Quercetin inhibits collagen-stimulated platelet activation through inhibition of multiple components of the glycoprotein VI signaling pathway

Background: The regulation of platelet function by pharmacological agents that modulate platelet signaling haspharmacolo proven a successful approach to the prevention of thrombosis. A variety of molecules present in the diet have been shown to inhibit platelet activation, including the antioxidant quercetin. Objectives: In this report we investigate the molecular mechanisms through which quercetin inhibits collagen-stimulated platelet aggregation. Methods: The effect of quercetin on platelet aggregation, intracellular calcium release, whole cell tyrosine phosphorylation and intracellular signaling events including tyrosine phosphorylation and kinase activity of proteins involved in the collagen-stimulated glycoprotein (GP) signaling pathway were investigated. Results: We report that quercetin inhibits collagen-stimulated whole cell protein tyrosine phosphorylation and intracellular mobilization of calcium, in a concentration-dependent manner. Quercetin was also found to inhibit various events in signaling generated by the collagen receptor GPVI. This includes collagen-stimulated tyrosine phosphorylation of the Fc receptor gamma-chain, Syk, LAT and phospholipase Cgamma2. Inhibition of phosphorylation of the Fc receptor gamma-chain suggests that quercetin inhibits early signaling events following stimulation of platelets with collagen. The activity of the kinases that phosphorylate the Fc receptor gamma-chain, Fyn and Lyn, as well as the tyrosine kinase Syk and phosphoinositide 3-kinase was also inhibited by quercetin in a concentration-dependent manner, both in whole cells and in isolation. Conclusions: The present results provide a molecular basis for the inhibition by quercetin of collagen-stimulated platelet activation, through inhibition of multiple components of the GPVI signaling pathway, and may begin to explain the proposed health benefits of high quercetin intake.

Components of verbal working memory: Evidence from neuroimaging

We review research on the neural bases of verbal working memory, focusing on human neuroimaging studies. We first consider experiments that indicate that verbal working memory is composed of multiple components. One component involves the subvocal rehearsal of phonological information and is neurally implemented by left-hemisphere speech areas, including Broca’s area, the premotor area, and the supplementary motor area. Other components of verbal working memory may be devoted to pure storage and to executive processing of the contents of memory. These studies rest on a subtraction logic, in which two tasks are imaged, differing only in that one task presumably has an extra process, and the difference image is taken to reflect that process. We then review studies that show that the previous results can be obtained with experimental methods other than subtraction. We focus on the method of parametric variation, in which a parameter that presumably reflects a single process is varied. In the last section, we consider the distinction between working memory tasks that require only storage of information vs. those that require that the stored items be processed in some way. These experiments provide some support for the hypothesis that, when a task requires processing the contents of working memory, the dorsolateral prefrontal cortex is disproportionately activated.

COLLABORATIVE TESTING ACROSS SHARED SOFTWARE COMPONENTS

Large component-based systems are often built from many of the same components. As individual component-based software systems are developed, tested and maintained, these shared components are repeatedly manipulated. As a result there are often significant overlaps and synergies across and among the different test efforts of different component-based systems. However, in practice, testers of different systems rarely collaborate, taking a test-all-by-yourself approach. As a result, redundant effort is spent testing common components, and important information that could be used to improve testing quality is lost. The goal of this research is to demonstrate that, if done properly, testers of shared software components can save effort by avoiding redundant work, and can improve the test effectiveness for each component as well as for each component-based software system by using information obtained when testing across multiple components. To achieve this goal I have developed collaborative testing techniques and tools for developers and testers of component-based systems with shared components, applied the techniques to subject systems, and evaluated the cost and effectiveness of applying the techniques. The dissertation research is organized in three parts. First, I investigated current testing practices for component-based software systems to find the testing overlap and synergy we conjectured exists. Second, I designed and implemented infrastructure and related tools to facilitate communication and data sharing between testers. Third, I designed two testing processes to implement different collaborative testing algorithms and applied them to large actively developed software systems. This dissertation has shown the benefits of collaborative testing across component developers who share their components. With collaborative testing, researchers can design algorithms and tools to support collaboration processes, achieve better efficiency in testing configurations, and discover inter-component compatibility faults within a minimal time window after they are introduced.

As interfaces entre imagem corporal e a representação simbolica de Carl Gustav Jung

Universidade Estadual de Campinas . Faculdade de Educação Física

A Nonstationary Model of Newborn EEG

The detection of seizure in the newborn is a critical aspect of neurological research. Current automatic detection techniques are difficult to assess due to the problems associated with acquiring and labelling newborn electroencephalogram (EEG) data. A realistic model for newborn EEG would allow confident development, assessment and comparison of these detection techniques. This paper presents a model for newborn EEG that accounts for its self-similar and non-stationary nature. The model consists of background and seizure sub-models. The newborn EEG background model is based on the short-time power spectrum with a time-varying power law. The relationship between the fractal dimension and the power law of a power spectrum is utilized for accurate estimation of the short-time power law exponent. The newborn EEG seizure model is based on a well-known time-frequency signal model. This model addresses all significant time-frequency characteristics of newborn EEG seizure which include; multiple components or harmonics, piecewise linear instantaneous frequency laws and harmonic amplitude modulation. Estimates of the parameters of both models are shown to be random and are modelled using the data from a total of 500 background epochs and 204 seizure epochs. The newborn EEG background and seizure models are validated against real newborn EEG data using the correlation coefficient. The results show that the output of the proposed models has a higher correlation with real newborn EEG than currently accepted models (a 10% and 38% improvement for background and seizure models, respectively).

Active Assistance for Senior Healthcare: A Wearable System for Fall Detection

Elders lose independence and wellbeing, accompanied by decreased functions in terms of hearing, vision, strength and coordination abilities. These factors contribute to balance difficulties that eventually lead to falls. The injuries due to falls, at this age, are risky, since most of the times may cause a significant – and permanent – decrease of quality of life or, in extreme cases, death. In this context, a fall detection system can bring an added value to assist elderly people.This paper describes a system consisting of a wearable sensor unit, a smartphone and a website. When the sensor detects a fall it sends an alert using the smartphone via Bluetooth 4.0, to notify the family members or stakeholders. The sensor device includes an inertial unit, a barometer, and a temperature and humidity sensor. The website displays the log of previous falls and enables the configuration of emergency contact numbers. The proposed fall detection system is one of multiple components within a larger project under development that offers a holistic perspective on falls; the complete wearable solution will also feature, among others, physical protection (minimizing the impact of falls that occur).

Characterization of Endotrypanum Parasites Using Specific Monoclonal Antibodies

A large number of Endotrypanum stocks (representing an heterogeneous population of strains) have been screened against a panel of monoclonal antibodies (MAbs) derived for selected species of Endotrypanum or Leishmania, to see whether this approach could be used to group/differentiate further among these parasites. Using different immunological assay systems, MAbs considered specific for the genus Endotrypanum (E-24, CXXX-3G5-F12) or strain M6159 of E. schaudinni (E-2, CXIV-3C7-F5) reacted variably according to the test used but in the ELISA or immunofluorescence assay both reacted with all the strains tested. Analyses using these MAbs showed antigenic diversity occurring among the Endotrypanum strains, but no qualitative or quantitative reactivity pattern could be consistently related to parasite origin (i.e., host species involved) or geographic area of isolation. Western blot analyses of the parasites showed that these MAbs recognized multiple components. Differences existed either in the epitope density or molecular forms associated with the antigenic determinants and therefore allowed the assignment of the strains to specific antigenic groups. Using immunofluorescence or ELISA assay, clone E-24 produced reaction with L. equatorensis (which is a parasite of sloth and rodent), but not with other trypanosomatids examined. Interestingly, the latter parasite and the Endotrypanum strains cross-reacted with a number of MAbs that were produced against members of the L. major-L. tropica complex

Developmental, metabolic and immunological costs of flea infestation in the common vole

Parasites use resources from their hosts, which can indirectly affect a number of host functions because of trade-offs in resource allocation. In order to get a comprehensive view of the costs imposed by blood sucking parasites to their hosts, it is important to monitor multiple components of the development and physiology of parasitized hosts over long time periods. The effect of infestation by fleas on body mass, body length growth, haematocrit, resistance to oxidative stress, resting metabolic rate and humoral immune response were experimentally evaluated. During a 3-month period, male common voles, Microtus arvalis, were either parasitized by rat fleas (Nosopsyllus fasciatus), which are naturally occurring generalist ectoparasites of voles, or reared without fleas. Then voles were challenged twice by injecting Keyhole Limpet Haemocyanin (KLH) to assess whether the presence of fleas affects the ability of voles to produce antibodies against a novel antigen. During the immune challenge we measured the evolution of body mass, haematocrit, resistance to oxidative stress and antibody production. Flea infestation negatively influenced the growth of voles. Moreover, parasitized voles had reduced haematocrit, higher resting metabolic rate and lower production of antibodies against the KLH. Resistance to oxidative stress was not influenced by the presence of fleas. During the immune challenge with KLH, body mass decreased in both groups, while the resistance to oxidative stress remained stable. In contrast, the haematocrit decreased only in parasitized voles. Our experiment shows that infestation by a haematophageous parasite negatively affects multiple traits like growth, energy consumption and immune response. Fleas may severely reduce the survival probability and reproductive success of their host in natural conditions.

Characterization of the expression, regulation and function of Sorting Nexin 9 and Sorting Nexin 18

Summary : Sorting nexin (SNX) family members play important roles in intracellular protein and membrane trafficking, The membrane-tubulating SNX9 protein has been shown to interact with multiple components of the endocytic machinery and to participate in clathrin-mediated endocytosis of cell surface receptors. It has not been investigated if SNX9 may also participate in other protein sorting pathways that involve vesicular transport, specifically the biogenesis of lysosome-related organelles (LROs). Closely related to SNX9 is SNXl8, whose function is largely unknown. In this work, we have characterized the expression of SNX9 and SNXl8 in LRO-containing cells and investigated their role in protein trafficking during the formation of LROs. Our results indicate that SNX9 and SNXl8 are not essential for the formation of LROs, nor for the sorting of melanosomal proteins. We investigated how the level of intracellular SNX9 protein is regulated and found that it is a substrate of the ubiquitin ligase Itch, a member of the NEDD4 family of E3 ubiquitin ligases. Itch ubiquitylates SNX9 and regulates SNX9 levels by enhancing its degradation. Using ? truncated proteins we found that the interaction with SNX9 is mediated by the proline-rich domain of Itch, a domain distinct from the conventional WW recognition domain, and the SH3 domain of SNX9. Interaction with the PRD of Itch is essential for SNX9 ubiquitylation and degradation. We further showed that Itch binding is not affected by tyrosine phosphorylation of SNX9. Using lentivector-mediated siRNA techniques, we found that Itch regulates the level of melanosomal proteins, while knock-down of SNX9 does not alter their level. Interestingly, we revealed that silencing of SNXIS affects the amount of the melanosomal protein Melan-A, but also of SNX9, and that SNXl8 can interact with SNX9. Taken together, our results highlight that the pool of substrates of NEDD4 family E3 ligases extends to proteins containing SH3 domains and provide insight into the potential functions of SNXI8. Résumé : Les membres de la famille des Sorting Nexins (SNX) jouent des rôles importants dans le trafic intracellulaire de protéines et membranes. Il a été démontré que la protéine SNX9, qui génère les tubules membranaires, interagit avec plusieurs composants de la machinerie d'endocytose et participe à l'endocytose des récepteurs de surface mediée par la clathrine. Aucune étude n'a investigué si SNX9 pourrait aussi participer à d'autres voies de trafic de protéines tel que le transport vésiculaire, et plus particulièrement la biogenèse des organites lysosomaux ("lysosome-related organelles", LR©s). SNXl8 est similaire à SNX9, mais sa fonction est largement inconnue. Dans ce travail, nous avons caractérisé l'expression de SNX9 et SNX18 dans des cellules contenants des LROs et investigué leur rôle dans le trafic de protéines pendant la formation des LROS. Nos résultats indiquent que SNX9 et SNXI8 ne sont essentiels ni pour la formation des LR©s, ni pour le trafic de protéines mélanosomales. Nous avons examiné la régulation du niveau intracellulaire de la protéine SNX9 et avons trouvé qu'elle est un substrat de l'ubiquitine ligase Itch, un membre de la famille NEDD4 des ubiquitine ligases E3. Itch ubiquitine SNX9 et régule les niveaux de SNX9 en augmentant sa dégradation. En utilisant des protéines mutées nous avons découvert que l'interaction avec SNX9 est médiée par le domaine riche en proline de Itch, qui est différent du domaine conventionnel de reconnaissance WW, et par le domaine SH3 de SNX9. L'interaction avec le domaine riche en proline de Itch est essentielle pour l'ubiquitination et la dégradation de SNX9. De plus, nous avons montré que cette liaison n'est pas affectée par la phosphorylation des résidus tyrosine de SNX9. En utilisant des vecteurs lentiviraux exprimant des siARN, nous avons trouvé que Itch régule les niveaux de protéines mélanosomales, alors que l'extinction de l'expression de SNX9 ne change pas leurs niveaux. En autre, nous avons révélé que la diminution de SNXl8 affecte le niveau de la protéine mélanosomale Melan-A et de SNX9, et aussi que SNXl8 peut interagir avec SNX9. En résumé, nos résultats démontrent que l'ensemble des substrats de la famille NEDD4 des ubiquitine ligases E3 s'élargit aux protéines contenant des domaines SH3 et ouvrent des perspectives sur les fonctions potentielles de SNXl8.

The Lin28/let-7 axis regulates glucose metabolism.

The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism.

Aktiivinen jännitteensäätö hajautetussa sähköntuotannossa

Hajautetun tuotannon määrä kasvaa jakeluverkossa tulevaisuudessa ja siksi jakeluverkon toiminta tulee muuttumaan aktiivisempaan suuntaan. Nykyisin tuotannon aiheuttamaa jännitteennousua rajoitetaan yleensä passiivisilla menetelmillä kuten vahvistamalla verkkoa. Tuotantolaitos ei tällöin osallistu jakeluverkon jännitteensäätöön. Tämä saattaa nostaa kapasiteetiltaan suurehkon tuotannon liittymiskustannukset niin korkeiksi, ettei tuotantolaitosta kannata rakentaa. Aktiivisella jännitteensäädöllä tuotantokapasiteettia voitaisiin merkittävästi kasvattaa nykyisissä jakeluverkoissa. Aktiivinen jännitteensäätö voi perustua joko paikalliseen säätöön, jolloin esim. tuotantolaitosta säädetään paikallisen jännitteen perusteella tai koordinoituun säätöön, jolloin verkon komponentteja säädetään kokonaisuutena. Työssä tutustutaan hajautettuun tuotantoon ja sen vaikutuksiin jakeluverkon jännitetasoissa sekä jännitteensäädössä. Työssä edetään passiivisesta jännitteensäädöstä aktiiviseen jännitteensäätöön. Aktiivisessa jännitteensäädössä tutustutaan muutamaan kirjallisuudessa esitettyyn algoritmiin ja käytännön toteutukseen. Työssä keskitytään vain verkon jännitetasoon, eikä muita jännitteen laadun ominaisuuksia oteta huomioon.

Kuka suunnittelee mainokset? Tutkimus mainosalan kulisseista,yhteistyökäytännöistä ja ristiriidoista. Mainonnan suunnittelijan näkökulma

Tutkimus kuvaa tapahtumia mainonnan suunnittelun kulissien takana ja niiden vaikutusta suunnittelutyöhön mainonnan suunnittelijan näkökulmasta. Lähestymistapa on systeemiteoreettinen: tutkimuksessa tarkastellaan sekä mainostoimiston suunnittelijoiden, projektijohtajien ja muiden mainonnan suunnitteluun osallistuvien keskinäistä vuorovaikutusta että mainostoimiston ja mainoksia tilaavan asiakkaan vuorovaikutuksen asettamia rajoja ja mahdollisuuksia. Keskeinen työväline on Kurt Lewinin kentän käsite. Tutkimuksessa se konkretisoituu esitystavaksi mainonnan suunnittelun olennaisista piirteistä, jotka ovat toisistaan riippuvaisia. Tutkimusta pohjustaa ajatus mainonnan suunnittelun perusrakenteesta, joka on riippumaton taloudellisista, yhteiskunnallisista tai mainostoimialan liiketoimintaympäristön muutoksista. Mainostoimistossa työtä tehdään usein ryhmässä. Ydinryhmä muodostuu kirjoittavan ja visuaalisen suunnittelijan työparista, mutta projektijohtaja on avainasemassa hoitaessaan yhteydenpitoa mainostoimiston asiakkaaseen. Tutkimustyötä viitoittivat kysymykset mainonnan suunnittelijoiden tehtävästä ja asemasta, työssä koetuista haasteista sekä osuudesta ja vastuusta lopullisissa töissä. Keskiössä ovat suunnittelutyötä raamittavat haasteet, jotka ohjaavat suunnittelijoiden kykyjä ja haluja toteuttaa luovuuttaan. Tutkimus ammentaa teoreettisia aineksia työnjaon ja tiimityön käsitteiden ohella vallan tilanteisuudesta ja suhteista sekä sosiaalisen pääoman ja luottamuksen moniaineksisuudesta. Tutkimuksen aineisto kerättiin syksyllä 2008 ja alkuvuodesta 2009 haastattelemalla suomalaisten mainostoimistojen suunnittelijoita. Haastatteluaineisto koostuu kymmenestä ryhmähaastattelusta, johon kuhunkin osallistui 3–4 suunnittelijaa. Muu aineisto sisältää toimialan tilastoja ja julkaisuja sekä yksityisiä sähköpostikirjeenvaihtoja ja keskusteluja mainosammattilaisten kanssa. Haastatteluaineisto analysoitiin Milesin ja Hubermannin aineistolähtöisen sisällönanalyysin avulla ja sitä täydennettiin retorisella diskurssianalyysilla. Analyysin alkuvaiheessa koemetodina sovellettiin Straussin ja Corbinin aineistolähtöisen teorian (grounded theory) kolmivaiheista koodausta. Tutkimuksen tuloksena on malli mainonnan suunnittelun kentän jännitteistä, jotka johtavat toimimaan tietyllä tavalla. Mainonnan suunnittelijan tehtävinä näyttäytyvät vaikuttaminen, asiakkaan tarpeiden tunnistaminen ja tyydyttäminen sekä omakohtainen menestyminen. Suunnittelijan asema näyttää työssä koettujen haasteiden kautta häilyvän asiantuntijuuden ja alihankkijuuden välimaastossa. Työn henkilökohtaisina haasteina piirtyvät tarmokkuuden ja jatkuvan oivaltamisen vaateet. Ulkoisina tekijöinä talouden, teknologian ja sen myötä median murros sekä haastaa että kehittää: alituiseen kiireeseen näytetään verhoavan pulmia, joiden todellinen alkuperä paikantuu muualle. Keskeiset ristiriidat ja toiminnan edellytykset ilmenevät juuri yhteistyössä: mainostoimiston sisäinen yhteistyö ja asiakkaan antama palaute ovat merkittäviä tekijöitä luottamuksen taustalla. Siten avoin ja vastavuoroinen kommunikaatio piirtyy olennaiseksi asetettujen tavoitteiden saavuttamisessa ja asiakkaan menestymisessä. Mainonnan suunnittelussa tärkeäksi kysymykseksi nousevat portinvartijoiden roolit. Mainostoimiston sisäisessä työskentelyssä projektijohtajat hallinnoivat suunnitteluresursseja, välittävät tietoa asiak kaalta suunnittelijalle ja päinvastoin sekä tekevät tärkeimmät päätökset. Asiakkaan puolella mainoksia tilaava asiakashenkilö hallinnoi valjastamiaan resursseja, mutta varsinainen päätöksenteko tapahtuu tämän esimiehen toimesta. Tulosten valossa on perusteltua uskoa, että mainonnan suunnittelijat kokevat oman työnsä arvon alentuneen ja päätösvaltansa vähentyneen. Mainostoimialan murroksen kannalta tutkimus tuo esiin uudenlaisen tiimityön ymmärtämisen ja korostaa yksilöiden vahvuuksien tunnistamisen merkitystä. Kiristyvässä taloudessa se suuntaa huomion sekä mainostoimistojen että niiden asiakasyritysten sisäisten ja ulkoisten resurssien tehokkaaseen ja tuottavaan hyödyntämiseen ja organisoimiseen. Sosiologisesti tutkimus tarjoaa yhdenlaisen näkökulman ryhmätyön ulottuvuuksiin ja työelämän yhteistyöhaasteiden pohtimiseen. Siten tutkimuksen tuloksilla voi nähdä arvoa myös muiden kuin mainosalan yhteistyökäytäntöjentarkasteluun.

Influence du financement sur la performance des systèmes de soins

La thèse a pour objectif d’étudier l’influence du financement des soins de santé sur la performance des systèmes de soins compte tenu des caractéristiques organisationnelles sanitaires des systèmes. Elle s’articule autour des trois objectifs suivants : 1) caractériser le financement des soins de santé à travers les différents modèles émergeant des pays à revenu élevé ; 2) apprécier la performance des systèmes de soins en établissant les divers profils apparaissant dans ces mêmes pays ; 3) examiner le lien entre le financement et la performance en tenant compte du pouvoir modérateur du contexte organisationnel des soins. Inspirée du processus de circulation de l’argent dans le système de soins, l’approche a d’abord consisté à classer les pays étudiés – par une analyse configurationnelle opérationnalisée par les analyses de correspondance multiples (ACM) et de classification hiérarchique ascendante (CHA) – dans des modèles types, chacun représentant une configuration particulière de processus de financement des soins de santé (article 1). Appliquée aux données recueillies auprès des 27 pays de l’OCDE à revenu élevé via les rapports Health Care in Transition des systèmes de santé des pays produits par le bureau Européen de l’OMS, la banque de données Eco-Santé OCDE 2007 et les statistiques de l’OMS 2008, les analyses ont révélé cinq modèles de financement. Ils se distinguent selon les fonctions de collecte de l’argent dans le système (prélèvement), de mise en commun de l’argent collecté (stockage), de la répartition de l’argent collecté et stocké (allocation) et du processus de paiement des professionnels et des établissements de santé (paiement). Les modèles ainsi développés, qui vont au-delà du processus unique de collecte de l’argent, donnent un portrait plus complet du processus de financement des soins de santé. Ils permettent ainsi une compréhension de la cohérence interne existant entre les fonctions du financement lors d’un éventuel changement de mode de financement dans un pays. Dans un deuxième temps, nous appuyant sur une conception multidimensionnelle de la performance des systèmes, nous avons classé les pays : premièrement, selon leur niveau en termes de ressources mobilisées, de services produits et de résultats de santé atteints (définissant la performance absolue) ; deuxièmement, selon les efforts qu’ils fournissent pour atteindre un niveau élevé de résultats de santé proportionnellement aux ressources mobilisées et aux services produits en termes d’efficience, d’efficacité et de productivité (définissant ainsi la performance relative) ; et troisièmement, selon les profils types de performance globale émergeant en tenant compte simultanément des niveaux de performance absolue et relative (article 2). Les analyses effectuées sur les données collectées auprès des mêmes 27 pays précédents ont dégagé quatre profils de performance qui se différencient selon leur niveau de performance multidimensionnelle et globale. Les résultats ainsi obtenus permettent d’effectuer une comparaison entre les niveaux globaux de performance des systèmes de soins. Pour terminer, afin de répondre à la question de savoir quel mode – ou quels modes – de financement générerait de meilleurs résultats de performance, et ce, dans quel contexte organisationnel de soins, une analyse plus fine des relations entre le financement et la performance (tous définis comme précédemment) compte tenu des caractéristiques organisationnelles sanitaires a été réalisée (article 3). Les résultats montrent qu’il n’existe presque aucune relation directe entre le financement et la performance. Toutefois, lorsque le financement interagit avec le contexte organisationnel sanitaire pour appréhender le niveau de performance des systèmes, des relations pertinentes et révélatrices apparaissent. Ainsi, certains modes de financement semblent plus attrayants que d’autres en termes de performance dans des contextes organisationnels sanitaires différents. Les résultats permettent ainsi à tous les acteurs du système de comprendre qu’il n’existe qu’une influence indirecte du financement de la santé sur la performance des systèmes de soins due à l’interaction du financement avec le contexte organisationnel sanitaire. L’une des originalités de cette thèse tient au fait que très peu de travaux ont tenté d’opérationnaliser de façon multidimensionnelle les concepts de financement et de performance avant d’analyser les associations susceptibles d’exister entre eux. En outre, alors que la pertinence de la prise en compte des caractéristiques du contexte organisationnel dans la mise en place des réformes des systèmes de soins est au coeur des préoccupations, ce travail est l’un des premiers à analyser l’influence de l’interaction entre le financement et le contexte organisationnel sanitaire sur la performance des systèmes de soins.

Non-genomic effects of PPARgamma ligands: inhibition of GPVI-stimulated platelet activation

BACKGROUND: Peroxisome proliferator-activated receptor-(gamma) (PPAR(gamma)) is expressed in human platelets although in the absence of genomic regulation in these cells, its functions are unclear. OBJECTIVE: In the present study, we aimed to demonstrate the ability of PPAR(gamma) ligands to modulate collagen-stimulated platelet function and suppress activation of the glycoprotein VI (GPVI) signaling pathway. METHODS: Washed platelets were stimulated with PPAR(gamma) ligands in the presence and absence of PPAR(gamma) antagonist GW9662 and collagen-induced aggregation was measured using optical aggregometry. Calcium levels were measured by spectrofluorimetry in Fura-2AM-loaded platelets and tyrosine phosphorylation levels of receptor-proximal components of the GPVI signaling pathway were measured using immunoblot analysis. The role of PPAR(gamma) agonists in thrombus formation was assessed using an in vitro model of thrombus formation under arterial flow conditions. RESULTS: PPAR(gamma) ligands inhibited collagen-stimulated platelet aggregation that was accompanied by a reduction in intracellular calcium mobilization and P-selectin exposure. PPAR(gamma) ligands inhibited thrombus formation under arterial flow conditions. The incorporation of GW9662 reversed the inhibitory actions of PPAR(gamma) agonists, implicating PPAR(gamma) in the effects observed. Furthermore, PPAR(gamma) ligands were found to inhibit tyrosine phosphorylation levels of multiple components of the GPVI signaling pathway. PPAR(gamma) was found to associate with Syk and LAT after platelet activation. This association was prevented by PPAR(gamma) agonists, indicating a potential mechanism for PPAR(gamma) function in collagen-stimulated platelet activation. CONCLUSIONS: PPAR(gamma) agonists inhibit the activation of collagen-stimulation of platelet function through modulation of early GPVI signalling.

Effects of time-periodic linear coupling on two-component Bose-Einstein condensates in two dimensions

We examine two-component Gross-Pitaevskii equations with nonlinear and linear couplings, assuming self-attraction in one species and self-repulsion in the other, while the nonlinear inter-species coupling is also repulsive. For initial states with the condensate placed in the self-attractive component, a sufficiently strong linear coupling switches the collapse into decay (in the free space). Setting the linear-coupling coefficient to be time-periodic (alternating between positive and negative values, with zero mean value) can make localized states quasi-stable for the parameter ranges considered herein, but they slowly decay. The 2D states can then be completely stabilized by a weak trapping potential. In the case of the high-frequency modulation of the coupling constant, averaged equations are derived, which demonstrate good agreement with numerical solutions of the full equations. (C) 2007 Elsevier B.V. All rights reserved.