This master thesis presents the development of an auxiliary power supply to provide energy to sensors, gate drivers, instrumentation circuits and control of a three-stage Solid State Transformer (SST). These devices require an insulated power supply of ±15V and 5V. For reason of reliability and modularity, a distributed auxiliary source is proposed. Thus, it is necessary a power supply to provide energy to the low voltage (LV) side and another to the medium voltage (MV) side. With this proposal, the auxiliary power supply does not need to have the same galvanic insulation of the SST, 25kV. However, a local power supply must operate at high voltage levels and, consequently, contain a high step-down voltage gain. Relative to LV side, the most generally used topologies as an auxiliary power supply are discussed. However, these topologies cannot be used at the MV converters, due to the high voltage stress levels involved. A study of topologies used on medium and high voltage and which enable to reach a high step-down voltage gain is realized, and two interesting topologies for this application were found. One of them uses a Flying capacitor converter connected in cascade with a Double-Ended Flyback converter. The Flying capacitor converter lowers the DC bus voltage in a controlled manner to low voltage levels. So the Double-ended Flyback converter operates in LV and provides the insulated outputs to command circuits of SST. The other topology is a unidirectional four-level NPC converter operating as Double-ended Flyback converter. For this case, a modulation strategy that allows the converter to reach a high step-down voltage gain was also proposed. These topologies were evaluated and the one which showed the best result was the four-level Double-ended Flyback converter. This converter was implemented and the experimental results prove to be effective. For the LV side, a Half-bridge LLC resonant converter as auxiliary power supply was used. This converter operates in ZVS and performs the output voltage regulation through the operating frequency variation. The experimental results of this converter are also presented. / Este trabalho de mestrado apresenta o desenvolvimento de fontes auxiliares para alimentar sensores, circuitos de comando, instrumentação e o controle de um Transformador de Estado Sólido (SST) de três estágios. Estes dispositivos necessitam de alimentação isolada com tensões de ±15V e 5V e por questões de confiabilidade e modularidade, propõe-se a utilização de fontes auxiliares distribuídas. Assim, emprega-se uma fonte auxiliar para alimentar o lado de média tensão (MT) e outra para alimentar o lado de baixa tensão (BT). Com essa proposta, as fontes auxiliares não necessitam ter a mesma isolação galvânica do SST, 25kV. Entretanto, uma das fontes locais deve operar em níveis de tensão elevados e, por consequência, apresentar baixo ganho estático. No lado de BT, as principais topologias normalmente utilizadas como fonte auxiliar são discutidas. No entanto, devido aos altos níveis de tensão envolvidos, estas topologias não podem ser aplicadas ao conversor que opera em MT. Um estudo sobre topologias aplicadas a média tensão e que possibilitam alcançar um baixo ganho estático é realizado, sendo que duas topologias se mostram interessantes para esta aplicação. Uma consiste na utilização de um conversor de capacitores flutuantes conectado em cascata com um conversor Double-Ended Flyback. O conversor de capacitores flutuantes rebaixa a tensão do barramento CC, de forma controlada, para baixa tensão. Assim o Double-Ended Flyback opera em BT e fornece as saídas isoladas para alimentar os circuitos de comando do SST. A outra topologia trata-se de um conversor NPC de quatro níveis unidirecional operando como conversor Double-Ended Flyback. Para este caso, também foi proposta uma estratégia de modulação que permite o conversor alcançar o baixo ganho estático. Essas topologias foram avaliadas, apresentando melhor resultado a esta aplicação o conversor Double-ended Flyback de quatro níveis, conforme será demonstrado neste trabalho. Esse conversor foi implementado e os resultados experimentais comprovam o seu funcionamento. Para a fonte do lado de BT utilizou-se um conversor Half-Bridge LLC ressonante que opera em ZVS e realiza a regulação da tensão de saída pela variação da frequência de operação. Os resultados experimentais deste conversor também são apresentados.

Compostos α-aminocarbonilícos como ácido 5-aminolevulínico (ALA) e aminoacetona (AA) apresentam um grande potencial pró-oxidante, pois sofrem reações de enolização e subseqüente oxidação aeróbica, com a formação de espécies radicalares de oxigênio, íons NH4+ e α-oxoaldeídos potencialmente citotóxicos. A α-aminocetona 1,4-diamino-2-butanona (DAB), um análogo da putrescina, é um agente microbicida de vários parasitas incluindo Trypanosoma cruzi. Acredita-se que o mecanismo de morte desencadeado por DAB nos parasitas seja por meio da inibição competitiva da ornitina descarboxilase (ODC), importante enzima do metabolismo de poliaminas, muito embora tenha sido observado de igual forma danos oxidativos nestes parasitas quando tratados com DAB. O objetivo deste trabalho é esclarecer o mecanismo de oxidação química de DAB e sua ação pró-oxidante à cultura de células de mamíferos (LLC-MK2 e RKO), assim como sua atividade microbicida contra tripomastigotas de Trypanosoma cruzi. Demonstramos aqui que DAB, quimicamente similar ao ALA e AA, sofre reação de oxidação catalisada por íons fosfato, e por íons de metais de transição como Fe(II) e Cu(II), resultando na formação de radicais de oxigênio, H2O2, NH4+, 2-oxo-4-aminobutanal como produto principal da oxidação de DAB e de compostos ciclicos de caracter pirrólico. Danos oxidativos observados em ferritina, apotransferrina e liposomos de cardiolipina e fosfatidilcolina (20:80) contribuem para a nossa hipótese de ação pró-oxidante de DAB. O tratamento de células de mamíferos das linhagens LLC-MK2 (IC50 1,5 mM, tratamento de 24 h) e RKO (IC50 0,3 mM, tratamento de 24 h) com DAB levou à alteração do balanço redox celular, à ativação de resposta antioxidante e ao desencadeamento de morte celular via apoptose e parada de ciclo celular. Em culturas de tripomastigotas de T. cruzi o tratamento com DAB culminou na redução da motilitidade e viabilidade destes parasitas (IC50 0,2 mM, tratamento de 4 h), assim como depleção do conteúdo tiólico acompanhado pelo aumento da atividade de TcSOD. Além do mais, DAB mostrou-se eficiente em limitar a invasão de tripomastigotas às células hospedeiras (LLC-MK2) e reduzir a proliferação de amastigotas intracelulares, contudo fortemente relacionada à necrose das células hospedeiras infectadas, uma vez que são alvos mais susceptíveis de ação oxidativa. Estes resultados suportam nossa hipótese que DAB exerce ação pró-oxidante e contribui deste modo com o mecanismo já descrito de morte celular associada à inibição da biossíntese de poliaminas em vários microorganismos. / α-Aminocarbonyl componds such as 5-aminolevunilic acid (ALA) and aminoacetone (AA) have been shown to exhibit pro-oxidant properties. These compounds undergo phosphate-catalyzed enolization in physiological pH and subsequent aerobic oxidation, yielding reactive oxygen species, NH4+ ions and an α-oxoaldehyde highly cytotoxic. The &#945-aminoketone 1,4-diamino-2-butanone (DAB) is a putrescine analogue and a microbicidal agent to various parasites including Trypanosoma cruzi. The mechanism of DAB toxicity to these parasites is attributed to DAB competitive inhibition of ornithine decarboxylase (ODC), a key enzyme on polyamine biosynthesis, although it has also been shown DAB isto implicated in oxidative damage to these parasites. Our aim is to clarify the mechanism of DAB aerobic oxidation and of its putative pro-oxidant activity to mammalian cell cultures (LLC-MK2 and RKO cell linages) and to Trypanosoma cruzi trypomastigotes. Here we show that, similar to ALA and AA, DAB undergoes aerobic oxidation in presence of phosphate ions and of transition metal ions such as Fe(II) and Cu(II), yielding oxygen radicals, H2O2, NH4+ and 2-oxo-4-aminobutanal accompanied by its condensation cyclic products displaying pyrrolic characteristics. Oxidative alterations to ferritin, apotransferrin and liposomes of cardiolipin and phosphatidylcholine (20:80) were observed under DAB treatment strongly supporting our hypothesis of DAB pro-oxidative activity. DAB treatment of mammalian cultured cells LLC-MK2 (IC50 1.5 mM, 24 h incubation) and RKO (IC50 0.3 mM, 24 h incubation) resulted in redox imbalance, induction of antioxidant response, activation of apoptosis pathway and cell cycle arrest. DAB is shown here to trigger Trypanosoma cruzi trypomastigotes decreased parasite motility and viability (IC50 0.2 mM, 4 h incubation), as well as redox thiol imbalance parallel to increase TcSOD activity. In addition, DAB efficiently hampered host cell (LLC-MK2) invasion by trypomastigotes. In addition, intracellular amastigotes showed to be susceptible to DAB toxicity, although strongly related to necrosis of infected host cells, which are more vulnerable to oxidative stress. Altogether, these data support our hypothesis that oxidative stress contributes to DAB cytotoxicity.

La leucémie lymphoïde chronique (LLC), hémopathie lymphoïde fréquente, se caractérise par une évolution clinique extrêmement variable. Bien que les marqueurs de pronostic soient nombreux dans la LLC, aucun n'est univoque. Dans ce contexte, identifier de nouveaux facteurs prédictifs et comprendre la pathophysiologie de marqueurs pronostiques déjà établis constituent deux objectifs importants pour améliorer la prise en chargethérapeutique de cette hémopathie. Nous avons tout d'abord choisi d'étudier la valeur pronostique et les mécanismes de régulation de l'expression du gène anti-apoptotique MCL1. Nous avons montré que l'expression de MCL1 est un marqueur prédictif de la survie globale parmi l'ensemble despatients et parmi les stades précoces ; ce marqueur est également prédictif de la survie sans traitement des patients en stade A. Ainsi, l'expression de MCL1 permet d'identifier précocement les formes de LLC à haut risque et faible risque d'évolution défavorable. Nous avons également démontré que l'expression de MCL1 est fortement corrélée à l'expression de VEGF, confirmant le rôle de cette voie de signalisation dans la survie des lymphocytes tumoraux et suggérant que VEGF pourrait réguler positivement l'expression de MCL1 selon un mode autocrine. Nous avons ensuite exploré la fonction télomérique en rapport avec les anomalies chromosomiques à valeur pronostique, reflets de l'instabilité génomique. Notre travail a contribué à démontrer la relation entre l'instabilité génomique et le statut télomérique, évalué par la longueur des télomères et l'expression de hTERT et des gènes du complexe shelterin. Nous avons ainsi mis en évidence trois groupes de patients présentant des profilscytogénétiques et télomériques distincts : le premier groupe combine une cytogénétique favorable, des télomères longs, une expression faible ou absente de hTERT et une expression forte des gènes du complexe shelterin ; le troisième groupe se caractérise par de multiples aberrations chromosomiques (notamment délétions 17p et 11q), une augmentation de l'expression de hTERT et une diminution de la longueur des télomères et des niveaux d'expression de TRF1, TRF2 et POT1 ; le deuxième groupe est intermédiaire. Ces résultats confirment l'existence d'un lien entre statut télomérique et instabilité génomique au cours de la LLC et soulignent le rôle de la perte de TP53 ou ATM dans cette dysfonction télomérique. L'altération du statut télomérique est par ailleurs associée à des caractéristiques de pronostic défavorable, comme l'absence de mutation des IgVH, l’expression de CD38 et le doublement rapide de la lymphocytose. Enfin, nous avons évalué l’intérêt de la technique de MLPA pour la mise en évidence des anomalies cytogénétiques récurrentes à valeur pronostique de la LLC. Nous avons montré qu'il existe une bonne concordance entre la technique de référence et la MLPA, qui constitue une approche rapide et peu coûteuse pour la recherche d'anomalies génomiques présentes dans une majorité de cellules malignes. Nous avons cependant mis en évidence des cas intéressants de faux-positifs et de faux-négatifs avec la MLPA, indiquant que cette méthode ne peut pas remplacer les techniques classiques, mais constitue une approche complémentaire permettant une évaluation simultanée de divers déséquilibres. / Chronic lymphocytic leukemia (CLL) is a frequent lymphoid hemopathy characterized by an extremely variable clinical course. Although there are numerous prognostic markers in CLL, none is univocal. In this context, identifying new predictive factors and understanding the pathophysiology of previously established prognostic markers represent two important aims to improve therapeutic management of this hemopathy. We first chose to study the prognostic value and mechanisms of regulation of antiapoptotic MCL1 gene expression. We showed that MCL1 expression is a predictive marker of overall survival within the whole patient cohort and among early stages; this marker is also a predictor of treatment free survival of stage A patients. Thus, MCL1 expression allows early identification of CLL forms with high risk and low risk of unfavourable evolution. We alsodemonstrated that MCL1 expression is strongly correlated to VEGF expression, confirming the role of this signalling pathway in tumour lymphocytes survival and suggesting that VEGF may be a positive autocrine regulator of MCL1 expression. We then explored telomeric function regarding prognosis-related chromosomal anomalies, reflecting genomic instability. Our work contributed to demonstrate the relationship between genomic instability and telomeric status, evaluated by telomere length and expression of hTERT and shelterin complex genes. We described three groups of patients with distinct cytogenetic and telomeric profile: first group combines good-prognosis cytogenetics, long telomeres, low or negative hTERT expression and high expression of the shelterin complex genes; third group displays multiple chromosome aberrations (particularly 17p and 11q deletions), increased hTERT expression and decreased telomere length and TRF1, TRF2 and POT1 expression levels; second group is intermediate. These results confirm the relationship between telomeric status and genomic instability in CLL and underline the role of TP53 or ATM loss in this telomeric dysfunction. The alteration of telomeric status is also associated with poor-prognosis features, such as unmutated IgVH, CD38 expression and rapid lymphocytosis doubling time. Finally, we evaluated the contribution of MLPA approach for detection of recurrent prognosis-related cytogenetic anomalies. We found a good concordance between the goldstandard technique and MLPA, which represent a time and cost-effective approach for the detection of genomic aberrations affecting most malignant cells. We however described interesting MLPA false-positive and false-negative cases, indicating that this method may not replace classic techniques, but may constitute a complementary approach allowingsimultaneous evaluation of various imbalances.

Étude sur l'intégration de protocoles de communication de données dans les circuits intégrés. Cette intégration est examinée sous deux aspects: architecture fonctionnelle et méthodologie de conception. Deux classes de circuits de communication ont été étudiés: la première traite des méthodes d'accès série et parallèle et la deuxième concerne l'implantation des couches hautes du modèle OSI : de la couche LLC d'IEEE à la couche session. La méthodologie de conception des circuits de communication est basée sur la définition et le développement des bibliothèques d'opérateurs flexibles spécialisés et des bibliothèques de modules paramétrables spécialisés

The purpose of this study was to establish whether curcumin protects renal proximal tubule cells against ischemic injury, determine whether this postulated cytoprotective effect is mediated through the upregulation of HSP70, and investigate whether the mechanism by which curcumin induces HSP70 expression and confers its protective effect is through activation of the Unfolded Protein Response. LLC-PK1 cells were cultured on collagen-coated filters to mimic conditions of in vivo renal proximal tubule cells and induce cell polarization. Injury with and without curcumin treatment was studied by using chemically-induced ATP-depletion which mimics renal ischemic injury. Cell injury was assessed using a TUNEL assay in order to evaluate DNA cleavage associated with ischemia-induced apoptosis and actin staining used to assess cytoskeletal disruption. Renal ischemic damage was further investigated by determining detachment of the Na-K ATPase from the basolateral membrane, which represents loss of cell polarity. Cells were incubated with curcumin in a dose- and time-response fashion and subsequent levels of HSP70 expression were assessed. Cells were then incubated with AEBSF, an inhibitor of the Unfolded Protein Response (UPR) and HSP70 and BiP/GRP78 (an ER resident chaperone that is upregulated by the UPR) expression levels were evaluated. Results demonstrated that treatment with curcumin during two hours of injury results in significantly less injury-related apoptosis and cytoskeletal disruption compared to control injured cells. It was demonstrated that curcumin induces HSP70 in both a dose- and time-response fashion. Moreover, curcumin treatment resulted in profound stabilization of Na-K ATPase on the basolateral membranes as there was significantly less Na-K ATPase detachment in cells treated with curcumin during two hours of injury compared to control injured cells. Finally, treatment with AEBSF inhibited HSP70 upregulation in curcumin-treated cells as well as inhibiting the GRP78 over-expression otherwise demonstrated in curcumin-treated cells. Protection of proximal tubule cells against renal ischemic injury by curcumin was therefore indicated to be mediated by the activation of the UPR through which HSP70 is upregulated. Curcumins activation of the UPR and induction of HSP70 explains the stabilization of Na-K ATPase on the cytoskeleton and also provides a potential mechanism explaining many of curcumins therapeutic and protective qualities.

Thesis (Ph.D.)--University of Toledo, 2006. / "In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences." Major advisor: Zi-Jian Xie. Includes abstract. Document formatted into pages: iii, 156 p. Title from title page of PDF document. Bibliography: pages 64-67, 97-100, 116-117, 125-155.

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This qualitative case study describes how first year students perceived the impact of living within a living learning community by giving voice to students who wished to not only describe their living experience, but also have this description heard. While living learning communities are not new to Residential Life departments on college campuses, the studies of such programs have predominantly been large scale quantitative studies conducted to assess the overall satisfaction that students feel with living in such a program or to ask one very specific question, typically related to drinking patterns or academic successes. Through the studying of one particular academic living learning community at a specific mid-Atlantic, urban university, I was able to delve deeper into the lives of students and develop a detailed holistic picture of the student experience specifically through the use of student interviews. My small sample, and immersion in the field, permitted an in depth understanding of all aspects of their residential and academic life related to their living learning community experience. The residents took advantage of the research as an opportunity to speak freely about issues that more macro researchers had not considered as potential impacts of student life within a living learning community. The research took place in one residential hall over an entire year. The data was gathered from a series of in-depth interviews and almost daily observations. Studying a select number of students within the community for a full academic year provided the opportunity to ask the same questions on numerous occasions and study how the students' responses changed or remained the same over time. This year long endeavor also permitted my immersion into the community and attendance at programs and events held within the living learning community allowing me to discover five themes relating to the student perspective of living learning communities: The Importance of Family, Social Activities as Opportunities to Bond, Accountability with Regards to Academics, Sense of Exclusivity, and the Importance of Personality on Perception of LLC Success. Through these themes, this study provides one of the few rigorous insights into life in a living learning community from the student perspective directly through the use of student voice, allowing for higher educational leaders and planners to take this individualized perspective into account in the organization, implementation, funding, and assessment of future living learning community endeavors. / Educational Administration

The battery charger plays an important role in the development of electric vehicles (EVs) and plug-in hybrid electric vehicles (PHEVs).This thesis focuses on the DC-DC converter for high voltage battery charger and is divided into four chapters. The background related to EV battery charger is introduced, and the topologies of isolated DC-DC converter possibly applied in battery charge are sketched in Chapter 1. Since the EV battery charger is high voltage high power, the phase-shifted full bridge and LLC converters, which are popularly used in high power applications, are discussed in detail in Chapter 2. They are generally considered as high efficiency, high power density and high reliability, but their prominent features are also limited in certain range of operation. To make full use of the advantages and to avoid the limitation of the phase-shifted full bridge and LLC converters, a novel hybrid resonant and PWM converter combining resonant LLC half-bridge and phase shifted full-bridge topology is proposed and is described in Chapter 3. The converter achieves high efficiency and true soft switching for the entire operation range, which is very important for high voltage EV battery charger application. A 3.4 kW hardware prototype has been designed, implemented and tested to verify that the proposed hybrid converter truly avoids the disadvantages of LLC and phase-shifted full bridge converters while maintaining their advantages. In this proposed hybrid converter, the utilization efficiency of the auxiliary transformer is not that ideal. When the duty cycle is large, LLC converter charges one of the capacitors but the energy stored in the capacitor has no chance to be transferred to the output, resulting in the low utilization efficiency of the auxiliary transformer. To utilize the auxiliary transformer fully while keeping all the prominent features of the previous hybrid converter in Chapter 3, an improved hybrid resonant and PWM converter is proposed in Chapter 4. The idea has been verified with simulations. The last chapter is the conclusion which summaries the key features and findings of the two proposed hybrid converters. / Master of Science