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No description available.

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The field of cancer therapeutic development has been dominated by two research and discovery paradigms, the cytotoxicity-based or phenotype driven strategy and the target-based rational approach. This thesis describes the standardization of novel assays used in both approaches and the discoveries made using these processes. Rational drug design or the target-based approach to discovering novel anti-cancer agents requires a basic understanding of the oncogenic signals that induce uncontrolled cellular proliferation. c-MET is a proto-oncogene, linked to a number of different cancers, that encodes a receptor tyrosine kinase. As an oncogene, c-MET has been shown to transform cells in the laboratory setting and is dysregulated in number of malignancies. Thus, we sought to discover a small molecule inhibitor of c-MET kinase activity by screening a novel library of small molecules. In the second part of this dissertation, we describe the standardization of a high-throughput assay to identify putative c-MET inhibitors and the results of our screening attempt. Cytotoxicity-based screening is another validated approach that is used to discover anti-cancer agents. As a parallel program to our c-MET discovery effort, we designed a high-throughput cytotoxicity assay to identify a novel small molecule with high cytotoxic activity towards tumor cells. The result of this screen was the identification of ON015640, a novel anti-cancer therapeutic with tubulin-depolymerizing activity. Throughout the course of this project, we tried to discern the advantages and disadvantages of the two predominant paradigms in cancer therapeutic research. Both strategies require careful assay design and an acute understanding of the molecular and genetic underpinnings of cancer. While it is clear that structure-based rational drug design has its merits and its success stories, it has become increasingly clear that seeking out a desired biological effect may serve as a more effective staring point when dealing with cancers for which no clear oncogene addiction phenotype has been observed. / Molecular and Cellular Physiology

Thesis (LL.M.). / Written for the Institute of Comparative Law. Title from title page of PDF (viewed 2008/01/14). Includes bibliographical references.

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Destination USA examines the works of the travel writer William Least Heat-Moon and his place ·in the tradition of American travel writing. The study begins with an overview of the current scholarship and trends within contemporary American travel writing and then moves on to limit and to define its scope. Next an outline and an in-depth explanation of the structure and thematics of such works is presented. Contemporary American travel writing has two dominant structures: the on-the~road motif and the intimate journey Of~ place. Woven into these two structures are three main themes common to both. The first theme focuses on the role of selfdiscovery in travel writing. The second theme highlights the role of travel writing in discovering hidden or marginalised American voices. The third theme centres around travel writing's use as a warning about or an assessment of the current American situation. Next a historical overview of the roots of American travel writing is undertaken which highlights the role it has played in the foundation of the country as well as providing the basis for those structures and themes outlined above. From there the dissertation moves onto an analysis of the works of William Least Heat-Moon: Blue Highways (1982), PrairyErth (1991) and River-Horse (1999). Heat-Moan's works provide an effective focal point for the understanding of contemporary American travel writing as a whole. They are forward looking and experimental while retaining a continuity with the tradition of American travel writing. An in-depth analysis of his trilogy on the American landscape is supported by previously unpublished interviews by the author. His works are then examined to uncover how they point to travel writing's elision with naturalist prose and work together to form a multifaceted vision of America. !

Most of the service discovery protocols available on the Internet are built upon its logical structure. This phenomenon can be observed frequently from the way in which they behave. For instance, Jini and SLP service providers announce their presence by multicasting service advertisements, an approach that is neither intended to scale nor capable of scaling to the size of the Internet. With mobile and wireless devices becoming increasingly popular, there appears to be a need for performing service discovery in a wide-area context, as there is very little direct correlation between the Internet topology and geographic locations. Even for desktop computers, such a need can arise from time to time. This problem suggests the necessity for an architecture that allows users to locate resources on the Internet using geographic criteria. This thesis presents an architecture that can be deployed with minimal effort in the existing network infrastructure. The geographic information can be shared among multiple applications in a fashion similar to the way DNS is shared throughout the Internet. The design and implementation of the architecture are discussed in detail, and three case studies are used to illustrate how the architecture can be employed by various applications to satisfy dramatically different needs of end-users.

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.