1,720,965 research outputs found
Identification of cellular kinases responsible for Hepatitis C Virus NS5A hyperphosphorylation
Full text linkHepatitis C virus (HCV) has been the subject of intensive studies for nearly
two decades. Nevertheless, some aspect of the virus life cycle are still a
mystery. The HCV Nonstructural protein 5A (NS5A) has been shown to be a
modulator of cellular processes possibly required for the establishment of
viral persistence. NS5A is heavily phosphorylated, and a switch between a
basally phosphorylated form of NS5A (p56) and a hyperphosphorylated
form of NS5A (p58) seems to play a pivotal role in regulating HCV
replication.
Efficient replication of HCV subgenomic RNA in cell culture requires the
introduction of adaptive mutations. Some of the most effective adaptive
mutations occur at the serine residues that have been shown to be implicated
in NS5A hyperphosphorylation and adaptive mutations at these sites result in
a significant reduction of NS5A hyperphosphorylation (p58).
After screening of a panel of kinase inhibitors, we selected three compounds
which inhibited NS5A phosphorylation in vitro, as well as the formation of
NS5A p58 in cell culture. Cells transfected with the HCV wild type replicon
sequence supported HCV RNA replication upon addition of any of the three
compounds.
Thus, reduction of the formation of p58 below a certain threshold either by
adaptive mutations or by inhibition of the NS5A–specific kinase(s) would
enable HCV replication in cell culture.
Although large amounts of NS5A-p58 appear to inhibit HCV RNA
replication, the complete inhibition of NS5A hyperphosphotylation by the
kinase inhibitors we identified abolishes HCV replication of already adapted
replicons indicating that a small quantity of p58 is required for replication.
Using kinase inhibitors that specifically inhibit the formation of NS5A-p58
in cells, we identified CK1 kinase family as a target.
NS5A-p58 increased upon overexpression of CK1alpha, CK1δ and CK1ε,
whereas the RNA interference of only CK1alpha reduced NS5A
hyperphosphorylation. Rescue of inhibition of NS5A-p58 was achieved by
CK1 alpha overexpression, and we demonstrated that the CK1 alpha isoform is
targeted by NS5A hyperphosphorylation inhibitors in living cells and that the
down-regulation of NS5A attenuates HCV RNA replication.
Finally, we demonstrate here that NS5A is a direct substrate of CKI- alpha and
phosphorylation of NS5A in vitro by CKI- alpha resulted in the production of two
phosphorylated forms that resemble those products produced in cells.
In vitro kinase reactions performed with NS5A peptides show that S2204 is
a preferred substrate residue for CKI- alpha after pre-phosphorylation of S220
Lower to Middle Ordovician acritarchs and chitinozoans from Northern Karakorum Mountains, Pakistan
No full textImmagini di cose presenti, immagini di cose assenti: aspetti storici della riproduzione d'arte
No full text
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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