A sinalização celular desencadeada na presença do hormônio andrógeno em células da próstata é dependente da ativação do receptor de andrógeno (AR), que é um fator de transcrição codificado pelo gene NR3C4. O AR quando não ligado ao hormônio andrógeno é encontrado no citoplasma, e a ligação do hormônio ao AR promove seu deslocamento para o núcleo. O AR se liga a motivos de DNA, promovendo a transcrição de determinados genes por meio de um complexo mecanismo de regulação ainda não totalmente conhecido. Neste trabalho exploramos a capacidade dos RNAs longos intergênicos não-codificadores (lincRNAs) se ligarem ao AR e contribuírem para a regulação transcricional de genes. Utilizamos a imunoprecipitação de RNA, seguida de sequenciamento em larga escala (RIP-Seq) para a identificação e quantificação de lincRNAs associados fisicamente ao AR na linhagem celular de próstata LNCaP. Em paralelo utilizamos dados de transcriptoma e de marcas epigenéticas para verificar se a interação física dos lincRNAs com o AR influenciaria a composição da cromatina e a expressão dos genes vizinhos desses ARA-lincRNAs (Androgen Receptor Associated LincRNAs). Como resultado deste estudo descrevemos pela primeira vez centenas de LincRNAs associados fisicamente ao receptor de andrógeno após o tratamento com o hormônio. Observamos que uma parte desses ARA-lincRNAs pode modificar in cis a expressão de genes codificadores de proteínas vizinhos e essa capacidade de regulação é reforçada pela presença de marcas epigenéticas que são características de reguladores in cis. Além disso, mostramos que as regiões da cromatina contendo domínios topologicamente associativos (TADs) que possuem ARA-lincRNAs apresentam fatores de transcrição, marcas epigenéticas e nível de transcrição gênica diferenciadas. Os resultados apresentados neste trabalho estendem a importância dos lincRNAs durante eventos regulatórios complexos e mostra pela primeira a atuação dessas moléculas em sinergia com um fator de transcrição modificando a cromatina e alterando a regulação gênica. / The cell signaling events triggered in the presence of the androgen hormone in prostate cells is dependent on the activation of the androgen receptor (AR), which is a transcription factor encoded by the NR3C4 gene. AR when not bound to the androgen hormone is found in the cytoplasm, and binding of the hormone to AR promotes its displacement to the nucleus. AR binds to DNA motifs, promoting the transcription of certain genes through a complex regulatory mechanism not yet fully undestood. In this work we explore the ability of long non-coding intergenic RNAs (lincRNAs) to bind to AR and contribute to the transcriptional regulation of genes. We used immunoprecipitation of RNA, followed by large-scale sequencing (RIP-Seq) for the identification and quantification of lincRNAs physically associated with AR in the LNCaP prostate cell line. In parallel we used transcriptome data and data on epigenetic marks to verify whether the physical interaction of lincRNAs with AR would influence the chromatin composition and the expression of genes neighboring these ARA-lincRNAs (Androgen Receptor Associated LincRNAs). As a result of this study we described for the first time in the literature hundreds of LincRNAs physically associated with the androgen receptor after treatment with the hormone. We have observed that part of these ARA-lincRNAs can modify in cis the expression of neighboring protein coding genes and this regulatory ability is enhanced by the presence of epigenetic marks that are characteristic of in cis regulators. In addition, we have shown that chromatin regions containing topologically associating domains (TADs) that possess ARA-lincRNAs have different transcription factors, epigenetic marks and gene transcription levels. The results presented in this work extend the importance of the lincRNAs during complex regulatory events and shows for the first time the performance of these molecules in synergy with a transcription factor modifying the chromatin and altering gene regulation.

Submitted by PPG Ci?ncia da Computa??o (ppgcc@pucrs.br) on 2018-04-03T14:37:48Z No. of bitstreams: 1 MARCELO_RUARO_TES.pdf: 4683751 bytes, checksum: 6eb242e44efbbffa6fa556ea81cdeace (MD5) / Approved for entry into archive by Tatiana Lopes (tatiana.lopes@pucrs.br) on 2018-04-13T17:30:40Z (GMT) No. of bitstreams: 1 MARCELO_RUARO_TES.pdf: 4683751 bytes, checksum: 6eb242e44efbbffa6fa556ea81cdeace (MD5) / Made available in DSpace on 2018-04-13T17:37:13Z (GMT). No. of bitstreams: 1 MARCELO_RUARO_TES.pdf: 4683751 bytes, checksum: 6eb242e44efbbffa6fa556ea81cdeace (MD5) Previous issue date: 2018-03-16 / Sistemas multi-n?cleos intra-chip s?o o estado-da-arte em termos de poder computacional, alcan?ando de d?zias a milhares de elementos de processamentos (PE) em um ?nico circuito integrado. Sistemas multi-n?cleos de prop?sito geral assumem uma admiss?o din?mica de aplica??es, onde o conjunto de aplica??es n?o ? conhecido em tempo de projeto e as aplica??es podem iniciar sua execu??o a qualquer momento. Algumas aplica??es podem ter requisitos de tempo real, requisitando n?veis de qualidade de servi?o (QoS) do sistema. Devido ao alto grau de imprevisibilidade do uso dos recursos e o grande n?mero de componentes para se gerenciar, propriedades autoadaptativas tornam-se fundamentais para dar suporte a QoS em tempo de execu??o. A literatura fornece diversas propostas de QoS autoadaptativo, focado em recursos de comunica??o (ex., redes intra-chip), ou computa??o (ex., CPU). Contudo, para fornecer um suporte de QoS completo, ? fundamental uma autoconsci?ncia abrangente dos recursos do sistema, e assumir t?cnicas adaptativas que permitem agir em ambos os n?veis de comunica??o e computa??o para atender os requisitos das aplica??es. Para suprir essas demandas, essa Tese prop?e uma infraestrutura e t?cnicas de gerenciamento de QoS autoadaptativo, cobrindo ambos os n?veis de computa??o e comunica??o. No n?vel de computa??o, a infraestrutura para QoS consiste em um escalonador din?mico de tarefas de tempo real e um protocolo de migra??o de tarefas de baixo custo. Estas t?cnicas fornecem QoS de computa??o, devido ao gerenciamento da utiliza??o e aloca??o da CPU. A novidade do escalonador de tarefas ? o suporte a requisitos de tempo real din?micos, o que gera mais flexibilidade para as tarefas em explorar a CPU de acordo com uma carga de trabalho vari?vel. A novidade do protocolo de migra??o de tarefas ? o baixo custo no tempo de execu??o comparado a trabalhos do estado-da-arte. No n?vel de comunica??o, a t?cnica proposta ? um chaveamento por circuito (CS) baseado em redes definidas por software (SDN). O paradigma SDN para NoCs ? uma inova??o desta Tese, e ? alcan?ado atrav?s de uma arquitetura gen?rica de software e hardware. Para QoS de comunica??o, SDN ? usado para definir caminhos CS em tempo de execu??o. Essas infraestruturas de QoS s?o gerenciadas de uma forma integrada por um gerenciamento de QoS autoadaptativo, o qual segue o paradigma ODA (Observar, Decidir, Agir), implementando um la?o fechado de adapta??es em tempo de execu??o. O gerenciamento de QoS ? autoconsciente dos recursos do sistema e das aplica??es em execu??o, e pode decidir por adapta??es no n?vel de computa??o ou comunica??o, baseado em notifica??es das tarefas, monitoramento do ambiente, e monitoramento de atendimento de QoS. A autoadapta??o decide reativamente assim como proativamente. Uma t?cnica de aprendizagem do perfil das aplica??es ? proposta para tra?ar o comportamento das tarefas de tempo real, possibilitando a??es proativas. Resultados gerais mostram que o gerenciamento de QoS autoadaptativo proposto pode restaurar os n?veis de QoS para as aplica??es com um baixo custo no tempo de execu??o das aplica??es. Uma avalia??o abrangente, assumindo diversos benchmarks mostra que, mesmo sob diversas interfer?ncias de QoS nos n?veis de computa??o e comunica??o, o tempo de execu??o das aplica??es ? restaurado pr?ximo ao cen?rio ?timo, como 99,5% das viola??es de deadlines mitigadas. / Many-core systems-on-chip are the state-of-the-art in processing power, reaching from a dozen to thousands of processing elements (PE) in a single integrated circuit. General purpose many-cores assume a dynamic application admission, where the application set is unknown at design-time and applications may start their execution at any moment, inducing interference between them. Some applications may have real-time constraints to fulfill, requiring levels of quality of service (QoS) from the system. Due to the high degree of resource?s utilization unpredictability and the number of components to manage, self-adaptive properties become fundamental to support QoS at run-time. The literature provides several self-adaptive QoS proposals, targeting either communication (e.g., Network-on-Chip) or computation resources (e.g., CPU). However, to offer a complete QoS support, it is fundamental to provide a comprehensive self-awareness of the system?s resources, assuming adaptive techniques enabling to act simultaneously at the communication and computation levels to meet the applications' constraints. To cope with these requirements, this Thesis proposes a self-adaptive QoS infrastructure and management techniques, covering both the computation and communication levels. At the computation level, the QoS-driven infrastructure comprises a dynamic real-time task scheduler and a low overhead task migration protocol. These techniques ensure computation QoS by managing the CPU utilization and allocation. The novelty of the task scheduler is the support for dynamic real time constraints, which leverage more flexibility to tasks to explore the CPU according to a variable workload. The novelty of the task migration protocol is its low execution time overhead compared to the state-of-the-art. At the communication level, the proposed technique is a Circuit-Switching (CS) approach based on the Software Defined Networking (SDN) paradigm. The SDN paradigm for NoCs is an innovation of this Thesis and is achieved through a generic software and hardware architecture. For communication QoS, SDN is used to define CS paths at run-time. A self-adaptive QoS management following the ODA (Observe Decide Act) paradigm controls these QoS-driven infrastructures in an integrated way, implementing a closed loop for run time adaptations. The QoS management is self-aware of the system and running applications and can decide to take adaptations at computation or communication levels based on the task feedbacks, environment monitoring, and QoS fulfillment monitoring. The self-adaptation decides reactively as well as proactively. An online application profile learning technique is proposed to trace the behavior of the RT tasks and enabling the proactive actions. Results show that the proposed self-adaptive QoS management can restore the QoS level for the applications with a low overhead over the applications execution time. A broad evaluation, using known benchmarks, shows that even under severe QoS disturbances at computation and communication levels, the execution time of the application is restored near to the optimal scenario, mitigating 99.5% of deadline misses.

A computação reconfigurável está se fortalecendo cada vez mais devido ao grande avanço dos dispositivos reprogramáveis e ferramentas de projeto de hardware utilizadas atualmente. Isso possibilita que o desenvolvimento de hardware torne-se bem menos trabalhoso e complicado, facilitando assim a vida do desenvolvedor. A tecnologia utilizada atualmente em projetos de computação reconfigurável é denominada FPGA (Field Programmable Gate Array), que une algumas características tanto de software (flexibilidade), como de hardware (desempenho). Isso fornece um ambiente bastante propício para desenvolvimento de aplicações que precisam de um bom desempenho, sem que estas devam possuir uma configuração definitiva. O objetivo deste trabalho foi implementar um barramento eficiente para possibilitar a comunicação entre diferentes CORES de um robô reconfigurável, que podem estar dispersos em diferentes dispositivos FPGAs. Tal barramento seguirá o padrão AMBA (Advanced Microcontroller Bus Architecture), pertencente à ARM. Todo o desenvolvimento do core completo do AMBA foi realizado utilizando-se a linguagem VHDL (Very High Speed Integrated Circuit Hardware Description Language) e ferramentas EDAs (Electronic Design Automation) apropriadas. É importante notar que, embora o barramento tenha sido projetado para ser utilizado em um robô, o mesmo pode ser usado em qualquer sistema on-chip. / The reconfigurable computing is each time more fortified, what leads to a great advance of reprogrammable devices and hardware design tools. This has become hardware development less laborious and complicated, thus, facilitating the life of the designer. The technology currently used in projects of reconfigurable computing is called FPGA (Field Programmable Gate Array), which combines some characteristics of software (flexibility) and hardware (performance). This technology provides a propitious environment to the development of applications that need a good performance. Those that don’t need a definitive configuration. The purpose of this work was to implement an efficient bus to make possible the communication among different modules of a reconfigurable robot. This bus is based on a bus standard called AMBA (Advanced Microcontroller Bus Architecture), which belongs to ARM. All the development of full AMBA core was carried through using VHDL (Very High Speed Integrated Circuit the Hardware Description Language) language and appropriated EDA (Electronic Design Automation) tools. It is important to notice that, even so the bus have been projected to be used in a robot, it could be used in any system on-chip.

Li, Ming Hin. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 42-46). / Abstracts in English and Chinese. / Chapter 1 --- Introduction --- p.1 / Chapter 2 --- Inference for Fractional Cointegration --- p.5 / Chapter 2.1 --- Concept of Fractional Cointegration --- p.5 / Chapter 2.1.1 --- Fractional Integration --- p.5 / Chapter 2.1.2 --- Fractional Cointegration --- p.8 / Chapter 2.2 --- Fractional Cointegration Modeling --- p.9 / Chapter 2.2.1 --- Engle-Granger's Methodology --- p.9 / Chapter 2.2.2 --- Johansen's Methodology --- p.10 / Chapter 2.2.2.1 --- Maximum Likelihood Estimators --- p.12 / Chapter 2.2.2.2 --- Cofractional Rank Test --- p.16 / Chapter 3 --- Pairs Trading Strategy --- p.19 / Chapter 3.1 --- Statistical Arbitrage --- p.19 / Chapter 3.2 --- Fractional Cointegration Pairs Trading --- p.20 / Chapter 3.2.1 --- Trading Procedures --- p.22 / Chapter 4 --- Empirical Study --- p.27 / Chapter 4.1 --- Backgrounds --- p.27 / Chapter 4.2 --- Settings --- p.28 / Chapter 4.3 --- Empirical Results --- p.29 / Chapter 5 --- Conclusions and Further Research --- p.39 / Bibliography --- p.42

Made available in DSpace on 2014-06-12T17:40:28Z (GMT). No. of bitstreams: 2 arquivo7018_1.pdf: 3136549 bytes, checksum: 280ee1ed895aab2c310600bb6667d8ae (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2003 / Uma questão central no emergente campo da Biologia Molecular Computacional diz respeito ao problema de seqüenciamento de DNA. Seqüenciar uma molécula de DNA significa determinar a ordem das suas bases componentes adenina (A), citosina (C), guanina (G) e timina (T). Em vista do comprimento de tais moléculas, muitas vezes da ordem de bilhões de bases, e das limitações existentes nos processos laboratoriais, os quais são capazes de manipular, no máximo, apenas 700 bases, esse se tornou um problema de natureza combinatorial e normalmente requer técnicas matemáticas e recursos computacionais para a sua solução. Dentre os vários métodos de seqüenciamento de DNA desenvolvidos nas últimas décadas, um que se tem mostrado particularmente promissor é o método denominado Seqüenciamento por Hibridização (do inglês Sequencing by Hybridization SBH), o qual se caracteriza por utilizar um chip de DNA para identificar o espectro da seqüência investigada, isto é, o conjunto de todas as subseqüências de um determinado tamanho que a compõem; e por tentar seqüenciá-la a partir das informações nele contidas. Recentemente, Halperin et al. (2002) apresentou duas variantes para o SBH. A primeira é baseada em um algoritmo, denominado algoritmo A, projetado para lidar com os dados gerados pelo chip clássico de seqüenciamento; e a segunda, mais abrangente, inclui um novo modelo de chip que conta com bases universais distribuídas randomicamente, e, para lidar com os dados provenientes dele, inclui também um outro algoritmo, denominado algoritmo B. Halperin et al. (2002) ainda sugeriu que a combinação adequada de alguns aspectos positivos dessas abordagens talvez pudesse gerar resultados práticos melhores do que os obtidos com a solução baseada apenas no algoritmo B. Este trabalho de pesquisa aponta os problemas de se implementar tal sugestão e, então, propõe uma abordagem alternativa que tende a superá-los, a qual mostrou-se ser mais geral, tendo, inclusive, a solução baseada no algoritmo B como um caso particular. Além disso, as simulações realizadas evidenciaram que os demais casos conseguem alcançar melhor rendimento em termos do tamanho da seqüência que pode ser corretamente determinada, empregando chips de menor custo

Atualmente, o Brasil é considerado o maior exportador mundial e terceiro maior produtor mundial de carne de frango. Este destaque é resultado, principalmente, do melhoramento animal baseado na estimação do valor genético a partir da mensuração de fenótipos e informações de pedigree. Entretanto, é comum que a seleção não seja feita para cada característica isoladamente devido à correlação genética entre elas. Esta correlação tem como causas a pleiotropia ou a ligação genética. Com este trabalho objetivou-se detectar associações entre características fenotípicas de interesse para a avicultura e SNPs em uma região do cromossomo 1 (168 - 208 cM e 57 - 71 Mbp), onde possíveis QTL ligados foram previamente mapeados. Utilizou-se o Beadchip de SNPs de 60k para genotipar 14 animais da geração Parental (machos TT e fêmeas CC) e 28 F1 da população TCTC desenvolvida pela Embrapa Suínos e Aves. A linhagem TT apresentou maior variabilidade genotípica que CC, porém, os F1 foram superiores às linhagens Parentais com base no número de heterozigotos e MAF. O polimorfismo com maior ocorrência em ambas as gerações foram as transições com 84,3%. Foram selecionados 144 SNPs mais informativos com base na heterozigosidade dos cinco casais F1 que geraram os 453 F2. Houve redução de heterozigotos e MAF em F2, em função da média de F1, decorrente de certo grau de parentesco e endogamia entre os animais que compuseram esta geração. Os blocos de haplótipos construídos demonstraram que os machos TT apresentaram 25 blocos, fêmeas CC (17), F1 (32) e F2 (23) com tamanho médio de 278, 467, 242 e 160 kpb, respectivamente. Foi evidenciado que 236 (42,7%) correlações fenotípicas foram significativas, das quais o maior número constatado foi entre PB_MS e outras 17 características e, o maior valor estimado foi entre PB_MS e EE_MS (-0,90). Do total esperado de 3.456 testes de associação, 609 (17,6%) foram considerados significativos (p < 0,05), sendo 424 (69,6%) com efeito aditivo e 185 com efeito de dominância (30,4%). PV41 apresentou maior número de associações (123), enquanto DOR não foi associado a nenhum SNP. Proporcionalmente, o maior número de SNPs foi associado próximo ao QTL pleiotrópico 2 para 17 características. Já os maiores níveis de significância (p < 9,59 x 10-8) para o efeito aditivo foram evidenciados para SNPs localizados próximos ao QTL pleiotrópico 1 e associados somente com PV41, a saber: Gga_rs13869715 (A < C), Gga_rs13870613 (T < C), Gga_rs14827719 (A < G), GGaluGA019336 (T < C) e GGaluGA019533 (A < C). Foram detectadas associações ainda não descritas na literatura para GP3541, CA3541, INT, PES, CAB, FIG, COR, MOE, PUL, HEM, COL, TRI, TC, PB_MS, EE_MS, CZ_MS. Finalmente, foram indicados possíveis genes candidatos posicionais e funcionais, tais como, IGF1, MYBPC1, MTPN, SOX-5, FGFR1OP2 e TTLL12 que poderão ser empregados na análise de expressão gênica. / Actually, Brazil is considered the world\'s first- and third-biggest exporter and producer of poultry meat, respectively. These performances are mainly consequence of animal breeding based on the estimation of breeding value combining phenotypes and pedigree information. However, usually the selection is not carried out for each trait separately due to genetic correlation between them. This correlation is caused by pleiotropy or linkage. We aimed to detect associations between phenotypic traits of interest to poultry industry and SNPs on a region of chromosome 1 (168 - 208 cM and 57 - 71 Mbp), where putative linked-QTL were previously mapped. A chicken 60k SNP BeadChip was used to genotype 14 animals from Parental generation (TT males and CC females) and 28 F1 of the TCTC population that was developed by Embrapa Swine and Poultry. The TT line showed greater genotypic variability than CC, however, F1 were higher than Parental generation based on the number of heterozygotes and MAF. The polymorphism more frequent in both generations was the transitions with 84.3%. The 144 most informative SNPs were selected based on heterozygosity of the five F1 couples which generated the 453 F2. There was a reduction of heterozygotes and MAF in F2, based on the F1 mean value, as consequence of some degree of relationship and inbreeding between animals that formed this generation. Haplotype blocks demonstrated that the TT males showed 25 blocks, CC female (17) F1 (32) and F2 (23) with an average size of 278, 467, 242 and 160 kbp, respectively. It was observed that 236 (42.7%) phenotypic correlations were significant. Out of these, the highest number was found between PB_MS and other 17 traits and the highest estimated value was between PB_MS and EE_MS (-0.90). Out of 3,456 expected association tests, 609 (17.6 %) were considered significant (p < 0.05), being 424 (69.6%) with additive effect and 185 with dominance effect (30.4%). PV41 presented the highest number of associations (123), while DOR was not associated to any SNP. Proportionally, the highest number of SNPs was associated close to the pleiotropic QTL 2 with 17 traits. On the other hand, the highest significance levels (p < 9.59 x 10-8) for the additive effect were evidenced for SNPs located close to the pleiotropic QTL 1 and associated only with PV41 (Gga_rs13869715 (A < C), Gga_rs13870613 (T < C), Gga_rs14827719 (A < G), GGaluGA019336 (T < C) and GGaluGA019533 (A < C)). Novel associations were detected for GP3541, CA3541, INT, PES, CAB, FIG, COR, MOE, PUL, HEM, COL, TRI, TC, PB_MS, EE_MS, CZ_MS when we compared our results with literature. Finally, putative positional and functional candidate genes were indicated such as IGF1, MYBPC1, MTPN, SOX-5, FGFR1OP2 and TTLL12, which may be used in gene expression analysis.

abstract: In this research, a new cutting edge wear estimator for micro-endmilling is developed and the reliabillity of the estimator is evaluated. The main concept of this estimator is the minimum chip thickness effect. This estimator predicts the cutting edge radius by detecting the drop in the chip production rate as the cutting edge of a micro- endmill slips over the workpiece when the minimum chip thickness becomes larger than the uncut chip thickness, thus transitioning from the shearing to the ploughing dominant regime. The chip production rate is investigated through simulation and experiment. The simulation and the experiment show that the chip production rate decreases when the minimum chip thickness becomes larger than the uncut chip thickness. Also, the reliability of this estimator is evaluated. The probability of correct estimation of the cutting edge radius is more than 80%. This cutting edge wear estimator could be applied to an online tool wear estimation system. Then, a large number of cutting edge wear data could be obtained. From the data, a cutting edge wear model could be developed in terms of the machine control parameters so that the optimum control parameters could be applied to increase the tool life and the machining quality as well by minimizing the cutting edge wear rate. In addition, in order to find the stable condition of the machining, the stabillity lobe of the system is created by measuring the dynamic parameters. This process is needed prior to the cutting edge wear estimation since the chatter would affect the cutting edge wear and the chip production rate. In this research, a new experimental set-up for measuring the dynamic parameters is developed by using a high speed camera with microscope lens and a loadcell. The loadcell is used to measure the stiffness of the tool-holder assembly of the machine and the high speed camera is used to measure the natural frequency and the damping ratio. From the measured data, a stability lobe is created. Even though this new method needs further research, it could be more cost-effective than the conventional methods in the future. / Dissertation/Thesis / Doctoral Dissertation Mechanical Engineering 2019

Communication has become a bottleneck for modern microprocessors and multi-core chips because metal wires don't scale. The problem becomes worse as the number of components increases and chips become bigger. Traditional Systems-on-Chips (SoCs) interconnect architectures are based on shared-bus communication, which can carry only one communication transaction at a time. This limits the communication bandwidth and scalability. Networks-on-Chip (NoC) were proposed as a promising solution for designing large and complex SoCs. The NoC paradigm provides better scalability and reusability for future SoCs, however, long-distance multi-hop communication through traditional metal wires suffers from both high latency and power consumption. A radical solution to address this challenge is to add long-range, low power, and high-bandwidth single-hop links between distant cores. The use of optical or on-chip RF wireless links has been explored in this context. However, all previous work has focused on regular mesh-based metal wire fabrics that were expanded with one or two additional link types only for long-distance communication. In this thesis we address the following main research questions to address the above-mentioned challenges: (1) What library of different link types would represent an optimum in the design space? (2) How would these links be used to design an application-specific NoC architecture? (3) How would applications use the resulting NoC architecture efficiently? We hypothesize that networks with a higher degree of heterogeneity, i.e., three or more link types, will improve the network throughput and consume less energy compared to traditional NoC architectures. In order to verify our hypothesis and to address the research challenges, we design and analyze optimal heterogeneous networks under different realistic traffic models by considering different cost and performance trade-offs in a comprehensive technology-agnostic simulation framework that uses metaheuristic optimization techniques. As opposed to related work, our heterogeneous links can be placed anywhere in the network, which allows to explore the entire search space. The resulting application-specific networks are then analyzed by using complex network techniques, such as community detection and small-worldness, to understand how heterogeneous link types are used to improve the NoCs performance and cost. Next, we use the application-specific networks as a target architecture for other applications. The goal is to evaluate the performance of our new NoCs for applications they have not been designed for by finding optimal resource allocations. Our results show that there is an optimal number of heterogeneous link types for each set of constraints and that networks with three or more heterogeneous link types provide significantly higher throughput along with lower energy consumption compared to both homogeneous link type and regular 2D mesh networks under three different traffic scenarios. Our evolved networks with three different technology-driven link types, namely metal wires, wireless, and optical links, provide 15% more throughput and fourteen times less energy consumption compared to homogeneous link type network. When ten different abstract link types are used in the design, 12% more throughput and 52% less energy consumption are obtained compared to networks with three different technology-driven link types. This shows that heterogeneous NoC designs based on traditional metal wires, wireless, and optical links, occupy a non-optimal spot in the entire design space. Our results further show that heterogeneous NoCs scale up significantly better in terms of performance and cost compared to mesh networks. We uncovered that network communities evolve robustly and that heterogeneous link types are efficiently establishing inter- and intra-subnet connections depending on their link type properties. We also show that mapping an application on our application-specific NoC architecture provides on average 45% more throughput at 70% less energy consumption compared to regular 2D mesh networks. The NoCs are therefore not only good for the application they were designed for, but for a broad range of other applications as well.

Com o desenvolvimento do sequenciamento em larga escala, novas tecnologias surgiram para auxiliar o estudo de sequências de ácidos nucleicos (DNA e cDNA); como consequência, o desenvolvimento de novas ferramentas para analisar o grande volume de dados gerados fez-se necessário. Entre essas novas tecnologias, uma, em particular, chamada Imunoprecipitação de Cromatina seguida de sequenciamento de DNA em larga escala ou CHIP-Seq, tem recebido muita atenção nos últimos anos. Esta tecnologia tornou-se um método usado amplamente para mapear sítios de ligação de proteínas de interesse no genoma. A análise de dados resultantes de experimentos de ChIP-Seq é desaadora porque o mapeamento das sequências no genoma apresenta diferentes formas de viés. Os métodos existentes usados para encontrar picos em dados de ChIP-Seq apresentam limitações relacionadas ao número de amostras de controle e tratamento usadas, e em relação à forma como essas amostras são combinadas. Nessa tese, mostramos que métodos baseados em testes estatísticos de hipótese tendem a encontrar um número muito maior de picos à medida que aumentamos o tamanho da amostra, o que os torna pouco conáveis para análise de um grande volume de dados. O presente estudo descreve um método estatístico Bayesiano, que utiliza meta-análise para encontrar sítios de ligação de proteínas de interesse no genoma resultante de experimentos de ChIPSeq. Esse métodos foi chamado Meta-Analysis Bayesian Approach ou MABayApp. Nós mostramos que o nosso método é robusto e pode ser utilizado com diferentes números de amostras de controle e tratamentos, assim como quando comparando amostras provenientes de diferentes tratamentos. / With the development of high-throughput sequencing, new technologies emerged for the study of nucleic acid sequences (DNA and cDNA) and as a consequence, the necessity for tools to analyse a great volume of data was made necessary. Among these new technologies, one in special Chromatin Immunoprecipitation followed by massive parallel DNA Sequencing, or ChIP-Seq, has been evidenced during the last years. This technology has become a widely used method to map locations of binding sites for a given protein in the genome. The analysis of data resulting from ChIP-Seq experiments is challenging since it can have dierent sources of bias during the sequencing and mapping of reads to the genome. Current methods used to nd peaks in this ChIP-Seq have limitations regarding the number of treatment and control samples used and on how these samples should be used together. In this thesis we show that since most of these methods are based on traditional statistical hypothesis tests, by increasing the sample size the number of peaks considered signicant changes considerably. This study describes a Bayesian statistical method using meta-analysis to discover binding sites of a protein of interest based on peaks of reads found in ChIP-Seq data. We call it Meta- Analysis Bayesian Approach or MABayApp. We show that our method is robust and can be used for dierent number of control and treatment samples, as well as when comparing samples under dierent treatments.

La méiose est une étape de la différenciation germinale qui permet la formation des gamètes. Elle est composée de deux divisions successives. La ségrégation des chromosomes homologues à la première division nécessite des connexions entre homologues, mises en place par des événements de crossing-over (CO). Les CO augmentent également la diversité génétique, et leur fréquence et leur distribution sont étroitement régulées. Ils sont générés par un mécanisme de formation et réparation de cassures double brins de l'ADN (CDBs), catalysées par la protéine SPO11 et préférentiellement localisées dans des régions de 1-2 kb appelées points chauds de recombinaison méiotique. Une question majeure est de comprendre comment sont régulés ces CO, ce qui détermine leur fréquence et leur distribution, car toute altération de cette régulation peut conduire à des anomalies chromosomiques graves.Dans ce travail de thèse, pour la première fois chez les mammifères, nous avons montré que des modifications de la chromatine sont associées à l'initiation de la recombinaison méiotique (formation des CDBs par SPO11). Ces résultats ont été obtenus par des analyses d'immunoprécipitation de chromatine (ChIP) sur des spermatocytes purifiés ou non, isolés de différentes lignées de souris. Une des modifications associées à l'activité de deux points chauds testés est la triméthylation de la lysine 4 de l'histone H3 (H3K4Me3). Une analyse fonctionnelle et temporelle de cette modification a permis de montrer qu'elle ne dépend pas de SPO11 et apparaît avant la formation de CDBs. Nous avons montré ici que c'est la protéine PRDM9, récemment identifiée comme un déterminant majeur des points chauds de recombinaison chez les mammifères et possédant une activité méthyltransférase, qui appose H3K4Me3. Nous proposons un modèle où H3K4Me3 et d'autres caractéristiques inconnues constitueraient un substrat pour la machinerie d'initiation et recruteraient SPO11 en des points précis du génome, qui deviendront des points chauds. / Meiosis is a specialized cell division to produce haploid gametes from a diploid cell. It segregates parental genomes by two successive divisions. The faithful segregation of homologous chromosomes is achieved during the first unique division via formation of crossovers (COs). COs establish physical connections between homologs by the reciprocal exchange of genetic material and require the formation and subsequent repair of SPO11-dependent DNA double-strand breaks (DSBs). Studies in many organisms revealed that COs are distributed in highly localized regions (1-2Kb) of genomes called recombination hotspots. The mechanisms of COs regulation are elusive and a main question in the field is to understand how the frequency and distribution of CO are regulated, because either absence or defects of recombination can lead to aneuploidy or reduced fertility. In the present study, for the very first time in mammals, we investigate whether recombination hotspots are associated with any chromatin modifications. We performed chromatin immunoprecipitation (ChIP) on spermatocytes isolated from different mice strains harbouring either active or inactive hotspots. Comparison of hot and cold spots revealed that a specific histone modification i.e. trimethylation of the lysine 4 of histone H3 (H3K4Me3) is enriched at two tested hotspots in mice. Temporal and functional analysis show that H3K4Me3 is not dependent on SPO11 and appears before DSBs formation. Furthermore, we demonstrate here that H3K4Me3 is methylated via the histone methyltransferase activity of PRDM9, recently identified as a major determinant of recombination hotspots in mammals. We propose a model that H3K4Me3 and other unknown chromatin features may specify recruitment of SPO11 initiation machinery to initiate meiotic recombination at the hotspots.