1,720,962 research outputs found
Étude de l'oligomérisation du récepteur de l'urotensine ii et son impact sur la sélectivité fonctionnelle de ses ligands
Get PDFLes récepteurs couplés aux protéines G (RCPG) sont impliqués dans le contrôle d'un large éventail de
fonctions physiologiques, dont la régulation des réponses hormonales, neuronales et musculaires. Au
cours de la dernière décennie, de nombreux concepts sont venus bouleverser notre compréhension des
mécanismes régulant leur activation et la signalisation qui y est associée. Parmi ces nouveaux concepts en
émergence, on retrouve notamment l'oligomérisation des RCPG. Les premières théories stipulaient que
les RCPG exerçaient leurs fonctions sous forme de monomères. Par contre, aujourd'hui , des preuves
irréfutables et multiples montrent clairement l'existence d'homomères et d 'hétéromères. Ce phénomène
produit un changement conformationnel au niveau des deux protomères constituant le dimère et peut
avoir un impact sur leur transport à la surface cellulaire, leur pharmacologie, leur signalisation et/ou leurs
propriétés d'internalisation. Le sujet de la présente thèse est axé sur le système urotensinergique composé
de deux ligands endogènes, l'urotensine II (UII) et l'urotensin-related peptide II (URP), et d'un RCPG
(UT). Bien que les deux ligands partagent le même récepteur, des données récentes ont démontré que
ceux-ci pouvaient exercer des actions physiologiques divergentes et qu ' ils étaient donc fonctionnellement
sélectifs. Avec l'émergence du concept que l'oligomérisation des RCPG contribuerait à leur diversité
pharmacologique, il nous est apparu important d'analyser les mécanismes moléculaires impliqués dans
l'activation de !'UT en relation avec la présence ou non d'oligomères de ce récepteur.
L'hypothèse du présent projet de recherche stipule que le récepteur hUT, sous la forme d'homodimères,
ou d'oligomères, serait responsable de la sélectivité fonctionnelle observée avec UII et URP. Nos
objectifs pour ce projet de recherche étaient i) d'établir l'existence d'homodimère de h UT, ii) de
déterminer les composantes structural es impliquées dans cette oligomérisation et iii) d' utiliser ces
déterminants comme modulateurs allostériques.
Lors de ce doctorat, nous avons réussi à démontrer l'existence d'une forme oligomérique du récepteur
hUT par la technique du photomarquage et par des essais de liaison. La présence de coopérativité
distincte pour hUII et URP pourrait, en autres, laisser présager d 'un rôle de l'oligomérisation dans leur
sélectivité fonctionnelle. De même, il semble que Gaq soit impliquée clans ce phénomène . En revanche,
cette coopérativité ne semble pas impliquée dans la signalisation induite par ces cieux peptides du moins
dans celles analysées. Par la suite, nous avons synthétisé et testé, comme précédemment, des composés
mimant les domaines transmembranaires (DTM) de hUT. Nous avons ainsi pu déterminer que les DTM 4
et 5 étaient capables de moduler la coopérativité des deux peptides endogènes . De plus, nous avons aussi
pu observer une potentialisation de la puissance d'activation de la voie Gaq de hUII et de URP en présence
des DTM4-5. L'utilisation de tels peptides mimant les DTM pourrait représenter une piste intéressante
pour le développement de nouveaux modulateurs allostériques.G protein-coupled receptors (GPCRs) are involved in the control of a wide range of physiological
fonctions , including the regulation of hormonal, neuronal and muscle responses. Over the past decade,
many concepts have changed our understanding of the mechanisms regulating their activation and the
signaling associated with them. Among these new emerging concepts is the oligomerization of GPCRs.
Early theories stated that GPCRs perform their fonctions as monomers. On the other hand, today,
irrefotable and multiple evidence clearly ·shows the existence of homomers and heteromers. This
phenomenon produces a conformational change at the level of the two protomers constituting the dimer
and can have an impact on their transport to the cell surface, their pharrnacology, their signaling and/ or
their internalization properties. The subject of this thesis focuses on the urotensinergic system composed
of two endogenous ligands, urotensin II (UII) and urotensin-related peptide II (URP), and a GPCR (UT).
Although the two ligands share the same receptor, recent data have shown that they can exert divergent
physiological actions and that they are therefore fonctionally selective. With the emergence of the concept
that GPCR oligomerization can contribute to their pharmacological diversity, it seemed important tous to
analyze the molecular mechanisms involved in the activation of UT in relation to the presence or not of
oligomers of this receptor.
The hypothesis of this research project states that the UT receptor, in the form of homodimers, or
oligomers, would be responsible for the fonctional selectivity observed with UII and URP. Our objectives
for this research project were i) to establish the existence of UT homodimer, ii) to determine the structural
components involved in this oligomerization and iii) to use these deterrninants as allosteric modulators.
During this PhD, we succeeded in demonstrating the existence of an oligomeric form of the UT receptor
using the photolabelling technique and various binding assays. The presence of distinct cooperativity for
UII and URP could, among other things, suggest a role for oligomerization in their fonctional selectivity.
Similarly, it seems that the Gaq protein is involved in this phenomenon. On the other hand, this
cooperativity does not seem to be involved in the signaling induced by these two peptides at least for
those tested. Subsequently, as previously, we synthesized and tested compounds mimicking the
transmembrane domains (DTM) of hUT. We were thus able to determine that DTMs 4 and 5 were
capable of modulating the cooperative nature of the two endogenous peptides. In addition, we also
observed a potentiation of the activation power of the Gaq pathway of hUII and URP in the presence of
DTM4-5. The use of such peptides mimicking DTMs could represent an interesting avenue for the
development of new allosteric modulators.</br
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Impact of the Modernization of Tax Administration on Efficiency of Tax Administration and Tax Compliance of Taxpayers in Algeria
Get PDFThis study aims to determine the impact of the modernization of tax administration on efficiency of tax administration and tax compliance of taxpayers in Algeria, to assess this impact we used statistical data reflecting the activity DGI services, such as tax revenue, overall administrative cost, number of litigation files relating to tax fraud, amount of recoveries after tax audit and number of fraudsters registered in the national fraudsters file, through the evolution of the different statistical data for the period 2012-2018 it has been concluded that the modernization of tax administration has made it possible to improve efficiency of tax administration but efforts remain to be made to improve it further, on the other hand the program of modernization did not improve tax compliance of taxpayers in Algeri
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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