A rápida e crescente demanda por tecnologias que permitam a redução das dimensões dos transistores planares de porta única leva a uma nova era de dispositivos tensionados mecanicamente. Os transistores de múltiplas portas (MuGFET) com canal de silício e o MOSFET planar convencional com canal de germânio são alguns destes promissores dispositivos avançados a receberem o tensionamento mecânico para aumento da mobilidade dos portadores. O tensionamento mecânico uniaxial, biaxial e ambos combinados são analisados através de simulação numérica de processos e dispositivos e medidas experimentais em três técnicas de tensionamento diferentes, além da análise de medidas obtidas de dispositivos experimentais para análise do aumento da mobilidade dos portadores através da transcondutância máxima. A linha de corte 1D de cada componente do tensionamento simulado é estudado de acordo com a sua dependência com a largura, altura, comprimento do canal e materiais utilizados, assim como a influência que as componentes de tensionamento exercem sobre os parâmetros elétricos analógicos, como transcondutância, ganho intrínseco de tensão e frequência de ganho de tensão unitário. A operação dos dispositivos de silício sobre isolante (SOI Silicon On Insulator) MuGFETs de porta tripla com variações no formato da secção transversal do canal do transistor e variações no comprimento e largura da aleta é estudada em casos selecionados. Um completo estudo da distribuição do tensionamento mecânico gerado por tensionamento global e por tensionamento local é realizado em estruturas com aleta retangular e trapezoidal, juntamente com o impacto destas na mobilidade e nos parâmetros analógicos são realizados. Estruturas nMuGFET SOI com comprimento de canal mais curto alcançaram aumentos maiores de mobilidade utilizando-se o tensionamento uniaxial, enquanto que as estruturas com comprimento de canal mais longo retornaram maior mobilidade com o tensionamento biaxial, resultado da diferente efetividade de cada técnica de tensionamento em cada estrutura. Estruturas MOSFETs convencionais planares com tensionadores embutidos na fonte e dreno em canal de germânio para incremento da mobilidade também são analisadas. Simulações numéricas do processo de fabricação são realizadas e calibradas com dispositivos experimentais em transistores tipo n e tipo p, possibilitando o estudo futuro de estruturas MuGFET de germânio. / The fast and growing demand for technologies that enable the reduction of dimensions of planar single gate transistors leads to a new era of mechanically stressed devices. Multiple gate transistors (MuGFET) with silicon channel and planar bulk MOSFET with germanium channel are some of these promising advanced devices to receive the mechanical stress to increase carriers mobility. The uniaxial stress, biaxial stress and both of them combined are analyzed by process and device numerical simulations in three different strain techniques and also the analysis of experimental measurements for analysis of carriers mobility increase through maximum transconductance. The 1D cut line of each simulated stress component is studied according to their dependence on the width, height and length of the channel and the materials used, as well as the influence that stress components causes on analog electrical parameters, such as transconductance, intrinsic voltage gain and unity gain frequency. The operation of silicon-on-insulator (SOI) triple gate MuGFETs with variations in the shape of the cross section of the transistor channel and variations in the length and width of the fin is studied in selected cases. A complete study in the distribution of the mechanical stress generated by the local and global stress is performed in rectangular and trapezoidal fins and also the impact of these on mobility and analog parameters are studied. SOI nMuGFET structures with shorter channel length achieved higher mobility increases using the uniaxial stress, while structures with longer channel lengths returned higher mobility using the biaxial stress, result of the different effectiveness in each stress technique for each structure. Conventional MOSFET structures with embedded stressors in the source and drain regions with germanium channel are also analyzed. Numerical process simulations are realized and calibrated with experimental devices in both n and p type transistors, making possible the future study of MuGFET structures with germanium.

A rápida e crescente demanda por tecnologias que permitam a redução das dimensões dos transistores planares de porta única leva a uma nova era de dispositivos tensionados mecanicamente. Os transistores de múltiplas portas (MuGFET) com canal de silício e o MOSFET planar convencional com canal de germânio são alguns destes promissores dispositivos avançados a receberem o tensionamento mecânico para aumento da mobilidade dos portadores. O tensionamento mecânico uniaxial, biaxial e ambos combinados são analisados através de simulação numérica de processos e dispositivos e medidas experimentais em três técnicas de tensionamento diferentes, além da análise de medidas obtidas de dispositivos experimentais para análise do aumento da mobilidade dos portadores através da transcondutância máxima. A linha de corte 1D de cada componente do tensionamento simulado é estudado de acordo com a sua dependência com a largura, altura, comprimento do canal e materiais utilizados, assim como a influência que as componentes de tensionamento exercem sobre os parâmetros elétricos analógicos, como transcondutância, ganho intrínseco de tensão e frequência de ganho de tensão unitário. A operação dos dispositivos de silício sobre isolante (SOI Silicon On Insulator) MuGFETs de porta tripla com variações no formato da secção transversal do canal do transistor e variações no comprimento e largura da aleta é estudada em casos selecionados. Um completo estudo da distribuição do tensionamento mecânico gerado por tensionamento global e por tensionamento local é realizado em estruturas com aleta retangular e trapezoidal, juntamente com o impacto destas na mobilidade e nos parâmetros analógicos são realizados. Estruturas nMuGFET SOI com comprimento de canal mais curto alcançaram aumentos maiores de mobilidade utilizando-se o tensionamento uniaxial, enquanto que as estruturas com comprimento de canal mais longo retornaram maior mobilidade com o tensionamento biaxial, resultado da diferente efetividade de cada técnica de tensionamento em cada estrutura. Estruturas MOSFETs convencionais planares com tensionadores embutidos na fonte e dreno em canal de germânio para incremento da mobilidade também são analisadas. Simulações numéricas do processo de fabricação são realizadas e calibradas com dispositivos experimentais em transistores tipo n e tipo p, possibilitando o estudo futuro de estruturas MuGFET de germânio. / The fast and growing demand for technologies that enable the reduction of dimensions of planar single gate transistors leads to a new era of mechanically stressed devices. Multiple gate transistors (MuGFET) with silicon channel and planar bulk MOSFET with germanium channel are some of these promising advanced devices to receive the mechanical stress to increase carriers mobility. The uniaxial stress, biaxial stress and both of them combined are analyzed by process and device numerical simulations in three different strain techniques and also the analysis of experimental measurements for analysis of carriers mobility increase through maximum transconductance. The 1D cut line of each simulated stress component is studied according to their dependence on the width, height and length of the channel and the materials used, as well as the influence that stress components causes on analog electrical parameters, such as transconductance, intrinsic voltage gain and unity gain frequency. The operation of silicon-on-insulator (SOI) triple gate MuGFETs with variations in the shape of the cross section of the transistor channel and variations in the length and width of the fin is studied in selected cases. A complete study in the distribution of the mechanical stress generated by the local and global stress is performed in rectangular and trapezoidal fins and also the impact of these on mobility and analog parameters are studied. SOI nMuGFET structures with shorter channel length achieved higher mobility increases using the uniaxial stress, while structures with longer channel lengths returned higher mobility using the biaxial stress, result of the different effectiveness in each stress technique for each structure. Conventional MOSFET structures with embedded stressors in the source and drain regions with germanium channel are also analyzed. Numerical process simulations are realized and calibrated with experimental devices in both n and p type transistors, making possible the future study of MuGFET structures with germanium.

<p>In the future network-based Swedish Defence (NBD), attaining information superiority will be of great importance. This will be achieved by a network of networks where decision-makers, information- and weapon-systems are linked together. As a part of the development of NBD, we have performed a study of user interface design for a future network-based tool package for analysis of sensor systems, referred to as the C2SR-system. </p><p>This thesis was performed at Ericsson Microwave Systems AB, Sensor and Information Networks, during the autumn 2002. A pre-study concerning the requirements of usability, trustworthiness and functionality of a userinterface for the C2SR-system was performed. Officers representing the future users in the NBD played an important role when gathering these requirements. Another important part of the pre-study was the evaluation of software that contains parts of the functionality necessary for the C2SR-system. </p><p>On the basis of the results from the pre-study, we have designed a user interface to the future C2SR-system. To demonstrate the most important conclusions, a prototype was implemented.</p>

<p>In the future network-based Swedish Defence (NBD), attaining information superiority will be of great importance. This will be achieved by a network of networks where decision-makers, information- and weapon-systems are linked together. As a part of the development of NBD, we have performed a study of user interface design for a future network-based tool package for analysis of sensor systems, referred to as the C2SR-system. </p><p>This thesis was performed at Ericsson Microwave Systems AB, Sensor and Information Networks, during the autumn 2002. A pre-study concerning the requirements of usability, trustworthiness and functionality of a user interface for the C2SR-system was performed. Officers representing the future users in the NBD played an important role when gathering these requirements. Another important part of the pre-study was the evaluation of software that contains parts of the functionality necessary for the C2SR-system. </p><p>On the basis of the results from the pre-study, we have designed a user interface to the future C2SR-system. To demonstrate the most important conclusions, a prototype was implemented.</p>

In the future network-based Swedish Defence (NBD), attaining information superiority will be of great importance. This will be achieved by a network of networks where decision-makers, information- and weapon-systems are linked together. As a part of the development of NBD, we have performed a study of user interface design for a future network-based tool package for analysis of sensor systems, referred to as the C2SR-system. This thesis was performed at Ericsson Microwave Systems AB, Sensor and Information Networks, during the autumn 2002. A pre-study concerning the requirements of usability, trustworthiness and functionality of a userinterface for the C2SR-system was performed. Officers representing the future users in the NBD played an important role when gathering these requirements. Another important part of the pre-study was the evaluation of software that contains parts of the functionality necessary for the C2SR-system. On the basis of the results from the pre-study, we have designed a user interface to the future C2SR-system. To demonstrate the most important conclusions, a prototype was implemented.

In the future network-based Swedish Defence (NBD), attaining information superiority will be of great importance. This will be achieved by a network of networks where decision-makers, information- and weapon-systems are linked together. As a part of the development of NBD, we have performed a study of user interface design for a future network-based tool package for analysis of sensor systems, referred to as the C2SR-system. This thesis was performed at Ericsson Microwave Systems AB, Sensor and Information Networks, during the autumn 2002. A pre-study concerning the requirements of usability, trustworthiness and functionality of a user interface for the C2SR-system was performed. Officers representing the future users in the NBD played an important role when gathering these requirements. Another important part of the pre-study was the evaluation of software that contains parts of the functionality necessary for the C2SR-system. On the basis of the results from the pre-study, we have designed a user interface to the future C2SR-system. To demonstrate the most important conclusions, a prototype was implemented.

Platinum-based chemotherapeutics are used for the treatment of a wide range of cancers and a number of attempts have been made toward developing compounds with better cellular stability and similar or enhanced cytotoxicity as compared to their predecessors. The first part of the work reported here focuses on the cellular effects of the metabolically stable dinuclear platinum compound, BBR3610-DACH. Comet assay showed this compound to form interstrand crosslinks, a highly toxic DNA lesion in HCT116 cells, at equimolar concentrations to its parental compound, BBR3610. Cell cycle studies showed that BBR3610-DACH causes G1/S and G2/M cell cycle arrest with S phase depletion, which was p21 dependent and partially p53 dependent in contrast to BBR3610 which showed initial S phase accumulation followed by a classical G2/M arrest. BBR3610-DACH-induced G1/S and G2/M cell cycle arrest interestingly was found to be independent of the DNA damage response mediated via the activation of ATM and ATR kinases. Also, the cell cycle arrest culminated in apoptosis, although apparently through a non-canonical pathway. The second project explores the cellular effects of trans-4-NBD which is a fluorescent derivative of transplatin. Like cisplatin, trans-4-NBD induced interstrand crosslinks in HCT116 cells as detected by the comet assay. Treatment with trans-4-NBD showed a G2/M arrest in HCT116 cells and a transient S phase accumulation in A2780 cells, with a marked increase in p53 and p21 protein levels. A robust apoptotic response is also seen via caspase activation and PARP cleavage in both the cell lines. Finally, the focus is shifted toward the nucleolar targeting platinum complex, TriplatinNC. Confocal studies in TriplatinNC-treated HCT116 and A2780 cells showed disruption of rRNA transcription as an early event followed by a robust G1 cell cycle arrest. Apoptotic induction was observed with the onset of cellular morphological changes and apparent caspase activation which was independent of the p53 status of the cells. Overall, these studies explore novel platinum based compounds that show promising anti-cancer activities by affecting various facets of cellular signaling.

L'acquisition du phénotype de résistance des cancers est souvent corrélée à l'expression de transporteurs membranaires appartenant à la superfamille des transporteurs ABC (« ATP-Binding Cassette »). Un de ces transporteurs, MRP1 (« Multidrug Resistance Protein 1 »), permet l'efflux de nombreux substrats, de type anioniques, conjugués au GSH, glucuronates ou sulfates, ou en co-transport avec le GSH.<br />Dans un premier temps, ce travail a porté sur l'étude des domaines de fixation des nucléotides isolés. Une étude biochimique a montré leur caractère fonctionnel asymétrique concernant les nucléotides, prouvant que seul la séquence primaire de ces NBD est responsable de cette fonctionnalité différentielle. L'étude de la fixation de substrats sur les NBD, a montré que ceux-ci pourraient, de part leur proximité avec les domaines transmembranaires, avoir un rôle dans la fixation des substrats.<br />La deuxième étape de ce travail a concerné la caractérisation de l'activité des énantiomères du vérapamil. Les résultats ont montré que le S-vérapamil est l'isomère responsable de la stimulation du transport du GSH, conduisant à la mort des cellules surexprimant MRP1. Le R-vérapamil est caractérisé comme un inhibiteur de MRP1. Ces résultats ont des répercussions importantes en terme de thérapie.<br />Deux études préliminaires de relation structure/fonction ont été menées en ce qui concerne des dérivés du vérapamil et des dérivés de flavonoïdes, afin de trouver des molécules plus efficaces contre MRP1.

Les transporteurs ABC forment une vaste famille de protéines présentes dans tous les organismes vivants. Ces protéines utilisent l'énergie fournie par l'hydrolyse de l'ATP pour transporter à travers les membranes biologiques des substances très variées. Plusieurs protéines ABC sont importantes pour la santé humaine. Par exemple, le défaut fonctionnel de la protéine CFTR cause la mucoviscidose et la surproduction de protéine MRP1 est associée aux phénomènes de résistance aux traitements anti-tumoraux. La levure Saccharomyces cerevisiae possède une famille de protéines (Yor1p, Ycf1p, Bpt1p, Ybt1p, Vmr1p, Nft1p) apparentées à CFTR et MRP1. Cette famille peut servir de modèle à l'étude des protéines humaines. La première partie de ce travail de thèse a été consacrée à l'étude biochimique de la protéine de levure Yor1p. Nous avons fusionné YOR1 avec un fragment d'ADN codant un peptide de poly-histidine et avons placé cette construction sous contrôle d'un promoteur permettant une surproduction dans la levure. Nous avons alors montré que la protéine Yor1p poly-histidylée était produite sous forme fonctionnelle dans la levure, puis avons mis au point une méthode permettant de solubiliser puis de purifier cette protéine en une seule étape par chromatographie d'affinité sur une colonne greffée avec des ions métalliques. La deuxième partie de ce travail a consisté à produire sous forme isolée chez la bactérie Escherichia coli et à purifier à homogénéité les deux domaines de Yor1p impliqués dans la liaison et l'hydrolyse de l'ATP. Nous avons étudié la fixation de l'ATP sur ces deux domaines, ce qui nous a permis de conclure que ces domaines étaient bien structurés. Ils peuvent maintenant être utilisés pour des études structurales. Enfin, nous nous sommes intéressés au rôle la protéine Ycf1p dans la détoxication du sélénite. Nous avons observé que la toxicité du sélénite pour la levure était considérablement accrue par la présence de composés thiolés dans le milieu de culture. La formation de dérivés réactifs de l'oxygène est vraisemblablement à l'origine de cette hypertoxicité.

Generation of foam cells, an essential step for reverse cholesterol transport (RCT) studies, uses the technique of receptor dependent macrophage loading with radiolabeled acetylated Low Density Lipoprotein (Ac-LDL). In this study, we used the ability of a biologically relevant detergent molecule, Lysophosphatidylcholine (Lyso PtdCho), to form mixed micelles with cholesterol or cholesteryl ester (CE) to generate macrophage foam cells. Fluorescent or radiolabelled cholesterol / Lyso PtdCho mixed micelles were prepared and incubated with RAW 264.7 or mouse peritoneal macrophages. Results showed that such micelles were quite stable at 4°C and retained the solubilized cholesterol during one month storage. Macrophages incubated with cholesterol or CE (unlabeled, fluorescently labeled or radiolabeled) / Lyso PtdCho mixed micelles accumulated CE as documented by microscopy, lipid staining, labeled oleate incorporation, and by thin layer chromatography (TLC). Such foam cells unloaded cholesterol when incubated with high density lipoprotein (HDL) and not with oxidized HDL (Ox-HDL). We propose that stable cholesterol or CE / Lyso PtdCho micelles would offer advantages over existing methods. Oxidative stress is associated with heart failure (HF). Previously our research group observed that the patients with low left-ventricular ejection fraction showed accumulation of high level of oxidized LDL (Ox-LDL) when compared with the heart failure patients with normal range of ejection fraction (EF). HDL is known to be atheroprotective and one of its important antioxidative functions is to protect LDL from oxidative modifications. However, HDL itself undergoes oxidation and Ox-HDL becomes functionally poor. It is expected to have a diminished ability to promote reverse cholesterol transport. Therefore, it was hypothesized that the quality of HDL present in the patients with EF would more compromised than those present in the patients with normal EF. Functionality of HDL was evaluated by measuring its cholesterol efflux capacity from foam cells generated in vitro. Functionality of HDL, which is strongly related to the oxidative modifications of HDL was further estimated by measuring paraoxonase 1 (PON1) enzyme activity associated with HDL. Higher the PON1 activity and RCT ability, better is the functionality of HDL.