1,720,959 research outputs found
Shedding light on the STAT3 small molecule inhibitor field
No full textSTAT3 is one of the seven family members of the STAT transcription factor family. STAT3 has become a very attractive target for cancer therapy and other diseases. It has a prominent role in cancer development as well as progression. However, there are still no STAT3 inhibitors applied in the clinic. One of the underlying reasons might be the complicated regulation of STAT3 function. Not only do many signaling pathways converge on STAT3, it is also a redox sensitive transcription factor. Therefore, STAT3 activity is determined by a plethora of different intracellular and extracellular signals. STAT3 also affects many different cellular functions and has a role in each hallmark of cancer, either through its role as a transcription factor or through one of its diverse non-transcriptional functions. This thesis focuses on the STAT3 small molecule inhibitor field, by trying to further explore the mechanism of action of novel and widely used STAT3 inhibitors. In addition, we developed a new method to discover specific STAT3 inhibitors. Interestingly, we found that STAT3 was not targeted directly, but rather STAT3 is inactivated due to oxidation of cysteine residues on the protein.In Paper I, we developed a cell-based high-throughput screening system to evaluate STAT3 transcriptional activity. This was used to screen 28.000 compounds, where after several additional screening steps four lead compounds were selected for further evaluation. All four compounds inhibited STAT3 transcriptional activity. Their mechanisms of action however appeared to be diverse. One compound, KI16, was found to preferentially inhibit STAT3 function compared to STAT1, and inhibited STAT3-driven phenotypes. In Paper II, we used differential scanning fluorimetry (DSF) to highlight some of the shortcomings of other in vitro STAT3 inhibitor methods. Two STAT3 protein truncations were used to evaluate SH2 domain binders of STAT3 as well as binding specificity of wellknown STAT3 small molecule inhibitors. Phosphopeptides were able to specifically bind to the STAT3 SH2 domain and increase protein thermal stability. While two small molecule inhibitors did not affect thermal stability of either truncation, two other small molecules, Stattic and BP1-102 decreased stability of both truncations. Which was an indication that both small molecules are not specific SH2 domain binders, but rather target STAT3 in multiple sites leading to its destabilization.In Paper III, we performed structure-activity relationship (SAR) on a selected series of compounds that were identified in the high-throughput screening in Paper I. Sub 1 μM compounds were generated that potently inhibited STAT3 transcriptional activity. These compounds were found to have electrophilic properties, which were essential for STAT3 inhibition. With the use of a fluorescently-tagged compound we were able to pinpoint the cellular protein target, thioredoxin reductase 1 (TrxR1). The top compounds as well as Stattic were potent inhibitors of TrxR1 function, and were found to induce oxidative stress. Vice versa, TrxR1 inhibitors were also able to inhibit STAT3 transcriptional activity. Oxidative stress induction leads to the oxidation of Prx2, which can relay its oxidative equivalents to STAT3 that forms oxidized dimers and is transcriptionally inactivated. TrxR1 is the main reductase that reduces Prx2 and STAT3 through consumption of NADPH. However due to the compounds inhibiting its function, the proteins remain oxidized, and eventually leads to cell death.List of scientific papersI. Iryna Kolosenko, Yasmin Yu, Sander Busker, Matheus Dyczynski, Jianping Liu, Martin Haraldsson, Caroline Palm Apergi, Thomas Helleday, Katja Pokrovskaja-Tamm, Brent D.G. Page. Identification of novel small molecules that inhibit STAT3-dependent transcription and function. PLoS One. 2017 June 21; 12(6): e0178844. https://doi.org/10.1371/journal.pone.0178844 II. Matthieu Desroses, Sander Busker, Juan Astorga-Wells, Sanaz Attarha, Iryna Kolosenko, Roman A. Zubarev, Thomas Helleday, Dan Grandér, Brent D. G. Page. STAT3 differential scanning fluorimetry and differential scanning light scattering assays: Addressing a missing link in the characterization of STAT3 inhibitor interactions. J Pharm Biomed Anal (JPBA). 2018 July 14; 160: 80-88. https://doi.org/10.1016/j.jpba.2018.07.018 III. Sander Busker, Weixing Qian, Martin Haraldsson, Lars Johansson, Belen Espinosa, Sanaz Attarha, Iryna Kolosenko, Jianping Liu, Markus Dagnell, Dan Grandér, Elias S. J. Arnér, Katja Pokrovskaja-Tamm, Brent D.G. Page. Disrupting oncogenic STAT3 activity by targeting TrxR1 with irreversible covalent inhibitors. [Submitted]</p
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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