1,720,987 research outputs found
Het achterhalen van de complexe rol van BMP-SMAD signalering in lymfevat endotheelcellen
No full textThe formation of the cardiovascular and lymphatic system is crucial for normal development and physiology. In this thesis we investigate the lymphatic system which plays an important role in the uptake of interstitial fluid and fat, but also in the immune system. Failure to establish a lymphatic vascular network leads to severe embryonic defects, whereas misregulation after birth can lead to disorders such as cancer metastasis, lymphedema, obesity and inflammatory diseases. The first lymphatic endothelial cells (LECs) differentiate from venous ECs in the cardinal vein and express lymphatic markers such as e.g. PROX1 and LYVE1. PROX1 is considered the master regulator gene of lymphangiogenesis and deletion of PROX1 in mice leads to a complete lack of lymphatic vessels and early embryonic death.
The Notch signaling pathway is a key regulator of cell fate and patterning in many tissues and it also plays a critical role in angiogenesis. The role of Notch signaling in lymphangiogenesis, however, is not fully understood. Some groups describe Notch to be crucial for lymphatic vessel development, whereas others demonstrate its inhibitory effect on lymphangiogenesis. We report here that silencing NOTCH1 in human dermal ECs (LECs) – in the context of BMP9 signaling - resulted in decreased PROX1 expression levels, suggesting that the Notch pathway positively regulates lymphatic development.
The bone morphogenetic protein (BMP) signaling pathway has emerged as a fundamental pathway of EC identity and regulates cardiovascular and lymphatic development. Major downstream mediators of BMP signaling are SMAD1, -5 and -8, which are activated by phosphorylation and subsequently regulate transcription of target genes such as e.g. IDs. Mutations in components of this pathway lead to several vascular diseases such as hereditary hemorrhagic telangiectasia (HHT) and pulmonary arterial hypertension (PAH). Furthermore, deletion of BMP9 or its receptor ALK1 in mice results in dilated lymphatic vessels, indicating an inhibitory role for the BMP pathway in lymphatic vessel development.
The objectives were to investigate I) the possible interplay between the BMP and Notch signaling pathways, II) to document regional differences in BMP-SMAD transcriptional activity and III) to examine the effect of SMAD1/5 on the LEC identity and specification.
Here, we showed a synergy between the Notch and BMP signaling cascades. Knockdown of SMAD1/5 or NOTCH1 in DLECs resulted in reduced expression levels of both Notch and BMP responsive genes.
Furthermore, we documented regional differences in BMP-SMAD dependent transcriptional activity in murine endothelium. For this analysis, we used the BRE::gfp reporter mouse in which the BMP response element (BRE) from the ID1-promoter, a SMAD1/5/8 target gene, drives the expression of green fluorescent protein (GFP). We defined regions with stereotypic mosaic and continuous BRE::gfp localization patterns in sprouting angiogenesis and embryonic lymphatic vessels, respectively, and showed dynamic changes of BRE::gfp activity over time.
Moreover, we showed that LEC-specific Smad1/5 knockout embryos (E14.5) displayed enlarged lymphatic sacs with increased numbers of PROX1-positive cells, whereas mutant pups failed to downregulate PROX1 in the area between lymphatic valves. In contrast to these in vivo results, knockdown of SMAD1/5 in DLECs stimulated with BMP9 in cell culture, did not affect PROX1 mRNA or protein levels, whereas ALK1 depletion increased PROX1 expression levels compared to NT samples. This discrepancy between the in vivo and in vitro data suggests that PROX1 is not (solely) regulated by ALK1-SMAD1/5 signaling. Remarkably, co-silencing of ALK1 and SMAD1/5 in DLECs did not alter PROX1 levels, suggesting that SMAD1/5 can integrate opposing signals and that BMP9 signaling may be mediated by other receptor complexes. Indeed, we show that BMP9 signaling can be mediated by ALK3 and that silencing ALK3 in DLECs resulted in decreased PROX1 levels. Moreover, ALK3 expression levels were regulated by BMP9-ALK1 signaling in a SMAD1/5-dependent manner. Overall, we conclude that BMP signaling is highly complex in DLECs, where BMP9 signaling, mediated by ALK1 and ALK3, executes opposing effects on PROX1. We propose a model that shows the duality of BMP signaling in DLECs, which can be used for further investigation of the significance of BMP signaling in the development of lymphatic vessels and possible treatment of lymphatic disorders. This work demonstrates the context dependency of BMP-SMAD signaling, including that one ligand can regulate a target gene differentially through different receptor complexes, and shows that it is important to study the interaction between this pathway and other pathways. This work might help the field get one step closer to understanding the downstream molecular regulation of BMP signaling in lymphatic endothelium.status: Publishe
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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