1,720,984 research outputs found
Deregulation of the AR non genomic signaling pathways in an in vitro SBMA model
No full textL'atrophie musculaire bulbo-spinale (SBMA) est une dégénérescence lente et progressive des motoneurones causée par l'élongation du triplet nucléotidique (CAG) dans le gène codant pour le récepteur aux androgènes (RA) localisé sur le chromosome X. Dans la SBMA, ce récepteur à extension polyglutaminique (polyQ) pathogène s'accumule de manière ligand dépendante dans le cytoplasme sous forme d'agrégats mais également dans le noyau y créant des corps d'inclusions nucléaires considérés comme la marque identitaire histologique, dont le caractère cytotoxique est aujourd'hui remis en question. Nous avons développé un modèle SBMA in vitro basé sur l'expression inductible d'un RA51Q dans la lignée hybride NSC34, qui est comparé au modèle normal NSC34 exprimant un RA contenant 20Q. Nous avons démontré que l'expression du RA51Q entraîne une diminution de la viabilité ainsi qu'une altération de la croissance neuritique sans formation d'agrégats insolubles dans le noyau ou le cytoplasme des cellules. Le RA en tant que membre de la superfamille des récepteurs nucléaires est un facteur de transcription mais peut également induire des voies de signalisation non génomiques via sa localisation membranaire. Après avoir montré une localisation du RA20Q et du RA51Q dans les « lipid rafts », nous avons corrélé la diminution de la viabilité et de la pousse neuritique induite par le RA51Q à une altération de la signalisation cellulaire non génomique. Les résultats obtenus mettent en évidence une dérégulation des voies de signalisation PI3K/Akt et JNK/c-jun induite par l'expression du RA muté dans notre modèle SBMA.Spinal Bulbar Muscular Atrophy (SBMA) is a progressive inherited motoneuron disease caused by the expansion of a trinucleotide (CAG) repeat in the gene coding for the androgen receptor (AR) located on the X chromosome. This rare disease causes muscle weaknesses, hypotonia, hyporeflexia, fasciculations of facial muscles in male patients. The androgen-dependent formation of cytoplasmic aggregates and nuclear inclusions are pathological hallmarks of this polyglutamine disease but their potential neurotoxicity is still under debate. We developed a SBMA model based on a doxycycline-inducible AR51Q expression system in the NSC34 hybrid cell line. We have shown that the expression of the mutated AR leads to a reduced viability and to an alteration of neurite outgrowth compared to cells expressing the normal AR20Q. The AR belongs to the nuclear receptor superfamily of transcription factors. However, recent data have put in evidence a membrane localization of AR initiating non-genomic signaling pathways. Because we have not observed insoluble aggregates, reduced viability and neurite outgrowth could not be correlated to AR aggregation. We hypothesized that motoneuron death is not only due to aggregate formation but also to the alteration of AR signaling pathways. We focused on a correlation between the AR localization in lipid rafts and the observed phenotypes. Our results highlight the deregulation of PI3K/Akt and JNK/c-jun signaling pathways induced by the expression of AR51Q in our SBMA model
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
The impact of the extracellular matrix on glioblastoma stem cells migration : a tridimensional culture model and a new therapeutic strategy
No full textLes glioblastomes multiformes (GBM) comptent parmi les tumeurs au pronostic le plus sombre. L’extraordinaire capacité invasive des cellules tumorales rend toutes les interventions thérapeutiques actuelles totalement impuissantes. Une sous-population de Cellules Souches de Glioblastome (CSG) hautement invasive est responsable de la récurrence tumorale. Dans le cerveau, les GBM migrent principalement le long des vaisseaux sanguins au sein de l’espace périvasculaire riche en laminine, fibronectine et collagène ainsi qu’en suivant l’alignement des fibres myélinisées du corps calleux. La Matrice Extracellulaire (MEC) de ces régions joue un rôle important dans l’invasion des GBM, mais les mécanismes mis en jeu n’ont pas été complètement dévoilés. De plus, le développement de nouvelles thérapies anti-migratrices ciblant l’interaction des GBM avec la MEC reste encore limité. Dans le but de mimer la composition biochimique et les propriétés mécaniques de la MEC cérébrale et d’étudier leur rôle(s) dans la migration des CSG, nous avons développé un nouveau support de nanofibres (NF) alignées et fonctionnalisées avec de la laminine. Mes travaux de thèse ont montré que les NF génèrent un microenvironnement tridimensionnel (3D) favorisant l’adhésion et la migration des CSG. Cette adhésion est améliorée en comparaison avec les supports planaires (SP) conventionnels (2D) et récapitule mieux les mécanismes d’interaction des CSG avec la MEC au cours de l’invasion dans le modèle murin de tumeurs xénogreffées. Dans ces conditions physiologiques plus convenables générées par les NF, la variation des composantes biochimiques et mécaniques de la MEC affecte la migration des CSG. La présence ou l’absence de laminine régule le mode migratoire et l’orientation de fibres contrôle la direction de migration des CSG. D’un autre coté, l’altération de la glycosylation des protéines de la surface cellulaire module l’interaction des cellules tumorales du cerveau avec la MEC et augmente leur invasion. La deuxième partie de mes travaux de thèse a permis de démontrer que les glycomimétiques phostines « 3.1a » réorganisent le processus de la N-glycosylation des CSG diminuant leur invasivité in vitro et in vivo en inhibant les voies de signalisation de la kinase FAK et du récepteur de TGF-β impliqués dans l’interconnexion cellule-MEC.Glioblastoma Multiforme (GBM) is a biologically aggressive tumor with an extremely poor prognosis. The highly invasive capacity of a subpopulation of Glioblastoma Initiating Cells (GIC) makes complete surgical resection impossible. GBM dissemination occurs along preexisting brain structures such as the perivascular space rich in laminin, fibronectine and collagen as well as the aligned myelinated fibers of the corpus callosum. The Extracellular Matrix (ECM) of these cerebral regions plays an important role during GBM invasion, but the underlying mechanisms remain largely unknown. Accordingly, the development of new anti-migratory therapies targeting the cell-ECM interactions is lacking. In order to mimic the compositional and physical properties of the cerebral ECM and to investigate their role(s) in GBM invasion, we have set up a new aligned nanofibers (NF)scaffold functionalized with laminin. My work demonstrated that the NFs constitute a tridimensional (3D) microenvironment supporting GIC adhesion and migration. The cell-ECM adhesion is improved on the NF in comparison to the conventional 2D planar surfaces (PS). Furthermore, the mechanisms of GIC interaction with the ECM on the NF are similar to those observed in the human GBM xenograft murine model. In this physiologically more relevant 3D microenvironment reproduced by the NF, the variation of the different biochemical and mechanical components of the ECM affects the migration of GIC. The presence or absence of laminin on the NF regulates the mode of migration and the orientation of the fibers dictates the direction of migration of GIC. On the other hand, the glycosylation that decorates cell surface proteins modulates the interaction of GBM tumor cells with the ECM and its alteration increases their invasion. The second part of my thesis demonstrated that the glycomimetics phostines « 3.1a » remodel the N-glycosylation of GIC and decrease their invasivity in vitro and in vivo via the inhibition of FAK and TGFβ-R signaling pathways known to be implicated in the cell-ECM intercommunication
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
Mechanotransduction of glioblastoma stem cells in a new 3D matrix for cell culture
No full textLes cellules souches de glioblastomes (GSC) sont sensibles aux propriétés mécaniques de leur microenvironnement et utilisent la rigidité pour favoriser leur invasion.Dans ce contexte, nous avons développé une matrice 3D fibrillaire artificielle permettant de récapituler in vitro les comportements migratoires observés in vivo. Cette matrice étant hautement plastique, nous avons pu moduler la rigidité, la chimie de surface ou encore l'alignement des fibres.Dans un premier temps nous avons modifié leur chimie de surface grâce à l’ajout de protéines de la matrice extracellulaire (MEC) puis déposé des neurosphères (NS) de GSC sur ce tissu artificiel. L’ajout de laminine nous a permis d’observer le passage d’un comportement migratoire collectif à individuel.Dans un deuxième temps nous avons modulé la rigidité des fibres. Après cinq jours de migration des GSC dans différentes conditions de rigidités, nous avons constaté une augmentation de la vitesse de migration à la rigidité intermédiaire de 166kPa par rapport à la condition plus souple de 3,2 kPa et à la condition plus rigides de 1260kPa. Cette capacité migratoire maximale dans nos conditions est associée à des changements de morphologie des GSC, à une augmentation de l'expression des protéines associée à la transition épithélio-mésenchymateuse (EMT) et à une modification de la régulation des protéines des adhérences focales.La surexpression de Mannoside acetyl glucosaminyltransférase 5 (MGAT5) est associée aux tumeurs malignes et est impliquée dans la formation de regroupement de protéines membranaires grâce à la formation d’un treillis. Elle favorise également la maturation des adhérences focales, la migration cellulaire, l'invasion et l’EMT, entraînant ainsi des avantages fonctionnels pour les cellules tumorales. Au vu des résultats précédents sur l'expression des protéines EMT et des modifications de la régulation des protéines des adhérences focales, nous avons généré des GSC n’exprimant plus la MGAT5 grâce à la technique CRISPR Cas9 et les avons placées en NS sur les matrices 3D présentant différentes rigidité. Nous avons alors observé une diminution de la vitesse de migration à 166kPa par rapport aux GSC contrôles, associée à une diminution de l'EMT et de la maturation des adhérences focales. Par conséquent, cette étude démontre l'implication de la glycosylation et plus particulièrement de la glycosylation médiée par la MGAT5 sur la mécanotransduction des GSC.Glioblastoma stem cells (CSC) have been reported to be sensitive to the mechanical properties of the surrounding tissue/microenvironment and to use the microenvironment stiffness to enhance invasion.In this context, we developed a 3D artificial fibrillary tissue which can allow in vitro recapitulation of the migration behavior observed in vivo. This 3D matrix is highly plastic which allows for modulation of stiffness, surface chemistry and fibers alignment.On the first hand, we functionalized the fibers with extracellular matrix proteins and then we plated GSCs neurospheres (NS) on the developed 3D artificial tissue. The addition of laminin modulates the migration behaviour from single cell to collective mode.On the second hand we have modified stiffness of the fibers. After five days of GSCs NS migration on 3D electrospun fibers of different stiffnesses, we have seen an increase in migration velocity for an intermediate stiffness of 166kPa in comparison with our softest 3.2 kPa and stiffest stiffnesses (1260 kPa). This maximum migration rate is associated with changes in cell shape, increase of EMT proteins expressions and modifications of focal adhesion proteins regulation.Mannoside acetyl glucosaminyltransferase 5 (MGAT5) overexpression is associated with malignant tumors and it is implicated in the clustering of membrane proteins through lattice formation, focal adhesions, cell migration, invasion, and epithelial-to-mesenchymal transition (EMT), resulting in functional advantages for tumor cells.In light of previous results about of EMT proteins expressions and modifications of focal adhesion proteins regulation, we generated MGAT5 CRISPR Cas9 GSCs and placed it on 3D matrix with different stiffnesses. We observe a decrease in migration velocity at the intermediate stiffness in comparison with GSCs WT associated with a decrease in focal adhesion maturation and EMT. This study demonstrates the implication of glycosylation and more particularly MGAT5-mediated glycosylation on GSCs mechanotransduction
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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