1,721,704 research outputs found
Tecniques: recent developments in computer aided engineering of GPCR ligands using the human A3 adenosine receptor as an example.
No full textG-protein-coupled receptors (GPCRs) represent the largest known family of signal-transducing molecules, and convey signals for light and many extracellular regulatory molecules. GPCRs are dysfunctional or dysregulated in several human diseases and are estimated to be the targets of O40% of the drugs used in clinical medicine today. The crystal structure of rhodopsin provides the first information on the three-dimensional structure of GPCRs, which now supports homology modeling studies and structure-based drug-design approaches
TRIAZOLE DERIVATIVES AS P2Y14 RECEPTOR ANTAGONISTS
No full textThe Molecular Recognition Section of NIDDK announces the availability of a novel triazole-based probes, structures which act as antagonists at human P2Y14 receptors. Although the physiologic functions of this receptor remain undefined, recently it has been strongly implicated in immune and inflammatory responses. Prior work with a 4,7-disubstituted 2 naphthoic acid derivative (PPTN) established the ability to inhibit chemotaxis of human neutrophils in the lung and kidney.
In this series, the triazole moiety is used as a bioisosteric replacement for the naphthoic acid core of PPTN. This substitution imparts more stability. This triazole ring has increased polarity and additional H-bond accepting groups when compared to a naphthalene core. The new triazole scaffold can form additional interactions that stabilize the ligand within the receptor binding pocket. It has also been identified that substitution at the para-position of the phenyl ring is favored
TRIAZOLE DERIVATIVES AS P2Y14 RECEPTOR ANTAGONISTS
No full textThe Molecular Recognition Section of NIDDK announces the availability of a novel triazole-based probes, structures which act as antagonists at human P2Y14 receptors. Although the physiologic functions of this receptor remain undefined, recently it has been strongly implicated in immune and inflammatory responses. Prior work with a 4,7-disubstituted 2 naphthoic acid derivative (PPTN) established the ability to inhibit chemotaxis of human neutrophils in the lung and kidney.
In this series, the triazole moiety is used as a bioisosteric replacement for the naphthoic acid core of PPTN. This substitution imparts more stability. This triazole ring has increased polarity and additional H-bond accepting groups when compared to a naphthalene core. The new triazole scaffold can form additional interactions that stabilize the ligand within the receptor binding pocket. It has also been identified that substitution at the para-position of the phenyl ring is favored
FLUORESCENT ANTAGONISTS OF THE A3 ADENOSINE RECEPTOR
No full textDisclosed are compounds which are fluorescently labeled antagonists of the A3 adenosine receptor. Also disclosed are diagnostic of a patient for a possible treatment by an antagonist if the A3 adenosine receptor, involving the use of one or more of these compounds as diagnostic agents
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
ADP-, and ATP-mimetics derived from 2'(3')-C-methyladenosine as human P2Y1 and P2Y2 ligands
No full textNucleotides and their hydrolytic products act through specific nucleotide receptors which are divided in: ionotropic P2X and metabotropic P2Y receptors coupled to G proteins. The P2Y receptor family consists of at least eight human subtypes (P2Y1,2,4,6,11-14), that are activated by either or both adenine and uracil nucleotides [1]. Activation of P2Y receptors generally results in the stimulation of phospholipase C (PLC), which generates inositol phosphates and diacylglycerol from phosphatidyl inositol(4,5)bisphosphate, leading to the rise in intracellular calcium and activation of protein kinase C. According to a dendrogram relating sequence homology, the P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11 receptors form a cluster of preferentially Gq-coupled receptors, and the P2Y12, P2Y13, and P2Y14 form a cluster of preferentially Gi-coupled receptors.
The P2Y1 and P2Y2 receptors are expressed in most human tissues, including brain, heart, placenta, lungs, liver, skeletal muscle, kidneys, pancreas and variuos blood cells. P2Y1 receptor is activated by ADP, while P2Y2 is activated equipotently by both ATP and UTP. Several ADP and ATP analogues have been investigated to explore structure-activity relationships for P2Y1 and P2Y2 receptors. It was reported that constraining the riboselike ring as methanocarba analogues of ADP and ATP, the Northern (N, 2'-exo) conformation was associated with increased agonist potency at recombinant human P2Y1 and P2Y2 receptors, while the Southern (S, 2'-endo) conformer was less potent. A similar conformational preference of the ribose moiety in binding to uridine nucleotide-activated hP2Y2 receptor was detected with the methanocarba analogues of UTP [2].
In order to further investigate the influence of conformation of ribose-modified ADP and ATP analogues on affinity and efficacy at hP2Y1 and hP2Y2 receptors, we have synthesized the 2'- and 3'-C-methyl derivatives of ADP and ATP. These nucleotides were evaluated for their capacity to promote hP2Y1 and hP2Y2 receptor-mediated activation of phospholipase C at recombinant human receptors expressed in astrocytoma cells. The results of the functional assay will be discussed.
[1] Abbracchio MP et al. International Union of Pharmacology LVIII: Update on the P2Y G Protein-Coupled Nucleotide Receptors: From Molecular Mechanisms and Pathophysiology to Therapy. Pharmacol Rev. 2006, 58: 281-341.
[2] Kim, H. S.; Ravi, R. G.; Marquez, V. E.; Maddileti, S.; Wihlborg, A.-K.; Erlinge, D.; Malmsjö, M.; Boyer, J. L.; Harden, K.; Jacobson, K. A. Methanocarba Modification of Uracil and Adenine Nucleotides: High Potency of Northern Ring Conformation at P2Y1, P2Y2, P2Y4 and P2Y11 but not P2Y6 Receptors. J. Med. Chem. 2002, 45: 208-18
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
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