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<p> The development of high-quality screening assays for the identification of biologically active ligands is critical in drug discovery. This thesis is aimed at developing new advances m capillary electrophoresis (CE) for the characterization of the conformational stability and enzymatic activity of protein targets with small molecules. CE provides a convenient platform for unbiased assessment of multiple thermodynamic and kinetic parameters associated with biomolecular interactions involving regulatory protein or isomerase enzymes, where various sample pretreatment steps can be integrated directly in-capillary during analysis. The first two chapters of the thesis (Chapters II, III) outline the development of dynamic ligand exchange-affinity capillary electrophoresis (DLEACE) as a novel strategy for the screening of allosteric ligands based on the differential stability of urea-induced unfolding of various apolholo-protein states of cAMP receptor protein constructs. This work introduced a label-free and multivariate approach for ligand selection based on complementary thermodynamic parameters that allowed for determination of the dissociation constant of protein-ligand interactions over a wide dynamic range (> 10^4, Kd = nM-mM). The subsequent two chapters of the thesis (Chapters IV, V) describe the development of a novel kinetic assay for unbiased characterization of isomerase activity associated with D/L-amino acid metabolism using hydroxyproline epimerase as a model system. Stereoselective resolution of various hydroxyproline isomers was accomplished via off-line or on-line chemical derivatization with dynamic complexation usmg chiral selector(s) in order to screen potential inhibitors for putative epimerase and racemase activity. The integration of both thermodynamic and kinetic strategies for differentiation of mutant from wild-type enzymes was important for revealing the function of a catalytic acid/base cysteine pair in the epimerase active site. Overall, this thesis outlines an integrative framework based on CE for high-quality screening, which is relevant in reducing the high attrition rate of lead candidates in drug development. </p> / Thesis / Doctor of Philosophy (PhD)

Final qualifying work (master's thesis) is devoted to the study of the financing of outpatient care during the transition to predominantly single-channel: funding, in order to provide high-quality and affordable medical care. The main purpose of the master's thesis is to develop methods of financing and approaches to the provision of medical care, to identify problems and proposals for their solution, for the effective use of financial means of compulsory health insurance through the implementation of optimal and stimulating mechanism of payment of medical organizations -Fund holders. In conclusion, the recommendations on improving the funding mechanism for the object of study are outlined. / Выпускная квалификационная работа (магистерская диссертация) посвящена исследованию финансирования амбулаторно-поликлинического звена в период перехода на преимущественно одноканальное финансирование, в целях оказания качественной и доступной медицинской помощи. Основной целью магистерской диссертации является проработка методов финансирования и подходов оказания медицинской помощи, для выявления проблем и предложений по их решению, для эффективного использования финансовых средств обязательного медицинского страхования путем реализации оптимального и стимулирующего механизма оплаты медицинских организаций - фондодержателей. В заключении обозначены рекомендации по совершенствованию механизма финансирования для объекта исследования.

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Professional development is used by teachers to improve their teaching to enhance student learning, and research indicates that the National Board Certification (NBC) process contains high-quality professional development characteristics. Engagement in the NBC process can lead to professional growth by changing teachers’ knowledge, instructional practices, and students’ learning. This quantitative study investigated the extent to which characteristics of the NBC process influenced National Board Certified Teachers’ (NBCTs) professional growth. Using an online survey, the study collected responses from 119 NBCTs who participated in a specific NBC support program. Key findings included that all 20 high-quality professional development characteristics investigated had a perceived positive influence on professional growth, with some notable differences. The characteristics involving individual analysis of student work and teaching videos along with reflection were perceived to be most important, while those centering on collaboration with other candidates were perceived as less important. Second, characteristics that had the greatest perceived impact were those that focused on changing pedagogy rather than increasing content knowledge. Furthermore, a significant relationship was found between the perceived importance of duration in the experience and the length of time the candidate was in the process: NBCTs who achieved in one year, as compared to NBCTs who achieved in two or three years, had statistically significant lower ratings on the influence that the duration had on their professional growth. Additionally, those who engaged in the process for financial reasons, as compared to professional growth, had a lower rating of perceived importance when all characteristics were combined.

Le secteur de la construction est considéré comme un des facteurs principaux qui affectent la dépense énergétique et les émissions des gaz à effet de serre. Dès lors, la valorisation de la qualité environnementale des bâtiments constitue une réponse importante aux enjeux du développement durable. Dans ce contexte, notre recherche aborde le problème de l'incertitude inhérente aux démarches HQE®, notamment dans l'évaluation de la qualité environnementale des bâtiments tertiaires. Notre étude s'appuie sur la théorie des possibilités qui présente des atouts intéressants au regard de notre problématique, notamment sa capacité à modéliser l'expertise humaine et la présentation simple et unique des incertitudes et des imprécisions sur la base d'un volume limité d'informations. Ce travail vise à associer une crédibilité à l'évaluation de la qualité environnementale du bâtiment en traitant des paramètres tant quantitatifs que qualitatifs. La modélisation des incertitudes permet aux concepteurs de mieux hiérarchiser les impacts des différents paramètres contribuant à l'amélioration de la qualité environnementale d'un bâtiment et d'identifier les informations qui nécessiteraient en priorité une instigation plus poussée afin de crédibiliser l'évaluation environnementale / It is well known that the construction sector is considered one of the main factors that affect the energy consumption and the emissions of greenhouse gases. Thus, the enhancement of the environmental quality of buildings is an important response to the challenges of sustainable development. In such context, this research discusses the problem of the uncertainty inherent in the French approach HQE®, particularly the assessment of the environmental quality of tertiary buildings. In fact, this study is based on possibility theory, which presents interesting advantages in terms of our problem, especially its ability to model human expertise or knowledge in addition to simple and unique presentation of uncertainties and inaccuracies on the basis of a limited amount of information. Moreover, this work aims to associate a credibility assessment of the environmental quality of buildings by handling two types of input parameters which are the quantitative and the qualitative ones. This uncertainty modeling offers the designers a better prioritization of the impacts of the different parameters, which thus contribute to the improvement of the environmental quality of a building, and identify the information that would require more instigation to enhance the credibility of the environmental assessment

La littérature scientifique internationale montre la réalité des apprentissages informels des enseignants sur leur lieu de travail, au sein des établissements scolaires. Toutefois ces apprentissages présentent plusieurs limites et sont qualitativement de moins bonne qualité que les apprentissages réalisés en environnement organisé. La présente recherche a précisément pour objet le développement professionnel des enseignants expérimentés à travers un dispositif de formation continue prenant en compte leurs apprentissages informels. Cette étude s’inscrit dans un programme de recherche anthropoculturel (Bertone, 2011 ; Chaliès, 2012) dont les principaux présupposés théoriques sont empruntés à la philosophie du langage ordinaire (Wittgenstein, 2004). Elle a été menée dans le cadre de deux dispositifs innovants de formation permettant à un enseignant expérimenté (le pair formateur) d’enseigner ostensivement l’une de ses pratiques spécifiques jugées efficaces à un pair enseignant expérimenté (le pair formé). Les principaux résultats de la recherche montrent la modélisation de l’activité professionnelle des pairs formateurs et contribuent ainsi à documenter la recherche internationale sur les apprentissages informels des enseignants du primaire. Ils montrent également l’apprentissage de nouvelles pratiques professionnelles de la part des pairs formés entendu comme l’acquisition de nouveaux systèmes de règles. Les résultats montrent enfin le développement professionnel des pairs formés entendu comme l’interprétation des règles apprises dans des circonstances nouvelles ainsi que le développement réflexif de l’activité professionnelle des pairs formateurs. / The international scientific literature shows the reality of teachers' informal learning in the workplace, within schools. However, these learnings have several limitations and are of lower quality than those that are carried out in an organized environment. The purpose of this research is precisely the professional development of experienced teachers through a professional development program that considers their informal learning.This study is part of an anthropocultural research program (Bertone, 2011; Chaliès, 2012) whose main theoretical assumptions are borrowed from the philosophy of ordinary language (Wittgenstein, 2004). It was conducted within the framework of two innovative training devices allowing an experienced teacher (the peer trainer) to ostensibly teach one of his specific practices considered effective to an experienced peer teacher (the trained peer). The main research results show the modelling of the professional activity of peer trainers and thus contribute to documenting international research on informal learning by primary school teachers. They also show the learning of new professional practices from trained peers understood as the acquisition of new rule systems. Finally, the results show the professional development of the trained peers understood as the interpretation of the rules learned in new circumstances as well as the reflexive development of the professional activity of the trained peers.

This dissertation focuses on high-performance LC-tank CMOS VCO design at 2 GHz. The high-Q inductors are realized using wiring metal lines in advanced packages. Those inductors are used in the resonator of the VCO to achieve low phase noise, low power consumption, and a wide frequency tuning range. In this dissertation, a fine-pitch ball-grid array (FBGA) package, a multichip module (MCM)-L package, and a wafer-level package (WLP) are incorporated to realize the high-Q inductor. The Q-factors of inductors embedded in packages are compared to those of inductors monolithically integrated on Si and GaAs substrates. All the inductors are modeled with a physical, simple, equivalent two-port model for the VCO design as well as for phase noise analysis. The losses in an LC-tank are analyzed from the phase noise perspective. For the implementation of VCOs, the effects of the interconnection between the embedded inductor and the VCO circuit are investigated. The VCO using the on-chip inductors is designed as a reference. The performance of VCOs using the embedded inductor in a FBGA and a WLP is compared with that of a VCO using the on-chip inductor. The VCO design is optimized from the high-Q perspective to enhance performance. Through this optimization, less phase noise, lower power consumption, and a wider frequency tuning range are obtained simultaneously.

Le thème du vieillissement de la population française est bien connu. Les effets sont plus importants qu’on le pense souvent. L’habitat, les pratiques urbaines, les services et commerces doivent être adaptés. Le géographe aborde le thème par la relation des usagers aux territoires en faisant appel aux outils scientifiques donnés par la psychologie environnementale et aux indications de la médecine.Ce travail répond à une demande professionnelle d’ICADE, un des principaux promoteurs immobiliers du pays. L’auteur met en œuvre des méthodes très concrètes : cartes mentales, GPS, qui permettent de saisir le mieux possible les besoins des usagers. Plusieurs expérimentations ont été conduites, à différentes échelles, sur divers terrains (Lyon et Rhône-Alpes, Région parisienne, Nice). La troisième partie de l’ouvrage est une réflexion sur la gouvernance la plus efficiente qui devrait présider à la mise en œuvre de pôles gérontologiques et de réseaux de santé. / The aging of the French population is a well- known topic but its effects are more important than is usually thought. The dwelling, the urban living habits, the services and amenities have to be adapted to seniors.The geographer tackles the problem through the relation of elder people to their living territory by using scientific tools provided by environmental psychology, and by referring to medical data.This research work has been made at the professional request of ICADE, one of the leading estate developers in France. The author applies very concrete methods, such as the use of mental maps and GPS trackers, so as to grasp the needs of seniors as accurately as possible. Several experiments have been conducted, at different scales and in different surroundings -Lyon and the Rhône-Alpes region, the Paris region, and also the city of Nice. The third part of the study consists in reflecting on the governance that would be the most efficient to implement the “gerontopôles” (structures associating geriatrics, medical and social care and gerontology).

La traduction automatique (TA) a connu des progrès significatifs ces dernières années et continue de s'améliorer. La TA est utilisée aujourd'hui avec succès dans de nombreux contextes, y compris les environnements professionnels de traduction et les scénarios de production. Cependant, le processus de traduction requiert souvent des connaissances plus larges qu'extraites de corpus parallèles. Étant donné qu'une injection de connaissances humaines dans la TA est nécessaire, l'un des moyens possibles d'améliorer TA est d'assurer une collaboration optimisée entre l'humain et la machine. À cette fin, de nombreuses questions sont posées pour la recherche en TA: Comment détecter les passages où une aide humaine devrait être proposée ? Comment faire pour que les machines exploitent les connaissances humaines obtenues afin d'améliorer leurs sorties ? Enfin, comment optimiser l'échange: minimiser l'effort humain impliqué et maximiser la qualité de TA? Diverses solutions sont possibles selon les scénarios de traductions considérés. Dans cette thèse, nous avons choisi de nous concentrer sur la pré-édition, une intervention humaine en TA qui a lieu ex-ante, par opposition à la post-édition, où l'intervention humaine qui déroule ex-post. En particulier, nous étudions des scénarios de pré-édition ciblés où l'humain doit fournir des traductions pour des segments sources difficiles à traduire et choisis avec soin. Les scénarios de la pré-édition impliquant la pré-traduction restent étonnamment peu étudiés dans la communauté. Cependant, ces scénarios peuvent offrir une série d'avantages relativement, notamment, à des scénarios de post-édition non ciblés, tels que : la réduction de la charge cognitive requise pour analyser des phrases mal traduites; davantage de contrôle sur le processus; une possibilité que la machine exploite de nouvelles connaissances pour améliorer la traduction automatique au voisinage des segments pré-traduits, etc. De plus, dans un contexte multilingue, des difficultés communes peuvent être résolues simultanément pour de nombreuses langues. De tels scénarios s'adaptent donc parfaitement aux contextes de production standard, où l'un des principaux objectifs est de réduire le coût de l’intervention humaine et où les traductions sont généralement effectuées à partir d'une langue vers plusieurs langues à la fois. Dans ce contexte, nous nous concentrons sur la TA de revues systématiques en médecine. En considérant cet exemple, nous proposons une méthodologie indépendante du système pour la détection des difficultés de traduction. Nous définissons la notion de difficulté de traduction de la manière suivante : les segments difficiles à traduire sont des segments pour lesquels un système de TA fait des prédictions erronées. Nous formulons le problème comme un problème de classification binaire et montrons que, en utilisant cette méthodologie, les difficultés peuvent être détectées de manière fiable sans avoir accès à des informations spécifiques au système. Nous montrons que dans un contexte multilingue, les difficultés communes sont rares. Une perspective plus prometteuse en vue d'améliorer la qualité réside dans des approches dans lesquelles les traductions dans les différentes langues s’aident mutuellement à résoudre leurs difficultés. Nous intégrons les résultats de notre procédure de détection des difficultés dans un protocole de pré-édition qui permet de résoudre ces difficultés par pré-traduction. Nous évaluons le protocole dans un cadre simulé et montrons que la pré-traduction peut être à la fois utile pour améliorer la qualité de la TA et réaliste en termes d'implication des efforts humains. En outre, les effets indirects sont significatifs. Nous évaluons également notre protocole dans un contexte préliminaire impliquant des interventions humaines. Les résultats de ces expériences pilotes confirment les résultats obtenus dans le cadre simulé et ouvrent des perspectives encourageantes pour des tests ultérieures. / Machine Translation (MT) has made significant progress in the recent years and continues to improve. Today, MT is successfully used in many contexts, including professional translation environments and production scenarios. However, the translation process requires knowledge larger in scope than what can be captured by machines even from a large quantity of translated texts. Since injecting human knowledge into MT is required, one of the potential ways to improve MT is to ensure an optimized human-machine collaboration. To this end, many questions are asked by modern research in MT: How to detect where human assistance should be proposed? How to make machines exploit the obtained human knowledge so that they could improve their output? And, not less importantly, how to optimize the exchange so as to minimize the human effort involved and maximize the quality of MT output? Various solutions have been proposed depending on concrete implementations of the MT process. In this thesis we have chosen to focus on Pre-Edition (PRE), corresponding to a type of human intervention into MT that takes place ex-ante, as opposed to Post-Edition (PE), where human intervention takes place ex-post. In particular, we study targeted PRE scenarios where the human is to provide translations for carefully chosen, difficult-to-translate, source segments. Targeted PRE scenarios involving pre-translation remain surprisingly understudied in the MT community. However, such PRE scenarios can offer a series of advantages as compared, for instance, to non-targeted PE scenarios: i.a., the reduction of the cognitive load required to analyze poorly translated sentences; more control over the translation process; a possibility that the machine will exploit new knowledge to improve the automatic translation of neighboring words, etc. Moreover, in a multilingual setting common difficulties can be resolved at one time and for many languages. Such scenarios thus perfectly fit standard production contexts, where one of the main goals is to reduce the cost of PE and where translations are commonly performed simultaneously from one language into many languages. A representative production context - an automatic translation of systematic medical reviews - is the focus of this work. Given this representative context, we propose a system-independent methodology for translation difficulty detection. We define the notion of translation difficulty as related to translation quality: difficult-to-translate segments are segments for which an MT system makes erroneous predictions. We cast the problem of difficulty detection as a binary classification problem and demonstrate that, using this methodology, difficulties can be reliably detected without access to system-specific information. We show that in a multilingual setting common difficulties are rare, and a better perspective of quality improvement lies in approaches where translations into different languages will help each other in the resolution of difficulties. We integrate the results of our difficulty detection procedure into a PRE protocol that enables resolution of those difficulties by pre-translation. We assess the protocol in a simulated setting and show that pre-translation as a type of PRE can be both useful to improve MT quality and realistic in terms of the human effort involved. Moreover, indirect effects are found to be genuine. We also assess the protocol in a preliminary real-life setting. Results of those pilot experiments confirm the results in the simulated setting and suggest an encouraging beginning of the test phase.