1,720,955 research outputs found
Structural and Functional Characterization of Human Transcription-regulating Kinases
No full textAccurate regulation of RNA polymerase II by transcriptional kinases is essential for normal development and dysregulation can promote cancer onset and progression. Small molecules targeting transcriptional kinases, such as CDKs and DYRKs, hold promise for novel treatment options in oncology and beyond.
HIPKs are regulators of various cellular signalling pathways and belong to the DYRK kinase family. They are involved in the pathology of cancer, chronic fibrosis, diabetes, and multiple neurodegenerative diseases. In this study, characteristic structural features of the HIP kinase family were identified based on the HIPK3 crystal structure in the apo form at 2.5 Å resolution. Recombinant HIPKs and its close relative DYRK1A phosphorylate core components of the transcription machinery, such as the negative elongation factor SPT5, the transcription factor c-Myc, as well as pol II CTD, suggesting a direct role in transcriptional regulation. Abemaciclib, a Cdk4/Cdk6 inhibitor, which was approved by the FDA for the treatment of metastatic breast cancer, was identified in a database screen as a potent inhibitor of HIPK2, HIPK3, and DYRK1A. The crystal structures of HIPK3 and DYRK1A bound to abemaciclib were determined and demonstrated a binding mode to the kinase hinge region similar to Cdk6. Remarkably, abemaciclib inhibits DYRK1A to the same extent as Cdk4/Cdk6 in vitro, raising the question of whether transcriptional inhibition through DYRK1A contributes to the therapeutic activity of this breast cancer drug and whether abemaciclib may be a suitable treatment option for Alzheimer´s disease.
CDKs are dependent on a Cyclin subunit for activation and are central regulators of cell cycle and transcription. In contrast to cell cycle CDKs that can be activated promiscuously by multiple different Cyclins, transcriptional CDKs are thought to be activated by only one particular Cyclin partner. Although this long-established dogma exists, an unbiased approach to systematically test the formation of transcriptional CDK/Cyclin complexes revealed that both Cyclins, CycK and CycT1, are able to activate Cdk9, Cdk12 and Cdk13 in vitro. Cdk9/CycK has been a little appreciated phenomenon ever since the discovery of Cdk9 and we recently discovered a Cdk13/CycT1 complex mediating RNA surveillance in melanoma (Insco et al., Science, 2023). The crystal structure of the novel Cdk12/CycT1 complex at 2.0 Å resolution revealed a highly identical CDK/Cyclin interface compared to cognate Cdk12/CycK. Cdk13/CycT1 co-exists with Cdk13/CycK in HEK293T and A375 cells and ChIP-seq analysis confirmed co-localization of Cdk13 and CycT1 at transcription start sites of similar genes. Furthermore, Hex1 and Brd4 regulate Cdk9/CycT1, but no other transcriptional CDKs. Finally, small-molecular compounds inhibit CDKs independent of the bound Cyclin and Targeted protein degraders are highly specific for their targeted Cdk or Cyclin. The discovery of these novel CDK/Cyclin pairs challenges a long-standing dogma of CDK biology and may facilitate advances in the development of therapeutics targeting transcriptional CDKs
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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