1,721,042 research outputs found
Zimmerman Laband syndrome: identification of novel disease causative genes and characterization of the underlying molecular mechanisms
No full textZimmermann-Laband syndrome (ZLS; MIM135500) is a rare developmental disorder characterized by facial dysmorphism, including coarsening of the face, bulbous soft nose and gingival enlargement, and nail aplasia or hypoplasia, hypertrichosis, and intellectual disability, with or without seizures. Recently, our group reported that heterozygous missense mutations in KCNH1 and ATP6V1B2 genes account for a significant proportion of ZLS cases (Kortüm & Caputo et al., 2015). KCNH1 encodes the voltage-gated K+ channel Eag1 (Kv10.1) (Garg et al., 2012), that is highly expressed in brain. ATP6V1B2 encodes the B2 subunit of the multimeric vacuolar H+ ATPase. Notably, while biochemical and functional studies shed light on the molecular mechanisms underlying KCNH1 mutations, no data has been collected on the consequences of the ATP6V1B2 mutation on the assembly/function of the ATPase complex. Based on these considerations, major goals of my PhD project are to identify the “missing” disease-gene(s) implicated in ZLS and to explore the functional impact of the ATP6V1B2 mutations by using cellular and yeast models. With the aim of identifying novel ZLS causative gene(s), a selected panel of clinically well-characterized ZLS patients was enrolled to be analyzed by WES. WES analysis was performed in five subjects negative for mutations in KCNH1 and ATP6V1B2. This approach allowed us to identify a de novo missense mutation in ATP6V1C1 (c.865G>A; p.Glu289Lys) in a patient showing coarse face, gingival hyperplasia and aplasia/hypoplasia of nails and terminal phalanges. Interestingly, these clinical features resembles the cardinal signs observed in the ATP6V1B2 mutation-positive subjects that has been described by our group (Kortüm & Caputo et al., 2015). Of note, mosaicism for the ATP6V1C1 mutant allele was recognized in the father’s proband, consistent with the relatively mild clinical ZLS features observed in this subject. ATP6V1C1 encodes the C1 subunit of the V1 subcomplex of the V-ATPase (the same complex involving ATP6V1B2). 3D modeling indicated a probably deleterious effect of the Glu289Lys amino acid substitution on proper assembly and activity of the ATPase complex. To test this hypothesis and explore the impact of the ATP6V1B2 and ATP6V1C1 mutations on subcellular localization, lysosomal function, and autophagy, we performed functional studies. These assays allowed to demonstrate that in fibroblasts derived from the patient carrying the Arg485Pro change, the ATP6V1B2 subunit co-localize predominantly with perinuclear lysosomes, suggesting that the V-ATPase containing the mutant subunit does not work properly and might prevent the lysosomes to reach the right pH required for proper localization within the cell. Confocal microscopy analysis revealed defects in the de-quenching process of DQ-BSA in fibroblasts from ZLS patients, indicating impaired lysosomal function. Furthermore, ceramide and cholesterol were strongly enhanced in patient’s fibroblasts compared to control cells, indicating a disruptive effect of the disease-causing mutations on ceramide and cholesterol catabolism. Finally, fibroblasts from ZLS patients displayed high levels of LC3-II in basal condition, and higher levels of this protein compared to control cells at any times after starvation. In the presence of the vacuolar V-ATPase inhibitor bafilomycin A1, we did not observe a significant LC3 increase in ZLS starved cells. These data indicate impaired autophagic flux in ZLS. Yeast data confirmed the deleteriousness of both the ATP6V1B2 mutations, with a stronger disrupting effect of the Arg485 change, while no effect of the mutant ATP6V1C1 subunit was observed in this system. Overall, these findings provide first evidence that ZLS caused by dysregulated V-ATPase function underlies a previously unrecognized metabolic disorder characterized by aberrant storage of undigested material inside the cell
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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