1,721,095 research outputs found
A complex phosphodiesterase system controls β-adrenoceptor signalling in cardiomyocytes
No full textβ-Adrenergic signalling mediates the positive inotropic effect of catecholamines on cardiomyocytes, mainly through cAMP generation and subsequent activation of PKA (protein kinase A). Given the large diversity of PKA targets within cardiac cells, a precisely regulated and confined activity of such signalling pathways is essential for the specificity of response. PDEs (phosphodiesterases) constitute the only cAMP-degrading mechanism and are expressed in the cardiomyocyte in at least 5 family variants. Each PDE family is characterized by unique functional properties and contributes to a cAMP-degrading system enabling the modulation of PKA activity in a stimulus-dependent fashion. ©2006 Biochemical Society
The effect of high-frequency random mutagenesis on in vitro protein evolution: a stuudy on TEM-1 beta-lactamase.
No full textcAMP signaling in subcellular compartments.
No full textIn the complex microcosm of a cell, information security and its faithful transmission are critical for maintaining internal stability. To achieve a coordinated response of all its parts to any stimulus the cell must protect the information received from potentially confounding signals. Physical segregation of the information transmission chain ensures that only the entities able to perform the encoded task have access to the relevant information. The cAMP intracellular signaling pathway is an important system for signal transmission responsible for the ancestral 'flight or fight' response and involved in the control of critical functions including frequency and strength of heart contraction, energy metabolism and gene transcription. It is becoming increasingly apparent that the cAMP signaling pathway uses compartmentalization as a strategy for coordinating the large number of key cellular functions under its control. Spatial confinement allows the formation of cAMP signaling "hot spots" at discrete subcellular domains in response to specific stimuli, bringing the information in proximity to the relevant effectors and their recipients, thus achieving specificity of action. In this report we discuss how the different constituents of the cAMP pathway are targeted and participate in the formation of cAMP compartmentalized signaling events. We illustrate a few examples of localized cAMP signaling, with a particular focus on the nucleus, the sarcoplasmic reticulum and the mitochondria. Finally, we discuss the therapeutic potential of interventions designed to perturb specific cAMP cascades locally
Local modulation of Cystic Fibrosis Conductance Regulator: cytoskeleton and compartmentalised cAMP signalling.
No full textThe cystic fibrosis conductance regulator (CFTR) is a cAMP-regulated Cl(-) channel expressed predominantly at the apical membrane of secreting epithelial cells. Mutations in the CFTR gene lead to cystic fibrosis, the most frequent genetic disease in the Caucasian population. The most common mutation, a deletion of phenylalanine at position 508 (F508del), impairs CFTR folding and chloride channel function. Although an intense effort is underway to identify compounds that target the F508del CFTR structural defect and promote its expression and stability at the plasma membrane, so far their clinical efficacy has proven to be poor, highlighting the necessity to better understand the molecular mechanism of CFTR regulation and of the pathogenesis of the disease. Accumulating evidence suggests that the inclusion of the CFTR in macromolecular complexes and its interaction with the cortical cytoskeleton may play a key role in fine-tuning the regulation of channel function. Here we review some recent findings that support a critical role for protein-protein interactions involving CFTR and for the cytoskeleton in promoting local control of channel activity. These findings indicate that compounds that rescue and stabilise CFTR at the apical membrane may not be sufficient to restore its function unless the appropriate intracellular milieu is also reconstituted
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
Dimerization of Fab fragments enables ready screening of phage antibodies that affect hepatocyte growth factor/scatter factor activity on target cells.
No full textVariations 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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