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Simultaneous measurement of the expression levels of thousands to ten thousand genes in multiple tissue types is a result of advancement in microarray technology. These expression levels provide clues about the gene functions and that have enabled better diagnosis and treatment of serious disease like cancer. To solve the mystery of unknown gene functions, biological to statistical mapping is needed in terms of classifying the genes. Here we introduce a novel approach of combining both statistical consistency and biological relevance of the clusters produced by a clustering method. Here we employ two performance measures in combination for measuring statistical stability and functional similarity of the cluster members using a set of gene expressions with known biological functions. Through this analysis we construct a platform to predict about unknown gene functions using the outperforming clustering algorithm.

Simultaneous measurement of the expression levels of thousands to ten thousand genes in multiple tissue types is a result of advancement in microarray technology. These expression levels provide clues about the gene functions and that have enabled better diagnosis and treatment of serious disease like cancer. To solve the mystery of unknown gene functions, biological to statistical mapping is needed in terms of classifying the genes. Here we introduce a novel approach of combining both statistical consistency and biological relevance of the clusters produced by a clustering method. Here we employ two performance measures in combination for measuring statistical stability and functional similarity of the cluster members using a set of gene expressions with known biological functions. Through this analysis we construct a platform to predict about unknown gene functions using the outperforming clustering algorithm.

Résumé trop long / Mosquitoes transmit several human and animal diseases and their control represents a public health challenge worldwide. In most tropical countries, efficient control of mosquitoes relies on the use of chemical insecticides targeting adults or larvae. However, resistance to the four main classes of chemical insecticides has been reported worldwide and threatens vector control programs. In this context, there is an urgent need to find alternatives to conventional insecticides used in vector control. In this thesis, I explored the potential use of the neonicotinoid insecticide imidacloprid for mosquito control, focusing on the identification of metabolic resistance mechanisms, cross-resistance with other insecticides and the impact of environmental pollutants on imidacloprid tolerance. The mosquito Aedes aegypti was used as a model species for this research work. Basal tolerance of Ae. aegypti to imidacloprid was first evaluated at the larval and adult stages. Effects of a larval exposure across a single generation to a sub-lethal dose of imidacloprid were then investigated at the toxicological and molecular levels using transcriptome profiling. Short sub-lethal exposures were also used to identify potential cross-responses between imidacloprid, other chemical insecticides and anthropogenic pollutants. Long-term adaptive response of Ae. aegypti to imidacloprid was then investigated across several generations by selecting an insecticide-susceptible strain (Bora-Bora strain) with imidacloprid at the larval stage for 14 generations in the laboratory. Such artificial selection allowed obtaining the Imida-R strain. This strain showed an increased resistance to imidacloprid in larvae while no significant resistance was measured in adults. Resistance mechanisms were then investigated using various approaches including the use of detoxification enzyme inhibitors, biochemical assays and transcriptome profiling with DNA microarray and massive mRNA sequencing. Several protein families potentially involved in resistance were identified including detoxifications enzymes and cuticle proteins. Among the formers, 8 cytochrome P450s and 1 glutathione S-transferase appears as good candidates for a role in imidacloprid metabolism. The role of P450s in the elevated resistance of the Imida-R strain was confirmed by comparative P450-dependent in vitro metabolism assays conducted on microsomal fractions of the susceptible and Imida-R strains. At the gene level, substrate binding modeling allowed restricting the panel of P450 candidates. Meantime, heterologous expression of one P450 was performed and its ability to metabolize imidacloprid confirmed. Bioassay with other insecticides revealed potential cross-resistance of the Imida-R at the larval stage to other neonicotinoids but also to an insect growth inhibitor and in a lesser extent to DDT, confirming the probable role of detoxification enzymes. Relaxing the selection pressure of the Imida-R strain for few generations led to a rapid decrease of resistance, suggesting a cost of resistance mechanisms. Comparing the inducibility of candidate detoxification genes by imidacloprid in susceptible and resistant strains revealed a higher induction of these genes in the resistant strain, suggesting the selection of both a higher constitutive expression but also a greater phenotypic plasticity of these enzymes in the Imida-R strain. Finally, the potential role of cuticle protein in resistance was preliminary investigated by exposing larvae to a chitin synthesis inhibitor before bioassays. Overall, although this research work requires additional functional validation experiments, these data provide a better understanding of imidacloprid resistance mechanisms in mosquitoes and its potential use as an alternative to conventional insecticides in vector control.

Les travaux présentés dans ce mémoire de thèse s'intéressent à la validation fonctionnelle de contrôleurs logiques par des techniques de test de conformité et de validation en boucle fermée. Le modèle de spécification est décrit dans le langage industriel Grafcet et le contrôleur logique est supposé être un automate programmable industriel (API) mono-tâche. Afin de contribuer à ces techniques de validation fonctionnelle, ces travaux présentent : - Une extension d'une méthode de formalisation du Grafcet par traduction sous la forme d'une machine de Mealy. Cette extension permet de produire un modèle formel de la spécification lorsque le Grafcet est implanté selon un mode d'interprétation sans recherche de stabilité, qui n'est pas préconisé dans la norme IEC 60848 mais largement utilisé dans les applications industrielles. - Une contribution au test de conformité par la définition d'un ensemble de relations de conformité basées sur l'observation de plusieurs cycles d'exécution pour chaque pas de test. - Une contribution à la validation en boucle fermée par la définition d'un critère de fin d'observation et par une technique d'identification en boite grise pour la construction et l'analyse du système en boucle fermée. / The results presented in this PhD thesis deal with functional validation of logic controllers using conformance test and closed-loop validation techniques. The specification model is written in the Grafcet language and the logic controller is assumed to be a Programmable Logic Controller (PLC). In order to contribute to these validation techniques, this thesis presents: - An axtension to a fomalization methods for Grafcet languages by translation to a Mealy machine. This extension generates a formal model of a Grafcet specification that is interpreted without search of stability. This mode of interpretation is not recommended by the standard IEC 60848 but is widely used in industrial applications. - A contribution to conformance test by a definition of a set of conformance relation based on the observation of several execution cycles for each test step. - A contribution to closed-loop validation by the definition of a termination criterion and by a new gray-box identification technique that is used for construction and analysis of the closed-loop system.

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