103 research outputs found
CalDAG-GEFI deficiency protects mice in a novel model of FcγRIIA-mediated thrombosis and thrombocytopenia
No full textAbstractPlatelet activation via Fcγ receptor IIA (FcγRIIA) is a critical event in immune-mediated thrombocytopenia and thrombosis syndromes (ITT). We recently identified signaling by the guanine nucleotide exchange factor CalDAG-GEFI and the adenosine diphosphate receptor P2Y12 as independent pathways leading to Rap1 small GTPase activation and platelet aggregation. Here, we evaluated the contribution of CalDAG-GEFI and P2Y12 signaling to platelet activation in ITT. Mice transgenic for the human FcγRIIA (hFcR) and deficient in CalDAG-GEFI−/− (hFcR/CDGI−/−) were generated. Compared with controls, aggregation of hFcR/CDGI−/− platelets or P2Y12 inhibitor-treated hFcR platelets required more than 5-fold and approximately 2-fold higher concentrations of a FcγRIIA stimulating antibody against CD9, respectively. Aggregation and Rap1 activation were abolished in P2Y12 inhibitor-treated hFcR/CDGI−/− platelets. For in vivo studies, a novel model for antibody-induced thrombocytopenia and thrombosis was established. FcγRIIA-dependent platelet thrombosis was induced by infusion of Alexa750-labeled antibodies to glycoprotein IX (CD42a), and pulmonary thrombi were detected by near-infrared imaging technology. Anti-GPIX antibodies dose-dependently caused thrombocytopenia and pulmonary thrombosis in hFcR-transgenic but not wild-type mice. CalDAG-GEFI-deficient but not clopidogrel-treated hFcR-transgenic mice were completely protected from ITT. In summary, we established a novel mouse model for ITT, which was used to identify CalDAG-GEFI as a potential new target in the treatment of ITT.</jats:p
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Rap1-Rac1 circuits potentiate platelet activation.
No full textOBJECTIVE:
The goal of this study was to investigate the potential crosstalk between Rap1 and Rac1, 2 small GTPases central to platelet activation, particularly downstream of the collagen receptor GPVI.
METHODS AND RESULTS:
We compared the activation response of platelets with impaired Rap signaling (double knock-out; deficient in both the guanine nucleotide exchange factor, CalDAG-GEFI, and the Gi-coupled receptor for ADP, P2Y12), to that of wild-type platelets treated with a small-molecule Rac inhibitor, EHT 1864 (wild-type /EHT). We found that Rac1 is sequentially activated downstream of Rap1 on stimulation via GPVI. In return, Rac1 provides important feedback for both CalDAG-GEFI- and P2Y12-dependent activation of Rap1. When analyzing platelet responses controlled by Rac1, we observed (1) impaired lamellipodia formation, clot retraction, and granule release in both double knock-out and EHT 1864-treated wild-type platelets; and (2) reduced calcium store release in EHT 1864-treated wild-type but not double knock-out platelets. Consistent with the latter finding, we identified 2 pools of Rac1, one activated immediately downstream of GPVI and 1 activated downstream of Rap1.
CONCLUSIONS:
We demonstrate important crosstalk between Rap1 and Rac1 downstream of GPVI. Whereas Rap1 signaling directly controls sustained Rac1 activation, Rac1 affects CalDAG-GEFI- and P2Y12-dependent Rap1 activation via its role in calcium mobilization and granule/ADP release, respectively
"Je reve de Catherine. Je suis Catherine" : le jeu des "je" narratifs dans ”La maison Trestler ou le 8e jour d’Amérique” de Madeleine Ouellette-Michalska
No full textIn the present article, the author discusses literary games as exemplified by
the novel La M aison Trestler ou le 8e jo u r d ’Amérique by the Canadian writer Madeleine
Ouellette-Michalska. The game that we are invited to play turns out to be complex
because it occurs on many levels, particularly on the level of the narration. Ouellette-
Michalska’s novel is based on a game played by multiple female identities, questioning the
exclusively masculine point of view dominant in the historical discourse. Asking whether
history is able to depict every aspect of an event truthfully, the novel allows the intrusion
of memories and feelings into the presentation of the past. Suggesting “settling the score”
between the male and female history, the writer reconsiders the question of historical
truth. In her opinion, women’s memory partly escapes the male logic of space/time and
facilitates the coming of the eighth day, the day of America
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The kinetics of αIIbβ3 activation determines the size and stability of thrombi in mice: implications for antiplatelet therapy.
No full textTwo major pathways contribute to Ras-proximate-1-mediated integrin activation in stimulated platelets. Calcium and diacyglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI, RasGRP2) mediates the rapid but reversible activation of integrin αIIbβ3, while the adenosine diphosphate receptor P2Y12, the target for antiplatelet drugs like clopidogrel, facilitates delayed but sustained integrin activation. To establish CalDAG-GEFI as a target for antiplatelet therapy, we compared how each pathway contributes to thrombosis and hemostasis in mice. Ex vivo, thrombus formation at arterial or venous shear rates was markedly reduced in CalDAG-GEFI(-/-) blood, even in the presence of exogenous adenosine diphosphate and thromboxane A(2). In vivo, thrombosis was virtually abolished in arterioles and arteries of CalDAG-GEFI(-/-) mice, while small, hemostatically active thrombi formed in venules. Specific deletion of the C1-like domain of CalDAG-GEFI in circulating platelets also led to protection from thrombus formation at arterial flow conditions, while it only marginally increased blood loss in mice. In comparison, thrombi in the micro- and macrovasculature of clopidogrel-treated wild-type mice grew rapidly and frequently embolized but were hemostatically inactive. Together, these data suggest that inhibition of the catalytic or the C1 regulatory domain in CalDAG-GEFI will provide strong protection from athero-thrombotic complications while maintaining a better safety profile than P2Y12 inhibitors like clopidogrel
Aspects de la procédure et de la preuve devant les tribunaux administratifs
No full textLes organismes administratifs ont été constitués pour être différents
des cours de justice. Les cours doivent donc éviter d'imposer
aux organismes administratifs leur mode de fonctionnement,
mais respecter l'autonomie et l'expertise des organismes.
En l'absence en droit fédéral comme en droit québécois de
législation sur la procédure et la preuve administrative, la jurisprudence
a élaboré un important corpus de règles de procédure et de
preuve inspiré des principes de justice fondamentale.
En matière de procédure, les cours d'appel ont énoncé la règle
de l'autonomie de la procédure administrative par rapport a la
procédure judiciaire: les organismes sont maîtres de leur procédure
sous réserve des principes de justice fondamentale. L'application de
cette règle d'or doit cependant se faire de façon modulée, en tenant
compte de la nature des pouvoirs exercés, de l'existence ou non
d'un lis inter partes et de degré de judiciarisation envisagé par le
législateur.
Lorsque la loi impose la tenue d'une audience publique, celle-ci
devra être précédée d'un préavis dont le degré de précision varie
suivant les circonstances. Le droit de faire valoir ses moyens inclut
celui de contredire la preuve, mais pas nécessairement celui de
contre-interroger.
L'autonomie de la procédure administrative se manifeste aussi
au stade du délibéré.
En certaines circonstances, la jurisprudence accepte que des
décideurs se fassent aider de conseillers juridiques aux fins de la
mise en forme juridique de leur opinion ou de la compréhension
d'un dossier, mais aucune théorie cohérente de la décision institutionnelle
n'a encore été élaborée en droit canadien.
Les cours d'appel ont également reconnu l'autonomie des organismes
administratifs au plan des règles de preuve. Les règles techniques de preuve appliquées au Canada par les cours sont le produit
du système de procès par jury. Rien ne justifie de les imposer
aux organismes administratifs; ceux-ci doivent cependant fonder
leurs décisions quasi-judiciaires sur la preuve soumise à l'audience
et non sur des informations obtenues a l'insu des parties.
La jurisprudence canadienne n'a pas non plus élaboré une
théorie cohérente de la connaissance d'office (official notice) et
aurait peut-être intérêt a s'inspirer de l'expérience américaine.
Tout au plus peut-on suggérer que les cours d'appel sont en cette
matière relativement tolérante a l'égard des agences de régulation.
L'auteur évoque finalement les inconvénients et avantages de
la codification des règles jurisprudentielles de procédure et de
preuve administrative. Le droit administratif canadien et québécois
n'a peut-être pas encore atteint un degré suffisant de développement
et de maturité pour supporter d'être codifié.Abstract: Administrative organisms were meant to be different than
judicial tribunals. Thus, courts must avoid imposing their own
modus operandi: rather, they should respect the autonomy and
expertise of such organisms.
In the absence of federal or Québec legislation specifically
concerning administrative procedure and evidence, the courts have
elaborated a body of procedural and evidentiary rules based on
principles of fundamental justice.
For questions of procedure, appellate courts have certified the
autonomy of administrative organisms vis-à-vis judicial rules. Such
organisms are masters of their own procedure, as long as principles
of fundamental justice are respected. The application of this basic
rule is tempered in several cases, depending on the nature of the
organism's powers, the existence of a lis inter partes, and the
degree of court-like formalities provided for by the enabling statute.
Thus, when a statute requires a public hearing, advance
notice (of varying degrees of detail, depending on the case) must
be given. The right to present one's case includes that of contradicting
one's adversary, but does not necessarily include the right of
cross-examination.
The autonomy of the administrative organism is also apparent
once its "case" is under advisement. In certain circumstances, courts
permit decision-makers to obtain legal counsel conceming the form of their decision or their understanding of a dossier. No coherent theory of institutional decision has, however, been elaborated in
Canadian law.
Appeal courts have also recognized administrative autonomy
in evidentiary matters. The technical rules of evidence applied by
Canadian courts are the product of a jury system, and nothing justifiès
their transfer to the administrative level. Nonetheless, administrative
decisions must be based on evidence produced at the
hearing, and not on privately obtained facts. Canadian courts have
not elaborated a coherent theory of judicial notice, and might be
well advised to emulate the American experience. At the very least,
appellate courts might be more tolerant of such notice taken by
regularoty agencies.
The author discusses, in conclusion, the advantages and drawbacks
of a codification of the case-law rules of administrative procedure
and evidence. He concludes that Canadian and Québec
case-law have perhaps not yet reached a degree of maturity sufficient
to enable such codification
Kinetics of the oxidation of cyclohexene by thallium(II1) acetate
No full textPT: J; CR: ABLEY P, 1973, J AM CHEM SOC, V95, P2591 ANDERSON CB, 1963, J ORG CHEM, V28, P605 BRIODY JM, 1972, J CHEM SOC, P179 BYRD JE, 1973, J AM CHEM SOC, V95, P2586 DRENTH W, 1980, KINETICS APPLIED ORG, P35 GRINSTEAD RR, 1961, J ORG CHEM, V26, P238 HALPERN J, 1968, J CHEM EDUC, V45, P372 HENRY PM, 1965, J AM CHEM SOC, V87, P4423 HENRY PM, 1965, J AM CHEM SOC, V87, P990 HENRY PM, 1966, J AM CHEM SOC, V88, P1597 HENRY PM, 1968, ADVANCES CHEMISTRY S, V70, P126 KABBE HJ, 1962, ANN, V656, P204 KITCHING W, 1968, ORGANOMET CHEM REV, V3, P61 LEE AG, 1971, CHEM THALLIUM LEE JB, 1964, TETRAHEDRON, V20, P1017 MCKILLOP A, 1970, TETRAHEDRON LETT, V60, P5275 MCKILLOP A, 1970, TETRAHEDRON LETT, V60, P5281 NADON L, 1974, CAN J CHEM, V52, P2667 NARASIMHAN S, 1978, INT J CHEM KINET, V10, P581 OUELLETTE RJ, 1969, J ORG CHEM, V34, P4104 RADHAKRISHNAMUR.PS, 1983, INT J CHEM KINET, V15, P587 SEEMAN JI, 1983, CHEM REV, V83, P83 SOUTH A, 1968, J AM CHEM SOC, V90, P7064; NR: 23; TC: 0; J9: INT J CHEM KINET; PG: 13; GA: ALQ49Source type: Electronic(1
Crowdsourcing biocuration: the Community Assessment of Community 1 Annotation with Ontologies (CACAO)
No full textArticle describing an approach to expand biocuration through crowdsourcing with undergraduates in the community-oriented wiki framework for GO annotation called the Gene Ontology Normal Usage Tracking System (GONUTS). This multiplies the number of high-quality annotations in international databases, enriches the coverage of the literature on normal gene function, and pushes the field in new directions
Noncovalent Interactions in Paired DNA Nucleobases Investigated by Terahertz Spectroscopy and Solid-State Density Functional Theory
No full textSocial adaptation of 2 - 3-year-old children in preschool
No full textDarba nosaukums: „2 – 3 gadus vecu bērnu sociālā adaptācija pirmsskolā”. Darba autore: Ligita Koleda Darba vadītāja: Asoc.prof. Dr. paed. Sanita Baranova Darba apjoms: 45 lappuses, 17 attēli, 9 tabulas, 23 literatūras avoti, darbā pievienots 1 pielikums. Darbs sastāv no: ievada, divām daļām, secinājumiem, priekšlikumiem un pielikumiem. Kvalifikācijas darba mērķis: izpētīt 2 – 3 gadus vecu bērnu sociālās adaptācijas pirmsskolā pedagoģiskos nosacījumus. Pētījuma teorētiskajā daļā tika analizēta literatūra un citi avoti par 2 – 3 gadus vecu bērnu vecumposmu un sociālās adaptācijas izpratni un veicināšanas iespējām. Teorētiskā daļa balstās uz Ž. Piažē, R. Špallakas, G. Svences, A. Randohas, Ē. Kalvāna, V. Romenkovas, I. Jurgenas, I. Puškareva, D. Kājiņas, I. Aunītes, A. Vorobjova, V. Kalniņas, S. Gailumas, I. Serovas (Сеpoва) atziņām. Analizēti Lielbritānijas pētnieces H. Ouellette-Kuncas (Ouellette-Kuntz) pētījums par 2 – 3 gadus vecu bērnu vecumposma īpatnībām, L. Āboltiņas, Zviedrijas zinātnieku K. Nilfiras, J. Aspelina, A. Lanca-Andersones (Nilfyr, Aspelin, Lantz–Andersson), Kanādas zinātnieku R. J. Koplāna, A. Boukeres, S. M. Kūperes (Coplan, Bowker, Cooper) un ASV zinātnieka D. H. Danielsas (Daniels) pētījumus par sociālo adaptāciju. Pētījuma empīriskajā daļā tika veikts pētījums 2 – 3 gadus vecu bērnu pirmsskolas grupā, pētot šo bērnu sociālo adaptāciju pirmsskolā. Pētījumā piedalījās 20 bērni un viņu vecāki. Pētījumā tika konstatēts, ka pirmsskolā sabiedriski bērni adaptējas ātrāk, zēni adaptējas lēnāk un tieši zēniem arī novērojamas grūtas adaptācijas galējās izpausmes ar vemšanu un antisociālu uzvedību. Vecāki kā galveno grūtību adaptācijas procesā minējuši bērna nevēlēšanos apmeklēt pirmsskolas izglītības iestādi.Title of the thesis: „Social adaptation of 2-3-year-old children in preschool”. Author of the thesis: Ligita Koleda Supervisor: Asoc. prof. Dr. paed. Sanita Baranova Scope of the thesis: 45 pages, 17 figures, 9 tables, 23 sources of literature were analysed, 1 appendice were added to the thesis. The thesis consists of: an introduction, two parts, conclusions, propositions and appendices. The purpose of the qualification work: to study the pedagogical conditions of social adaptation of 2-3-year-old children in preschool. In the theoretical part of the research, the literature and other sources were analyzed on the understanding and promotion possibilities of the age stages and social adaptation of 2-3-yer-old children. The theoretical part is besed on Ž. Piget, R. Špallaka, G. Svence, A. Randoha, Ē. Kalvāns, V. Romenkova, I. Jurgena, I. Puškarevs, D. Kājiņa, I. Aunīte, A. Vorobyovs, V. Kalniņa, S. Gailuma, I. Serova (Сеpoва) for their options. The research of the British researcher H. Ouellette-Kuntz on the peculiarities of the age stage of 2-3-year-old children, L.Āboltinas, Swedisn scientists K. Nilfyr, J. Aspelin, A. Lantz-Andersson, the studies of Canadian scientists R. J. Coplan, A. Bowker, S. M. Cooper and the American scientist D. H. Daniels on social adaptation. In the empirical part of the study, a survey was conducted in a preschool group of 2-3-year-old children, studying the social adaptation of these children in preschool. 20 children and their parents participated in the study. The study found that in preschool social children adapt faster, boys adapt more slowly, and it is boys who also extreme manifestations of difficult adaptation with vomiting and antisocial behavior. Parents have mentioned the child’s reluctance to attend preschool as the main difficulty in the attend preschool as the main difficulty in the adaptation process
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