<p> </p><p>Platelets play a key role in primary haemostasis but are also related to the pathogenesis of arterial thrombosis. Thrombin is the most effective agonist inducing platelet activation. Human platelets express two G-protein coupled thrombin receptors (GPCRs), called protease activated receptor (PAR)1 and PAR4. The aim of this study was to clarify differences in the activities of PAR1 and PAR4, especially focusing on their resistance towards the platelet inhibitor nitric oxide (NO) and their ability to undergo desensitization. For this, PAR1- and PAR4- activating peptides (APs) (SFLLRN and AYPGKF, respectively) were used. Different aspects of platelet activities were studied: aggregation and the rise in intracellular Ca²⁺ concentrations ([Ca²⁺]_i). Aggregation was analyzed with lumiaggregometry, and [Ca²⁺]_i were studied using the fura-2 method. PKC substrate phosphorylation and the expression of PAR1 surface receptors were also analyzed, using Western blot and flow cytometry, respectively. The results from this study showed that NO exerted similar inhibitory effects on the two thrombin receptors. However, PAR1 and PAR4 differed in their ability to undergo desensitization. In cumulative dose-response studies, a low concentration of PAR1-AP induced desensitization of platelets towards higher PAR1-AP concentrations. This was not the case when studying PAR4-AP. The mechanism behind the desensitization of PAR1 to some part involved PKC, at least when studying the mobilization of intracellular Ca²⁺. PAR1 desensitization did not seem to involve receptor internalization and neither did it affect the activity of PAR4. This thus suggests that PAR4 might be a more suitable therapeutic target in the future management of thrombosis.</p><p> </p>

Platelets play a key role in primary haemostasis but are also related to the pathogenesis of arterial thrombosis. Thrombin is the most effective agonist inducing platelet activation. Human platelets express two G-protein coupled thrombin receptors (GPCRs), called protease activated receptor (PAR)1 and PAR4. The aim of this study was to clarify differences in the activities of PAR1 and PAR4, especially focusing on their resistance towards the platelet inhibitor nitric oxide (NO) and their ability to undergo desensitization. For this, PAR1- and PAR4- activating peptides (APs) (SFLLRN and AYPGKF, respectively) were used. Different aspects of platelet activities were studied: aggregation and the rise in intracellular Ca2+ concentrations ([Ca2+]i). Aggregation was analyzed with lumiaggregometry, and [Ca2+]i were studied using the fura-2 method. PKC substrate phosphorylation and the expression of PAR1 surface receptors were also analyzed, using Western blot and flow cytometry, respectively. The results from this study showed that NO exerted similar inhibitory effects on the two thrombin receptors. However, PAR1 and PAR4 differed in their ability to undergo desensitization. In cumulative dose-response studies, a low concentration of PAR1-AP induced desensitization of platelets towards higher PAR1-AP concentrations. This was not the case when studying PAR4-AP. The mechanism behind the desensitization of PAR1 to some part involved PKC, at least when studying the mobilization of intracellular Ca2+. PAR1 desensitization did not seem to involve receptor internalization and neither did it affect the activity of PAR4. This thus suggests that PAR4 might be a more suitable therapeutic target in the future management of thrombosis.

Les applications de pick-and-place à hautes cadences requièrent des caractéristiques très élevées en terme de performances dynamiques, que seuls les robots parallèles sont capables d'atteindre. Les robots à quatre degrés de liberté proposent le plus de flexibilité, mais l'amplitude de la rotation permettant l'orientation de l'objet est souvent le point faible de ces architectures. Cependant, le concept de nacelle articulée permet de dépasser cet inconvénient. Ainsi, trois nouvelles architectures de robots de pick-and-place à quatre degrés de liberté sont présentées dans ce manuscrit : les architectures Par4, Héli4 et Dual4. Pour chacun des robots présentés, une étude complète est effectuée et un démonstrateur est réalisé afin de valider les concepts et de les évaluer. Une méthode de modélisation dynamique simplifiée appliquée aux robots à nacelle articulée est ensuite présentée. Cette méthode est appliquée au robot Par4 et permet de mettre en avant un déséquilibre des couples moteurs sur ce mécanisme. Il est alors démontré qu'un changement mineur dans la cinématique de la nacelle permet de réduire de 30% les couples mis en jeux lors de trajectoires de prises-déposes. Une nouvelle version "équilibrée" du robot est donc proposée en se fondant sur l'étude dynamique présentée précédemment. Enfin, deux types d'optimisations appliquées aux robots de pick-and-place sont présentés. Tout d'abord, une méthode de recherche des paramètres géométriques dédiée aux robots de pick-and-place est présentée et appliquée au robot Par4. De plus, une génération de trajectoire utilisant les clothoïdes et une loi horaire adaptative est proposée afin d'optimiser les déplacements du robot lors de mouvements de pick-and-place à très hautes accélérations