Ces travaux de thèse s’inscrivent dans le cadre d’une collaboration entre les laboratoires G2ELAB et IMEP-LAHC en lien avec le projet BQR WiSiTUDe (Grenoble-INP). Le but de cette thèse concerne la conception, modélisation et caractérisation du gate driver intégré pour transistors de puissance à base d’un transformateur sans noyau pour le transfert isolé d'ordres de commutation. La thèse est composée de deux grandes parties : - Une partie de la conception, la modélisation et la caractérisation du transformateur intégré dans deux technologies CMOS 0.35 µm bulk et CMOS 0.18 µm SOI. - Une partie de la conception, la simulation et la mise en œuvre de deux circuits de commande intégrée dans ces deux technologies. Ainsi, l’aspect du système du convertisseur de puissance sera étudié en proposant une nouvelle conception couplée commande/puissance à faible charge. Les résultats de ce travail de thèse ont permis de valider les approches proposées. Deux modèles fiables (électrique 2D et électromagnétique 3D) du transformateur ont été établis et validés via une réalisation CMOS 0.35 µm standard. De plus, un driver CMOS bulk, intégrant l’ensemble du transformateur sans noyau avec plusieurs fonctions de pilotage de la commande rapprochée a été caractérisé et validé. Finalement, un gate driver générique a été conçu en technologie CMOS SOI, intégrant dans une seule puce les étages de commande éloignée, l’isolation galvanique et la commande rapprochée pour transistors de puissance. Ce gate driver présente nombre d’avantages en termes d’interconnexion, de la consommation de la surface de silicium, de la consommation énergétique du driver et de CEM. Les perspectives du travail de thèse sont multiples, à savoir d’une part l’assemblage 3D entre le gate driver et le composant de puissance et d’autre part les convertisseurs de multi-transistors. / This thesis work focuses on the design, modelling and the implementation of integrated gate drivers for power transistors based on CMOS coreless transformer. The main objectives of thesis are the design, modeling and characterization of coreless transformer in two technologies CMOS 0.35 µm bulk and CMOS 0.18 µm SOI, as well as the design and the characterization of two integrated gate drivers in these two technologies. The results of thesis allow us to validate our proposal models for coreless transformer: 2D electrical model and 3D electromagnetic model. Moreover, one CMOS bulk isolated gate driver which monolithically integrates the coreless transformer, the secondary side control circuit for power transistors has been fabricated and validated for both high side and low side configuration in a Buck converter. Finally, a CMOS SOI isolated gate driver is designed; integrates in one single chip the external control, the coreless transformer and the close gate driver circuit for power transistors. This one-chip solution presents a numerous advantages in term of interconnect parasitic, energy consumption, silicon surface consumption, and EMI with a high level of galvanic isolation. The perspectives of this SOI gate driver are multiple, on the one hand, are the 3D assemblies between gate driver/power transistors and on the other hand, are the multiple-switch converter.

Ces travaux de thèse s’inscrivent dans le cadre d’une collaboration entre les laboratoires G2ELAB et IMEP-LAHC en lien avec le projet BQR WiSiTUDe (Grenoble-INP). Le but de cette thèse concerne la conception, modélisation et caractérisation du gate driver intégré pour transistors de puissance à base d’un transformateur sans noyau pour le transfert isolé d'ordres de commutation. La thèse est composée de deux grandes parties : - Une partie de la conception, la modélisation et la caractérisation du transformateur intégré dans deux technologies CMOS 0.35 µm bulk et CMOS 0.18 µm SOI. - Une partie de la conception, la simulation et la mise en œuvre de deux circuits de commande intégrée dans ces deux technologies. Ainsi, l’aspect du système du convertisseur de puissance sera étudié en proposant une nouvelle conception couplée commande/puissance à faible charge. Les résultats de ce travail de thèse ont permis de valider les approches proposées. Deux modèles fiables (électrique 2D et électromagnétique 3D) du transformateur ont été établis et validés via une réalisation CMOS 0.35 µm standard. De plus, un driver CMOS bulk, intégrant l’ensemble du transformateur sans noyau avec plusieurs fonctions de pilotage de la commande rapprochée a été caractérisé et validé. Finalement, un gate driver générique a été conçu en technologie CMOS SOI, intégrant dans une seule puce les étages de commande éloignée, l’isolation galvanique et la commande rapprochée pour transistors de puissance. Ce gate driver présente nombre d’avantages en termes d’interconnexion, de la consommation de la surface de silicium, de la consommation énergétique du driver et de CEM. Les perspectives du travail de thèse sont multiples, à savoir d’une part l’assemblage 3D entre le gate driver et le composant de puissance et d’autre part les convertisseurs de multi-transistors. / This thesis work focuses on the design, modelling and the implementation of integrated gate drivers for power transistors based on CMOS coreless transformer. The main objectives of thesis are the design, modeling and characterization of coreless transformer in two technologies CMOS 0.35 µm bulk and CMOS 0.18 µm SOI, as well as the design and the characterization of two integrated gate drivers in these two technologies. The results of thesis allow us to validate our proposal models for coreless transformer: 2D electrical model and 3D electromagnetic model. Moreover, one CMOS bulk isolated gate driver which monolithically integrates the coreless transformer, the secondary side control circuit for power transistors has been fabricated and validated for both high side and low side configuration in a Buck converter. Finally, a CMOS SOI isolated gate driver is designed; integrates in one single chip the external control, the coreless transformer and the close gate driver circuit for power transistors. This one-chip solution presents a numerous advantages in term of interconnect parasitic, energy consumption, silicon surface consumption, and EMI with a high level of galvanic isolation. The perspectives of this SOI gate driver are multiple, on the one hand, are the 3D assemblies between gate driver/power transistors and on the other hand, are the multiple-switch converter.

Ces travaux de thèse proposent une approche de réalisation d'intégration d'isolation galvanique optique plus performante entre la partie de commande éloignée et la partie de puissance d'un convertisseur d'énergie. Ce mémoire de thèse est composé de trois chapitres. Après une étude bibliographique et un positionnement de l'approche dans le premier chapitre, la conception de la puce de commande, les différentes fonctions développées seront vus en détail, et les résultats pratiques et les performances des réalisations effectuées seront présentés, avec plusieurs études de photodétecteurs et circuits de traitement intégrés en technologie CMOS. Dans le dernier chapitre de la thèse, un autre aspect sera abordé, en intégrant une alimentation flottante isolée générée par voie optique. Les avantages résultant de cette approche seront également discutés. Les puces de commande sont fabriquées en technologie CMOS standard C35 AMS pour les premiers prototypes et transférées en technologie CMOS SOI Xfab 018 afin de tester nos fonctions à haute température. La mise en œuvre du circuit de commande par voie optique dans un convertisseur de puissance sera réalisée afin de valider le fonctionnement de notre « gate driver ». / This works proposes an approach of optical galvanic isolation between the control parts on one side and the power transistors and their associated drivers on the other side. This thesis consists of three chapters. After a literature review and the proposition of our approach in the first chapter, the design of the control chip and the different developed functions will be seen in detail in the second chapter. The practical results and performance achievements will be presented with several integrated photodetectors and signal processing circuit in CMOS technology. In the last chapter of the thesis, an integrated optically floating power supply will be investigated. The benefits of this approach will be discussed. These fabricated chips are manufactured in standard CMOS AMS C35 technology for first prototypes and transferred in SOI Xfab 018 CMOS technology to test these functions at high temperature. The implementation of the optically control circuit in a power converter will be presented to validate the operation of our "gate driver".

Millions of somatic mutations in human cancers have been identified by sequenc- ing. Identifying and distinguishing cancer driver genes amongst the millions of candi- date mutations remains a major challenge. Accurate identification of driver genes and mutations is essential for the progress of cancer research and personalizing treatment based on accurate stratification of patients. Because of inter-tumor genetic hetero- geneity, numerous driver mutations within a gene can be found at low frequencies. This makes them difficult to differentiate from other non-driver mutations. Inspired by these challenges, we devised a novel way of identifying cancer driver genes. Our approach utilizes multiple complementary types of information, specifically cellular phenotypes, cellular locations, function, and whole body physiological phenotypes as features. We demonstrate that our method can accurately identify known cancer driver genes and distinguish between their role in different types of cancer. In ad- dition to identifying known driver genes, we identify several novel candidate driver genes. We provide an external evaluation of the predicted genes using a dataset of 26 nasopharyngeal cancer samples that underwent whole exome sequencing. We find that the predicted driver genes have a significantly higher rate of mutation than non-driver genes, both in publicly available data and in the nasopharyngeal cancer samples we use for validation. Additionally, we characterize sub-networks of genes that are jointly involved in specific tumors.

O desenvolvimento de metodologias sobre integração de dados na área de biologia de sistemas é de grande importância devido ao aumento contínuo de dados resultantes de análises globais que são depositados em bancos de dados públicos. Poucas metodologias e ferramentas de bioinformática levam em consideração a diferenciação entre drivers e passengers, fundamental para a identificação de genes importantes para o desenvolvimento e progressão tumoral. Os perfis de expressão gênica têm possibilitado a identificação de assinaturas genéticas em uma grande variedade de tumores humanos. Além disso, as alterações epigenéticas, como a expressão de microRNAs (miRNA) e a metilação do DNA, também contribuem para o desenvolvimento de diversos tipos de doenças. Entretanto, a grande maioria destes estudos não mostra integração dos resultados obtidos pelas diferentes estratégias utilizadas, o que teria maior impacto na identificação de drivers moleculares. Neste estudo foi realizada a integração de quatro níveis de alterações em 31 amostras de câncer de pênis (CaPe): alteração do número de cópias do DNA, metilação de ilhas CpGs, expressão de miRNAs e expressão de transcritos codificadores. O conhecimento das alterações genéticas e epigenéticas relacionadas ao desenvolvimento de câncer de pênis é bastante limitado, devido principalmente a sua rara incidência. Uma parcela significativa dos casos de CaPe tem sido associada com a infecção pelo Papilomavírus Humano (HPV). A metodologia para integração de dados foi aplicada utilizando duas abordagens: (1) estudo das alterações em câncer de pênis (tumor e normal) independente da infecção pelo HPV e (2) estudo das alterações relacionadas à infecção pelo HPV. A análise foi dividida em duas etapas, com a seleção de genes alvos específicos da doença e inferência de módulos a partir desses alvos. Destacam-se na metodologia a seleção de genes candidatos a driver utilizando a atribuição de pesos para cada alteração seguindo critérios pré-determinados, e.g. se o gene estava presente em uma região rara, após classificação pelo DGV (Database of Genomic Variants) e a utilização desses genes como alvos para identificação das possíveis relações entre eles e os módulos. Também foi realizada a adaptação da metodologia de redes em módulos, com a inclusão de genes passengers e interação proteína-proteína (PPI) como um critério para seleção dos módulos. Essa análise se mostrou eficaz na identificação de módulos gênicos bem relacionados com os drivers, resultando na escolha de vias biológicas potencialmente responsáveis pelo desenvolvimento do tumor. Os genes identificados após a comparação entre amostras tumorais e normais (SOX17, TWIST1, CAV1, PPARG, FLI1 e TNFSF10) e no estudo entre amostras positivas e negativas para infecção pelo HPV (PCNA, SOX14 e RFC4) foram validados in situ por técnicas independentes. Para validação in silico das alterações encontradas na metodologia de integração de dados e para validação da metodologia de redes em módulos foram utilizadas 255 amostras de glioblastoma multiforme obtidas no banco de dados TCGA (The Cancer Genome Atlas). Foram identificadas vias biológicas importantes relacionadas ao processo tumoral, como regulação do crescimento celular (GO:0001558, p=0,0062), homeostase (GO:0048872, $p=0,0082) e regulação da transcrição (GO:0003700, p=0,00089). Também foi realizada uma meta-análise utilizando amostras do TCGA, que encontrou um perfil similar de expressão para os genes CAV1, DLC1,FLI1, MSX1, NRN1, PML, PPARG e SOX17 (T vs N) e PCNA e RFC4 (HPV+ vs HPV-). Para o nosso conhecimento, esse é o primeiro estudo em CaPe utilizando análise integrada de quatro níveis de alteração. Além disso, foram encontradas alterações não randômicas capazes de modificar transcritos específicos e contribuir para o conhecimento da patobiologia dos tumores de pênis. / Methodologies for data integration in systems biology area have great importance due to continuous increase of public data resulting from large-scale analysis, which are deposited in public databases. Few methodologies and bioinformatics tools take into consideration the differentiation between drivers and passengers, fundamental for the identification of important genes for tumor development and progression. The gene expression profiles have allowed the identification of genetic signatures in a wide variety of human tumors. In addition, epigenetic changes, such as the expression of microRNA (miRNA) and DNA methylation, also contribute to the development of a veriety of diseases. However, most of these studies did not show integration of results obtained by different strategies used, which would have increased impact to identify molecular drivers. This study provides a methodology for integration of four levels of changes in 31 samples of penile cancer (PeCa): copy number alterations, DNA methylation of CpG islands, miRNA expression and gene expression of coding transcripts. Knowledge about genetic and epigenetic changes related to the development of penile cancer is very limited, mainly due to its rare incidence. A significant portion of PeCa samples has been associated with infection by Human papillomavirus (HPV). The methodology for integrative data was applied using two approaches: (1) the study considering alterations in penile carcinoma (tumor and normal), independent of HPV infection and (2) the study considering alteration related to HPV infection in PeCa. In each study, the methodology was divided into two stages, with the selection of target genes and the inference of disease specific modules from these targets. It is highlighted in the methodology the selection of candidate genes using the driver assigning weights to each change following predetermined criteria, e.g if the gene was present in a rare region after classification using the DGV database (Database of Genomic Variants) and the use of these genes as seeds for identification of possible relationships between them and the modules. For this, another contribution of this study was the adaptation of module network methodology, with the inclusion of passengers genes and protein-protein interaction (PPI) as a criteria to select the modules. This analysis was effective in identifying gene modules and related drivers, resulting in the choice of biological pathway potentially responsible for the tumor development. The genes identified after comparing tumor and normal samples (SOX17, TWIST1, CAV1, PPARG, FLI1 and TNFSF10) and the genes identified in the study of positive and negative samples for HPV infection (PCNA, SOX14 and RFC4) were validated in situ by independent techniques. For in silico validation of the changes found in the integrative methodology and the modules network were used 255 samples of glioblastoma multiforme obtained at TCGA database (The Cancer Genome Atlas). Biological pathways have been identified related to the tumoral process, such as cell growth regulation (GO:0001558, p=0,0062), homeostasis (GO:0048872, p=0,0082) and transcription regulation (GO:0003700, p=0,00089). Also, a meta-analysis was performed using samples from TCGA, who found a similar expression profile for CAV1, DLC1, FLI1, MSX1, NRN1, PML, PPARG and SOX17 (T vs N) and PCNA and RFC4 genes (HPV + vs HPV-). To our knowledge, this is the first integrative analysis in PeCa using a four-level of gene alterations. In addition, it was found non-random alterations capable to modifying specific transcripts and contribute to the knowledge about the pathobiology of penile tumors.

Abstract also in Chinese. / Thesis (M.B.A.)--Chinese University of Hong Kong. / Bibliography: leaf 64.

This research investigates the safety performance of two types of pedestrian crossing control systems by examining driver compliance at these crosswalks in Winnipeg. The research analyzes driver compliance as a function of type of treatment, weather conditions, pedestrian approach location, and site characteristics. In addition, the research analyzes driver compliance before-and-after the implementation of 30 km/h speed limits in school zones. The findings from this research suggest that: (1) treatment and certain site characteristics (i.e., number of lanes) have a significant impact on driver compliance at crosswalks; and (2) weather conditions, pedestrian approach locations, and reduced speed school zones likely impact driver compliance at crosswalks but the findings were not always statistically significant. The research recognizes numerous factors that influence driver compliance and in turn pedestrian safety at crosswalks and highlights the importance of considering these factors in the provision, selection, and maintenance of pedestrian crossing control systems. / October 2015

O desenvolvimento de metodologias sobre integração de dados na área de biologia de sistemas é de grande importância devido ao aumento contínuo de dados resultantes de análises globais que são depositados em bancos de dados públicos. Poucas metodologias e ferramentas de bioinformática levam em consideração a diferenciação entre drivers e passengers, fundamental para a identificação de genes importantes para o desenvolvimento e progressão tumoral. Os perfis de expressão gênica têm possibilitado a identificação de assinaturas genéticas em uma grande variedade de tumores humanos. Além disso, as alterações epigenéticas, como a expressão de microRNAs (miRNA) e a metilação do DNA, também contribuem para o desenvolvimento de diversos tipos de doenças. Entretanto, a grande maioria destes estudos não mostra integração dos resultados obtidos pelas diferentes estratégias utilizadas, o que teria maior impacto na identificação de drivers moleculares. Neste estudo foi realizada a integração de quatro níveis de alterações em 31 amostras de câncer de pênis (CaPe): alteração do número de cópias do DNA, metilação de ilhas CpGs, expressão de miRNAs e expressão de transcritos codificadores. O conhecimento das alterações genéticas e epigenéticas relacionadas ao desenvolvimento de câncer de pênis é bastante limitado, devido principalmente a sua rara incidência. Uma parcela significativa dos casos de CaPe tem sido associada com a infecção pelo Papilomavírus Humano (HPV). A metodologia para integração de dados foi aplicada utilizando duas abordagens: (1) estudo das alterações em câncer de pênis (tumor e normal) independente da infecção pelo HPV e (2) estudo das alterações relacionadas à infecção pelo HPV. A análise foi dividida em duas etapas, com a seleção de genes alvos específicos da doença e inferência de módulos a partir desses alvos. Destacam-se na metodologia a seleção de genes candidatos a driver utilizando a atribuição de pesos para cada alteração seguindo critérios pré-determinados, e.g. se o gene estava presente em uma região rara, após classificação pelo DGV (Database of Genomic Variants) e a utilização desses genes como alvos para identificação das possíveis relações entre eles e os módulos. Também foi realizada a adaptação da metodologia de redes em módulos, com a inclusão de genes passengers e interação proteína-proteína (PPI) como um critério para seleção dos módulos. Essa análise se mostrou eficaz na identificação de módulos gênicos bem relacionados com os drivers, resultando na escolha de vias biológicas potencialmente responsáveis pelo desenvolvimento do tumor. Os genes identificados após a comparação entre amostras tumorais e normais (SOX17, TWIST1, CAV1, PPARG, FLI1 e TNFSF10) e no estudo entre amostras positivas e negativas para infecção pelo HPV (PCNA, SOX14 e RFC4) foram validados in situ por técnicas independentes. Para validação in silico das alterações encontradas na metodologia de integração de dados e para validação da metodologia de redes em módulos foram utilizadas 255 amostras de glioblastoma multiforme obtidas no banco de dados TCGA (The Cancer Genome Atlas). Foram identificadas vias biológicas importantes relacionadas ao processo tumoral, como regulação do crescimento celular (GO:0001558, p=0,0062), homeostase (GO:0048872, $p=0,0082) e regulação da transcrição (GO:0003700, p=0,00089). Também foi realizada uma meta-análise utilizando amostras do TCGA, que encontrou um perfil similar de expressão para os genes CAV1, DLC1,FLI1, MSX1, NRN1, PML, PPARG e SOX17 (T vs N) e PCNA e RFC4 (HPV+ vs HPV-). Para o nosso conhecimento, esse é o primeiro estudo em CaPe utilizando análise integrada de quatro níveis de alteração. Além disso, foram encontradas alterações não randômicas capazes de modificar transcritos específicos e contribuir para o conhecimento da patobiologia dos tumores de pênis. / Methodologies for data integration in systems biology area have great importance due to continuous increase of public data resulting from large-scale analysis, which are deposited in public databases. Few methodologies and bioinformatics tools take into consideration the differentiation between drivers and passengers, fundamental for the identification of important genes for tumor development and progression. The gene expression profiles have allowed the identification of genetic signatures in a wide variety of human tumors. In addition, epigenetic changes, such as the expression of microRNA (miRNA) and DNA methylation, also contribute to the development of a veriety of diseases. However, most of these studies did not show integration of results obtained by different strategies used, which would have increased impact to identify molecular drivers. This study provides a methodology for integration of four levels of changes in 31 samples of penile cancer (PeCa): copy number alterations, DNA methylation of CpG islands, miRNA expression and gene expression of coding transcripts. Knowledge about genetic and epigenetic changes related to the development of penile cancer is very limited, mainly due to its rare incidence. A significant portion of PeCa samples has been associated with infection by Human papillomavirus (HPV). The methodology for integrative data was applied using two approaches: (1) the study considering alterations in penile carcinoma (tumor and normal), independent of HPV infection and (2) the study considering alteration related to HPV infection in PeCa. In each study, the methodology was divided into two stages, with the selection of target genes and the inference of disease specific modules from these targets. It is highlighted in the methodology the selection of candidate genes using the driver assigning weights to each change following predetermined criteria, e.g if the gene was present in a rare region after classification using the DGV database (Database of Genomic Variants) and the use of these genes as seeds for identification of possible relationships between them and the modules. For this, another contribution of this study was the adaptation of module network methodology, with the inclusion of passengers genes and protein-protein interaction (PPI) as a criteria to select the modules. This analysis was effective in identifying gene modules and related drivers, resulting in the choice of biological pathway potentially responsible for the tumor development. The genes identified after comparing tumor and normal samples (SOX17, TWIST1, CAV1, PPARG, FLI1 and TNFSF10) and the genes identified in the study of positive and negative samples for HPV infection (PCNA, SOX14 and RFC4) were validated in situ by independent techniques. For in silico validation of the changes found in the integrative methodology and the modules network were used 255 samples of glioblastoma multiforme obtained at TCGA database (The Cancer Genome Atlas). Biological pathways have been identified related to the tumoral process, such as cell growth regulation (GO:0001558, p=0,0062), homeostasis (GO:0048872, p=0,0082) and transcription regulation (GO:0003700, p=0,00089). Also, a meta-analysis was performed using samples from TCGA, who found a similar expression profile for CAV1, DLC1, FLI1, MSX1, NRN1, PML, PPARG and SOX17 (T vs N) and PCNA and RFC4 genes (HPV + vs HPV-). To our knowledge, this is the first integrative analysis in PeCa using a four-level of gene alterations. In addition, it was found non-random alterations capable to modifying specific transcripts and contribute to the knowledge about the pathobiology of penile tumors.

Software engineers spend much of their time checking the correctness of software. Software testing is the most widely used technique for accomplishing this task. Most of the test cases used for checking software are manually created, and may not always cover all execution paths of the software. If key test cases are not executed, then the possibility of errors within the software still exists. By using tools that can automate the testing of software, software engineers can run exhaustive tests on their applications to provide verification and validation. Symbolic execution is a program analysis technique that can be utilized to achieve this. KLEE is an open-source dynamic test generation tool based on symbolic execution. In this report I present my results from evaluating KLEE on the Texas Instruments® Stellaris® Peripheral Driver Library. The Stellaris® Peripheral Driver Library consists of software drivers for controlling the peripherals on the Stellaris suite of ARM® Cortex-M based microcontrollers. In total 554 functions within the library were tested, and a total of 14763 test cases were generated. There were 32 bugs found in the software, which include assertion violations, memory errors, and arithmetic errors (division by zero, and shift errors). / text

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