Platelet-derived microparticles, released as a result of platelet activation, promote coagulation through the surface exposure of phosphatidylserine, acting as the catalytic site for the conversion of prothrombin to thrombin by the activated coagulation factors X and V. Although elevated numbers of circulating platelet-derived microparticles can be detected in a number of clinical disorders, the methods for the detection of these microparticles are far from standardised. In addition, recent reports have also speculated that not all microparticles may expose phosphatidylserine, demonstrating that the binding of Annexin V, a phosphatidylserine-specific binding protein, is not detectable on a population of microparticles. The initial stage of this thesis was to establish a flow cytometric method for the detection and enumeration of microparticles based on their capacity to bind Annexin V and to utilise this assay to investigate a number of the issues that have limited assay standardisation. The assay could be performed on either stimulated or unstimulated plasma or whole blood samples. Interestingly, plasma microparticle counts were significantly higher than whole blood microparticle counts. The effects of centrifugation alone could not be attributed as the sole source of this discrepancy. The antigenic characteristics of platelet-derived microparticles were also investigated, with platelet-derived microparticles demonstrated to express the platelet glycoproteins CD31, CD41a, CD42a and CD61. Platelet-derived microparticles also expressed CD42b, and this expression was significantly decreased when compared to their progenitor platelets. The expression of the platelet activation markers CD62p, CD63, CD40L and PAC-1 was dependent upon the sample milieu, suggesting that the centrifugation conditions required to generate platelet-poor plasma may lead to artefactual increases in the expression of platelet activation markers. An investigation of the role of the GpIIb/IIIa complex on the formation of platelet-derived microparticles was also performed. A monoclonal antibody to the GpIIb/IIIa complex (Abciximab) significantly inhibited in vitro collagen-stimulated platelet-derived microparticle formation. Interestingly, platelets obtained from two subjects with impaired GpIIb/IIIa activation, demonstrated normal microparticle formation following collagen stimulation, suggesting that the presence of GpIIb/IIIa complex, but not its activation, is required for collagen-induced microparticle formation. A novel mechanism for microparticle formation was also investigated, with platelet-derived microparticles demonstrated to form in response to the sclerosing agents sodium-tetradecyl sulphate and polidocanol. Interestingly, the removal of plasma proteins by the washing of platelets left platelets more susceptible to sclerosant-induced microparticle formation, suggesting that plasma proteins may protect platelets from microparticle formation. The procoagulant activity of platelet-derived microparticles was also investigated using a novel coagulation assay (XACT) specific for the procoagulant phospholipid. An evaluation of this assay demonstrated a significant correlation between Annexin V binding microparticle counts and procoagulant activity in both whole blood and plasma samples. There was more procoagulant activity in whole blood samples than in plasma samples, suggesting that the procoagulant phospholipid activity was also associated with erythrocytes or leukocytes. To further investigate this phenomenon, a whole blood flow cytometric assay was developed to assess Annexin V binding to erythrocytes, leukocytes, platelets and microparticles. This assay demonstrated that a large proportion of Annexin V binding (51.0%) was associated with erythrocytes. Interestingly, a proportion of the Annexin V binding erythrocytes (24.5%) and leukocytes (78.8%) were also associated with platelet CD61 antigen, suggesting that they also bound a platelet or platelet-derived microparticle. The effect of sample anticoagulant on microparticle procoagulant activity was investigated. Microparticle counts were most stable in EDTA anticoagulated samples, but were stable in sodium citrate for up to 15 minutes following sample collection. The procoagulant activity of microparticles was significantly inhibited by EDTA in collagen-stimulated platelet-rich plasma samples, when compared to sodium citrate anticoagulated samples. Although the initial method used to investigate microparticles was based upon their ability to bind Annexin V, it was consistently observed that a large proportion of events in the size region of a microparticle were Annexin V negative. An investigation was therefore commenced into the procoagulant activity of microparticles based on their capacity to bind Annexin V. The presence of Annexin V negative microparticles was confirmed by flow cytometry and the proportion of microparticles that bound Annexin V was dependent upon type of agonist used to stimulate microparticle formation. Varying the assay constituents (calcium concentration / Annexin V concentration / buffer type) did not alter the proportion of Annexin V binding microparticles. When compared to Annexin V positive microparticles, Annexin V negative microparticles expressed significantly higher levels of CD42b on their surface, but possessed significantly decreased expressions of CD62p, and CD63. A significant correlation between the percentage of Annexin V binding and XACT procoagulant activity was found (p=0.03). Furthermore, Annexin V binding inhibited greater than 98% of procoagulant phospholipid activity, suggesting that Annexin V binding was a true reflection of procoagulant activity. Microparticles could be sorted using either a flow cytometric or magnetic sorting strategy. By electron microscopy, Annexin V negative events isolated following magnetic sorting were vesicular structures and not small platelets or the remnants of activated platelets. In summary, this thesis has demonstrated the ability of the flow cytometer and XACT assays to detect microparticles and their procoagulant activity. It has also shown that the use of Annexin V to detect microparticles may warrant further investigation.

In order to correctly perform circuit simulation, it is crucial that parasitic capacitances near devices are accurately extracted and are consistent with the SPICE models. Although 3D device simulation can be used to extract such parasitics, it is expensive and does not consider the effects of nearby interconnect and devices in a layout. Conventional rule-based layout parasitic extraction (LPE) tools which are used for interconnect extraction are inaccurate in modeling 3D effects near devices. In this thesis, we propose a methodology which combines 3D field solver based extraction with the ability to exclude specific parasitics from among the parameters in the SPICE model. We use this methodology to extract parasitics due to fringing fields and sidewall capacitances in MOSFETs, bipolar transistors and FinFETs in advanced process nodes. We analyze the importance of considering layout and process variables in device extraction by comparing with standard SPICE models. The results are validated by circuit simulation using predictive technology models and test chips. We also demonstrate the versatility of this flow by modeling the capacitance contributions of the raised gate profile in nanoscale FinFETs.

Les Syst emes sur puce (soc) sont de plus en plus complexes. Leur concep- tion repose largement sur la r eutilisation des blocs, appel es ip (Intellectual Pro- perty). Ces ip sont construites par des concepteurs di erents travaillant avec des outils di erents. Aussi existe-t-il une demande pressante concernant l'in- terop erabilit e des ip, c'est- a-dire d'assurer la compatibilit e des formats et l'uni- cit e d'interpr etation de leurs descriptions. ip-xact constitue un standard de facto d e ni dans le cadre de la conception de syst emes electroniques pour fournir des repr esentations portables de composants ( electroniques) et d'ip. ip-xact a r eussi a assurer la compatibilit e syntaxique, mais il a n eglig e les aspects comportemen- taux. uml est un langage de mod elisation classique pour le g enie logiciel. Il four- nit des el ements de mod ele propres a couvrir tous les aspects structurels et com- portementaux d'une conception. Nous pr^onons une utilisation conjointe d'uml et d'ip-xact pour r ealiser la n ecessaire interop erabilit e. Plus pr ecis ement, nous r eutilisons le pro l uml pour marte pour etendre uml avec des caract eristiques temps r eel embarqu ees. Le paquetage Mod elisation G en erique de Ressources de marte est etendu pour prendre en compte des sp eci cit es structurelles d'ip- xact. Le Mod ele de temps de marte etend le mod ele atemporel d'uml avec le concept de temps logique bien adapt e a la mod elisation au niveau syst eme electronique. La premi ere contribution de cette th ese est la d e nition d'un mod ele de do- maine pour ip-xact. Ce mod ele de domaine est utilis e pour construire un pro l uml pour ip-xact qui r eutilise autant que possible les st er eotypes de marte et en d e nit de nouveaux uniquement en cas de besoin. Une transformation de mod ele a et e mise en uvre dans ATL permettant d'utiliser des editeurs graphiques uml comme front-end pour la sp eci cation d'ip et la g en eration des sp eci cations ip- xact correspondantes. Inversement, des chiers ip-xact peuvent ^etre import es dans un outil uml par une autre transformation de mod eles. La deuxi eme contribution porte sur la mod elisation de propri et es et de con- traintes temporelles portant sur des ip. Les diagrammes comportementaux d'uml sont enrichis avec des horloges logiques et des contraintes d'horloge exprim ees dans le langage de speci cation de contraintes d'horloge (ccsl) de marte. La sp eci cation ccsl peut alors servir de mod ele de r ef erence pour le com- portement temporel attendu et la v eri cation des impl ementations a di erents niveaux d'abstraction (rtl ou tlm). Les propri et es temporelles sont v eri ees en utilisant une biblioth eque sp ecialis ee d'observateurs.

Platelet-derived microparticles, released as a result of platelet activation, promote coagulation through the surface exposure of phosphatidylserine, acting as the catalytic site for the conversion of prothrombin to thrombin by the activated coagulation factors X and V. Although elevated numbers of circulating platelet-derived microparticles can be detected in a number of clinical disorders, the methods for the detection of these microparticles are far from standardised. In addition, recent reports have also speculated that not all microparticles may expose phosphatidylserine, demonstrating that the binding of Annexin V, a phosphatidylserine-specific binding protein, is not detectable on a population of microparticles. The initial stage of this thesis was to establish a flow cytometric method for the detection and enumeration of microparticles based on their capacity to bind Annexin V and to utilise this assay to investigate a number of the issues that have limited assay standardisation. The assay could be performed on either stimulated or unstimulated plasma or whole blood samples. Interestingly, plasma microparticle counts were significantly higher than whole blood microparticle counts. The effects of centrifugation alone could not be attributed as the sole source of this discrepancy. The antigenic characteristics of platelet-derived microparticles were also investigated, with platelet-derived microparticles demonstrated to express the platelet glycoproteins CD31, CD41a, CD42a and CD61. Platelet-derived microparticles also expressed CD42b, and this expression was significantly decreased when compared to their progenitor platelets. The expression of the platelet activation markers CD62p, CD63, CD40L and PAC-1 was dependent upon the sample milieu, suggesting that the centrifugation conditions required to generate platelet-poor plasma may lead to artefactual increases in the expression of platelet activation markers. An investigation of the role of the GpIIb/IIIa complex on the formation of platelet-derived microparticles was also performed. A monoclonal antibody to the GpIIb/IIIa complex (Abciximab) significantly inhibited in vitro collagen-stimulated platelet-derived microparticle formation. Interestingly, platelets obtained from two subjects with impaired GpIIb/IIIa activation, demonstrated normal microparticle formation following collagen stimulation, suggesting that the presence of GpIIb/IIIa complex, but not its activation, is required for collagen-induced microparticle formation. A novel mechanism for microparticle formation was also investigated, with platelet-derived microparticles demonstrated to form in response to the sclerosing agents sodium-tetradecyl sulphate and polidocanol. Interestingly, the removal of plasma proteins by the washing of platelets left platelets more susceptible to sclerosant-induced microparticle formation, suggesting that plasma proteins may protect platelets from microparticle formation. The procoagulant activity of platelet-derived microparticles was also investigated using a novel coagulation assay (XACT) specific for the procoagulant phospholipid. An evaluation of this assay demonstrated a significant correlation between Annexin V binding microparticle counts and procoagulant activity in both whole blood and plasma samples. There was more procoagulant activity in whole blood samples than in plasma samples, suggesting that the procoagulant phospholipid activity was also associated with erythrocytes or leukocytes. To further investigate this phenomenon, a whole blood flow cytometric assay was developed to assess Annexin V binding to erythrocytes, leukocytes, platelets and microparticles. This assay demonstrated that a large proportion of Annexin V binding (51.0%) was associated with erythrocytes. Interestingly, a proportion of the Annexin V binding erythrocytes (24.5%) and leukocytes (78.8%) were also associated with platelet CD61 antigen, suggesting that they also bound a platelet or platelet-derived microparticle. The effect of sample anticoagulant on microparticle procoagulant activity was investigated. Microparticle counts were most stable in EDTA anticoagulated samples, but were stable in sodium citrate for up to 15 minutes following sample collection. The procoagulant activity of microparticles was significantly inhibited by EDTA in collagen-stimulated platelet-rich plasma samples, when compared to sodium citrate anticoagulated samples. Although the initial method used to investigate microparticles was based upon their ability to bind Annexin V, it was consistently observed that a large proportion of events in the size region of a microparticle were Annexin V negative. An investigation was therefore commenced into the procoagulant activity of microparticles based on their capacity to bind Annexin V. The presence of Annexin V negative microparticles was confirmed by flow cytometry and the proportion of microparticles that bound Annexin V was dependent upon type of agonist used to stimulate microparticle formation. Varying the assay constituents (calcium concentration / Annexin V concentration / buffer type) did not alter the proportion of Annexin V binding microparticles. When compared to Annexin V positive microparticles, Annexin V negative microparticles expressed significantly higher levels of CD42b on their surface, but possessed significantly decreased expressions of CD62p, and CD63. A significant correlation between the percentage of Annexin V binding and XACT procoagulant activity was found (p=0.03). Furthermore, Annexin V binding inhibited greater than 98% of procoagulant phospholipid activity, suggesting that Annexin V binding was a true reflection of procoagulant activity. Microparticles could be sorted using either a flow cytometric or magnetic sorting strategy. By electron microscopy, Annexin V negative events isolated following magnetic sorting were vesicular structures and not small platelets or the remnants of activated platelets. In summary, this thesis has demonstrated the ability of the flow cytometer and XACT assays to detect microparticles and their procoagulant activity. It has also shown that the use of Annexin V to detect microparticles may warrant further investigation.

La principale contribution de cette thèse porte sur la proposition et le développement d'une approche d'Ingénierie Dirigée par les Modèles (IDM), liée à une méthodologie basée sur des composants, pour faciliter la conception, design et implantation des Systèmes Dynamiquement Reconfigurables sur puce (FPGA). La méthodologie proposée repose sur l'utilisation du paradigme Metadata-based Composition Framework, et fortement basée sur des standards, tels qu'UML MARTE et, en particulier, l'IEEE IP-XACT, qui est exploitée comme représentation intermédiaire pour les IPs utilisés et pour la plateforme matérielle composée aux hautes-niveaux d'abstraction. Un procès d'emballage permet la réutilisation des bloques IP, qui ont été enveloppés par des interfaces PLB (IP statiques) et propriétaires (IP dynamiques). Subséquemment, la libraire est utilisée pour la composition d'un modèle de plateforme en UML, mais qui étant générative, permet la création d'une description cible de la composante matérielle de la plateforme, dans la forme d'un modèle spécifique à Xilinx Platform Studio, obtenu par des transformations des modèles. Les chaines de transformations pour la création de la libraire et de la plateforme, respectivement, ont été développées et implantées en utilisant Sodius MDWorkbench, un outil IDM conçu pour la création et manipulation des modèles et leur méta - modèles, ainsi que la définition et exécution des transformations des modèles associées / The main contribution of this thesis consists on the proposition and development a Model-driven Engineering (MDE) framework, in tandem with a component-based approach, for facilitating the design and implementation of Dynamic Partially Reconfigurable (DPR) Systems-on-Chip. The proposed methodology has been constructed around the Metadata-based Composition Framework paradigm, and based on common standards such as UML MARTE and the IEEE IP-XACT standard, an XML representation used for storing metadata about the IPs to be reused and of the platforms to be obtained at high-levels of abstraction. In fact, a componentizing process enables us to reuse the IP blocks, in UML MARTE, by wrapping them with PLB (static IPs) and proprietary (DPR blocks) interfaces. This is attained by reflecting the associated IP metadata to IP-XACT descriptions, and then to UML MARTE templates (IP reuse). Subsequently, these IP templates are used for composing a DPR model that can be exploited to create a Xilinx Platform Studio FPGA-design, through model transformations. The IP reflection and system generation chains were developed using Sodius MDWorkbench, an MDE tool conceived for the creation and manipulation of models and their meta-models, as well as the definition and execution of the associated transformation rules.

As Moore's law continues to progress, it is becoming increasingly difficult for hardware designers to fully utilize the increasing number of transistors available semiconductor devices including FPGAs. This design productivity gap must be addressed to allow designs to take full advantage of the increased logic density that results from rising transistor density. The reuse of previously developed and verified intellectual property (IP) is one approach that has claimed to narrow the design productivity gap. Reuse, however, has proved difficult to realize in practice because of the complexity of IP and the reluctance of designers to reuse IP that they do not understand. This thesis proposes to narrow the design productivity gap for FPGAs by simplifying the reuse problem by encapsulating IP with extra machine-readable information or meta-data. This meta-data simplifies reuse by providing a language independent format for composing complex systems, providing a parameter representation system, defining high-level data types for FPGA IP, and allowing arbitrary IP to be described as actors in the homogeneous synchronous dataflow model of computation.This work implements meta-data in XML and presents two XML schemas that enable reuse. A new XML schema known as CHREC XML is presented as well as extensions that enable IP-XACT to be used to describe FPGA dataflow IP. Two tools developed in this work are also presented that leverage meta-data to simplify reuse of arbitrary IP. These tools simplify structural composition of IP, allow designers to manipulate parameters, check and validate high-level data types, and automatically synthesize control circuitry for dataflow designs. Productivity improvements are also demonstrated by reusing IP to quickly compose software radio receivers.

La complexité des systèmes sur puce s'accentue pour supporter les nouvelles applications dans le domaine des télécommunications et du multimédia. La tendance actuelle des nouvelles architectures matérielles converge vers des plateformes multi-cœurs à plusieurs unités de calcul (processeurs, DSP, IP) interconnectées par un réseau sur puce qui peut être configurable au niveau de ses interfaces réseau. Pour ce genre d'architectures, les environnements de génération de code classiques ne sont plus adaptés. Cette thèse propose un flot de génération de code de configuration pour le déploiement des applications de type flots de données sur les architectures à base d'IPs interconnectés à travers un réseau sur puce configurable. Le flot commence par un modèle de haut niveau de l'application et de l'architecture et propose une méthodologie de partitionnement des ressources. Le processus de génération de code passe par plusieurs étapes modélisées par diverses représentations intermédiaires du système. Le flot a été développé par la suite dans un environnement basé sur le standard IEEE 1685 (IP-XACT). Le flot proposé a été appliqué pour la génération et la validation du code de configuration en vue de déployer une application 3GPP-LTE de télécommunication sur la plateforme Magali. Le flot a ensuite été généralisé pour supporter, en plus de la génération du code de configuration, la génération du code logiciel exécutable par les processeurs.

The main contribution of this thesis consists on the proposition and development a Model-driven Engineering (MDE) framework, in tandem with a component-based approach, for facilitating the design and implementation of Dynamic Partially Reconfigurable (DPR) Systems-on-Chip. The proposed methodology has been constructed around the Metadata-based Composition Framework paradigm, and based on common standards such as UML MARTE and the IEEE IP-XACT standard, an XML representation used for storing metadata about the IPs to be reused and of the platforms to be obtained at high-levels of abstraction. In fact, a componentizing process enables us to reuse the IP blocks, in UML MARTE, by wrapping them with PLB (static IPs) and proprietary (DPR blocks) interfaces. This is attained by reflecting the associated IP metadata to IP-XACT descriptions, and then to UML MARTE templates (IP reuse). Subsequently, these IP templates are used for composing a DPR model that can be exploited to create a Xilinx Platform Studio FPGA-design, through model transformations. The IP reflection and system generation chains were developed using Sodius MDWorkbench, an MDE tool conceived for the creation and manipulation of models and their meta-models, as well as the definition and execution of the associated transformation rules.