Viral proteases are often considered to be attractive drug targets because of their crucial function in the viral replication machinery. In order to increase our knowledge of these important targets and to contribute to the discovery and development of new antiviral drugs, the proteases from hepatitis C virus (HCV) and human cytomegalovirus (HCMV) have been produced and their interactions with inhibitors and fragments have been characterized, using enzyme inhibition and SPR biosensor based interaction assay. The structure activity relationships and the resistance profiles of a series of HCV NS3 protease inhibitors based on either P2 proline or phenylglycine residues were analyzed using wild type genotype 1a and the major resistant variants A156T and D168V. The observed susceptibility to substitutions associated with these resistance variants was concluded to depend on the P2 and the P1 residue, and not only on the P2 residue as previously had been suggested. In order to be able to evaluate how the potency of inhibitors is affected by genetic variation, their effect was evaluated on wild type NS3 from genotype 1a, 1b and 3a as well as on the resistant variant R155K from genotype 1a. To enable a comparison of the inhibitory effect on the enzyme variants, the compounds were analyzed under conditions optimized for each variant. VX-950 was found to be the least susceptible compound to resistance and genetic variation. A more detailed analysis showed that the kinetic and mechanistic features of the inhibitors were significantly different for the different genotypes. The reversible non covalent macrocyclic inhibitor ITMN 191 was revealed to have favorable kinetics for all three genotypes. This is an advantage for the design of broad spectrum drugs. A fragment based procedure for identifying and validating novel scaffolds for inhibitors of HCMV protease was established. It identified fragments that may serve as starting points for the discovery of effective inhibitors against this challenging target.   The procedures developed for the evaluation and identification of novel HCV NS3 and HCMV protease inhibitors have contributed to a deeper understanding of protease-inhibitor interactions that is expected to have an impact on the design of novel antiviral drugs.

In this exploration, participatory planning workshops are used to implement the Education for Sustainable Development (ESD) initiative in a grade six class in Winnipeg. The approach is an effective student-centered strategy that meets the needs of children with a range of learning abilities. The benefits of participatory planning workshops for students with special needs emerged as a key success of the process. Grounded in the principles of community engagement, this document connects children’s rights to citizenship with the need to engage children in planning for sustainable development. Semi-structured interviews were integral to understanding the unique needs of the participant class. Challenges that emerged during the parental consent and student assent process are examined and strategies for future interdisciplinary collaborations are identified. An extensive literature review explores the emergence of youth participation in planning and a range of best practices for engaging children in participatory student-led processes. This research investigates international strategies for implementing the ESD initiative and considers emergent best practices at student, institutional and government levels. Schools are examined as components of community infrastructure that influence neighbourhood design and shape development. As school infrastructure ages and school facilities are challenged to become more sustainable, engaging with school communities in planning, design, renovation or building will be an important skill for planning professionals. Developing the necessary knowledge, skills and values to engage children in planning processes is illustrated as an integral component of this process.

<p>Dengue viruses (DENV) are mosquito&#8208;borne flaviviruses that pose a continued and growing threat to global health. There are estimated to be 390 million DENV infections each year, and because there is no vaccine or approved therapeutic treatment, developing a small&#8208;molecule treatment is imperative. Possible small&#8208;molecule drug therapies for DENV could be immune system modulators, inhibitors of DENV&#8208;required host factor, or inhibitors of a viral gene product. In this study, we chose to take the latter approach and focused our drug discovery efforts on the most highly conserved flaviviral protein, non&#8208;structural protein 5 (NS5). NS5 contains two major domains, each with different enzymatic activities. The N&#8208;terminus has methyltransferase activity, and the C terminus, an RNA&#8208;dependent RNA polymerase (RdRp). The activities of both domains are purine&#8208;dependent, and therefore both domains contribute to the purine&#8208;binding properties of NS5. Inhibition of either of these domains in NS5 results in inadequate propagation of DENV, and the purine&#8208;binding domains present ideal drug targets for disrupting these activities. These factors make NS5 protein an ideal candidate target for our small&#8208;molecule library screen.</p><p>A high&#8208;throughput fluorescence&#8208;based screen was employed to identify anti&#8208;DENV compounds based on their ability to competitively bind NS5. The screen was performed by binding green fluorescent protein NS5 fusion protein (GFP&#8208;NS5) to immobilized ATP resin, and then performing parallel elutions using over 3,000 distinct compounds. One compound in particular, HS&#8208;205020, was able to competitively elute GFP&#8208;NS5 from the ATP resin and also exhibited antiviral activity in both the U937+DCSIGN human monocyte cell line and BHK&#8208;21 cells. Additionally, HS&#8208;205020 was able to inhibit DENV NS5 RNA polymerase activity in vitro. HS&#8208;205020 is chemically distinct from the majority of previously reported NS5 inhibitors, which are nucleoside analogs that can cause severe toxicity in animal studies. In contrast, over the concentration range that produced anti&#8208;DENV effects, HS&#8208;205020 showed comparable viabilities to ribavirin, an FDA approved hepatitis C virus (HCV) therapeutic. These findings support HS&#8208;205020 as a potential dengue antiviral candidate, and its chemical scaffold represents as an ideal starting compound for future structure&#8208;activity relationship studies.</p> / Dissertation

Encouraging the use of computer algorithms by developing new algorithms and introducing uncommonly known algorithms for use on environmental science problems is a significant contribution, as it provides knowledge discovery tools to extract new aspects of results and draw new insights, additional to those from general statistical methods. Conducting analysis with appropriately chosen methods, in terms of quality of performance and results, computation time, flexibility and applicability to data of various natures, will help decision making in the policy development and management process for environmental studies. This thesis has three fundamental aims and motivations. Firstly, to develop a flexibly applicable attribute selection method, Tree Node Selection (TNS), and a decision tree assessment tool, Tree Node Selection for assessing decision tree structure (TNS-A), both of which use decision trees pre-generated by the widely used C4.5 decision tree algorithm as their information source, to identify important attributes from data. TNS helps the cost effective and efficient data collection and policy making process by selecting fewer, but important, attributes, and TNS-A provides a tool to assess the decision tree structure to extract information on the relationship of attributes and decisions. Secondly, to introduce the use of new, theoretical or unknown computer algorithms, such as the K-Maximum Subarray Algorithm (K-MSA) and Ant-Miner, by adjusting and maximizing their applicability and practicality to assess environmental science problems to bring new insights. Additionally, the unique advanced statistical and mathematical method, Singular Spectrum Analysis (SSA), is demonstrated as a data pre-processing method to help improve C4.5 results on noisy measurements. Thirdly, to promote, encourage and motivate environmental scientists to use ideas and methods developed in this thesis. The methods were tested with benchmark data and various real environmental science problems: sea container contamination, the Weed Risk Assessment model and weed spatial analysis for New Zealand Biosecurity, air pollution, climate and health, and defoliation imagery. The outcome of this thesis will be to introduce the concept and technique of data mining, a process of knowledge discovery from databases, to environmental science researchers in New Zealand and overseas by collaborating on future research to achieve, together with future policy and management, to maintain and sustain a healthy environment to live in.

Drug discovery is a complicated and expensive process in the billion dollar range. One way of making the drug development process more efficient is better information handling, modelling and visualisation. The majority of todays drugs are small molecules, which interact with drug targets to cause an effect. Since the 1980s large amounts of compounds have been systematically tested by robots in so called high-throughput screening. Ligand-based drug discovery is based on modelling drug molecules. In the field known as Quantitative Structure–Activity Relationship (QSAR) molecules are described by molecular descriptors which are used for building mathematical models. Based on these models molecular properties can be predicted and using the molecular descriptors molecules can be compared for, e.g., similarity. Bioclipse is a workbench for the life sciences which provides ligand-based tools through a point and click interface.  The aims of this thesis were to research, and develop new or improved ligand-based methods and open source software, and to work towards making these tools available for users through the Bioclipse workbench. To this end, a series of molecular signature studies was done and various Bioclipse plugins were developed. An introduction to the field is provided in the thesis summary which is followed by five research papers. Paper I describes the Bioclipse 2 software and the Bioclipse scripting language. In Paper II the laboratory information system Brunn for supporting work with dose-response studies on microtiter plates is described. In Paper III the creation of a molecular fingerprint based on the molecular signature descriptor is presented and the new fingerprints are evaluated for target prediction and found to perform on par with industrial standard commercial molecular fingerprints. In Paper IV the effect of different parameter choices when using the signature fingerprint together with support vector machines (SVM) using the radial basis function (RBF) kernel is explored and reasonable default values are found. In Paper V the performance of SVM based QSAR using large datasets with the molecular signature descriptor is studied, and a QSAR model based on 1.2 million substances is created and made available from the Bioclipse workbench.

The purpose of this thesis is to examine how instruction librarians‟ perceptions of web scale discovery services and their perceptions of the impact of web scale discovery on students‟ information literacy are reflected in their instruction practices in academic libraries. This study addresses how instruction librarians generally perceive WSDS and students‟ information literacy as well as how instruction librarians conduct their instruction sessions. The study‟s empirical data consists of the responses received through seven semi-structured interviews with ten instruction librarians at three separate universities in the Västra Götaland region. The study concludes that library instruction practices reflect many of the librarians‟ perceptions surrounding WSDS, most notably in the areas of source criticism and critical assessment of search results. The study also shows that the search strategies, techniques, and tools taught in instruction sessions are greatly influenced by librarians‟ perceptions of the usefulness of WSDS in student search processes. The librarians‟ responses demonstrate the importance of teaching students search strategies and techniques as well as helping them develop critical evaluation skills that will remain relevant as search technologies continue to evolve.

In this exploration, participatory planning workshops are used to implement the Education for Sustainable Development (ESD) initiative in a grade six class in Winnipeg. The approach is an effective student-centered strategy that meets the needs of children with a range of learning abilities. The benefits of participatory planning workshops for students with special needs emerged as a key success of the process. Grounded in the principles of community engagement, this document connects children’s rights to citizenship with the need to engage children in planning for sustainable development. Semi-structured interviews were integral to understanding the unique needs of the participant class. Challenges that emerged during the parental consent and student assent process are examined and strategies for future interdisciplinary collaborations are identified. An extensive literature review explores the emergence of youth participation in planning and a range of best practices for engaging children in participatory student-led processes. This research investigates international strategies for implementing the ESD initiative and considers emergent best practices at student, institutional and government levels. Schools are examined as components of community infrastructure that influence neighbourhood design and shape development. As school infrastructure ages and school facilities are challenged to become more sustainable, engaging with school communities in planning, design, renovation or building will be an important skill for planning professionals. Developing the necessary knowledge, skills and values to engage children in planning processes is illustrated as an integral component of this process.

The Bluetooth Scatternet Formation (BSF) problem can be defined as the problem of forming wireless networks of Bluetooth devices in an efficient manner. A number of restrictions imposed by the Bluetooth specifications make the BSF problem challenging and unique. Many interesting solution algorithms have been proposed in the literature to solve this problem. In this thesis, we investigate the BSF problem. We concentrate on problems introduced by the procedures of device discovery of the Bluetooth specifications and on the different solutions used by BSF algorithms to deal with these problems. We study also in this thesis problems introduced by the specifications of link establishment in Bluetooth due to their close interaction with the device discovery specifications. We survey and categorize the different device discovery techniques used by BSF algorithms. This categorization is then used as a basis to identify the different theoretical computational models used to study BSF algorithms. We argue, in this thesis, that the currently available models for Bluetooth wireless networks do not model adequately, in most cases, the complexities of the Bluetooth specifications and we show that these models were oversimplified in many cases. A general computational model will be useful as a starting point to design BSF algorithms and to compare the different and numerous BSF algorithms – especially in term of the execution time efficiency. In this thesis, we provide a set of suggestions that will help in the creation of such model. We survey a number of studies that examined in more depth the specifications of device discovery in Bluetooth. We survey also other studies that attempted to simplify the Bluetooth network model, either by suggesting modifications on the Bluetooth specifications or by the use of communication technologies other than Bluetooth. Finally, we present some experiments accompanied with analyzes to show the complexities of the Bluetooth specifications and their sensitivity to minor changes (whether in the specifications or in their implementation).

Intelligent Transport System (ITS) has become a hot research topic over the past decades. ITS is a system that applies the following technologies to the whole transportation management system efficiently, including information technique, wireless communication, sensor networks, control technique, and computer engineering. ITS provides an accurate, real time and synthetically efficient transportation management system. Obviously, Vehicular Ad Hoc NETworks (VANETs) attract growing attention from both the research community and industry all over the world. This is because a large amount of applications are enabled by VANETs, such as safety related applications, traffic management, commercial applications and general applications. When connecting to the internet or communicating with different networks in order to access a variety of services using VANETs, drivers and passengers in different cars need to be able to exchange messages with gateways from their vehicles. A secure gateway discovery process is therefore critical, because vehicles should not be subject to security attacks while they are communicating; however, currently there is no existing protocol focusing on secure gateway discovery. In this thesis, we first analyze and compare current existing secure service discovery protocols and then we propose a Secure Gateway Localization and Communication System for Vehicular Ad Hoc Networks (SEGAL), which concentrates on the security issue in gateway discovery. We focus on the authentication aspect by proposing secure cluster based VANETs, that can ensure the gateway discovery messages exchanged through secure clusters. We present the principle and specific process of our SEGAL protocol and analyze its performance to guarantee its outstanding practical applicability.

In 2005 and 2010, high sea surface temperatures caused widespread coral bleaching on Jamaica’s north coast reefs. Three shallow (9m) reef sites were surveyed during each event to quantify the prevalence and intensity of coral bleaching. In October 2005, 29-57% of the colonies surveyed were bleached. By April 2006, 10% of the corals remained pale/partially bleached. Similarly, in October 2010, 23-51% of corals surveyed at the same sites were bleached. By April 2011, 12% of the colonies remained pale/partially bleached. Follow-up surveys revealed low coral mortality following both events, with an overall mean of 4% partial colony mortality across all species and sites observed in April 2006, and 2% in April 2011. Mixed effects models were used to quantify the relationship between colony size and (a) bleaching intensity, and (b) bleaching related mortality among coral species. The bleaching intensity model explained 51% of the variance in the bleaching response observed during the two events. Of this 51%, fixed effects accounted for ~26% of the variance, 17% of which was attributed to species-specific susceptibility to bleaching , 5% to colony size, <1% colony morphology and 4% to the difference in bleaching intensity between the two events. The random factor (site) accounted for the remaining ~25% of the variance. The mortality model explained 16% of the variance in post bleaching mortality with fixed effects, including colony size, morphology and species explaining ~11% of the variance, and the random effect (site) explaining 5%. On average, there was a twofold difference in bleaching intensity between the smallest and the largest size classes. Modelling the relationship between colony level characteristics and site-specific environmental factors on coral species’ susceptibility to thermal stress can shed light on community level responses to future disturbances.