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Influence des lipides sur la dynamique du transport du fer médié par la ferroportine-1 et sa modulation par des composés amphiphiles
No full textFerroportin-1(FPN1), the only known mammalian iron exporter, is expressed on the surface of various specialized cells involved in iron metabolism. This protein belongs to the Major Facilitator Superfamily (MFS) and releases intracellular iron through conformational changes oscillating between an open structure towards the cytoplasm (Inward-Facing) and an open structure towards the bloodstream (Outward-Facing; OF). It has been reported that FPN1 is preferentially localized in lipid-rafts, microdomains of the plasma membrane particularly enriched in cholesterol (CHOL). Early in the thesis, we hypothesized that direct interactions between FPN1 and surrounding lipids, notably CHOL, are necessary to stabilize FPN1 in the OF conformation and/or promote certain conformational changes. I confirmed the preferential colocalization of FPN1 in the lipid rafts of human embryonic kidney cells. The dependence of FPN1's iron export function on CHOL was examined by depletion/repletion (CHOL/epicholesterol). Mutational screening experiments supported by structural analyses of the experimental 3D structure of FPN1 in an OF state have identified three possible CHOL-binding sites (of the CARC/CRAC type). Based on molecular dynamics simulations in a simplified POPC-type lipid environment, we identify certain interactions between charged residues of the human FPN1 3D structure and the polar heads of the surrounding phospholipids, which could facilitate conformational changes of the transporter. Besides, I show, for the first time, that FPN1 function is modulated by synthetic amphiphilic compounds, ohmline and its derivatives. Through the development of a novel in vitro approach (PLA: Proximity Ligation Assay), I show that ohmline delocalizes FPN1 from lipid-rafts, thereby decreasing its interaction with its functional partner, ceruloplasmin (CP), a ferroxidase that catalyzes the oxidation of ferrous iron, and consequently its iron export function.La ferroportine-1 (FPN1), seul exportateur de fer connu chez les mammifères, est exprimée à la surface de différentes cellules spécialisées du métabolisme de fer. Cette protéine appartient à la famille des protéines MFS « Major Facilitator Superfamily » et libère le fer intracellulaire au travers de changements conformationnels oscillant entre une structure ouverte vers le cytoplasme (« Inward-Facing ») et une structure ouverte vers la circulation sanguine (« Outward-Facing » ; OF). Il a été rapporté que FPN1 est préférentiellement localisée dans les radeaux lipidiques, des microdomaines de la membrane plasmique particulièrement enrichies en cholestérol (CHOL). Au début de la thèse nous avons formulé l’hypothèse que des interactions directes entre FPN1 et les lipides environnants, notamment le CHOL, sont nécessaires pour stabiliser FPN1 dans la conformation OF et/ou favoriser certains changements conformationnels. J’ai confirmé la colocalisation préférentielle de FPN1 dans les radeaux lipidiques des cellules embryonnaires de rein humain. La dépendance de la fonction d’export de fer de FPN1 au CHOL a été examinée par déplétion/réplétion (CHOL/épicholestérol). Des expériences de criblage mutationnel appuyées par des analyses structurelles de la structure expérimentale 3D de FPN1 dans un état OF ont permis d’identifier trois sites de liaison possibles au CHOL (de types CARC/CRAC). Sur la base de simulations de dynamique moléculaire dans un environnement lipidique simplifié de type POPC, nous identifions certaines interactions entre des résidus chargés de la structure 3D FPN1 humaine et les têtes polaires de phospholipides environnants, qui pourraient faciliter les changements conformationnels du transporteur. Je montre également, pour la première fois, que la fonction de FPN1 est modulée par des composés amphiphiles de synthèse, l’ohmline et ses dérivés. Au travers du développement d’une nouvelle approche in vitro (PLA : « Proximity Ligation Assay »), j’indique que l’ohmline délocalise FPN1 des radeaux lipidiques, diminuant ainsi son interaction avec son partenaire fonctionnel, la céruloplasmine (CP), une ferroxydase qui catalyse l'oxydation du fer ferreux, et en conséquence la fonction d’export du fer
Influence des lipides sur la dynamique du transport du fer médié par la ferroportine-1 et sa modulation par des composés amphiphiles
No full textFerroportin-1(FPN1), the only known mammalian iron exporter, is expressed on the surface of various specialized cells involved in iron metabolism. This protein belongs to the Major Facilitator Superfamily (MFS) and releases intracellular iron through conformational changes oscillating between an open structure towards the cytoplasm (Inward-Facing) and an open structure towards the bloodstream (Outward-Facing; OF). It has been reported that FPN1 is preferentially localized in lipid-rafts, microdomains of the plasma membrane particularly enriched in cholesterol (CHOL). Early in the thesis, we hypothesized that direct interactions between FPN1 and surrounding lipids, notably CHOL, are necessary to stabilize FPN1 in the OF conformation and/or promote certain conformational changes. I confirmed the preferential colocalization of FPN1 in the lipid rafts of human embryonic kidney cells. The dependence of FPN1's iron export function on CHOL was examined by depletion/repletion (CHOL/epicholesterol). Mutational screening experiments supported by structural analyses of the experimental 3D structure of FPN1 in an OF state have identified three possible CHOL-binding sites (of the CARC/CRAC type). Based on molecular dynamics simulations in a simplified POPC-type lipid environment, we identify certain interactions between charged residues of the human FPN1 3D structure and the polar heads of the surrounding phospholipids, which could facilitate conformational changes of the transporter. Besides, I show, for the first time, that FPN1 function is modulated by synthetic amphiphilic compounds, ohmline and its derivatives. Through the development of a novel in vitro approach (PLA: Proximity Ligation Assay), I show that ohmline delocalizes FPN1 from lipid-rafts, thereby decreasing its interaction with its functional partner, ceruloplasmin (CP), a ferroxidase that catalyzes the oxidation of ferrous iron, and consequently its iron export function.La ferroportine-1 (FPN1), seul exportateur de fer connu chez les mammifères, est exprimée à la surface de différentes cellules spécialisées du métabolisme de fer. Cette protéine appartient à la famille des protéines MFS « Major Facilitator Superfamily » et libère le fer intracellulaire au travers de changements conformationnels oscillant entre une structure ouverte vers le cytoplasme (« Inward-Facing ») et une structure ouverte vers la circulation sanguine (« Outward-Facing » ; OF). Il a été rapporté que FPN1 est préférentiellement localisée dans les radeaux lipidiques, des microdomaines de la membrane plasmique particulièrement enrichies en cholestérol (CHOL). Au début de la thèse nous avons formulé l’hypothèse que des interactions directes entre FPN1 et les lipides environnants, notamment le CHOL, sont nécessaires pour stabiliser FPN1 dans la conformation OF et/ou favoriser certains changements conformationnels. J’ai confirmé la colocalisation préférentielle de FPN1 dans les radeaux lipidiques des cellules embryonnaires de rein humain. La dépendance de la fonction d’export de fer de FPN1 au CHOL a été examinée par déplétion/réplétion (CHOL/épicholestérol). Des expériences de criblage mutationnel appuyées par des analyses structurelles de la structure expérimentale 3D de FPN1 dans un état OF ont permis d’identifier trois sites de liaison possibles au CHOL (de types CARC/CRAC). Sur la base de simulations de dynamique moléculaire dans un environnement lipidique simplifié de type POPC, nous identifions certaines interactions entre des résidus chargés de la structure 3D FPN1 humaine et les têtes polaires de phospholipides environnants, qui pourraient faciliter les changements conformationnels du transporteur. Je montre également, pour la première fois, que la fonction de FPN1 est modulée par des composés amphiphiles de synthèse, l’ohmline et ses dérivés. Au travers du développement d’une nouvelle approche in vitro (PLA : « Proximity Ligation Assay »), j’indique que l’ohmline délocalise FPN1 des radeaux lipidiques, diminuant ainsi son interaction avec son partenaire fonctionnel, la céruloplasmine (CP), une ferroxydase qui catalyse l'oxydation du fer ferreux, et en conséquence la fonction d’export du fer
Influence of lipids on the dynamics of ferroportin-1-mediated iron transport and its modulation by amphiphilic compounds
No full textLa ferroportine-1 (FPN1), seul exportateur de fer connu chez les mammifères, est exprimée à la surface de différentes cellules spécialisées du métabolisme de fer. Cette protéine appartient à la famille des protéines MFS « Major Facilitator Superfamily » et libère le fer intracellulaire au travers de changements conformationnels oscillant entre une structure ouverte vers le cytoplasme (« Inward-Facing ») et une structure ouverte vers la circulation sanguine (« Outward-Facing » ; OF). Il a été rapporté que FPN1 est préférentiellement localisée dans les radeaux lipidiques, des microdomaines de la membrane plasmique particulièrement enrichies en cholestérol (CHOL). Au début de la thèse nous avons formulé l’hypothèse que des interactions directes entre FPN1 et les lipides environnants, notamment le CHOL, sont nécessaires pour stabiliser FPN1 dans la conformation OF et/ou favoriser certains changements conformationnels. J’ai confirmé la colocalisation préférentielle de FPN1 dans les radeaux lipidiques des cellules embryonnaires de rein humain. La dépendance de la fonction d’export de fer de FPN1 au CHOL a été examinée par déplétion/réplétion (CHOL/épicholestérol). Des expériences de criblage mutationnel appuyées par des analyses structurelles de la structure expérimentale 3D de FPN1 dans un état OF ont permis d’identifier trois sites de liaison possibles au CHOL (de types CARC/CRAC). Sur la base de simulations de dynamique moléculaire dans un environnement lipidique simplifié de type POPC, nous identifions certaines interactions entre des résidus chargés de la structure 3D FPN1 humaine et les têtes polaires de phospholipides environnants, qui pourraient faciliter les changements conformationnels du transporteur. Je montre également, pour la première fois, que la fonction de FPN1 est modulée par des composés amphiphiles de synthèse, l’ohmline et ses dérivés. Au travers du développement d’une nouvelle approche in vitro (PLA : « Proximity Ligation Assay »), j’indique que l’ohmline délocalise FPN1 des radeaux lipidiques, diminuant ainsi son interaction avec son partenaire fonctionnel, la céruloplasmine (CP), une ferroxydase qui catalyse l'oxydation du fer ferreux, et en conséquence la fonction d’export du fer.Ferroportin-1(FPN1), the only known mammalian iron exporter, is expressed on the surface of various specialized cells involved in iron metabolism. This protein belongs to the Major Facilitator Superfamily (MFS) and releases intracellular iron through conformational changes oscillating between an open structure towards the cytoplasm (Inward-Facing) and an open structure towards the bloodstream (Outward-Facing; OF). It has been reported that FPN1 is preferentially localized in lipid-rafts, microdomains of the plasma membrane particularly enriched in cholesterol (CHOL). Early in the thesis, we hypothesized that direct interactions between FPN1 and surrounding lipids, notably CHOL, are necessary to stabilize FPN1 in the OF conformation and/or promote certain conformational changes. I confirmed the preferential colocalization of FPN1 in the lipid rafts of human embryonic kidney cells. The dependence of FPN1's iron export function on CHOL was examined by depletion/repletion (CHOL/epicholesterol). Mutational screening experiments supported by structural analyses of the experimental 3D structure of FPN1 in an OF state have identified three possible CHOL-binding sites (of the CARC/CRAC type). Based on molecular dynamics simulations in a simplified POPC-type lipid environment, we identify certain interactions between charged residues of the human FPN1 3D structure and the polar heads of the surrounding phospholipids, which could facilitate conformational changes of the transporter. Besides, I show, for the first time, that FPN1 function is modulated by synthetic amphiphilic compounds, ohmline and its derivatives. Through the development of a novel in vitro approach (PLA: Proximity Ligation Assay), I show that ohmline delocalizes FPN1 from lipid-rafts, thereby decreasing its interaction with its functional partner, ceruloplasmin (CP), a ferroxidase that catalyzes the oxidation of ferrous iron, and consequently its iron export function
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Full text link“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
Full text linkWe 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
Full text linkWe 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
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