1,721,031 research outputs found
Notch Signaling: Mechanistic And Functional Studies In Intestinal Stem Cells And Colorectal Cancer Cells
No full text: The study of stem cell regulation in intestinal and colonic tissues is an area of significant focus within the scientific community, providing mechanistic insight into biological process and offering translational clinical potential. In this thesis we address the contribution of NOTCH signaling in maintaining the stem cell niche by modulating the mode of stem cell division and receptor-ligand interactions for cell-cell communication. Furthermore, we examine NOTCHmediated spatiotemporal recovery of the intestinal stem cell (ISC) niche following single cell ablation. Finally, we demonstrate that elevated NOTCH signaling exists under conditions of physiological stress and in colon cancer initiating cells (CCICs), promoting tumorigenic potential of the intestinal epithelium. Overall, our research highlights the underlying complexities of NOTCH signaling as an essential pathway to maintain intestinal homeostasis and may inspire development of novel CRC therapeutic strategies. Research efforts and findings during my graduate study have been consolidated into the following peer-reviewed publications, of which the four first co-author manuscripts are described in detail in this dissertation. 1. Srinivasan, Tara; Walters, Jewell; Bu, Pengcheng; Than, Elaine B.; Tung, Kuei-Ling; Chen, Kai-Yuan; Panarelli, Nicole; Milsom, Jeff; Augenlicht, Leonard; Lipkin, Steven M; Shen, Xiling. "NOTCH Signaling Regulates Asymmetric Division of Fast- and Slow-Cycling Colon Cancer Initiating Cells." Cancer Research, 2016. (in press) 2. Srinivasan, Tara; Than, Elaine B.; Bu, Pengcheng; Tung, Kuei-Ling; Chen, Kai-Yuan; Augenlicht, Leonard; Lipkin, Steven M.; Shen, Xiling. "NOTCH Signaling Regulates Fast- and Slow-Cycling Intestinal Stem Cells." Scientific Reports, 2016. (in press) 3. Chen, Kai-Yuan*; Srinivasan, Tara*; Choi, Jiahn*; Bu, Pengcheng; Tung, Kuei-Ling; Nishimura, Nozomi; Shen, Xiling. "Dynamic regulation of intestinal stem cell niche recovery in real-time." Cell Systems, 2015. (in review) 4. Murthy, Preetish KL*; Srinivasan, Tara*; Bochter, Skye; Bu, Pengcheng; Cole, Susan; Shen, Xiling. "FRINGE-dependent modification of NOTCH Ligands in Intestinal Stem Cells." 2016. (in preparation) 5. Rothschild, Daniel; Srinivasan, Tara; Aponte-Santiago, Linette; Shen, Xiling; Irving, Allen. "The Ex Vivo Culture and Pattern Recognition Receptor Stimulation of Mouse Intestinal Organoids." JoVE, 2015. (in press) 6. Bu, Pengcheng*; Wang, Lihua*; Chen, Kai-Yuan; Srinivasan, Tara; Lakshminarasimha, Preetish; Tung, Kuei-Ling; Varanko, Anastasia; Ai, Yiwei; Lipkin, Steven; Shen, Xiling. "miR34a and Numb synergize for asymmetric cell fate determination." Cell Stem Cell, 2016 Feb 4;18(2):189-202. 7. Crespo, Miguel; Tsai, Su-Yi; Srinivasan, Tara; Pipalia, Nina; Maxfield, Nina; Lipkin, Steven M; Evans, Todd; Chen, Shuibing. "Colonic Organoids Derived from Human Pluripotent Stem Cells for Modeling Colorectal Cancer and Drug Testing." Nature Medicine, 2015. (in review) 8. Wang, Lihua*; Bu, Pengcheng*; Ai, Yiwel; Srinivasan, Tara; Lipkin, Steven M; Shen, Xiling. "A Long Non-Coding RNA Targets MicroRNA miR-34a to Regulate Colon Cancer Stem Cell Asymmetric Division." eLife, 2016. (in press
Kang zhan: du mu xin ju xuan.
No full text在烽火中 / 沈西苓 -- 重逢 / 丁玲 -- 爭取最後勝利 / 塞克 -- 游擊隊的開始 / 張克 -- 我們打沖鋒 / 尤兢 -- 漢奸末路 / 姚時曉 -- 榮譽大隊 / 趙明, 呂復 -- 夜之歌 / 凌鶴 -- 我們放開恩怨 / 石靈 -- 舞女淚 / 集體創作.[沈西苓 ... [et al.]著] ; 戰時劇社編.[Shen Xiling ... [et al.] zhu] ; Zhan shi ju she bian.Zai feng huo zhong / Shen Xiling -- Chong feng / Ding Ling -- Zheng qu zui hou sheng li / Sai Ke -- You ji dui de kai shi / Zhang Ke -- Wo men da chong feng / You Jing -- Han jian mo lu / Yao Shixiao -- Rong yu da dui / Zhao Ming, Lü Fu -- Yan zhi ge / Ling He -- Mo men fang kai en yuan / Shi Ling -- Wu nü lei / Ji ti chuang zuo
Stochastic and Agent-based Modeling of Gene Expression and Cell Fate Decisions
No full textAs new experimental techniques expand our capacity to understand the internal states of single cells and to track the behavior of individual enzymes, classical modeling techniques for deterministic chemical kinetics break down. Thus, more flexible stochastic and agent-based modeling techniques need to be employed. Two paradigmatic are considered. First, a stochastic agent-based model of transcription with nucleosome-induced pausing that maps onto the ddTASEP was constructed to demonstrate a potential mechanism of transcriptional bursting. In lieu of using a mean-field approach, Markov chain techniques were used to calculate the moments of the first passage time from the nucleosome dynamic rate constants. A mean first passage rate was calculated and utilized to construct a new axis to the TASEP phase diagram that contained a jamming transition between initiation- and dynamic defect-limited regions. Second, an integrated Notch/Delta and Wnt/β-catenin gene circuit with crosstalk through the expression of Hes1 was constructed on a lattice model of the intestinal crypt. The distributed control of Hes1 expression, the mechanisms of Wnt secretion, and the redundant role of Paneth cells as a Wnt source were investigated. Tunable mosaic pattern formation at the crypt base was observed, and the addition of the secondary Wnt feedback loop offered a slight increase in model robustness to parameter changes and intrinsic stochasticity.</p
Cellular Reprogramming in Response to Viral Infection and Oncogenic Transformation
No full textIn this dissertation, I reported several cellular reprogramming mechanisms in response to different factors, such as viral infection and oncogenic transformation, by utilizing molecular biology and high-throughput sequencing tools. In the first part of the dissertation, I investigated how hepatocytes contain HBV replication and promote their own survival by orchestrating a translational defense mechanism via the stress-sensitive SUMO-2/3-specific peptidase SENP3. We found that SENP3 expression level decreased in HBV-infected hepatocytes in various models including HepG2-NTCP cell lines and a humanized mouse model. Downregulation of SENP3 reduced HBV replication and boosted host protein translation. We also discovered that IQGAP2, a Ras GTPase-activating-like protein, is a key substrate for SENP3-mediated de-SUMOylation. Downregulation of SENP3 in HBV infected cells facilitated IQGAP2 SUMOylation and degradation, which leads to suppression of HBV gene expression and restoration of global translation of host genes via modulation of AKT phosphorylation.
In the second part, I showed that, in Kras-mutant alveolar type II cells (AEC2), FOSL1-based AP-1 factor guides mSWI/SNF complex to increase chromatin accessibility at genomic loci controlling the expression of genes necessary for neoplastic transformation. I identified two orthogonal processes in Kras-mutant distal airway club cells. The first process was step-like in behavior and promoted their trans-differentiation into an AEC2-like state through NKX2.1. The second was linear and controlled oncogenic transformation through the AP-1 complex. Our results suggest that the chromatin state of the cell influences its response to oncogenic Kras. Other than the cell-type-specific effects, a cross-tissue conserved AP-1-dependent chromatin remodeling program regulates carcinogenesis.
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Jie tou yan ju.
No full text沈西苓 [and others]著.Includes prefactory material.Includes 8 plays.Shen Xiling [and others] zhu
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
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