293 research outputs found

    Acta Universitatis Sapientiae - Mathematica 2010

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    The role of branched muscle fibres and ACTN3 polymorphism as a genetic disease modifier in Duchenne nuscular dystrophy

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    Duchenne muscular dystrophy (DMD) is the second most common fatal genetic disease in humans, with an incidence of 1 in 3300 live male births. DMD is characterized by progressive cycles of skeletal muscle necrosis/regeneration triggered by the absence of the protein dystrophin from the inner surface of the sarcolemma. In DMD and dystrophin-negative mdx mice, regenerated skeletal muscle fibres are branched and deterioration of muscle contractile function with age is correlated with an increase in both the number and complexity of branched fibres. In this thesis, I present four papers in support of my hypothesis, that when the number and complexity of branched fibres in dystrophin-negative muscles reaches a critical threshold, termed ‘tipping point’, the branches in and of themselves, mechanically weaken the muscle and are susceptible to rupturing when subjected to high forces such as those experienced during eccentric/lengthening contractions. Methodologically, the papers utilise a combination of isolated muscle function contractile measurements coupled with single fibre imaging and confocal microscopy of cleared whole muscles. All experiments use intact muscles isolated from the dystrophic mdx mouse, double knockout (dk)Actn3KO/mdx (dKO) mouse and littermate controls. In conclusion, I propose a two-phase model to explain the aetiology of DMD. Phase-one involves the absence of dystrophin triggering a pathological increase in [Ca2+]in resulting in skeletal muscle fibre necrosis followed immediately by regeneration. The process proceeds cyclically, increasing the number of abnormally branched regenerated dystrophin-deficient muscle fibres. Once the number and complexity of branched fibres passes a level I term ‘tipping point’, phase-two occurs; now eccentric contractions cause force deficits as a consequence of branches rupturing. In the final stage, phase-two will tend to have a positive feedback component, as breaking branches will no longer support the eccentrically contracting muscle, placing additional stress on the remaining branches during the contraction. It is important to note that depending on the complexity of branching and forces experienced by the muscle, phase-one and phase-two are not mutually exclusive and will occur simultaneously

    A semiotic evaluation of musical meaning in the works of Igor Stravinsky : decoding syntax and markedness and prototypicality theory.

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    SIGLEAvailable from British Library Document Supply Centre-DSC:DXN026379 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

    定量的構造物性相関/定量的構造活性相関モデルの逆解析を利用した化学構造創出に関する研究

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    学位の種別: 課程博士審査委員会委員 : (主査)東京大学教授 船津 公人, 東京大学教授 酒井 康行, 東京大学准教授 杉山 弘和, 東京大学准教授 伊藤 大知, 京都大学特任教授 奧野 恭史, スイス連邦工科大学教授 Gisbert SchneiderUniversity of Tokyo(東京大学

    Development and use of databases for ligand-protein interaction studies

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    This project applies structure-activity relationship (SAR), structure-based and database mining approaches to study ligand-protein interactions. To support these studies, we have developed a relational database system called EDinburgh University Ligand Selection System (EDULISS 2.0) which stores the structure-data files of +5.5 million commercially available small molecules (+4.0 million are recognised as unique) and over 1,500 various calculated molecular properties (descriptors) for each compound. A user-friendly web-based interface for EDULISS 2.0 has been established and is available at http://eduliss.bch.ed.ac.uk/. We have utilised PubChem bioassay data from an NMR based screen assay for a human FKBP12 protein (PubChem AID: 608). A prediction model using a Logistic Regression approach was constructed to relate the assay result with a series of molecular descriptors. The model reveals 38 descriptors which are found to be good predictors. These are mainly 3D-based descriptors, however, the presence of some predictive functional groups is also found to give a positive contribution to the binding interaction. The application of a neural network technique called Self Organising Maps (SOMs) succeeded in visualising the similarity of the PubChem compounds based on the 38 descriptors and clustering the 36 % of active compounds (16 out of 44) in a cluster and discriminating them from 95 % of inactive compounds. We have developed a molecular descriptor called the Atomic Characteristic Distance (ACD) to profile the distribution of specified atom types in a compound. ACD has been implemented as a pharmacophore searching tool within EDULISS 2.0. A structure-based screen succeeded in finding inhibitors for pyruvate kinase and the ligand-protein complexes have been successfully crystallised. This study also discusses the interaction of metal-binding sites in metalloproteins. We developed a database system and web-based interface to store and apply geometrical information of these metal sites. The programme is called MEtal Sites in Proteins at Edinburgh UniverSity (MESPEUS; http://eduliss.bch.ed.ac.uk/MESPEUS/). MESPEUS is an exceptionally versatile tool for the collation and abstraction of data on a wide range of structural questions. As an example we carried out a survey using this database indicating that the most common protein types which contain Mg-OATP-phosphate site are transferases and the most common pattern is linkage through the β- and γ-phosphate groups

    Binarism and indeterminacy in the novels of Thomas Pynchor

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    Bibliography: pages 397-401.I attempt in this thesis, to graft together a close critical, and predominantly thematic, reading of Thomas Pynchon's novels with selected issues treated in the work of Jacques Derrida on philosophy and textuality, illustrating how this work demands the revision and interrogation of several major critical issues, concepts, dualisms and presuppositions. The thesis consists of an Introduction which sets forth a brief rationale for the graft described above, followed by a short and unavoidably inadequate synopsis of Derrida's work with a brief review and explication of those of his 'concepts' which play an important role in my reading of Pynchon's texts. The Introduction is succeeded by three lengthy chapters in which I discuss, more or less separately, each of Pynchon's three novels to date. These are V. (1963), The Crying of Lot 49, (1966) and Gravity's Rainbow (1973), and I discuss them in the order of their appearance, devoting a chapter to each. I attempt to treat different but related issues, preoccupations, themes and tropes in each of the novels to avoid repeating myself, engaging the apparatuses derived from Derrida's writing where deemed strategic and instructive. I suggest moreover, that several of the issues examined apropos the novel under consideration in any one chapter apply mutandis rnutandi to the other novels. Each chapter therefore to some extent conducts a reading of the novels which it does not treat directly. Finally, supervising these separate chapters is a sustained focus on the epistemology of binarism and digitalism, and the conceptual dualisms which structure and inform major portions of the thematic and rhetorical dimensions The thesis concludes with a Bibliography and a summary Epilogue which seeks to assess briefly the 'achievement' of Pynchon's writing

    Hypertext Semiotics in the Commercialized Internet

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    Die Hypertext Theorie verwendet die selbe Terminologie, welche seit Jahrzehnten in der semiotischen Forschung untersucht wird, wie z.B. Zeichen, Text, Kommunikation, Code, Metapher, Paradigma, Syntax, usw. Aufbauend auf jenen Ergebnissen, welche in der Anwendung semiotischer Prinzipien und Methoden auf die Informatik erfolgreich waren, wie etwa Computer Semiotics, Computational Semiotics und Semiotic Interface Engineering, legt diese Dissertation einen systematischen Ansatz für all jene Forscher dar, die bereit sind, Hypertext aus einer semiotischen Perspektive zu betrachten. Durch die Verknüpfung existierender Hypertext-Modelle mit den Resultaten aus der Semiotik auf allen Sinnesebenen der textuellen, auditiven, visuellen, taktilen und geruchlichen Wahrnehmung skizziert der Autor Prolegomena einer Hypertext-Semiotik-Theorie, anstatt ein völlig neues Hypertext-Modell zu präsentieren. Eine Einführung in die Geschichte der Hypertexte, von ihrer Vorgeschichte bis zum heutigen Entwicklungsstand und den gegenwärtigen Entwicklungen im kommerzialisierten World Wide Web bilden den Rahmen für diesen Ansatz, welcher als Fundierung des Brückenschlages zwischen Mediensemiotik und Computer-Semiotik angesehen werden darf. Während Computer-Semiotiker wissen, dass der Computer eine semiotische Maschine ist und Experten der künstlichen Intelligenz-Forschung die Rolle der Semiotik in der Entwicklung der nächsten Hypertext-Generation betonen, bedient sich diese Arbeit einer breiteren methodologischen Basis. Dementsprechend reichen die Teilgebiete von Hypertextanwendungen, -paradigmen, und -strukturen, über Navigation, Web Design und Web Augmentation zu einem interdisziplinären Spektrum detaillierter Analysen, z.B. des Zeigeinstrumentes der Web Browser, des Klammeraffen-Zeichens und der sogenannten Emoticons. Die Bezeichnung ''Icon'' wird als unpassender Name für jene Bildchen, welche von der graphischen Benutzeroberfläche her bekannt sind und in Hypertexten eingesetzt werden, zurückgewiesen und diese Bildchen durch eine neue Generation mächtiger Graphic Link Markers ersetzt. Diese Ergebnisse werden im Kontext der Kommerzialisierung des Internet betrachtet. Neben der Identifizierung der Hauptprobleme des eCommerce aus der Perspektive der Hypertext Semiotik, widmet sich der Autor den Informationsgütern und den derzeitigen Hindernissen für die New Economy, wie etwa der restriktiven Gesetzeslage in Sachen Copyright und Intellectual Property. Diese anachronistischen Beschränkungen basieren auf der problematischen Annahme, dass auch der Informationswert durch die Knappheit bestimmt wird. Eine semiotische Analyse der iMarketing Techniken, wie z.B. Banner Werbung, Keywords und Link Injektion, sowie Exkurse über den Browser Krieg und den Toywar runden die Dissertation ab
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