1,720,953 research outputs found
Identification and functional characterization of the cytosolic form of the FKBP7 protein in chemoresistant prostate cancer using a cellular and structural approach
No full textLa résistance aux chimiothérapies représente toujours un frein dans la prise en charge thérapeutique des stades avancés des cancers de la prostate (CaP). Notre équipe a précédemment identifié la protéine FKBP7, une peptidyl prolyl cis- trans isomérase encore largement méconnue de la famille des FKBPs, comme cible thérapeutique potentielle dans le CaP chimiorésistant. FKBP7 est surexprimée dans les modèles chimiorésistants de CaP et son inhibition diminue la prolifération tumorale in vitro et in vivo. Enfin, elle interagit avec la sous-unité eIF4G du complexe d’initiation de la traduction eIF4F et pourrait donc intervenir dans une reprogrammation traductionnelle. Dans cette thèse, nous avons décrypté la fonction de FKBP7 au niveau moléculaire et cellulaire afin de mieux comprendre sa fonction dans la chimiorésistance, et également entrepris une étude structurale pour obtenir de premières informations sur son interactivité et sa spécificité. Compte-tenu de l’interaction entre FKBP7, qui est résidente du réticulum endoplasmique (RE), et eIF4G, qui est cytosolique, nous avons questionné la dynamique intracellulaire de FKBP7. Nos résultats montrent que FKBP7 présente une localisation cytosolique qui est enrichie par plusieurs chimiothérapies et par le stress oxydant. La forme cytosolique de FKBP7 est majoritairement N-glycosylée ce qui confirme qu’elle provient bien du RE, et elle n’est pas dégradée par le protéasome ce qui soutient l’hypothèse qu’elle possèderait une fonction spécifique dans le cytosol. Nous avons identifié les domaines d’interaction entre FKBP7 et l’isoforme eIF4G1 par co- immunoprécipitation. Nos résultats montrent que FKBP7 interagit avec eIF4G1 par son domaine structuré HEAT3 présent en C-terminal, mais aussi par son domaine central. La délétion du domaine HEAT3 n’est pas suffisante pour perdre l’interaction entre FKBP7 et eIF4G1, ce qui souligne que FKBP7 semble bien posséder plusieurs sites d’interaction avec eIF4G1. Par ailleurs, la proline P1497, de conformation cis dans la structure cristallographique du domaine HEAT3 d’eIF4G1, impacte fortement l’interaction entre FKBP7 et le domaine HEAT3. Comme les FKBPs sont connues pour posséder une activité proline cis-trans isomérase, ceci suggère que cette proline pourrait être la cible d’une isomérisation par FKBP7. En parallèle, des résultats de profilage des polysomes ont également identifié une interaction entre FKBP7 et la sous-unité ribosomique 40S, renforçant le rôle potentiel de FKBP7 dans la traduction. Au niveau fonctionnel, des expériences de profilage des polysomes suivies de RNAseq ont été réalisées pour évaluer l’impact de FKBP7 sur la traduction des cellules tumorales résistantes au docétaxel. Enfin, l’interaction de FKBP7 avec de premiers ligands a été étudiée par RMN. Nos résultats montrent que le domaine catalytique de FKBP7 interagit avec la rapamycine et l’évérolimus, deux ligands des FKBPs. En revanche, de façon surprenante, il n’interagit pas avec le composé FK506 qui est le ligand fondateur de la famille des FKBPs (FK506-Binding Proteins). Associés à l’alignement de séquences des domaines catalytiques des FKBPs humaines, ces résultats soulignent que FKBP7 semble bien présenter une spécificité d’interaction. En conclusion, les résultats obtenus au cours de ma thèse décrivent des propriétés de localisation intracellulaire atypiques pour la protéine FKBP7. Nous proposons un modèle dans lequel FKBP7 est enrichie dans le cytosol en réponse à des perturbations externes dont les chimiothérapies et le stress oxydant, et où elle posséderait une nouvelle fonctionnalité. Dans les cellules chimiorésistantes de CaP, FKBP7 pourrait intervenir dans la traduction en tant que partenaire d’un complexe protéique impliquant deux acteurs de l’initiation de la traduction : la sous-unité de scaffolding eIF4G1 et la sous-unité ribosomique 40S.Chemoresistance remains an obstacle in the therapeutic management of late stages of prostate cancer (PCa). Our team has previously identified FKBP7, a largely unknown peptidyl prolyl cis-trans isomerase of the FKBPs protein family, as a potential therapeutic target in chemoresistant PCa. FKBP7 is overexpressed in chemoresistant PCa models and its inhibition reduces chemoresistant cancer cell proliferation in vitro and in vivo. Finally, it interacts with the eIF4G subunit of the translation initiation complex eIF4F and could therefore be involved in translational reprogramming. In this thesis, we deciphered the function of FKBP7 at the molecular and cellular levels, in order to better understand its role in chemoresistance. We also undertook a structural study to obtain initial information on FKBP7 interactivity and specificity. Given the interaction between FKBP7, which is resident of the endoplasmic reticulum (ER), and eIF4G, which is cytosolic, we questioned the intracellular dynamics of FKBP7. Our results show that FKBP7 exhibits a cytosolic localization that is enriched by several chemotherapies and by oxidative stress. The cytosolic form of FKBP7 is predominantly N- glycosylated, confirming its ER origin, and is not degraded by the proteasome, supporting the hypothesis of its specific function in the cytosol. We identified the interaction domains between FKBP7 and the eIF4G1 isoform by co-immunoprecipitation. Our results show that FKBP7 interacts with eIF4G1 through its C-terminal HEAT3 structured domain, but also its central domain. Deletion of the HEAT3 domain is not sufficient to lose the interaction between FKBP7 and eIF4G1, highlighting the fact that FKBP7 does appear to possess multiple sites of interaction with eIF4G1. In addition, the cis- conforming proline P1497 in the crystallographic structure of the HEAT3 domain of eIF4G1 strongly impacts the interaction between FKBP7 and the HEAT3 domain. As FKBPs are known to possess cis- trans proline isomerase activity, this suggests that this proline could be a target for isomerization by FKBP7. In parallel, polysome profiling results also identified an interaction between FKBP7 and the 40S small ribosomal subunit, reinforcing the potential role of FKBP7 in translation. At the functional level, polysome profiling experiments, followed by RNAseq, were carried out to assess the impact of FKBP7 on the translation of docetaxel-resistant cancer cells. Finally, the interaction of FKBP7 with some ligands was studied by NMR. Our results show that the catalytic domain of FKBP7 interacts with rapamycin and everolimus, two ligands of the FKBPs. Surprisingly, however, it does not interact with FK506, the founding ligand of the FKBPs family (FK506-Binding Proteins). Taken together with the sequence alignment of the catalytic domains of human FKBPs, these results underline that FKBP7 appears to exhibit binding specificity. In conclusion, the results obtained during my PhD thesis describe atypical intracellular localization properties for the FKBP7 protein. We propose a model in which FKBP7 is enriched in the cytosol in response to external perturbations, including chemotherapies and oxidative stress, and where it could possess novel functionality. In prostate cancer chemoresistant cells, FKBP7 may be involved in translation regulation as a partner in a protein complex involving two actors of translation initiation: the eIF4G1 scaffolding subunit and the 40S small ribosomal subunit
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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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