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.

The widespread deployment of inexpensive communications technology, computational resources in the networking infrastructure and network-enabled end devices pose a problem for end users: how to locate a particular network service or device out of those accessible. Service providers use Service Discovery Services (SDS) to advertise the descriptions of available or already running services, while clients use SDS to compose queries for locating these services. Service descriptions and queries use the eXtensible Markup Language (XML) to encode vendor specific information and device- or service-specific capabilities as well as the actions addressed to the device or service. This report presents the architecture and implementation of a SDS used to locate enabled LCD projectors and use them for presentation. The presentation service provides all the capabilities to the end user so that he can choose the projector device of his interest and use the graphical user interface to navigate thorough the presentation. The presentation service also has the capability to use more than one projector at a time. We use the Universal Plug and Play suite of protocols to establish the communication between client and the projector device.

Recent years have seen an expansion beyond the more druggable biological targets into novel areas of biological space. However, drug discovery campaigns against these challenging targets have been afflicted with low hit rates during screening campaigns and high levels of candidate attrition during clinical trials. Subsequent studies have looked to explore the underlying factors to these challenges and have identified the lack of scaffold diversity and poor physicochemical properties in screening libraries as the leading causes. In an attempt to address this issue drug discovery strategies such as fragment-based drug discovery and lead-oriented synthesis have been developed which control and direct the compound properties within screening libraries towards relevant areas of chemical space. In addition, strategies such as diversity oriented synthesis aim to synthesise structurally complex and diverse compounds, expanding screening collections into previously under-explored areas of chemical space. This thesis reports the development of a step-efficient, modular and highly adaptable synthetic route for the synthesis of partially saturated bicyclic heteroaromatic scffolds (Figure i). The designed route takes advantage of the large chiral pool provided by amino acids, with each scaffold synthesised in just 4-6 steps from these readily available enantiopure starting materials. The mild conditions allow for excellent functional group tolerance, thus enabling the incorporation of growth vectors for chemical elaboration from the outset, a strong advantage in the drug discovery process. Overall, 29 partially saturated bicyclic heteroaromatic compounds were synthesised based around 7 different scaffolds. These demonstrated a number of possible areas for diversifation both on and around the scaffold, including variation of functional groups (Figure i, red), double (cis-diastereoisomers) and single (R2- and R3-positions) substitution patterns, variation of the 5-membered heterocycle (Figure i, green) and increased size of the saturated ring (Figure i, blue). Furthermore, careful selection of the substituents, heterocycle and size of the saturated ring would enable the synthesis of screening libraries within the constraints of fragment-like, lead-like or drug-like structures. The final library has been incorporated into the Diamond XChem high-throughput crystallography program and initial screening has identified a weakly binding hit for Activin A.

Natural products have been a fundamental source of medicinal scaffolds for decades; with sixty percent of marketed drugs. Many synthetic chemists are focused on synthesizing potent and nontoxic compounds for pharmaceutical targets, however, nature is still proving to be a source of new bioactive compounds. Produced by the host organism for defense, reproduction and communication, secondary metabolites also demonstrate promising bioactivity against human pathogens. Hence, natural product chemists continue their quest for new leads. As a continuation of these efforts, this thesis attempts to explore fungi and sponges for new chemistry, and ultimately, new drug candidates. Antarctica is largely untapped; hence herein two Antarctic sponges were chemically investigated. This resulted in isolation and characterization of two metabolites. Concurrently, chemical investigation of fungus, from Floridian mangrove species, resulted in the isolation of two structurally diverse metabolites. Further, a dereplication process was applied to MPLC fractions, which lead to the identification of known metabolites and mycotoxins. This enabled prioritization of fractions for future studies.

PhD / This thesis describes an interview study of forty five professionally accomplished male and female designers and architects. The study considers how each respondent designs and makes discoveries throughout conceptual design. How they start designing, what they attempt to achieve, the means they employ, how they cope with getting stuck, their breakthroughs and discoveries and the circumstances of these experiences, are the main ingredients of the study. The aim of the research is to estimate the extent to which designing may be regarded as an insightful activity, by investigating experiences of discoveries as reported by the respondents. Throughout the thesis, discoveries or ideas occurring to respondents when they are not actively designing, an apparent outcome of a latent designing or preparation activity, are referred to as cold discoveries. This label is used to distinguish these discoveries from discoveries that emerge in the run of play, when individuals are actively designing. The latter are referred to as hot discoveries. The relative insightfulness of hot and cold discoveries is also investigated. In general, the evidence from the research suggests that designing is significantly insightful. Most respondents (39:45) reported experiences of insights that have contributed to their designing. In addition there is strong evidence that cold discoveries are considerably more important, both quantitatively and qualitatively, than is currently recognized. More than half of the respondents (25:45) reported the experience of cold discoveries, many after disengaging from designing, when they had been stuck. Being stuck means they were experiencing frustration, or had recognised they were not making satisfactory progress in attempts to resolve some aspect of conceptual design. Typically these respondents reported experiencing discoveries while doing other work, performing some physical activity, resting, or very soon after resuming work. They had elected to let ideas come to them, rather than persist in searching and this strategy was successful. Moreover, many respondents (10:45) described positive attributes of cold discoveries using terms such as stronger, more potent, or pushes boundaries, which suggest their cold discoveries are more insightful than their hot discoveries. Many respondents associated their cold discoveries with mental activities such as incubation, a concept identified by Gestalt theorists nearly a century ago. They used a range of informal terms, such as ideas ticking over, or percolating away. These apparently uncontrolled mental experiences, which I refer to generically as latent preparation, varied from one respondent to another in when, where and how they occurred. Latent preparation or its outcomes, in the form of interruptive thoughts, apparently takes place at any time and during different states of consciousness and attentiveness. It appears to be, at different times, unplanned, unintentional, undirected, unnoticed, or unconscious, in combinations, not necessarily all at once. It is clearly not only an unconscious process. This suggests one, or more of the following; 1) that incubation is only a component of latent preparation, or 2) that the conventional view of incubation, as an unconscious process, does not adequately account for the range of insightful experiences of mentally productive people, such as designers, or 3) that the old issue of whether incubation is a conscious, or an unconscious process, is not vital to a systematic investigation of insightful discovery. The thesis concludes by considering prospects for further research and how the research outcomes could influence education. Apart from the findings already described, statements by the respondents about personal attributes, designing, coping with being stuck and discoveries, were wide ranging, resourceful and down-to-earth, suggesting there are many ways for individuals to become proficient, creative designers at the high end of their profession. A major implication for future research is that latent preparation may be found as readily among highly motivated and skilled individuals in other occupations unrelated to architecture or designing. The evidence of the research so far suggests there is much to be learned about latent preparation that can be usefully applied, for the benefit of individuals aiming to be designers, or simply wanting to become more adept at intervening, transforming and managing unexpected and novel situations of any kind.

TYPICAL is a package for describing and making automatic inferences about a broad class of SCHEME predicate functions. These functions, called types following popular usage, delineate classes of primitive SCHEME objects, composite data structures, and abstract descriptions. TYPICAL types are generated by an extensible combinator language from either existing types or primitive terminals. These generated types are located in a lattice of predicate subsumption which captures necessary entailment between types; if satisfaction of one type necessarily entail satisfaction of another, the first type is below the second in the lattice. The inferences make by TYPICAL computes the position of the new definition within the lattice and establishes it there. This information is then accessible to both later inferences and other programs (reasoning systems, code analyzers, etc) which may need the information for their own purposes. TYPICAL was developed as a representation language for the discovery program Cyrano; particular examples are given of TYPICAL's application in the Cyrano program.

This paper presents a DHT-based grid resource indexing and discovery (DGRID) approach. With DGRID, resource-information data is stored on its own administrative domain and each domain, represented by an index server, is virtualized to several nodes (virtual servers) subjected to the number of resource types it has. Then, all nodes are arranged as a structured overlay network or distributed hash table (DHT). Comparing to existing grid resource indexing and discovery schemes, the benefits of DGRID include improving the security of domains, increasing the availability of data, and eliminating stale data. / Singapore-MIT Alliance (SMA)

The process of drug discovery is very slow and expensive. There is a need for reliable in silico methods; however the performance of these methods differs. This work presents a targeted study on how the drug discovery methods used in OpenEye’s tools ROCS, EON and FRED perform on targets with small ligands. It was examined if 12 compounds (markers) somewhat similar to AMP could be detected by ROCS in a random data set comprised of 1000 compounds. It was also examined if EON could find any electrostatic similarities between the queries and the markers. The performance of FRED with respect to re-generation of bound ligand modes was examined on ten different protein/ligand complexes from the Brookhaven Protein Data Bank. It was also examined if FRED is suitable as a screening tool since several other docking methods are used in such a way. Finally it was also examined if it was possible to reduce the time requirements of ROCS when running multiconformer queries by using a combination of single conformer queries coupled with multiconformer queries. The conclusions that could be drawn from this project were that FRED is not a good screening tool, but ROCS performs well as such. It was also found that the scoring functions are the weak spots of FRED. EON is probably very sensitive to the conformers used but can in some cases strengthen the results from ROCS. A novel and simple way to reduce the time complexity with multiconformer queries to ROCS was discovered and was shown to work well.

During the route discovery process, each node receiving the route request packet (RReq) will retransmit it exactly once. A distant neighbor may accidentally receive/loose the only RReq and use it to announce a new route, although that link is inferior/superior for route reply packets (RRep) or actual message routing. Overall, the constructed route may be far from the optimal. All existing route discovery schemes (including DSR/AODV) apply retransmission during route discovery exactly once (1R). Based on a realistic physical layer model, we propose two new route discovery schemes: n-retransmission (nR, retransmitting exactly n times) and n-retransmission c-reception (ncRR), retransmitting until we either reach a total of n own retransmissions or c copies from neighbors are heard. We compare our two new scheme with the traditional one, under otherwise identical conditions (same metric, same packet reception probability on each link) and the same choices about possibly retransmitting again upon discovering a better route (R+) or discarding it (R1), generating route reply packet for every received RRep (B*), or for first and better discovered routes only (B2), and retransmitting RRep exactly once (A1), up to a maximum of three times (A3), or optimally u times decided by link quality (Au). Experimental results show that the proposed ncRR scheme (for n=2 and c=3 or c=4) achieves the best tradeoff between quality of route, success rate and message overhead in the route discovery process, followed by the nR scheme, and both of them are superior to the existing traditional schemes.