Les technologies actuelles permettent l'intégration sur une même puce de systèmes complexes (SoCs) qui sont composés de blocs préconçus (IPs) pouvant être interconnectés grâce à un réseau sur la puce (NoCs). De manière générale, les IPs sont validés par diverses techniques (simulation, test, vérification formelle) et le problème majeur reste la validation des infrastructures des communications. Cette thèse se concentre sur la vérification formelle des réseaux sur puce à l'aide d'un outil de preuve automatique, le démonstrateur de théorèmes ACL2. Un méta-modèle pour les réseaux sur puce a été développé et implémenté dans ACL2. Il satisfait des propriétés de correction générique, conséquences logiques d'un ensemble d'obligations de preuve sur les constituants principaux du réseau (topologie, routage, technique de commutation,...). La preuve de correction pour une instance spécifique de réseau sur puce est alors réduite à la vérification de ces obligations de preuve. Cette thèse poursuit les travaux entrepris dans ce domaine en étendant ce méta-modèle dans plusieurs directions : prise en compte plus fine de la modélisation temporelle, du contrôle de flux, des mécanismes de priorités,... Les résultats sont démontrés sur plusieurs réseaux actuels : Hermes (Université fédérale du Rio Grande do Sul, Brésil et LIRMM) et Nostrum (Royal Institute Of Technology, Suéde).

Type 1 diabetes (T1D) is a chronic autoimmune disease targeted against the pancreatic β-cells. Proinflammatory cytokines are considered to play a major role in the destruction of the insulin-producing β-cells. This thesis studied strategies to counteract proinflammatory cytokines in experimental T1D. Both animal models for T1D as well as β-cell preparations exposed in vitro to putative noxious conditions were examined. In the first study we observed that cytokine treatment of mouse pancreatic islets lacking inducible nitric oxide synthase (iNOS) induced a prolongation of the early stimulatory phase of glucose stimulated insulin secretion. Various experiments led to the conclusion that this prolonged stimulatory effect may involve the DAG/PLD/PKC pathway. Next, we transplanted mouse islets deficient in iNOS to spontaneously diabetic NOD mice. We observed a normalization of hyperglycemia but not a delayed allograft rejection compared to transplanted wild type islets. Thus, absence of iNOS in the graft was not sufficient to prolong allograft survival. In paper III we found that sustained glucose stimulation of rat pancreatic islets was coupled to a decreased conversion of proinsulin to insulin. Islet treatment with IL-1β was also coupled to a decreased proinsulin conversion. Islet proconvertase activity may be a target in islet damage. In paper IV prolactin (PRL) was administered to mice in the multiple low dose streptozotocin model and we observed that PRL enhanced a Th2 response. This may contribute to the protective action by PRL in this model of autoimmune T1D. Finally, by examining β-cells overexpressing Suppressor of cytokine signalling 3 (SOCS-3) it was found that this could inhibit IL-1β induced signalling through the NF-κB and MAPK pathways. SOCS-3 overexpression also inhibited apoptosis induced by cytokines in primary β-cells. Lastly, we demonstrated that SOCS-3 transgenic islets were protected in an allogeneic transplantation model.

Este trabalho consiste no estudo e análise da suscetibilidade a efeitos da radiação em projetos de circuitos gerados por ferramenta de Síntese de Alto Nível para FPGAs (Field Programmable Gate Array), ou seja, circuitos programáveis e sistemas em chip, do inglês System-on-Chip (SOC). Através de um injetor de falhas por emulação usando o ICAP (Internal Configuration Access Port) localizado dentro do FPGA é possível injetar falhas simples ou acumuladas do tipo SEU (Single Event Upset), definidas como perturbações que podem afetar o funcionamento correto do dispositivo através da inversão de um bit por uma partícula carregada. SEU está dentro da classificação de SEEs (Single Event Effects), efeitos transitórios em tradução livre, podem ocorrer devido a penetração de partículas de alta energia do espaço e do sol (raios cósmicos e solares) na atmosfera da Terra que colidem com átomos de nitrogênio e oxigênio resultando na produção de partículas carregadas, na grande maioria nêutrons. Dentro deste contexto além de analisar a suscetibilidade de projetos gerados por ferramenta de Síntese de Alto Nível, torna-se relevante o estudo de técnicas de redundância como TMR (Triple Modular Redundance) para detecção, correção de erros e comparação com projetos desprotegidos verificando a confiabilidade. Os resultados mostram que no modo de injeção de falhas simples os projetos com redundância TMR demonstram ser efetivos. Na injeção de falhas acumuladas o projeto com múltiplos canais apresentou melhor confiabilidade do que o projeto desprotegido e com redundância de canal simples, tolerando um maior número de falhas antes de ter seu funcionamento comprometido. / This work consists of the study and analysis of the susceptibility to effects of radiation in circuits projects generated by High Level Synthesis tool for FPGAs Field Programmable Gate Array (FPGAs), that is, system-on-chip (SOC). Through an emulation fault injector using ICAP (Internal Configuration Access Port), located inside the FPGA, it is possible to inject single or accumulated failures of the type SEU (Single Event Upset), defined as disturbances that can affect the correct functioning of the device through the inversion of a bit by a charged particle. SEU is within the classification of SEEs (Single Event Effects), can occur due to the penetration of high energy particles from space and from the sun (cosmic and solar rays) in the Earth's atmosphere that collide with atoms of nitrogen and oxygen resulting in the production of charged particles, most of them neutrons. In this context, in addition to analyzing the susceptibility of projects generated by a High Level Synthesis tool, it becomes relevant to study redundancy techniques such as TMR (Triple Modular Redundancy) for detection, correction of errors and comparison with unprotected projects verifying the reliability. The results show that in the simple fault injection mode TMR redundant projects prove to be effective. In the case of accumulated fault injection, the multichannel design presented better reliability than the unprotected design and with single channel redundancy, tolerating a greater number of failures before its operation was compromised.

Este trabalho consiste no estudo e análise da suscetibilidade a efeitos da radiação em projetos de circuitos gerados por ferramenta de Síntese de Alto Nível para FPGAs (Field Programmable Gate Array), ou seja, circuitos programáveis e sistemas em chip, do inglês System-on-Chip (SOC). Através de um injetor de falhas por emulação usando o ICAP (Internal Configuration Access Port) localizado dentro do FPGA é possível injetar falhas simples ou acumuladas do tipo SEU (Single Event Upset), definidas como perturbações que podem afetar o funcionamento correto do dispositivo através da inversão de um bit por uma partícula carregada. SEU está dentro da classificação de SEEs (Single Event Effects), efeitos transitórios em tradução livre, podem ocorrer devido a penetração de partículas de alta energia do espaço e do sol (raios cósmicos e solares) na atmosfera da Terra que colidem com átomos de nitrogênio e oxigênio resultando na produção de partículas carregadas, na grande maioria nêutrons. Dentro deste contexto além de analisar a suscetibilidade de projetos gerados por ferramenta de Síntese de Alto Nível, torna-se relevante o estudo de técnicas de redundância como TMR (Triple Modular Redundance) para detecção, correção de erros e comparação com projetos desprotegidos verificando a confiabilidade. Os resultados mostram que no modo de injeção de falhas simples os projetos com redundância TMR demonstram ser efetivos. Na injeção de falhas acumuladas o projeto com múltiplos canais apresentou melhor confiabilidade do que o projeto desprotegido e com redundância de canal simples, tolerando um maior número de falhas antes de ter seu funcionamento comprometido. / This work consists of the study and analysis of the susceptibility to effects of radiation in circuits projects generated by High Level Synthesis tool for FPGAs Field Programmable Gate Array (FPGAs), that is, system-on-chip (SOC). Through an emulation fault injector using ICAP (Internal Configuration Access Port), located inside the FPGA, it is possible to inject single or accumulated failures of the type SEU (Single Event Upset), defined as disturbances that can affect the correct functioning of the device through the inversion of a bit by a charged particle. SEU is within the classification of SEEs (Single Event Effects), can occur due to the penetration of high energy particles from space and from the sun (cosmic and solar rays) in the Earth's atmosphere that collide with atoms of nitrogen and oxygen resulting in the production of charged particles, most of them neutrons. In this context, in addition to analyzing the susceptibility of projects generated by a High Level Synthesis tool, it becomes relevant to study redundancy techniques such as TMR (Triple Modular Redundancy) for detection, correction of errors and comparison with unprotected projects verifying the reliability. The results show that in the simple fault injection mode TMR redundant projects prove to be effective. In the case of accumulated fault injection, the multichannel design presented better reliability than the unprotected design and with single channel redundancy, tolerating a greater number of failures before its operation was compromised.

Chronic hepatitis C virus (HCV) infection is associated with cirrhosis, autoimmunity and lymphoproliferative disorders. We have previously reported a differential regulation of T and B lymphocytes by HCV core protein in vitro. In this report, we employed a translational approach to characterize the activation status of peripheral B cells from individuals with chronic HCV infection and to explore potential mechanisms for B-cell dysregulation in the setting of HCV infection. In contrast to the T-cell suppression observed in HCV-infected individuals, B cells exhibit a non-specific polyclonal activation phenotype, characterized by significantly higher levels of (1) the early activation marker, CD69, (2) the costimulatory molecule, CD86, and (3) the CCR5 chemokine receptor, CD195, when compared with B cells from healthy donors in response to phytohaemagglutinin (PHA) stimulation. Importantly, tumour necrosis factor- and Apo-L-related leucocyte-expressed ligand-1 (TALL-1), also known as B-lymphocyte stimulator (BLYS), was found to be up-regulated on the surface of B cells from HCV patients in response to PHA as well as HCV core antigen stimulation. This up-regulation of TALL-1 was associated with vigorous memory B-cell responses to viral antigenic stimulation. Additionally, suppressor of cytokine signalling-1 (SOCS-1), a negative feedback immunoregulator that is inhibited in B lymphocytes by HCV core in vitro, was also inhibited in B cells from HCV patients when compared with healthy donors. These findings suggest that TALL-1 over-expression and SOCS-1 suppression are associated with aberrant B-cell activation, providing a plausible basis for the B-cell clonal expansion underlying the lymphoproliferative disorders and autoimmune phenomena observed during chronic HCV infection.

No description available.

Les systèmes d'information biomédicaux actuels reposent sur l'exploitation de données provenant de sources multiples. Les Systèmes d'Organisation de la Connaissance (SOC) permettent d'expliciter la sémantique de ces données, ce qui facilite leur gestion et leur exploitation. Bénéficiant de l'évolution des technologies du Web sémantique, un nombre toujours croissant de SOCs a été élaboré et publié dans des domaines spécifiques tels que la génomique, la biologie, l'anatomie, les pathologies, etc. Leur utilisation combinée, nécessaire pour couvrir tout le domaine biomédical, repose sur la définition de mises en correspondance entre leurs éléments ou mappings. Les mappings connectent les entités des SOCs liées au même domaine via des relations sémantiques. Ils jouent un rôle majeur pour l'interopérabilité entre systèmes, en permettant aux applications d'interpréter les données annotées avec différents SOCs. Cependant, les SOCs évoluent et de nouvelles versions sont régulièrement publiées de façon à correspondre à des vues du domaine les plus à jour possible. La validité des mappings ayant été préalablement établis peut alors être remis en cause. Des méthodes sont nécessaires pour assurer leur cohérence sémantique au fil du temps. La maintenance manuelle des mappings est une possibilité lorsque le nombre de mappings est restreint. En présence de SOCs volumineux et évoluant très rapidement, des méthodes les plus automatiques possibles sont indispensables. Cette thèse de doctorat propose une approche originale pour adapter les mappings basés sur les changements détectés dans l'évolution de SOCs du domaine biomédical. Notre proposition consiste à comprendre précisément les mappings entre SOCs, à exploiter les types de changements intervenant lorsque les SOCs évoluent, puis à proposer des actions de modification des mappings appropriées. Nos contributions sont multiples : (i) nous avons réalisé un travail expérimental approfondi pour comprendre l'évolution des mappings entre SOCs; nous proposons des méthodes automatiques (ii) pour analyser les mappings affectés par l'évolution de SOCs, et (iii) pour reconnaître l'évolution des concepts impliqués dans les mappings via des patrons de changement; enfin (iv) nous proposons des techniques d'adaptation des mappings à base d'heuristiques. Nous proposons un cadre complet pour l'adaptation des mappings, appelé DyKOSMap, et un prototype logiciel. Nous avons évalué les méthodes proposées et le cadre formel avec des jeux de données réelles contenant plusieurs versions de mappings entre SOCs du domaine biomédical. Les résultats des expérimentations ont démontré l'efficacité des principes sous-jacents à l'approche proposée. La maintenance des mappings, en grande partie automatique, est de bonne qualité. / Modern biomedical information systems require exchanging and retrieving data between them, due to the overwhelming available data generated in this domain. Knowledge Organization Systems (KOSs) offer means to make the semantics of data explicit which, in turn, facilitates their exploitation and management. The evolution of semantic technologies has led to the development and publication of an ever increasing number of large KOSs for specific sub-domains like genomics, biology, anatomy, diseases, etc. The size of the biomedical field demands the combined use of several KOSs, but it is only possible through the definition of mappings. Mappings interconnect entities of domain-related KOSs via semantic relations. They play a key role as references to enable advanced interoperability tasks between systems, allowing software applications to interpret data annotated with different KOSs. However, to remain useful and reflect the most up-to-date knowledge of the domain, the KOSs evolve and new versions are periodically released. This potentially impacts established mappings demanding methods to ensure, as automatic as possible, their semantic consistency over time. Manual maintenance of mappings stands for an alternative only if a restricted number of mappings are available. Otherwise supporting methods are required for very large and highly dynamic KOSs. To address such problem, this PhD thesis proposes an original approach to adapt mappings based on KOS changes detected in KOS evolution. The proposal consists in interpreting the established correspondences to identify the relevant KOS entities, on which the definition relies on, and based on the evolution of these entities to propose actions suited to modify mappings. Through this investigation, (i) we conduct in-depth experiments to understand the evolution of KOS mappings; we propose automatic methods (ii) to analyze mappings affected by KOS evolution, and (iii) to recognize the evolution of involved concepts in mappings via change patterns; finally (iv) we design techniques relying on heuristics explored by novel algorithms to adapt mappings. This research achieved a complete framework for mapping adaptation, named DyKOSMap, and an implementation of a software prototype. We thoroughly evaluated the proposed methods and the framework with real-world datasets containing several releases of mappings between biomedical KOSs. The obtained results from experimental validations demonstrated the overall effectiveness of the underlying principles in the proposed approach to adapt mappings. The scientific contributions of this thesis enable to largely automatically maintain mappings with a reasonable quality, which improves the support for mapping maintenance and consequently ensures a better interoperability over time.

Este trabalho consiste em um estudo acerca dos efeitos da radiação em circuitos programáveis e sistemas em chip, do inglês System-on-Chip (SoC), baseados em FPGAs (Field-Programmable Gate Array). Dentre os diversos efeitos que podem ensejar falhas nos circuitos integrados, destacam-se a ocorrência de Single Event Effects (SEEs), Efeitos Transitórios em tradução livre, e a Dose Total Ionizante, do inglês Total Ionizing Dose (TID). SEEs podem ocorrer em razão da incidência de nêutrons originários de interações de raios cósmicos com a atmosfera terrestre, íons pesados provenientes do espaço e prótons originários do Sol (vento solar) e dos cinturões de Van Allen. A Dose Total Ionizante diz respeito à exposição prolongada de um circuito integrado à radiação ionizante e cuja consequência é a alteração das características elétricas de partes do dispositivo em razão das cargas elétricas induzidas pela radiação e acumuladas nas interfaces dos semicondutores. Dentro desse contexto, este trabalho descreve em detalhes a caracterização do SoC-FPGA baseado em memória FLASH e de sinais mistos SmartFusion A2F200-FG484, da empresa Microsemi, quando exposto à radiação (SEEs e TID) através do uso da técnica de Redundância Diversificada visando a detecção de erros. Também, uma arquitetura que utiliza um esquema baseado em Redundância Modular Tripla e Diversificada é testada através da sua implementação no FPGA baseado em memória SRAM da família Spartan-6, modelo LX45, da empresa Xilinx, visando a detecção e correção de erros causados pela radiação (SEEs). Os resultados obtidos mostram que os diversos blocos funcionais que compõe SoC SmartFusion apresentam diferentes níveis de tolerância à radiação e que o uso das técnicas de Redundância Modular Tripla e Redundância Diversificada em conjunto mostrou-se extremamente eficiente no que se refere a tolerância a SEEs. / This work consists in a study about the radiation effects in programmable circuits and System-on-Chips (SoCs) based on FPGAs (Field-Programmable Gate Arrays). Single Event Effects (SEEs) and Total Ionizing Dose (TID) are the two main effects caused by the radiation incidence, and both can imply in the occurrence of failures in integrated circuits. SEEs are due to the incidence of neutrons derived from the interaction of the cosmic rays with the terrestrial atmosphere, as well as heavy ions coming from the space and protons provided from the solar wind and the Van Allen belts. Total Ionizing Dose regards the prolonged exposure of an integrated circuit to the ionizing radiation, which deviates the standard electrical characteristics of the device due to radiation-induced electrical charges accumulated in the semiconductors’ interfaces. In this context, this work aims to describe in details the characterization of Microsemi’s mixed-signal SoC-FPGA SmartFusion A2F200-FG484 when exposed to radiation (SEEs and TID), using a Diverse Redundancy approach for error detection. As well, an architecture using a Diversified Triple Modular Redundancy scheme was tested (SEEs) through its implementation in a Xilinx’s Spartan-6 LX45 FPGA, aiming error detection and correction. The results obtained show that several functional blocks from SmartFusion have different radiation tolerance levels and that the use of the Triple Modular Redundancy together with Diversified Redundancy proved to be extremely efficient in terms of SEEs tolerance.

Este trabalho consiste em um estudo acerca dos efeitos da radiação em circuitos programáveis e sistemas em chip, do inglês System-on-Chip (SoC), baseados em FPGAs (Field-Programmable Gate Array). Dentre os diversos efeitos que podem ensejar falhas nos circuitos integrados, destacam-se a ocorrência de Single Event Effects (SEEs), Efeitos Transitórios em tradução livre, e a Dose Total Ionizante, do inglês Total Ionizing Dose (TID). SEEs podem ocorrer em razão da incidência de nêutrons originários de interações de raios cósmicos com a atmosfera terrestre, íons pesados provenientes do espaço e prótons originários do Sol (vento solar) e dos cinturões de Van Allen. A Dose Total Ionizante diz respeito à exposição prolongada de um circuito integrado à radiação ionizante e cuja consequência é a alteração das características elétricas de partes do dispositivo em razão das cargas elétricas induzidas pela radiação e acumuladas nas interfaces dos semicondutores. Dentro desse contexto, este trabalho descreve em detalhes a caracterização do SoC-FPGA baseado em memória FLASH e de sinais mistos SmartFusion A2F200-FG484, da empresa Microsemi, quando exposto à radiação (SEEs e TID) através do uso da técnica de Redundância Diversificada visando a detecção de erros. Também, uma arquitetura que utiliza um esquema baseado em Redundância Modular Tripla e Diversificada é testada através da sua implementação no FPGA baseado em memória SRAM da família Spartan-6, modelo LX45, da empresa Xilinx, visando a detecção e correção de erros causados pela radiação (SEEs). Os resultados obtidos mostram que os diversos blocos funcionais que compõe SoC SmartFusion apresentam diferentes níveis de tolerância à radiação e que o uso das técnicas de Redundância Modular Tripla e Redundância Diversificada em conjunto mostrou-se extremamente eficiente no que se refere a tolerância a SEEs. / This work consists in a study about the radiation effects in programmable circuits and System-on-Chips (SoCs) based on FPGAs (Field-Programmable Gate Arrays). Single Event Effects (SEEs) and Total Ionizing Dose (TID) are the two main effects caused by the radiation incidence, and both can imply in the occurrence of failures in integrated circuits. SEEs are due to the incidence of neutrons derived from the interaction of the cosmic rays with the terrestrial atmosphere, as well as heavy ions coming from the space and protons provided from the solar wind and the Van Allen belts. Total Ionizing Dose regards the prolonged exposure of an integrated circuit to the ionizing radiation, which deviates the standard electrical characteristics of the device due to radiation-induced electrical charges accumulated in the semiconductors’ interfaces. In this context, this work aims to describe in details the characterization of Microsemi’s mixed-signal SoC-FPGA SmartFusion A2F200-FG484 when exposed to radiation (SEEs and TID), using a Diverse Redundancy approach for error detection. As well, an architecture using a Diversified Triple Modular Redundancy scheme was tested (SEEs) through its implementation in a Xilinx’s Spartan-6 LX45 FPGA, aiming error detection and correction. The results obtained show that several functional blocks from SmartFusion have different radiation tolerance levels and that the use of the Triple Modular Redundancy together with Diversified Redundancy proved to be extremely efficient in terms of SEEs tolerance.

Este trabalho consiste em um estudo acerca dos efeitos da radiação em circuitos programáveis e sistemas em chip, do inglês System-on-Chip (SoC), baseados em FPGAs (Field-Programmable Gate Array). Dentre os diversos efeitos que podem ensejar falhas nos circuitos integrados, destacam-se a ocorrência de Single Event Effects (SEEs), Efeitos Transitórios em tradução livre, e a Dose Total Ionizante, do inglês Total Ionizing Dose (TID). SEEs podem ocorrer em razão da incidência de nêutrons originários de interações de raios cósmicos com a atmosfera terrestre, íons pesados provenientes do espaço e prótons originários do Sol (vento solar) e dos cinturões de Van Allen. A Dose Total Ionizante diz respeito à exposição prolongada de um circuito integrado à radiação ionizante e cuja consequência é a alteração das características elétricas de partes do dispositivo em razão das cargas elétricas induzidas pela radiação e acumuladas nas interfaces dos semicondutores. Dentro desse contexto, este trabalho descreve em detalhes a caracterização do SoC-FPGA baseado em memória FLASH e de sinais mistos SmartFusion A2F200-FG484, da empresa Microsemi, quando exposto à radiação (SEEs e TID) através do uso da técnica de Redundância Diversificada visando a detecção de erros. Também, uma arquitetura que utiliza um esquema baseado em Redundância Modular Tripla e Diversificada é testada através da sua implementação no FPGA baseado em memória SRAM da família Spartan-6, modelo LX45, da empresa Xilinx, visando a detecção e correção de erros causados pela radiação (SEEs). Os resultados obtidos mostram que os diversos blocos funcionais que compõe SoC SmartFusion apresentam diferentes níveis de tolerância à radiação e que o uso das técnicas de Redundância Modular Tripla e Redundância Diversificada em conjunto mostrou-se extremamente eficiente no que se refere a tolerância a SEEs. / This work consists in a study about the radiation effects in programmable circuits and System-on-Chips (SoCs) based on FPGAs (Field-Programmable Gate Arrays). Single Event Effects (SEEs) and Total Ionizing Dose (TID) are the two main effects caused by the radiation incidence, and both can imply in the occurrence of failures in integrated circuits. SEEs are due to the incidence of neutrons derived from the interaction of the cosmic rays with the terrestrial atmosphere, as well as heavy ions coming from the space and protons provided from the solar wind and the Van Allen belts. Total Ionizing Dose regards the prolonged exposure of an integrated circuit to the ionizing radiation, which deviates the standard electrical characteristics of the device due to radiation-induced electrical charges accumulated in the semiconductors’ interfaces. In this context, this work aims to describe in details the characterization of Microsemi’s mixed-signal SoC-FPGA SmartFusion A2F200-FG484 when exposed to radiation (SEEs and TID), using a Diverse Redundancy approach for error detection. As well, an architecture using a Diversified Triple Modular Redundancy scheme was tested (SEEs) through its implementation in a Xilinx’s Spartan-6 LX45 FPGA, aiming error detection and correction. The results obtained show that several functional blocks from SmartFusion have different radiation tolerance levels and that the use of the Triple Modular Redundancy together with Diversified Redundancy proved to be extremely efficient in terms of SEEs tolerance.