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뼈 형성에서 Pin1 매개 프롤린 이성질화의 역할
Get PDF학위논문 (박사)-- 서울대학교 대학원 : 치의학대학원 치의과학과, 2018. 2. 류현모.One of the most reported post-translational modifications (PTMs) regulation of protein in the cell is prolin-directed phosphorylation, these phosphorylated resides also can be the targets of enzyme for other PTMs. Pin1 is an isomerase that recognizes phosphorylated Ser/Thr-Pro residues and causes the structural change of protein. Our previous studies have shown that Pin1 deficient exhibited a wide range of abnormal bone phenotypes. Moreover, in the signaling pathways such as FGF, BMP and PTH, which are responsible for osteoblast differentiation, isomerization of the molecule by Pin1 plays important role.
Wnt/β-catenin signaling pathway, in which β-catenin nuclear localization is a critical step, also plays a major role in the control of osteoblast differentiation. However, the association of Pin1 with Wnt/β-catenin signaling pathway during bone development and detailed mechanism is not clear. In Part 1, we observed a marked reduction of β-catenin in osteoblasts of Pin1 null mice tibia. From MC3T3-E1 cells, transcription activity, the nucleus β-catenin level and the target gene expression of β-catenin were all decreased when the activity of Pin1 was reduced by si RNA or by inhibitor. We also demonstrated that Pin1 directly interacted with β-catenin, and the isomerized β-catenin which could not bind to nuclear adenomatous polyposis coli (APC) only can be retention and act as a transcription factor in the nucleus. These results might explain the decrease of β-catenin ubiquitination and showed that Pin1 is a critical factor that can regulate bone formation regulated by Wnt/β-catenin signaling pathway.
In part 2, the importance of Pin1 in osteogenesis was confirmed in craniosynostosis (CS) disease animal model. CS is characterized by the premature closure of craniofacial sutures. It is follows autosomal dominant inheritance pattern, and the mutation of the FGFR2 gene is mainly the genetic cause of it. This study focused on the change of coronal suture fusion which is the major phenotype of Apert syndrome (AS) using S252W gain of function mutation of FGFR2. We aimed to treat CS caused by over-activated FGF/FGFR signal, and it was targeted that inhibiting Pin1-induced isomerization of Runx2 in FGF signaling pathway. As a result, we showed that fusion of coronal suture can be restored to close to the normal phenotype when the FGFR2S252W+ and the Pin1+/- genotype are present simultaneously. The similar results were obtained when juglone, Pin1 inhibitor, was administered to the fetus of FGFR2S252W/+ mice for drug therapy.
Collectively, we demonstrated here that isomerization of β-catenin through direct interaction of β-catenin with Pin1 during osteoblast differentiation is an important factor controlling nuclear β-catenin retention and stability. In addition, we demonstrated the drug target of CS by proving that the inactivation of Pin1 causes the recovery of disease through gain of function mutation in FGFR2.I. Abbreviations 1
II. Literature review 4
III. Purpose of study 16
IV.Part 1. Pin1-mediated modification prolongs the nuclear retention of β-catenin in Wnt3a-induced osteoblast differentiation 17
V. Part 2. Pin1 is a new therapeutic target of craniosynostosis 71
VI. Conclusion 134
VII. References 136
VIII. 국문 초록 150Docto
White Out
Get PDF“White Out” explores ideas about architecture that seeks ephemerality rather than legibility, eidetic effects rather than demanding of focused attention and atmospheric or emotional spaces rather than conventional spaces
Blur Out
Get PDFBlur Out explores ideas about architecture that seeks ephemerality rather than legibility, eidetic affects rather than demand of focused attention and atmospheric or emotional spaces rather than conventional spaces.
The exploration of Blur Out is situated within the research topic of different states of snow that are generated from avalanche phenomena of Iceland, which develops site specific understandings of the phenomena and effects. The project aims to build a blurred boundary both literally and experientially between the built and natural environment to challenge representing and re-presenting the spectrum of tangibility to intangibility. By exploring the dichotomy between the built and the natural context of Iceland, a new understanding of perceiving and experiencing the avalanche phenomena creates an uncanny relationship that would change and draw attention from sublime as the norm to sublime as the spectacular
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
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