1,720,978 research outputs found
C. elegans as a model to identify and functionally characterize novel genes causing RASopathies and other developmental diseases
Full text linkRASopathies are a family of syndromes affecting development and growth, sharing RAS signaling
dysregulation as pathogenetic mechanism. Past work of our group and others have significantly
contributed to our understanding of the molecular causes of these diseases. However, a large
fraction of RASopathy cases remains unexplained molecularly. Here, I used the nematode C.
elegans to reveal novel molecular mechanisms underlying RASopathies, as well as to identify new
candidate genes for these group of developmental disorders. C. elegans is an excellent model to
study RASopathies since the RAS-MAPK pathway is well conserved in worms, where it plays a
crucial role in vulval development.
Based on a gene candidacy approach, we identified two germline mutations in RRAS, a gene
encoding a small monomeric GTPase controlling cell adhesion, spreading and migration,
underlying a rare and atypical form of Noonan syndrome (NS), the most common RASopathy. We
also identified somatic RRAS mutations in 2 cases of non-syndromic juvenile myelomonocytic
leukaemia (JMML), a childhood myeloproliferative/myelodysplastic disease caused by upregulated
RAS signaling. Two of the three identified mutations affected known oncogenic hotspots of RAS
genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation.
Expression of an RRAS mutant homolog in C. elegans enhanced RAS signaling causing a
multivulva (Muv) phenotype, and engendered protruding vulva (Pvl), a phenotype previously linked
to the RASopathy-causing SHOC2S2G mutant. These findings provided evidence of a functional link
between RRAS and MAPK signaling and reveal an unpredicted role of enhanced RRAS function in
human disease.
Epistatic analyses performed on C. elegans transgenic lines allowed us to establish that the
RASopathy-causing SHOC2 and RRAS mutants belong to the same pathway. Within this signaling
network, both RAS-1/RRAS and RAS-2/MRAS are downstream to constitutively active SHOC2,
with the former being epistatic to the latter. By using a reverse genetic approach based on RNA
interference experiments, we demonstrated that the Muv phenotype was completely mediated by
LET-60/RAS, while the Pvl phenotype was modulated by the RHO-family small GTPases CDC-42
and RAC1. We then confirmed these results in fibroblasts derived from patients with Mazzanti
syndrome (NS with loose anagen hair) and transfected cell lines. In these models, we observed
constitutive RAC1 activation and aberrant lamellipodia formation in cells expressing SHOC2S2G
compared to wild-type cells.
These results suggested RHO GTPases as excellent candidate genes to be mutated in
RASopathies. To explore this hypothesis, mutation scanning of RAC1, RAC2 and CDC42 genes was
performed in RASopathy patients by targeted resequencing and identified seven different
germline CDC42 mutations in 11 unrelated subjects with a variable phenotype partially overlapping
NS and predisposing to thrombocytopenia. In vitro biochemical characterization demonstrated a
variable impact of the mutations on GTPase activity and defective binding to WASP. In vitro and in
vivo (C. elegans) functional characterization of these mutants allowed to define their impact on cell
migration and proliferation, as well as on vulval induction and morphogenesis. A first class of
mutations was shown to have an hypomorphic effect on processes mediating cell polarized
migration, with no effect on the RAS-MAPK signaling, while a second class of mutations had a
gain-of-function effect on both cell migration/proliferation and LET-60/RAS-mediated vulval
induction. Overall, our data highlighted the possible contribution of dysregulated signaling
controlling cell spreading and migration to certain features of RASopathies, such as lymphedema,
cardiac defects and lymphocytes infiltration in non-hematopoietic tissues in case of JMML
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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