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α2δ3 is the preferred auxiliary α2δ subunit of Cav2.1 channels in spiral ganglion neurons and is required for development of auditory nerve fiber synapses
Get PDFVoltage-gated calcium channels (VGCCs) are composed of a pore-forming α1 subunit and the
auxiliary β and α2δ subunits. The largely extracellular α2δ proteins α2δ1-4 modulate the Ca2+
current properties but the reasons for their partial redundancy/specificity are unknown.
VGCCs are expressed in a huge variety of tissues, including the auditory system. Acoustically
evoked signal processing is carried out in an ultrafast and timely precise way and requires
fully functional and developed connections. The cochlea converts mechanical into electrical
signals, and transmits these signals via spiral ganglion (SG) neurons to the auditory
brainstem. SG neurons are indispensable for a proper hearing function and their loss cannot
be compensated by any hearing aid or cochlea implant. The presynaptic Ca2+ channel
complex of the mature inner hair cell (IHC) is formed by Cav1.3, ß2 and α2δ2 (Fell et al.,
2016). Recently, α2δ subunits have become of interest due to their multiple roles in pain
processing, synapse formation and use as therapeutic targets for different drugs.
In this work, the role of the α2δ3 subunit of VGCCs was analyzed with respect to (i) its
contribution to the ICa in neonatal and mature SG neurons and (ii) the development of the
endbulb of Held synapse.
Lack of α2δ3 reduced Cav2.1 currents, the dominating Ca2+ channel in cultured SG neurons of
mice aged 3-weeks, by 60 %. Furthermore, we found malformed and smaller endbulbs of
Held in mice aged 3-weeks. Surprisingly, at P5, when P/Q-type (Cav2.1) channels in SG
neurons were not yet expressed, α2δ3 was nevertheless required for a normal endbulb of Held
synapse development. This indicates a specific function of α2δ3 in synapse development,
which was independent of the presence of the P/Q-type Ca2+ current.
The endbulb of Held synapse has been studied not only in the α2δ3 knockout mouse but also
in α2δ2 null mutants, to determine how the deletion of α2δ2 affects the development. Analysis
of the endbulb of Held synapse showed a decreased VGLUT1-labeled area as well as a
decreased number of boutons per bushy cell compared to the wildtype, indicating that also
α2δ2 is required for proper endbulb of Held formation at P20.
In contrast to IHCs, SG neurons express at least 6 pore-forming subunits and all three
neuronal α2δ subunits (α2δ1-3). Taken together, we could show that (i) only Cav2.1 channels
mediating P/Q currents were strongly reduced in SG neurons isolated from α2δ3-/- mice at
P20, (ii) α2δ3 has a function for synaptic development independent of Cav2.1 channels and
(iii) also deletion of α2δ2 affects the development and maturation of the endbulb of Held
synapse at P20.Zusammenfassung
Spannungsgesteuerte Kalziumkanäle (VGCCs) bestehen aus einer porenbildenden α1-
Untereinheit und den akzessorischen β und α2δ-Untereinheiten. Die weitgehend
extrazellulären α2δ Proteine α2δ1-4 modulieren die Eigenschaften von Ca2+-Kanälen, aber die
Gründe für ihre partielle Redundanz bzw. Spezifität sind unbekannt. VGCCs werden in einer
Vielzahl von Geweben, einschließlich der Cochlea, exprimiert. Die Cochlea ist für die
Schalltransduktion und die Übertragung der Informationen zum auditorischen Hirnstamm
verantwortlich.
Die Aufgabe der Spiralganglien (SG) Neurone ist die Übertragung von Schallinformationen
von den Haarzellen der Cochlea zu Neuronen im auditorischem Hirnstamm. SG-Neurone,
sind unerlässlich für die Hörfunktion, denn ihr Verlust kann nicht durch ein Hörgerät oder ein
Cochlea-Implantat ersetzt werden.
Der Ca2+-Kanal-Komplex der ausgereiften Präsynapsen der IHC wird von Cav1.3, β2 und α2δ2
gebildet (Fell et al. 2016). Besonders die α2δ-Untereinheiten sind aufgrund ihrer vielfältigen
Funktionen bei der Schmerzverarbeitung, Synapsenbildung und als therapeutische
Angriffspunkte für verschiedene Medikamente interessant geworden. In dieser Arbeit wurde
die Rolle der α2δ3-Untereinheit von VGCCs im Hinblick auf ihren Beitrag zum Ca2+-Strom
von neonatalen und reifen SG-Neuronen und die Entwicklung der Endbulb of Held-Synapse
an α2δ3-defizienten Mäusen analysiert.
Das Fehlen der α2δ3-Untereinheit reduzierte die Cav2.1-Ströme, welche die dominierenden
Ca2+-Ströme von reifen kultivierten SG-Neuronen von 3 Wochen alten Mäusen sind, um 60%.
Zudem zeigten α2δ3-defiziente Mäuse im Alter von drei Wochen deformierte und kleinere
Endbulb of Held-Synapsen. Überraschenderweise wurde bereits an P5, wenn P/Q (Cav2.1)-
Kanäle in SG-Neuronen noch nicht exprimiert werden, α2δ3 für eine normale Bildung von
Endbulb of Held-Synapsen benötigt. Dies weist auf eine spezifische Funktion von α2δ3 für
die Synapsentwicklung hin, die unabhängig vom P/Q-Ca2+-Strom ist.
Die Endbulb of Held-Synapse wurde auch in einer funktionellen α2δ2-null-Mutante
untersucht, da diese Mäuse verzerrte auditorische Hirnstammantworten in Welle I zeigten.
Ziel war es herauszufinden, wie sich die Deletion von α2δ2 auf die Synapsentwicklung
auswirkt. Die Analyse der Endbulb of Held-Synapse zeigte eine verringerte VGLUT1-
markierte Fläche der Axonterminale sowie eine geringere Anzahl von Boutons pro Bushy-
Zelle im Vergleich zum Wildtyp. Im Gegensatz zu IHCs exprimieren SG-Neurone mindestens
6 porenbildende α1-Untereinheiten und alle drei neuronalen α2δ-Untereinheiten α2δ1, 2 und 3. In dieser Arbeit konnten wir zeigen, dass (i) nur Cav2.1 Kanäle durch das Fehlen der α2δ3 in
adulten Mäusen betroffen sind, (ii) α2δ3 eine Funktion in der synpatischen Entwicklung hat,
welche unabhängig von Cav2.1 Kanälen ist und (iii) auch das Fehlen von α2δ2 einen Effekt
auf die Entwicklung der „Endbulb of Held“ synapse in adulten Mäusen hat
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Get PDFWe 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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