1,721,647 research outputs found
Structural and molecular determinants of the sensitivity of alpha4beta2 nicotinic acetylcholine receptors to the allosteric ligand desformylflustrabromine
Full text linkAllosteric modulation of neuronal nicotinic acetylcholine receptors (nAChRs) is considered
to be one of the most promising approaches for therapeutics. By binding to a site of the
receptor distinct from the neurotransmitter binding site, allosteric modulators alter the
response of the receptors to their agonists. There are two major locations of allosteric
modulator binding sites. One is in subunit interfaces of the extracellular N-terminal domain.
The other is in the transmembrane domain close to the channel gating machinery. This thesis
focuses on a positive allosteric modulator of the human α4β2 nAChR,
desformylflustrabromine (dFBr), which was found to exert its potentiating effects on this
receptor by binding to a site in the transmembrane region of the α4 subunit.
α4β2 nAChRs are the most abundant nAChR type in the brain, where they modulate a range
of brain functions such as mood, cognition, nociception and reward. This receptor subtype
has been shown to be sufficient and necessary for the rewarding and reinforcing properties of
nicotine. In addition, α4β2 nAChRs have been implicated in aging-related cognitive
dysfunction, Alzheimer’s and Parkinson’s diseases, mood disorders and a rare type of family
epilepsy. dFBr is a positive allosteric modulator of the α4β2 and α2β2 nAChRs that displays
selectivity against all other nAChRs. Using functional mutagenesis and structural modelling,
the molecular basis for the selective potentiation of α4β2 nAChRs has been identified. The
potentiating binding site of dFBr is located in the top-half of a transmembrane cavity between
the M3 and M4 helices of the α4 subunit. α4Y309, α4F312 and α4L617 influence dFBr
potentiation in accord with a role in dFBr binding. Alanine substitutions of these residues
annulled dFBr potentiation and experiments using MTSET showed that the residues in this
putative site are accessible to MTSET and that dFBr competes with MTSET for the access to
the cavity. These residues map to a highly conserved intra-subunit cavity in the pentameric
ligand gated ion channel (pLGIC) family. In addition, the effector system for the potentiating
effects of dFBr was also identified. The post-M4 region (C-terminal) and the Cys loop
residues F167 and F170 of the α4 subunit play central roles in transducing dFBr binding to
potentiation of the ACh responses of the α4β2 nAChR. Whilst the residues that contribute to
the dFBr binding site in the α4 are conserved across all nAChR subunits, except for α7, the
post-M4 region is not. It is this region that determines the selective potentiating effects of
dFBr on α4β2 nAChR. This finding, together with recent data on the effect of propofol in
bacterial and invertebrate evolutionary related pLGICs, suggest that for highly conserved
transmembrane domain allosteric binding sites, the effector machinery associated with these
sites, rather than the binding sites, define the receptor selectivity of the modulators
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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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