1,720,958 research outputs found
Advanced preclinical CRISPR mouse models to explore context-dependent effects of TP53 mutations in cancer
No full textThe tumor suppressor p53 is the most frequently mutated protein in cancer patients and exhibits a unique mutational spectrum that is dominated by missense mutations. In contrast to the most prevalent hotspot mutations, 70% of all missense mutations are non-hotspot mutations with yet poorly characterized functions in tumorigenesis. Non- hotspot mutants often retain some wildtype activity, which corresponds to a partial loss- of-function (pLOF). Mutations that affect the DNA binding cooperativity of p53 fall into this class of mutants.
This work demonstrates that the prototypical DNA binding cooperativity mutant E177R can either promote tumorigenesis or induce tumor regression dependent on the cellular and genetic context. Expression of E177R in normal tissues resulted in increased susceptibility to spontaneous and oncogene-driven tumor development, emphasizing the pathogenic role of pLOF mutants. In striking contrast, expression of E177R in p53- deficient tumor cells revealed that the residual transcriptional activity of the mutant is able to promote the regression of already manifested tumors. That the same p53 mutant can have opposite effects on tumor growth highlights how genetic context determines the consequences of a cancer mutation.
To investigate the impact of specific mutations in different genetic contexts, we have developed a new method for generating genetically defined mouse tumors for preclinical studies. We have applied the CRISPR technology to induce cancer mutations rapidly and precisely in somatic cells and present a flexible toolkit based on adenoviral vectors for in vivo delivery of CRISPR effectors. In addition, we have generated a conditional reporter mouse that expresses a Gaussia princeps luciferase (GLuc). When GLuc is secreted by tumor cells, it accumulates in the blood and serves as a tumor marker to monitor cancer development and therapy responses. By combining the use of CRISPR adenoviruses and GLuc reporter mice, we have established a preclinical mouse tumor model that allows the rapid and flexible induction of autochthonous tumors that are easily monitored using blood samples to study the impact of a cancer mutation on tumorigenesis and cancer therapy in a genetically defined context.Der Tumorsuppressor p53 ist das am häufigsten mutierte Protein in Krebspatienten und weist ein einzigartiges Mutationsspektrum auf, das von Missense-Mutationen dominiert wird. Im Gegensatz zu den am häufigsten vorkommenden Hotspot-Mutationen, sind 70% aller Missense-Mutationen Non-Hotspot-Mutationen, deren Funktion bei der Tumorentstehung noch nicht ausreichend bekannt ist. Non-hotspot-Mutationen behalten oft eine gewisse Wildtyp-Aktivität, was einem partiellen Funktionsverlust (pLOF) entspricht. Mutationen, die die DNA-Bindungskooperativität von p53 beeinträchtigen, fallen in diese Klasse von Mutanten.
Diese Arbeit zeigt, dass die prototypische DNA-Bindungskooperativitätsmutante E177R, je nach zellulärem oder genetischem Kontext, in der Lage ist, entweder Tumorentstehung oder Tumorregression zu fördern. Die Expression von E177R in normalen Geweben führte zu einer erhöhten Anfälligkeit für spontane und Onkogen- induzierte Tumorentwicklung, was die pathogenen Eigenschaften von pLOF-Mutanten verdeutlicht. In auffälligem Gegensatz dazu zeigte die Expression von E177R in p53- defizienten Tumorzellen, dass die transkriptionelle Restaktivität der Mutante die Regression von bereits manifestierten Tumoren ermöglicht. Dass ein und dieselbe p53- Mutante entgegengesetzte Auswirkungen auf das Tumorwachstum haben kann, verdeutlicht, wie der genetische Kontext die Folgen einer Tumormutation bestimmt. Um den spezifischen Einfluss solcher Mutationen in unterschiedlichen genetischen Kontexten zu untersuchen, haben wir eine neue Methode zur Erzeugung genetisch definierter Maustumore für präklinische Studien entwickelt. Wir haben die CRISPR- Technologie eingesetzt, um Krebsmutationen schnell und präzise in somatischen Zellen zu induzieren, und stellen ein flexibles Toolkit vor, das auf adenoviralen Vektoren für den Transfer von CRISPR-Effektoren basiert. Darüber hinaus haben wir eine konditionelle Reportermauslinie generiert, die die Gaussia princeps Luciferase (GLuc) exprimiert. Von Tumorzellen sezernierte GLuc reichert sich im Blut an und dient dort als Tumormarker zur Überwachung der Tumorentwicklung und des Therapieansprechens. Durch die Kombination von CRISPR-Adenoviren und GLuc-Reportermäusen haben wir ein präklinisches Maustumormodell etabliert, das die schnelle und flexible Induktion von autochthonen Tumoren ermöglicht, die sich leicht anhand von Blutproben überwachen lassen, um die Auswirkungen einer Krebsmutation auf Tumorentwicklung und Krebstherapie in einem genetisch definierten Kontext zu untersuchen
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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