1,721,003 research outputs found
Nonprofit foundations spur translational research
No full textEvery year, hundreds of promising basic discoveries in the pharmacological field are lost and will never have a chance to be exploited for patients due to difficulties in clinical translation. This is especially true for most neurodegenerative disorders lacking disease-modifying therapies. Here we present the current scenario and our vision of a 'collective-impact' multistakeholder approach to expedite the development of new drugs
Regulation Of The P2Y-Like Receptor GPR17 By Agonist-Induced Desensitization
Full text linkIn oligodendrocyte precursor cells (OPCs) the new P2Y-like receptor GPR17 expression is restricted to early stages of differentiation and segregated from that of mature myelin proteins to the point that mature oligodendrocytes no longer express the receptor1,2. The changes in GPR17 expression during olygodendrocyte differentiation suggest that this receptor may undergo regulatory mechanisms such as desensitization, internalization and down regulation that regulate its responsiveness over time.
On this basis, we analyzed, in a recombinant expression system, GPR17 regulation after prolonged agonist exposure. GPR17 is activated by both uracil-nucleotides (i.e. UDP-glucose3) and cysteynyl-leukotrienes (cysLTs) (i.e. LTD43). We demonstrated that both cysLT and purinergic ligands induced a time- and concentration-dependent GPR17 loss of response; this phenomenon was accompanied by receptor internalization. Upon agonist removal, receptor resensitization occurred with the typical kinetics of GPCR. Moreover, activation of GPR17 by UDP-glucose (but not viceversa) induced a partial heterologous desensitization of LTD4-mediated responses, suggesting that nucleotides have a hierarchy in producing desensitizing signals.
Finally, we showed that GPR17 desensitization occurs as a consequence of receptor phosphorylation on serine and threonine residues, through a mechanism likely involving GRK activation. Since GRK expression and functioning has been demonstrated to be altered in several neurodegenerative diseases, including multiple sclerosis4, studies are in progress to evaluate GRK2 expression and GRK2-mediated GPR17 regulation during OPC maturation, both in physiological and pathological conditions. The determination of the regulatory mechanisms controlling GPR17 responses over time is pivotal to find new ways to foster OPC differentiation and myelin repair in demyelinating diseases
The ubiquitin ligase Mdm2 controls oligodendrocyte maturation by intertwining mTOR with G protein-coupled receptor kinase 2 in the regulation of GPR17 receptor desensitization
Full text linkDuring oligodendrocyte precursor cell (OPC) differentiation, defective control of the membrane receptor GPR17 has been suggested to block cell maturation and impair remyelination under demyelinating conditions. After the immature oligodendrocyte stage, to enable cells to complete maturation, GPR17 is physiologically down-regulated via phosphorylation/desensitization by G protein-coupled receptor kinases (GRKs); conversely, GRKs are regulated by the "mammalian target of rapamycin" mTOR. However, how GRKs and mTOR are connected to each other in modulating GPR17 function and oligodendrogenesis has remained elusive. Here we show, for the first time, a role for Murine double minute 2 (Mdm2), a ligase previously involved in ubiquitination/degradation of the onco-suppressor p53 protein. In maturing OPCs, both rapamycin and Nutlin-3, a small molecule inhibitor of Mdm2-p53 interactions, increased GRK2 sequestration by Mdm2, leading to impaired GPR17 down-regulation and OPC maturation block. Thus, Mdm2 intertwines mTOR with GRK2 in regulating GPR17 and oligodendrogenesis and represents a novel actor in myelination
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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