Tuberculosis is an ancient infectious disease and a leading cause of death globally. Preclinical research is important for defining drugs and regimens which should be carried forward to human studies. This thesis aims to characterize the population pharmacokinetics and exposure-response relationships of anti-tubercular drugs alone and in combinations, and to suggest experimental designs for preclinical settings. The population pharmacokinetics of rifampicin, isoniazid, ethambutol and pyrazinamide were described for the first time in two mouse models. This allowed for linking the population pharmacokinetic model to the Multistate Tuberculosis Pharmacometric (MTP) model for biomarker response, which was used to characterize exposure-response relationships in monotherapy. Pharmacodynamic interactions in combination therapies were quantitatively described by linking the MTP model to the General Pharmacodynamic Interaction (GPDI) model, which provided estimates of single drug effects together with a quantitative model-based evaluation framework for evaluation of pharmacodynamic interactions among drugs in combinations. Synergism (more than expected additivity) was characterized between rifampicin and ethambutol, while antagonism (less than expected additivity) was characterized between rifampicin and isoniazid in combination therapies. The new single-dose pharmacokinetic design with enrichened individual sampling was more informative than the original design, in which only one sample was taken from each mouse in the pharmacokinetic studies. The new oral zipper design allows for informative pharmacokinetic sampling in a multiple-dose administration scenario for characterizing pharmacokinetic-pharmacodynamic relationships, with similar or lower bias and imprecision in parameter estimates and with a decreased total number of animals required by up to 7-fold compared to the original design. The optimized design for assessing pharmacodynamic interactions in the combination therapies, which was based on EC20, EC50 and EC80 of the single drug, provided lower bias and imprecision than a conventional reduced four-by-four microdilution checkerboard design at the same total number of samples required, which followed the 3Rs of animal welfare. In summary, in this thesis the population pharmacokinetic-pharmacodynamic models of first-line drugs in mice were characterized through linking each population pharmacokinetic model to the MTP model. Pharmacodynamic interactions were quantitatively illustrated by the MTP-GPDI model. Lastly, experimental designs were optimized and recommended to both pharmacokinetic and pharmacodynamic studies for preclinical settings.

With approximately nine million new cases and the attributable cause of death of an estimated two millions people every year there is an urgent need for new and effective drugs and treatment regimens targeting tuberculosis. The tuberculosis drug development pathway is however not ideal, containing non-predictive model systems and unanswered questions that may increase the risk of failure during late-phase drug development. The aim of this thesis was hence to develop pharmacometric tools in order to optimize the development of new anti-tuberculosis drugs and treatment regimens. The General Pulmonary Distribution model was developed allowing for prediction of both rate and extent of distribution from plasma to pulmonary tissue. A distribution characterization that is of high importance as most current used anti-tuberculosis drugs were introduced into clinical use without considering the pharmacokinetic properties influencing drug distribution to the site of action. The developed optimized bronchoalveolar lavage sampling design provides a simplistic but informative approach to gathering of the data needed to allow for a model based characterization of both rate and extent of pulmonary distribution using as little as one sample per subject. The developed Multistate Tuberculosis Pharmacometric model provides predictions over time for a fast-, slow- and non-multiplying bacterial state with and without drug effect. The Multistate Tuberculosis Pharmacometric model was further used to quantify the in vitro growth of different strains of Mycobacterium tuberculosis and the exposure-response relationships of three first line anti-tuberculosis drugs. The General Pharmacodynamic Interaction model was successfully used to characterize the pharmacodynamic interactions of three first line anti-tuberculosis drugs, showing the possibility of distinguishing drug A’s interaction with drug B from drug B’s interaction with drug A. The successful separation of all three drugs effect on each other is a necessity for future work focusing on optimizing the selection of anti-tuberculosis combination regimens. With a focus on pharmacokinetics and pharmacodynamics, the work included in this thesis provides multiple new methods and approaches that individually, but maybe more important the combination of, has the potential to inform development of new but also to provide additional information of the existing anti-tuberculosis drugs and drug regimen.

Cette thèse a pour objectif de développer une méthodologie d’évaluation environnementale de la mobilité quotidienne des personnes en prenant en compte ses dimensions sociales et spatiales mais également technologiques. La circulation des personnes, comme celle des marchandises, s’est énormément développée ces dernières décennies. L’automobile s’est imposée comme le mode de transport dominant, alimentant de nombreuses controverses du fait de son impact sur l’environnement ainsi que sur l’aménagement du territoire, les modes de vie, l’économie. L’évaluation environnementale de la mobilité quotidienne de personnes nécessite donc une approche intégrée représentant le système de transport, mais aussi le système urbain dans lequel elle s’insère. Pour ce faire, cette thèse propose une méthodologie reposant sur deux outils développés dans deux champs disciplinaires distincts, l’aménagement du territoire et les sciences de l’environnement, avec la modélisation des interactions transport-urbanisme et l’Analyse du Cycle de Vie. Couplés, ces outils permettent de représenter l’ensemble des processus technologiques impliqués pour la mobilité quotidienne ainsi que les différentes interactions entre les acteurs et les territoires. Tout au long de cette thèse, le cadre d’évaluation adopté est stratégique, s’intéressant aux mobilités réalisées au sein d’un territoire étendu à travers des indicateurs environnementaux globaux et locaux ainsi qu’aux différentes alternatives envisageables à moyen et long termes. La deuxième partie de la thèse met en œuvre la méthode SIMBAD-ACV, reposant sur le couplage entre un modèle LUTI existant, SIMBAD, et une ACV pour évaluer les impacts environnementaux de la mobilité quotidienne des habitants de l’aire urbaine de Lyon. Cette application a pour but d’illustrer la capacité d’analyse de la méthodologie à travers, d’une part, une approche multicritère et désagrégée au niveau des ménages et des territoires et, d’autre part, en estimant les impacts de scénarios contrastés représentant des alternatives variées. Finalement, grâce à la méthode SIMBAD-ACV, les effets sur les impacts environnementaux associés à la mobilité des paramètres technologiques, de la forme urbaine et des caractéristiques socio-économiques ont pu être comparés et discutés. / By considering social, spatial and technological dimensions of people’s daily mobility, this thesis aims to develop an original environmental assessment method. In the recent years, passenger travel, as well as freight transportation, have grown significantly. Car is now the predominant mode of passenger transport and its impacts on environment, land-use planning, lifestyle and economy are well documented and at the centre of heated academic and political debates. The environmental assessment of peoples’ daily mobility requires an integrated approach to account for the transport system, but also the urban system in which it operates. In order to achieve this, this thesis introduces a method coupling two tools developed in two distinct scientific fields - land-use planning and environmental sciences: on the one hand, Land-Use and Transport Interaction models (LUTI) and, on the other hand, Life Cycle Assessment (LCA) methods. Together, these tools can account for both technological processes involved in daily mobility, as well as interactions among stakeholders and territories. Throughout this thesis, the chosen evaluation framework is a strategic one, meaning that mobility is assessed through global and local environmental indicators on a large territory for medium and long-term alternatives. We describe the global context and the general approach in the first section of the thesis. The second part describes the SIMBAD-LCA method, which involves the integration of the LUTI model SIMBAD with a LCA method, in order to assess environmental impacts of the daily mobility of inhabitants in the Lyon urban area. The third part aims to illustrate the evaluation capability of the method in two steps. First, through a multicriteria assessment executed on disaggregated objects such as households and territories. Then, contrasted scenarios are built to assess broad and diversified alternatives. Finally, using the SIMBAD-LCA method, effects of technological, urban form and socio-economic parameters on environmental impacts associated with daily mobility are compared and discussed.

[pt] Como os usuários de computadores pessoais costumam enxergar um sistema computacional interativo como a própria interface, é desejável que esta seja construída de forma que eles entendam para que serve o sistema, o que ele permite que seus usuários façam e de que forma, para quem se destina etc. De acordo com a Engenharia Semiótica, fundamentação teórica deste trabalho, tais questões são transmitidas aos usuários por uma metamensagem do designer, comunicada pela sua interface, através de conversas entre usuário e designer - este último através de seu representante em tempo de interação, o preposto do designer. A Engenharia Semiótica propõe, antes da construção da interface concreta, uma etapa de modelagem da interação usuário-sistema, na qual o designer modela todas as possíveis conversas que consegue prever para que os usuários atinjam suas metas. Para a execução desta etapa, criou-se, em 2003, a MoLIC (Modeling Language for Interaction as Conversation), uma linguagem de modelagem que representa a interação como as possíveis conversas entre usuário e designer. Apesar de ter sido proposta como uma ferramenta epistêmica, a MoLIC ainda não tinha tido suas características epistêmicas exploradas explicitamente. Este trabalho visa explorar o valor epistêmico da MoLIC, apoiando a reflexão do designer através de um conjunto de perguntas que ele pode se fazer sobre a representação da interação, de forma a atingir dois objetivos. O primeiro é apoiar a atividade de (re)design em si, através da explicitação das conseqüências das decisões de design representadas na MoLIC. O segundo é apoiar a interpretação da interação humano-computador, a fim de que o próprio designer ou um outro leitor seja capaz de entender e explicar modelos MoLIC seguindo a metáfora de uma conversa entre usuário e designer. / [en] Personal computer users frequently view an interactive computational system as the user interface itself. Therefore, it´s desirable that such interface be developed in a way they can understand what the system is for, what it allows their users to do and in which way, for whom it´s made etc. Based on Semiotic Engineering, which is the theoretical foundation of this work, such issues are being conveyed to the users in a metamessage from the designer, communicated by its user interface, through conversations between the user and the designer - this one through his deputy at interaction time, the designer´s deputy. Before the concrete user interface is developed, Semiotic Engineering proposes to model the user-system interaction as a dialogue. In this stage, the designer models all the possible ways he anticipates that the users will be able to accomplish their goals. For this stage, a modeling language called MoLIC (Modeling Language for Interaction as Conversation) was created in 2003 to represent the interaction as the possible conversations between the user and the designer. Although it has been proposed as an epistemic tool, until now MoLIC had not had its epistemic features explored explicitly. This work aims to explore the epistemic value of MoLIC, supporting the designer`s reflection through a set of questions that he might ask for himself about the interaction representation, in order to accomplish two goals. The first one is to support the (re)design activity itself, by making explicit the consequences of the design decisions represented in MoLIC. The second one is to support the interpretation of the human-computer interaction represented in MoLIC, so that the designer or any other reader would be able to understand and explain MoLIC diagrams based on the conversation metaphor.

En bloquant les deux voies majeures de métabolisation de l’acide arachidonique, les inhibiteurs mixtes 5-LOX/COX-2 sont de puissants agents anti-inflammatoires non stéroïdiens minimisant les effets secondaires gastro-intestinaux et allergiques (asthme). Par ailleurs, ils offrent de nouvelles perspectives dans le traitement préventif de certains cancers. Contrairement à la COX-2, déjà largement étudiée, le niveau de connaissances concernant la 5-LOX humaine est beaucoup plus restreint. Notre objectif a donc été de caractériser sa structure ainsi que son mode d’interaction avec des inhibiteurs de type non redox, dans le but d’aider à la conception rationnelle d’inhibiteurs mixtes 5-LOX/COX-2. Dans un premier temps, la comparaison d’inhibiteurs 5-LOX non redox de la littérature a permis de mettre en évidence un modèle de pharmacophore à 5 points. Par ailleurs, la structure 3D de la 5-LOX humaine n’étant pas encore déterminée, nous l’avons modélisée par homologie avec la 15-LOX de lapin cristallisée et nous avons étudié, par docking, le mode d’interaction d’inhibiteurs 5-LOX non redox au sein du site actif. La combinaison des approches centrées, respectivement, sur les ligands et sur la protéine, nous a permis d’affiner l’hypothèse de pharmacophore et de proposer un modèle général d’interaction au sein du site actif 5-LOX./Dual 5-LOX/COX-2 inhibitors, acting on both major arachidonic acid metabolic pathways, are potent non-steroidal anti-inflammatory agents, with a reduced gastro-intestinal toxicity and fewer allergic adverse reactions. Moreover, they are promising in the treatment of several cancers. Whereas COX-2 has already been extensively studied, little structural or mechanistic information is available regarding human 5-LOX. Therefore, we focussed on this enzyme and characterized its 3D structure as well as its interaction with non redox inhibitors in order to help the design of dual 5-LOX/COX-2 inhibitors. Firstly, comparison of non redox 5-LOX inhibitors from the literature led to the generation of a five-point pharmacophore model. The 3D structure of human 5-LOX was then modelled based on the crystal structure of rabbit 15-LOX and, the binding modes of representative ligands were investigated through docking studies. Combination of both ligand-based and target-based approaches allowed the refinement of the pharmacophore hypothesis and led to the proposal of an interaction model for non redox inhibitors inside the 5-LOX active site.

People relate with one another in space and through imagined and technologically mediated networks. This thesis is concerned with the relationship between these two types of social connections – spatial and network. Spatial connections structure collectives of people in the same place at the same time. Network connections structure relations between people without regard to place or time. Spatial connections are complex, but rigid by nature, while network connections are simple, but flexible. Essential articulations emerge between these two connection types. These articulations create and evolve contemporary socio-spatial systems such as the city, its many places, and groups of people therein. However, the basic human experience of these systems remains largely polarized between spatial and network social practices to the disadvantage of human agency. This thesis proposes a teleodynamic, socio-spatial interaction model for the articulation of these social practices in human agency architecture. The model is a mobile experience design that functions through people with ‘smart’ mobile devices. It connects them with one another in public place and to global information and communication networks simultaneously. Sociological study informs the model’s design – constraints and conditions for the connection extents and integrity of social interaction. The model supports self-organizing circular relationships between human interaction dynamics and their trace structures based on a methodology for emergence in complex systems. It effects the emergence of the aforementioned socio-spatial, human agency architecture, with great flexibility. The model and architecture together serve to better articulate contemporary spatial and network social practices to the benefit of human agency in urban space.

Syftet med studien är att undersöka effekterna av en läs- och språksatsning. Fokus ligger på att identifiera faktorer som påverkar skolor att delta, huruvida dessa har förbättrade elevresultat samt läs- och språkutveck-larnas upplevelser av förändringar i undervisning, lärarkompetens och elevernas måluppfyllelse. Undersök-ningen omfattar två extremgrupper; dels åtta skolor som deltagit, dels åtta skolor som ej deltagit. Data kommer från Skolverkets databaser samt från en enkät ställd till skolornas läs- och språkutvecklare. Den teoretiska ramen utgörs av en pedagogisk samspelsmodell. Studien visar att deltagande skolor är större och har fler elever, utgör flerspråkiga miljöer samt rekryterar elever vars föräldrar har kortare utbildning. Resultat för betyg i svenska i årskurs 9 fluktuerar och är svårtolkade. För de skolor som deltagit finns en ökning av det genomsnittliga meritvärdet och andel behöriga till gymnasiernas nationella program ökade. / This study aims to investigate the effects of a literacy program. Focus lies on studying factors affecting school participation, examine whether participating schools have different results and explore the expe-riences of literacy developers regarding changes in teaching, teacher competence and student achievement. The survey is based on two groups: eight schools that participated and eight schools that did not. Data come from the National Agency databases and from a questionnaire addressed to the school literacy developers. An educational interaction model provides the theoretical framework. The study shows that participating schools have more students, are multilingual environments and recruit students whose parents have shorter education than non-participating schools. Results for grades in Swedish in grade 9 fluctuate and are difficult to interpret. The schools that participated have an increase in average merit rating and the proportion eligi-ble for upper secondary schools national programs.

People relate with one another in space and through imagined and technologically mediated networks. This thesis is concerned with the relationship between these two types of social connections – spatial and network. Spatial connections structure collectives of people in the same place at the same time. Network connections structure relations between people without regard to place or time. Spatial connections are complex, but rigid by nature, while network connections are simple, but flexible. Essential articulations emerge between these two connection types. These articulations create and evolve contemporary socio-spatial systems such as the city, its many places, and groups of people therein. However, the basic human experience of these systems remains largely polarized between spatial and network social practices to the disadvantage of human agency. This thesis proposes a teleodynamic, socio-spatial interaction model for the articulation of these social practices in human agency architecture. The model is a mobile experience design that functions through people with ‘smart’ mobile devices. It connects them with one another in public place and to global information and communication networks simultaneously. Sociological study informs the model’s design – constraints and conditions for the connection extents and integrity of social interaction. The model supports self-organizing circular relationships between human interaction dynamics and their trace structures based on a methodology for emergence in complex systems. It effects the emergence of the aforementioned socio-spatial, human agency architecture, with great flexibility. The model and architecture together serve to better articulate contemporary spatial and network social practices to the benefit of human agency in urban space.

La mobilité quotidienne est au cœur des réflexions sur la durabilité des villes. Moyen de réaliser ses activités quotidiennes et clé de voute des relations sociales, ses aspects économiques, et notamment ce que doivent dépenser les ménages pour se déplacer, sont un enjeu actuel majeur.Cette thèse propose une réflexion sur les interactions entre forme urbaine et mobilité quotidienne au travers du prisme des dépenses de mobilité. Pour questionner ces interactions, deux méthodes sont utilisées, indissociables l’une de l’autre.La première méthode consiste à acquérir une compréhension des effets de l’environnement construit du lieu de résidence sur le budget mobilité des ménages. Les données présentes dans les Enquêtes Ménages Déplacements sont particulièrement adaptées à cet exercice, car elles contiennent une richesse d’information importante sur les individus ainsi que leur mobilité,équipements, opinions et lieu d’habitation. Le terrain d’étude de ce travail est l’aire urbaine de Lyon, qui abrite une grande diversité de territoires et de modes de transport et où sont disponibles de nombreuses bases de données.Tout d’abord, une typologie de territoires a été construite, basée sur les principaux déterminants de la mobilité : densité, iversité, design, accessibilité aux destinations, distance aux transports collectifs et démographie. Ensuite, un cadre d’analyse systémique des relations entre forme urbaine et mobilité quotidienne a été élaboré afin d’identifier trois indicateurs qui permettent de les appréhender : la motorisation, le choix modal et les distances parcourues par modes. La typologiede territoires se révèle fortement explicative sur ces trois indicateurs. Une analyse des évolutions des mobilités entre 1995 et 2015 permet également d’identifier de nouveaux enjeux liés à l’évolution des prix, des comportements et de la démographie.Ce questionnement est ensuite prolongé à travers l’expression et la mesure des mécanismes d’intervention des caractéristiques du lieu de résidence sur le budget mobilité. A l’aide de la technique des modèles d’équations structurelles, les chemins causaux existant entre la forme urbaine locale et le budget mobilité sont explicités. Cette méthode est appliquée sur différentespopulations et types de territoires – ménages actifs puis retraités sur l’agglomération de Lyon puis sur les territoires périurbains – afin d’acquérir une compréhension fine du budget mobilité des ménages.La seconde méthode consiste à tester diverses organisations morphologiques et fonctionnelles du territoire à l’échelle du bassin de vie, afin de mesurer les effets sur le budget mobilité des ménages. Ce travail est réalisé à l’aide d’un modèle d’interaction transport-urbanisme, SIMBAD, qui permet de conduire une analyse systémique et multi-échelles des effets de la forme urbaine sur le budget mobilité. Divers scénarios de forme urbaine sont simulés, participant ainsi au débat sur la durabilité des formes urbaine monocentrique compacte, étalée diffuse et polycentrique dans une logique de Transit Oriented Development.Par ailleurs, les enseignements de la première méthode, c’est-à-dire le traitement des Enquêtes Ménages Déplacements pour étudier les effets de la forme urbaine locale sur le budget mobilité, nous incitent à conduire une analyse multi-échelles des résultats des simulations : une réflexion sur la différenciation des impacts selon l’organisation du territoire et selon le lieu de résidence à l’intérieur de l’aire urbaine est ainsi menée.Ce travail de thèse apporte donc à la fois des éléments méthodologiques pour analyser les interactions entre forme urbaine et budget mobilité, avec la construction de modèles d’équations structurelles et l’usage d’un modèle d’interaction transport-urbanisme dans un objectif de simulation, ainsi que divers résultats et éclairages qui viennent prolonger la littérature scientifiqueexistante. / Daily mobility is at the heart of debate on urban sustainability. A mean to carry out our daily activities and a key to social interactions, economic aspects and especially household expenditures linked to mobility are a major current issue.This thesis proposes a discussion on the interactions between urban form and daily mobility through mobility expenditures. Two interrelated methods of analysis are used to investigate these interactions.The first one relies on a comprehensive understanding of the effects of the built environment on daily mobility budgets. Household surveys are especially suited to this analysis because they provide a wealth of information on individuals’ attributes, their mobility, equipment, opinions and housing characteristics. Combined with various local or national databases, it is possible to estimate a household budget for every surveyed household. The case study for this analysis is the Lyon urban area. It contains very different built environments, and hosts a diverse array of transport modes. Furthermore, numerous databases are available for our analysis.First, we build a typology of territories based on the main daily mobility determinants: density, diversity, design, accessibility to destinations, distance to transit and demography. Then, an analytical framework of relations between urban form and daily mobility is built to identify three indicators to apprehend them: motorization, modal choice and distance per mode. This typology of territories is tested on these three indicators and appears to be highly significant. An analysis of the mobility evolution between 1995 and 2015 also identify various new issues related to prices, behavioral and demographic evolutionsThis line of questioning is extended through the identification and quantification of the effects of built environment characteristics on household mobility budgets. Using a Structural Equation Modelling method, causal paths between local urban form and household expenditures are presented. This method is applied to different types of population and territories – workers and retired households of the Lyon agglomeration then on the same types in suburban areas – in order to understand householdmobility budgets.The second method consists of testing various morphological and functional organizations of the territory in order to measure their effects on daily mobility budgets. This work is conducted using a land use and interaction model (LUTI), SIMBAD, which allows us to conduct a systemic and multiscale analysis of urban form on daily mobility budgets. Different scenarios of urban form are thereafter simulated, contributing to the debate on the durability of monocentric, sprawled or polycentric citiesin a Transit Oriented Development urban form. Besides, lessons learned from data processing of Households Surveys encourage us to conduct a multiscale analysis. A discussion on the differentiation of impacts depending on the global form of the territory is conducted.This thesis work presents innovative methodological elements to analyze the interactions between urban form and mobility budgets, including the construction of structural equations models and the use of a LUTI model to simulate urban environments. It also offers novel results, which contribute to the current scientific literature.

Urban greenbelts are considered a key instrument for shaping sustainable urban growth and protecting the environment in a large number of cities in the world. In most cities, there is a widely shared belief that urban greenbelts are beneficial to the natural environment. By contrast, there is little understanding of the underlying economic impacts of greenbelts and other green space configurations in fast growing cities. The unprecedented rate and scale of urbanisation in the emerging economies has brought the role of greenbelts into an even sharper focus. In cities within these fast growing economies, the urban population is expected to double in the coming decades, which means that greenbelts are under great pressures to adapt to the large forthcoming growth. Few existing urban models are capable of addressing the dynamic nature of the urban transformations and predicting the impacts of urban greenbelts in the developing world. This prompts us to develop a new modelling method that is capable of assessing the impacts of different configurations, scales and locations of green spaces. We then use it to examine alternative futures to the greenbelt through a case study of Greater Beijing. The method we developed is a new variant in the land use-transport interaction (LUTI) model family. This model is capable of addressing the non-equilibrium nature of urban land use and transport development and the equilibrium nature of the day-to-day adaptations made by businesses and citizens. This LUTI model aims to answer the following questions: what are the short-term and long-term economic impacts of a greenbelt on a fast growing city? Which alternative green space configuration performs better in terms of economic well-being and travel costs? Where and how much should the greenbelt land be progressively reshaped or released as the city grows? The new LUTI model is calibrated and validated using data collected for 1990, 2000 and 2010 for Greater Beijing, The model is first tested retrospectively through revisiting the past greenbelt policies in Beijing from 1990 to 2010. Then the impacts of different future green space configurations from 2010 to 2030 are predicted and assessed through quantifying economic costs/benefits and travel costs for socio-economic groups. The model results suggest that under rapid transformative urban change, the configuration, scale and location of a greenbelt have a significant impact on a city’s economic efficiency. Such impacts will transcend the greenbelt boundary, and even the boundary of Beijing Municipality, onto the entire city region. A narrow greenbelt launched in the early age of urban expansion could lead to spatial mismatch of residents and jobs. A wide and strictly controlled ring-shaped greenbelt is not the highest performing intervention either, in terms of economic well-being. The green-wedges configuration is a remedial policy that balances the economic efficiency and environmental benefits. Intensive development around metro/rail stations in the designated greenbelt could reduce spatial costs and promote sustainable travel modes. This implies that a careful siting of new development within existing designations of the greenbelt can be beneficial in terms of economic well-being and sustainable transport.