to determine the effect of fidelity of implementation of a modified system of least prompts strategy on the level of on-task student engagement. The results showed that early childhood teachers could implement the modified teaching strategy with fidelity while also increasing the level of on-task engagement.

This work is on Gaussian-process based approximation of a code which can be run at different levels of accuracy. The goal is to improve the predictions of a surrogate model of a complex computer code using fast approximations of it. A new formulation of a co-kriging based method has been proposed. In particular this formulation allows for fast implementation and for closed-form expressions for the predictive mean and variance for universal co-kriging in the multi-fidelity framework, which is a breakthrough as it really allows for the practical application of such a method in real cases. Furthermore, fast cross validation, sequential experimental design and sensitivity analysis methods have been extended to the multi-fidelity co-kriging framework. This thesis also deals with a conjecture about the dependence of the learning curve (ie the decay rate of the mean square error) with respect to the smoothness of the underlying function. A proof in a fairly general situation (which includes the classical models of Gaussian-process based metamodels with stationary covariance functions) has been obtained while the previous proofs hold only for degenerate kernels (ie when the process is in fact finite-dimensional). This result allows for addressing rigorously practical questions such as the optimal allocation of the budget between different levels of codes in the multi-fidelity framework.

We are currently in an era of accountability, so the need for measuring fidelity of implementation is gaining attention. However, there is little research in the area of fidelity of implementation and an inclusive early childhood classroom. In addition, most of the research is conducted using teachers. This study examined the fidelity of implementation by two teaching assistants using the teaching strategies of time delay and system of least prompts with children with and without disabilities in an inclusive early childhood setting. A multiple-probe design with conditions across two behaviors and across two participants design was used to determine the effects of teaching assistants’ fidelity of implementation of evidence-based teaching strategies. Also a multiple probe across two behaviors, replicated across children was used. Most importantly, the results showed that teaching assistants could implement systematic teaching strategies with fidelity. Secondly, the children were able to make progress towards their target skills.