De nos jours, des efforts majeurs pour la conception de systèmes sur puces performants et efficaces énergétiquement sont en cours. Le déclin de la loi de Moore au début du XX e siècle a poussé les concepteurs à augmenter le nombre de cœurs par processeur pour continuer d’améliorer les performances. En conséquence, la surface de silicium occupée par les mémoires caches a augmentée. La finesse de gravure toujours plus petite a également fait augmenter le courant de fuite des transistors CMOS. Ainsi, la consommation énergétique des mémoires occupe une part de plus en plus importante dans la consommation globale des puces. Pour diminuer cette consommation, de nouvelles technologies de mémoires émergent depuis une dizaine d’années : les mémoires non volatiles (NVM). Ces mémoires ont la particularité d’avoir un courant de fuite très faible comparé aux technologies CMOS classiques. De fait, leur utilisation dans une architecture permettrait de diminuer la consommation globale de la hiérarchie de caches. Cependant, ces technologies souffrent de latences d’accès plus élevées que la SRAM, de coûts énergétiques d’accès plus importants et d’une durée de vie limitée. Leur intégration à des systèmes sur puces nécessite de continuer à rechercher des solutions. Cette thèse cherche à évaluer l’impact d’un changement de technologie dans la hiérarchie de caches.Plus spécifiquement, elle s’intéresse au cache de dernier niveau (LLC) et la technologie non volatile considérée est la STT-MRAM. Nos travaux adoptent un point de vue architectural dans lequel une modification de la technologie n’est pas retenue. Nous cherchons alors à intégrer les caractéristiques différentes de la STT-MRAM lors de la conception de la hiérarchie mémoire. Une première étude a permis de mettre en place un cadre d’exploration architectural pour des systèmes contenant des mémoires émergentes. Une seconde étude sur les optimisations architecturales au niveau du LLC a été menée pour identifier quelles sont les opportunités d’intégration de la STT-MRAM. Le but est d’améliorer l’efficacité énergétique tout en atténuant les pénalités d’accès dues aux fortes latences de cette technologie. / Today, intensive efforts to design energy-efficient and high-performance systems-on-chip (SoCs) are underway. Moore’s end in the early 20 th century pushed designers to increase the number of core per processor to continue to improve the performance. As a result, the silicon area occupied by cache memories has increased. The ever smaller technology node also increased the leakage current of CMOS transistors. Thus, the energy consumption of memories represents an increasingly important part in the overall consumption of chips.To reduce this energy consumption, new memory technologies have emerged overthe past decade : non-volatile memories (NVM). These memories have the particularity of having a very low leakage current compared to conventional CMOS technologies. In fact, their use in an architecture would reduce the overall consumption of the cache hierarchy. However, these technologies sufferfrom higher access latencies than SRAM, higher access energy costs and limitedlifetime. Their integration into SoCs requires a continuous research effort.This thesis work aims to evaluate the impact of a change in technology in the cache hierarchy. More specifically, we are interested in the Last-Level Cache(LLC) and we consider the STT-MRAM technology. Our work adopts an architectural point of view in which a modification of the technology is not retained. Then,we try to integrate the different characteristics of the STT-MRAM atarchitectural level when designing the memory hierarchy. A first study set upan architectural exploration framework for systems containing emerging memories. A second study on architectural optimizations at LLC was conducted toidentify opportunities for the integration of STT-MRAM. The goal is to improve energy efficiency while reducing access penalties due to the high latency ofthis technology.

The NTPDase1 enzymatic activity (E.C.3.6.1.5, Apyrase, ecto-ATP-diphosphohydrolase, CD39) which hydrolyses ATP and ADP, was analyzed in peripheral lymphocytes from patients with B chronic lymphocytic leukemia (B-CLL) which the main characteristic is the accumulation of monoclonal mature B-lymphocyte. The sample was composed by 23 patients with B-CLL whose were diagnosed according to the clinical and laboratorial criteria and also by the immunophenotypic characteristics. The patients were divided, according to the Binet staging system, in 4 groups: stage A (early), stage B (intermediate), stage C (advanced) and control group. The results demonstrated a significant increase in ATP hydrolysis (F(29,3)=26.79 p<0.001) for all the stages of the disease and related to the control as a function of length of disease advance with higher activity in stage C. ADP hydrolysis (F(29,3)=23.76 p<0.001) was also enhanced according to ATP results. Besides this it was found a great correlation between the activity of NTPDase-1 and the total absolute white cells count in peripheral blood. The alteration in NTPDase-1activity in lymphocytes from patients with B-CLL at the different stages, contributes to confirm the ectonucleotidases role in regulate the ATP and ADP levels, which actuates like signalling molecules in many blood cells like the lymphocytes. Therefore more studies need to be done so that we can elucidate such enzymatic system in the nucleotides and its role in the B-CLL. / A atividade da enzima NTPDase1 (E.C.3.6.1.5, Apyrase, ecto-ATP-difosfoidrolase,CD39) que hidrolisa ATP e ADP, foi analisada em linfócitos periféricos de pacientes com leucemia linfocítica crônica (LLC-B), doença que possui como característica principal o acúmulo de linfócitos B maduros. A amostra foi composta por 23 pacientes com LLC-B, diagnosticados de acordo com critérios clínicos, laboratoriais e resultados de imunofenotipagem. Os pacientes foram divididos, conforme o sistema de classificação de Binet, em 4 grupos: estágio A (inicial), estágio B (intermediário), estágio C (avançado) e um grupo controle. Os resultados demonstraram que a hidrólise do ATP foi significativamente aumentada (F(29,3)=26.79 p<0.001) em todos os estágios da doença e em relação ao controle e esse aumento é compatível com o avanço da doença mostrando a maior hidrólise no estágio C. A hidrólise do ADP acompanhou os resultados do ATP e também estava aumentada (F(29,3)= 23.76 p<0.001). Além disso, verificou-se uma forte correlação entre a atividade da enzima NTPDase1 e a contagem absoluta de glóbulos brancos do sangue periférico. A alteração na atividade da enzima NTPDase1 em linfócitos de pacientes com LLC-B em seus diferentes estágios, vem confirmar o importante papel das ecto-nucleotidases na regulação dos níveis de ATP e ADP, os quais atuam como moléculas sinalizadores em várias células sangüíneas como os linfócitos. Entretanto, mais estudos são necessários para melhor elucidar as funções desse sistema enzimático no controle de nucleotídeos e o seu papel na LLC-B.

Contexte: La leucémie lymphoïde chronique (LLC) est une hémopathie maligne associée à des anomalies dans les réponses immunitaires. Ce qui contribue à la progression de la maladie. Certains LB peuvent induire une inhibition de la réponse anti-tumorale des LT et ainsi promouvoir la progression des tumeurs. Ces LB appelés LB régulateurs partagent des caractéristiques communes avec les LB de LLC.Objectif: L'objectif principal de ce projet est d'évaluer la fonction régulatrice des LB de LLC, afin d’estimer leur influence sur l'absence de réponses anti-tumorales par les cellules T.Méthode: Des modèles de co-culture in vitro ont été développés pour évaluer la capacité desLB à inhiber la prolifération des LT.Résultats: Nos résultats montrent qu’en absence de stimulation, les LB de LLC sont incapables d’inhiber la prolifération des LT contrairement aux LB de témoins. Cependant, deux groupes de patients ont été identifiés après stimulation du TLR-9 des LB. Dans le premier groupe, les LB présentent des fonctions régulatrices défectueuses par rapport aux LB de témoins. Dans le second groupe, aucune activité inhibitrice n’est détectée. L’expression différentielle des gènes associés à la voie TLR-9 entre les deux groupes de patients semble pouvoir expliquer cette dichotomie de réponse. Une corrélation a par ailleurs été retrouvée entre le doublement lymphocytaire et la faible activité régulatrice des LB de LLC.Conclusion: Pour aller plus loin, il convient d'identifier les mécanismes moléculaires endommageant la voie TLR-9. Ces nouvelles données aideront à la compréhension de l’absence de réponse anti-tumorale et des dysfonctionnements immunitaires retrouvés chez les patients. / Background: Chronic lymphocytic leukemia (CLL) is characterized by expansion of CD5+B cells associated with disruption of immune responses, contributing to the immunodeficiency and the disease progression. Regulatory B (Breg) cells may control the anti-tumor responses favoring tumor escape. Intriguingly, CLL B cells share phenotypical characteristics with these cells.Aims: The main focus of this project is to evaluate the regulatory function of CLL B cells, aiming to estimate their influence on the lack of anti-tumor responses mediated by T cells.Methods: In vitro models of co-cultures between T and B cells are used to appraise the regulatory capacity of CLL B cells on T cell proliferation.Results: We determined a defective spontaneous regulatory function for CLL B cells. Two groups of patients have been identified following CpG-ODN stimulation. The first group presents defective regulatory B cell functions compared with control B cells. In the second group, no inhibitory activity is detected. TLR-9 gene expression analysis highlighted differential gene expression between controls and the two groups of CLL patients. Moreover, ours observations indicate that patients with low Breg activity have more aggressive disease.Conclusion: These results suggest alteration of the TLR-9 pathway in CLL B cells. To go further, it will be of interest to identify the molecular mechanisms damaging the TLR-9 pathway. These results would contribute to clarify the lack of anti-tumor immune response found in the CLL patients.

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With each technology generation we get more transistors per chip. Whilst processor frequencies have increased over the past few decades, memory speeds have not kept pace. Therefore, more and more transistors are devoted to on-chip caches to reduce latency to data and help achieve high performance. On-chip caches consume a significant fraction of the processor energy budget but need to deliver high performance. Therefore cache resources should be optimized to meet the requirements of the running applications. Fixed configuration caches are designed to deliver low average memory access times across a wide range of potential applications. However, this can lead to excessive energy consumption for applications that do not require the full capacity or associativity of the cache at all times. Furthermore, in systems where the clock period is constrained by the access times of level-1 caches, the clock frequency for all applications is effectively limited by the cache requirements of the most demanding phase within the most demanding application. This motivates the need for dynamic adaptation of cache configurations in order to optimize performance while minimizing energy consumption, on a per-application basis. First, this thesis proposes an energy-efficient cache architecture for a single core system, along with a run-time support framework for dynamic adaptation of cache size and associativity through the use of machine learning. The machine learning model, which is trained offline, profiles the application’s cache usage and then reconfigures the cache according to the program’s requirement. The proposed cache architecture has, on average, 18% better energy-delay product than the prior state-of-the-art cache architectures proposed in the literature. Next, this thesis proposes cooperative partitioning, an energy-efficient cache partitioning scheme for multi-core systems that share the Last Level Cache (LLC), with a core to LLC cache way ratio of 1:4. The proposed cache partitioning scheme uses small auxiliary tags to capture each core’s cache requirements, and partitions the LLC according to the individual cores cache requirement. The proposed partitioning uses a way-aligned scheme that helps in the reduction of both dynamic and static energy. This scheme, on an average offers 70% and 30% reduction in dynamic and static energy respectively, while maintaining high performance on par with state-of-the-art cache partitioning schemes. Finally, when Last Level Cache (LLC) ways are equal to or less than the number of cores present in many-core systems, cooperative partitioning cannot be used for partitioning the LLC. This thesis proposes a region aware cache partitioning scheme as an energy-efficient approach for many core systems that share the LLC, with a core to LLC way ratio of 1:2 and 1:1. The proposed partitioning, on an average offers 68% and 33% reduction in dynamic and static energy respectively, while again maintaining high performance on par with state-of-the-art LLC cache management techniques.

Syftet med min uppsats är att undersöka om det finns ett behov för en ny bolagsform, som är enkel att bilda och administrera för fysiska eller juridiska personer som önskar bedriva näringsverksamhet i liten skala. Om en ny bolagsform skulle införas i svensk associationsrätt, ämnar jag undersöka om det kan bidra till att de mindre näringsverksamheternas administrativa börda minskar. Frågan om en ny bolagsform avslogs senast i utredningen om förenklingar i aktiebolagslagen med hänvisning till att förenklingar i ABL var att föredra framför införandet av en ny bolagsform. Regeringen har under de senaste åren uppsatt målsättningar som syftar till att sänka den administrativa bördan. Bland de åtgärder som genomförts har revisionskravet för mindre näringsverksamheter avskaffats, kapitalkravet för privata aktiebolag har sänkts och ytterligare förenklingsåtgärder avseende ABL planeras. Frågan kvarstår dock ifall en ny bolagsform, likt det tyska GmbH:et eller det amerikanska LLC:et, vore en bättre lösning för de mindre näringsverksamheterna i Sverige. GmbH:et och LLC:et är mycket populära bolagsformer för mindre näringsverksamheter på grund av det begränsade personliga ansvaret och den flexibilitet avtalsfriheten medför.   Jag anser att ABL är alltför omfattande för mindre näringsverksamheter och att adressaten inte är riktigt tydlig. En ny bolagsform med en egen lag, vid sidan av ABL behöver utarbetas. Bolagsformen bör rikta sig till verksamheter med en eller ett fåtal delägare och karakteriseras av ett begränsat ansvar. Dessutom skall bolagsformen ha ett ringare kapitalkrav med större avtalsfrihet för delägarna. Här kan erfarenheter från det tyska GmbH:et och det amerikanska LLC:et implementeras, särskilt gällande bolagets form men även hur missbruk av bolagsformen kan förhindras och motarbetas. De förenklingsåtgärder som riktar sig till mindre näringsverksamheter borde även gälla för den nya bolagsformen och direkt implementeras i den nya lagstiftningen, vilket skulle leda till att den administrativa bördan minskas.

In chip-multiprocessor (CMP) designs, when the number of core increases, the size of on-chip communication fabric and data storage grows accordingly and therefore the chip power challenge is exacerbated. This thesis work considers the power management for networks-on-chip (NoC) and the last level cache, which constitute the uncore in CMP designs. NoC is regarded as a scalable approach to cope with the increasing demand for on-chip communication bandwidth. The last level cache is shared among all cores. The focus of this work is on the control techniques for uncore dynamic voltage and frequency scaling. A realistic but not well-studied scenario is investigated. That is, the entire uncore shares a single voltage/frequency domain, as opposed to separated domains in most of previous works. One appealing advantage here is that data packets no longer experience the interfacing overhead across different voltage/frequency domains. The classic PI (Proportional and Integral) control method is adopted due to its simplicity, flexibility and low implementation overhead. This thesis research outcome includes three parts. First, stability of the PI control is analyzed. Second, a model-assisted PI control scheme is proposed and studied. The model assist is to address the problem that no universally good reference point exists for the control. Third, the windup issue for the PI control is investigated. Full architecture simulations are performed on public benchmark suites to validate the proposed techniques. The result show 76% energy reduction with less than 6% performance degradation compared to constantly high voltage/frequency for uncore.

Thesis (M.S.)--Kutztown University of Pennsylvania, 2006. / Source: Masters Abstracts International, Volume: 45-06, page: 2805. Typescript. Abstract precedes thesis as 2 leaves (iii-iv). Includes bibliographical references (leaves 58-59).

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Programa de Pós-Graduação em Ciências da Saúde, 2015. / Submitted by Fernanda Percia França (fernandafranca@bce.unb.br) on 2015-11-25T14:47:40Z No. of bitstreams: 1 2015_FlaviaZattarPiazera.pdf: 5140389 bytes, checksum: 90224636e1ced48a74926f8c49f65060 (MD5) / Approved for entry into archive by Patrícia Nunes da Silva(patricia@bce.unb.br) on 2016-05-27T14:32:09Z (GMT) No. of bitstreams: 1 2015_FlaviaZattarPiazera.pdf: 5140389 bytes, checksum: 90224636e1ced48a74926f8c49f65060 (MD5) / Made available in DSpace on 2016-05-27T14:32:09Z (GMT). No. of bitstreams: 1 2015_FlaviaZattarPiazera.pdf: 5140389 bytes, checksum: 90224636e1ced48a74926f8c49f65060 (MD5) / A Leucemia Linfocítica Crônica (LLC) é a neoplasia linfoide crônica mais comum na população ocidental. Assim, várias pesquisas têm sido desenvolvidas para elucidação dos fatores genéticos envolvidos na biologia e progressão da LLC. Alterações epigenéticas têm se mostrado cada vez mais relevantes na gênese de vários tumores e em especial nas neoplasias linfóides agudas e crônicas, e tem como características básicas não causar modificações na sequência do DNA. A metilação de histonas é um dos principais e mais estudados eventos epigenéticos. A família SETD é composta por 10 genes que codificam proteínas com domínio SET. Este domínio está envolvido na metilação de resíduos de lisina em histonas e proteínas não histonas. Até o momento, desconhece-se a relação de genes da família SETD com a leucemogênese da LLC. No presente estudo, foi realizada a avaliação de expressão relativa dos genes da família SETD em 59 amostras de sangue periférico de pacientes portadores de LLC e 10 controles normais através da técnica de PCR em tempo real. O perfil de expressão comparativa dessa família de genes foi correlacionado com as informações clínicas, citogenéticas, imunofenotípicas e hematológicas de maior relevância prognóstica dos pacientes. Notamos que a hipoexpressão do geneSETD1Aapresenta-se correlacionado com instabilidade cromossômica. O gene SETD2 apresentou elevada contagem de leucócitos no grupo de alta expressão, inferindo elevada massa tumoral. A superexpressão do gene SETD5 define um marcador de progressão da doença devido a elevada contagem de leucócitos nos pacientes do grupo de baixa expressão associado a anormalidades citogenéticas. O gene SETD6 apresentou hipoexpressão nos portadores de LLC em relação aos controles. O gene SETMAR apresentou-se hiperexpresso nos portadores de LLC em relação aos controles. Entretanto, no grupo de pacientes com baixa expressão a contagem leucocitária mostrou-se elevada estando associado a predominância de anormalidades citogenéticas e baixa contagem plaquetária. Sugerimos que nos portadores de LLC, a hipoexpressão do gene SETMAR esteja associada com instabilidade cromossômica e progressão da massa tumoral (aumento da leucocitose). Concluímos que os genes da família SETD possam futuramente ser considerados marcadores evolutivos da LLC. / The Chronic lymphocytic leukemia (CLL) is the most common chronic lymphoid malignancy in the western population. Thus, several studies have been developed to elucidate the genetic factors involved in biology and progression of CLL. Epigenetic changes have been shown to be increasingly important in the genesis of various tumors and especially in acute and chronic lymphoid malignancies, and its basic features do not cause changes in the DNA sequence. The histone methylation is one of the leading and most studied epigenetic events. The SETD family consists of 10 genes encoding proteins with SET domain. This domain is involved in methylation of lysine residues on histones and non-histone proteins. So far, unknown whether the genes ratio SETD family with the leukemogenesis LLC. In the present study, we evaluatedthe expression of all SETD family genes in peripheral blood from 59 CLL patients and 10 healthy donors by real time PCR. The expression profile of this gene family was correlated with the most relevant clinical, cytogenetic, immunophenotypic and hematologic prognostic factors of CLL patients. We note that hipoexpressionofSETD1A gene correlated with chromosomal instability.SETD2 gene expression was associated with a high white blood cell count in a dicotomized group of patients with high expression this gene, implying high tumor mass formation when SETD2 is over-expressed. In addition, overexpression of the gene SETD5 sets a marker of disease progression due to higher leukocyte count in patients in the low expression group associated with cytogenetic abnormalities. In the other hand, gene SETD6 was significantely downregulated in patients with CLL compared to controls. Finally, SETMAR gene was found to be upregulated in patients with CLL compared to controls. However, in patients with low expression of SETMAR, we found an increase in leukocyte count as well as in the predominance of cytogenetic abnormalities and low platelet count. We suggest that in patients with CLL, the low expression of SETMAR is associated with chromosomal instability and progression of the tumor mass (increased leukocytosis). We conclude that SETD family genes can be considered future evolutionary markers for CLL.