Les déficits en facteurs de la coagulation sont des pathologies hémorragiques congénitales rares. Le développement récent des techniques de biologie moléculaire ont permis l'indentification de nombreuses anomalies génétiques dans les gènes codant les facteurs de coagulation. Cependant, la détermination de l'impact clinique réel de ces nouveaux variants est souvent un défi pour le biologiste moléculaire.La première partie de ce travail a consisté à l'étude par analyse chromosomique sur puce à ADN de grands réarrangements génomiques identifiés chez des patients hémophiles A ou B ayant parfois des phénotypes cliniques atypiques. Nous avons montré que certains gènes voisins des gènes F8 et F9 étaient associés, lorsqu'ils sont concernés par ces réarrangements de grande taille, à des déficits mentaux (SOX3) ou des pathologies cardiovasculaires (BRCC3).La seconde partie de cette étude a été centrée sur l'étude des variants de signification indéterminée localisés au niveau des sites d'épissage. Nous avons démontré par l'utilisation conjointe d'algorithmes informatiques et de tests in vitro de type minigène la pathogénicité de 21 variants identifiés chez des hémophiles A.La dernière partie de ce travail a consisté en la description de nouveaux mécanismes moléculaires responsables de pathologies hémorragiques. Nous avons identifié une délétion intronique chez 6,1% des hémophiles A mineurs de notre cohorte. Nous avons montré que cette anomalie était probablement responsable d'une dérégulation de l'hnRNP C ce qui entrainait l'insertion d'une séquence AluY dans les transcrits du gène F8. Enfin, nous avons décrit les mécanismes moléculaires responsables de la présence de concentrations très élevées de thrombomoduline soluble dans les plasmas de patients porteur de la mutation du gène THBD c.1611C>A. Ces travaux ont permis de détecter et de mieux appréhender certains mécanismes moléculaires responsables de pathologies rares hémorragiques / Inherited coagulation disorders are caused by a large number of genetic abnormalities. However, the determination of the clinical impact for some of these genetic variations is challenging for the molecular biologist.In a first part, we characterized large genomic rearrangements in haemophilia patients using cytogentic microarray analysis. In a first study, we delineated six F9 complete deletions in order to investigate genotype/phenotype correlations. We identified SOX3 as a candidate gene for intellectual disability (ID) found Haemophilia B patients. In a second study, we described five complex Xq28 rearrangements in Haemophilia A (HA) patients. We showed that several F8 neighbouring genes are involved in these rearrangements and some of these genes are involved in other pathologies such as ID, physical abnormalities and cardiovascular disease. Such investigations would be particularly useful for genetic counseling in female carriers to assess the risk of transmitting haemophilia associated with other diseases.In a second, we developed a minigene assay to characterise putative splice site mutations in F8 and we showed that 21 out of the 26 variations studied are associated with splicing defect.In the third part, we described two original molecular mechanisms leading to coagulation disorders. In a first case, we reported a recurrent deep intronic deletion in mild HA. We gave some evidences that this deletion promoted AluY exonization in F8 transcrits. Due to its high prevalence (6.1%), this deletion must be investigated in all patients with mild HA in whom no mutation has been detected by standard genetic analysis. In the second study we investigated the mechanism responsible for bleeding tendency in patient carrying the THBD c.1611C>A and having high levels of soluble thrombomoduline (TM). We showed that a higher sensitivity of the mutated TM to the proteolysis by metalloproteases and a defect of TM synthesis seemed responsible for TM shedding

Thesis (Ph. D.)--University of Hawaii at Manoa, 2004. / Includes bibliographical references.

Made available in DSpace on 2018-08-01T23:43:51Z (GMT). No. of bitstreams: 1 tese_10771_Dissertação Ravena Brazil Vinter finalizada v6.pdf: 6898928 bytes, checksum: ad51959019cfa045ff59c61871384bb6 (MD5) Previous issue date: 2017-03-10 / O presente trabalho se insere nas discussões do grupo de pesquisa Literatura e Educação e investigou, no contexto de uma escola pública de Ensino Fundamental e Médio do município de Guarapari (ES), como são as relações entre livros e leitores - por meio das contribuições teóricas e metodológicas da Nova História Cultural - a partir de três diferentes versões da obra O cortiço do autor Aluísio Azevedo: versão adaptada por Fabio Pinto da coleção É só o começo (2009); adaptação com roteiro de Ivan Jaf e arte de Rodrigo Rosa em história em quadrinhos (2010) distribuída pelo PNBE; e c) versão com texto integral (2014 [1890]); todas encontradas na biblioteca da escola campo. A pesquisa foi desenvolvida em dois momentos, sendo o primeiro de cunho bibliográfico-documental, que buscou perceber como se dão as relações entre livro, leitor e leitura e pensar o modo como algumas adaptações literárias são inseridas no mercado, inclusive as que integram programas de distribuição de livros como o PNBE. O segundo momento foi um estudo de caso com questionário e grupo focal, constituído por alunos de segundo e terceiro ano do Ensino Médio da escola campo, que, no âmbito do processo de educação literária, tentou responder às seguintes questões: a) como se dá a apropriação do texto integral e das diversas adaptações de uma obra pelos estudantes?; b) os textos adaptados despertam no leitor o desejo de conhecer o texto integral?; c) como os alunos agem para (não) realizar as leituras propostas pelo currículo escolar?: A pesquisa justifica-se em face: a) do interesse, nos campos da História e da Literatura, pelas práticas de leitores literários empíricos e pelos usos que são feitos de materiais impressos, em contextos institucionais, em tensão com orientações oficiais; b) da necessidade de se pensar as questões econômico-ideológicas que circundam a leitura em tensionamento com o mercado editorial; c) do nosso diagnóstico tomado aqui como pressuposto de que muitos alunos não leem obras literárias sugeridas pelo currículo escolar; d) da necessidade de se pensar as não leituras literárias para além da culpabilização discente. Com a investigação, conhecemos as formas de aquisição dos livros, algumas preferências, os principais mediadores de leitura, traçando assim um perfil de leitor de leitura literária da escola campo. Chegamos também à conclusão de que algumas adaptações podem ser instrumentos de mediação de leitura em sala de aula. Os autores que nortearam nosso estudo foram: Regina Zilberman (1999, 2013), Márcia Abreu (2001), Edmir Perrotti (1999) e João Wanderlei Geraldi (2010) (livro e leitura no contexto brasileiro); Annie Rouxel (2013), Maria Amélia Dalvi (2012, 2013, 2013a) e Neide Rezende (2013) (educação literária); Roger Chartier (1999, 2002, 2002a, 2010, 2013, 2013a) (práticas e representações, apropriação).

Indiana University-Purdue University Indianapolis (IUPUI) / In this thesis, we investigated the 7 nm FinFET technology for its delay-power product performance. In our study, we explored the ASAP7 library from Arizona State University, developed in collaboration with ARM Holdings. The FinFET technology was chosen since it has a subthreshold slope of 60mV/decade that enables cells to function at 0.7V supply voltage at the nominal corner. An emphasis was focused on characterizing the Non-Ideal effects, delay variation, and power for the FinFET device. An exhaustive analysis of the INVx1 delay variation for different operating conditions was also included, to assess the robustness. The 7nm FinFET device was then employed into 6T SRAM cells and 16 function ALU. The SRAM cells were approached with advanced multi-corner stability evaluation. The system-level architecture of the ALU has demonstrated an ultra-low power system operating at 1 GHz clock frequency.

No description available.

Les éléments Alu sont les retrotransposons les plus prolifiques chez l’humain avec plus d’1 million de copies occupant plus de 10% du génome. Afin de contrecarrer l’expansion des rétro-éléments, les organismes ont développés différents mécanismes pour préserver l’intégrité de leurs génomes. Le plus proéminent, également utilisé pour lutter contre la réinsertion d’ADN viral dans le génome hôte, est l’édition de l’ARN. Chez les mammifères, la plus courante est la déamination de l’adénine en inosine catalysée par la famille de protéine ADAR dont Les principales cibles sont les éléments Alu chez l’humain. L’édition des éléments Alu conduit à leur séquestration dans le noyau des cellules, mute leurs promoteurs internes, cible de l’ARN polymérase III (POLIII), et leurs queues poly-A, prévenant ainsi leur future rétrotransposition. Dans la première partie de cette étude, l’analyse de données de séquençage haut-débit révèle que ~40% des éléments Alu sont reconnus par POLIII, qu’ils sont présents en tant que petits ARN dans le cytoplasme et le noyau des cellules, que certain d’entre eux sont associés à la chromatine, et que la transcription des éléments Alu est un phénomène courant dans les tissus somatiques qui concorde avec l’expression d’éléments LINE1 fonctionnels. Ceci suggère que la rétrotransposition peut être un mécanisme normal dans la plupart des tissus humains. Enfin, l’analyse de l’expression des éléments Alu et LINE1 chez la souris montre que la transcription de rétrotransposons n’est pas spécifique de l’humain. Dans la seconde partie de cette étude, une nouvelle méthode a été développée pour explorer l’impact de l’édition de l’ARN sur le transcriptome en identifiant les ARN édités par séquençage haut-débit. Dans un premier temps, un anticorps ciblant ADAR a été utilisé pour extraire les ARN associés aux protéines de l’édition. Cette méthode n’étant pas suffisamment efficace, une autre stratégie, qui extrait directement les ARN contenant de l’inosine, a été développée : dans un premier temps, l’ARN est fixé à des billes magnétiques par leurs extrémités 3’, ensuite, les billes sont traitées au glyoxal/acide borique et à la RNAse T1 pour libérer la région 5’ des ARN contenant une ou plusieurs inosines, et enfin, les ARN libérés sont séquencés par séquençage haut débit. En utilisant cette méthode, 1822 sites d’éditions ont été identifiés dans l’ARN de cerveau de souris, incluant 28 nouveaux sites présents dans des séquences codantes qui conduisent à des mutations non-synonymes des futures protéines. Des sites d’éditions ont aussi été observés pour la première fois dans les ARN ribosomaux, les snoRNA et les snRNA. / The Alu repeats comprise more than 10% of the human genome. They spread in the genome by retrotransposition. As a response to this invasion, organisms developed mechanisms to preserve the integrity of their genome, such as RNA editing. The most abundant type of editing in mammals is A-to-I editing where the ADAR proteins transform adenosine into inosine and targets mainly Alu elements in human. Editing of the Alu elements leads to their sequestration in the nucleus and mutates their internal POLIII promoter and their poly-A tail, thus preventing their subsequent transposition. In the first part of this study, we challenged the view that Alu elements are dormant occupant of the genome by characterizing their activity. Deep-sequencing data analyses revealed that ~40% of Alu elements can bind POLIII, they present a definite localization in the cell and associate with chromatin and polysomes, and that Alu elements transcription is a widespread phenomenon in normal tissues which correlates with functional LINE1 elements expression. This suggested that Alu element retrotransposition may be a natural mechanism in most normal human tissues. Further analyses showed that SINE and LINE expression in somatic tissues was not exclusive to human but also occurs in mouse. Finally, attempts were made to identify tissue specific insertions in the human genome resulting from retrotransposition events. In the second part of this study, a new method was developed to understand the full impact of RNA editing on transcriptomes by characterizing the edited RNA in a high-throughput fashion. First, immunoprecipitation was attempted to pull-down RNA associated with the editing enzymes ADARs. Since this method was inefficient, another approach purifying directly the edited RNA was developed. First, the RNA was sequestered on magnetic beads. Then an inosine specific cleavage based on RNAseT1 treatment of RNA protected with glyoxal and borate allowed the separation of the edited RNA from the total RNA. Finally, deep sequencing was used to identify edited RNA. 1,822 editing sites were found in mouse brain RNA by this method, including 28 new editing sites modifying the coding sequences of genes and editing in rRNA, snoRNA and snRNA which were never observed before.

<p>This thesis investigates how systolic architectures can be used in the implementation of an arithmetic unit for small finite fields of characteristic two with polynomial basis representation. </p><p>Systolic architectures provide very high performance but also consume a lot of chip area. A number of design methods for tailoring the systolic arrays for a specified requirement are presented, making it possible to trade throughput, chip area and propagation delays for oneanother. </p><p>A study is also made on how these systolic arrays can be combined to form an arithmetic logic unit, ALU, that canperform operations in many different fields. A number of design alternatives are presented, and an example ALU is presented to give an idea of the performance of such a circuit.</p>

Age-related macular degeneration (AMD) is a principal cause of blindness in the United States and other industrialized nations. An estimated 10 million Americans are afflicted with AMD, which is comparable in scope to the 12 million living with cancer, or the 5 million with Alzheimer’s disease. The prevalence of AMD steadily increases with age, affecting 2% of the population at age 40, and one in four people by age 80. For reasons that are not fully understood, AMD is more common in lightly-pigmented and female populations. Treatment of AMD is largely an unmet need: There are no FDA approved therapies except for a small percentage of individuals with end-stage disease. This dissertation investigates the mechanisms of AMD pathogenesis and offers insight into novel therapeutic strategies for this disease.

Thesis (Ph. D.)--University of Hawaii at Manoa, 2004. / Includes bibliographical references. / Also available by subscription via World Wide Web / xiii, 222 leaves, bound ill. (some col.) 29 cm. +

This thesis investigates how systolic architectures can be used in the implementation of an arithmetic unit for small finite fields of characteristic two with polynomial basis representation. Systolic architectures provide very high performance but also consume a lot of chip area. A number of design methods for tailoring the systolic arrays for a specified requirement are presented, making it possible to trade throughput, chip area and propagation delays for oneanother. A study is also made on how these systolic arrays can be combined to form an arithmetic logic unit, ALU, that canperform operations in many different fields. A number of design alternatives are presented, and an example ALU is presented to give an idea of the performance of such a circuit.