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The Grid has been recognised as the next-generation distributed computing paradigm by seamlessly integrating heterogeneous resources across administrative domains as a single virtual system. There are an increasing number of scientific and business projects that employ Grid computing technologies for large-scale resource sharing and collaborations. Early adoptions of Grid computing technologies have custom middleware implemented to bridge gaps between heterogeneous computing backbones. These custom solutions form the basis to the emerging Open Grid Service Architecture (OGSA), which aims at addressing common concerns of Grid systems by defining a set of interoperable and reusable Grid services. One of common concerns as defined in OGSA is the Grid accounting service. The main objective of the Grid accounting service is to ensure resources to be shared within a Grid environment in an accountable manner by metering and logging accurate resource usage information. This thesis discusses the origins and fundamentals of Grid computing and accounting service in the context of OGSA profile. A prototype was developed and evaluated based on OGSA accounting-related standards enabling sharing accounting data in a multi-Grid environment, the World-wide Large Hadron Collider Grid (WLCG). Based on this prototype and lessons learned, a generic middleware solution was also implemented as a toolkit that eases migration of existing accounting system to be standard compatible.

Despite many years of effort, linkage and candidate gene association studies have yielded disappointingly few risk loci for common human diseases such as diabetes, auto-immune disorders and cancers. Large sample sizes, increased understanding of the patterns of correlation in genetic variation, and plunging genotyping costs have enabled genome-wide association studies, which have good power to detect common risk alleles of modest effect. I present an evaluation of SNP choice in study design and show that overall, despite substantial differences in genotyping technologies, marker selection strategies and number of markers assayed, the first generation platforms all offer good levels of genome coverage (∼ 70%). I next describe the largest such project undertaken to date, the Wellcome Trust Case Control Consortium, which consisted of 2000 cases from each of seven common diseases and 3000 shared controls. It identified nearly two dozen new associations. I demonstrate the importance of careful data quality control, including both standard and unorthodox analyses. I next focus on the association results therein for Crohn’s disease. I present a replication experiment in over 1000 additional Crohn’s patients which unambiguously confirmed six previously published loci and four new loci. Next I describe, in a general context, several issues impeding the combination of genome-wide scans, including data annotation, population structure and differences in genotyping platform. Each of these problems is shown to be tractable with available methods, provided that these methods are applied prudently. I present the results of a meta-analysis of three genome-wide scans for Crohn’s disease. The data showed a striking excess of significant associations, and a replication experiment involving over 4000 independent Crohn’s patients verified twenty new risk loci. Finally, I discuss the early success of genome-wide association and its consequences for further understanding the biology of human disease.

Ultra-wideband (UWB) communication has been the subject of extensive research in recent years due to its unique capabilities and potential applications, particularly in short-range multiple access wireless communications. However, many important aspects of UWB-based communication systems have not yet been thoroughly investigated. The propagation of UWB signals inside very small enclosed environments is one of the important issues with significant impacts on the future direction, scope, and generally the extent of the success of UWB technology. The objective of this thesis is to obtain a more thorough and comprehensive understanding of ultra-small UWB channels for communication applications and design issues for enhancing the data rate of UWB systems. This works supports the postulation of a high capacity UWB wireless interconnect scheme for communicating devices within conducting enclosures – a wireless “backplane”. This thesis proposes the use of an Ultra-Wide Bandwidth (UWB) ultra-small scale wireless interconnect scheme for use within electrically small enclosures. Such ultra-small environments (size ≤ 10 wavelengths) are topologically much more complex, being more cluttered, than typical indoor environments (size ≥ 10 wavelengths). The concept is presented through two different scenarios. Firstly, a PC Tower case is presented as a model environment and the work seeks to present the optimum channel performance, where EMI issues are discussed and problem avoidance proposed. Secondly, in order to extrapolate the different results from the study inside the PC, an investigation is carried out using an Aluminium tower case as a more generic model environment. The analysis is based on the behaviour of box modes within a conducting resonator enclosure and the effective communications bandwidth for UWB systems for different sizes and components within. From these general considerations the research presents theoretical and experimental results from which are derived the communications metrics measured within enclosures. Simulations of the different scenarios are performed using different techniques such as ray tracing and a full wave model, based on CST Microstripes. Empirical data is recorded using a vector network analyser (VNA)-based wideband channel sounding system where channel measurements are carried out in every scenario regarding different aspects such as frequency response and time domain analysis, evaluation of the channel capacity, power delay study and the nature of the environment.

Of central importance in the dissection of the components that govern complex traits is understanding the architecture of natural genetic variation. Genetic interaction, or epistasis, constitutes one aspect of this, but epistatic analysis has been largely avoided in genome wide association studies because of statistical and computational difficulties. This thesis explores both issues in the context of two-locus interactions. Initially, through simulation and deterministic calculations it was demonstrated that not only can epistasis maintain deleterious mutations at intermediate frequencies when under selection, but that it may also have a role in the maintenance of additive variance. Based on the epistatic patterns that are evolutionarily persistent, and the frequencies at which they are maintained, it was shown that exhaustive two dimensional search strategies are the most powerful approaches for uncovering both additive variance and the other genetic variance components that are co-precipitated. However, while these simulations demonstrate encouraging statistical benefits, two dimensional searches are often computationally prohibitive, particularly with the marker densities and sample sizes that are typical of genome wide association studies. To address this issue different software implementations were developed to parallelise the two dimensional triangular search grid across various types of high performance computing hardware. Of these, particularly effective was using the massively-multi-core architecture of consumer level graphics cards. While the performance will continue to improve as hardware improves, at the time of testing the speed was 2-3 orders of magnitude faster than CPU based software solutions that are in current use. Not only does this software enable epistatic scans to be performed routinely at minimal cost, but it is now feasible to empirically explore the false discovery rates introduced by the high dimensionality of multiple testing. Through permutation analysis it was shown that the significance threshold for epistatic searches is a function of both marker density and population sample size, and that because of the correlation structure that exists between tests the threshold estimates currently used are overly stringent. Although the relaxed threshold estimates constitute an improvement in the power of two dimensional searches, detection is still most likely limited to relatively large genetic effects. Through direct calculation it was shown that, in contrast to the additive case where the decay of estimated genetic variance was proportional to falling linkage disequilibrium between causal variants and observed markers, for epistasis this decay was exponential. One way to rescue poorly captured causal variants is to parameterise association tests using haplotypes rather than single markers. A novel statistical method that uses a regularised parameter selection procedure on two locus haplotypes was developed, and through extensive simulations it can be shown that it delivers a substantial gain in power over single marker based tests. Ultimately, this thesis seeks to demonstrate that many of the obstacles in epistatic analysis can be ameliorated, and with the current abundance of genomic data gathered by the scientific community direct search may be a viable method to qualify the importance of epistasis.

Compared with conventional measurements from supervisory control and data acquisition (SCADA) system, phasor measurement units (PMUs) provide time-synchronized and direct measurements of phasors. The availability of synchronized phasor measurements can significantly improve power system protection and analysis. This dissertation is specifically committed to using synchronized measurements for estimation of fault locations in transmission systems. Transmission lines are prone to various short-circuit faults. Accurate fault location is critical for rapid power recovery. Chapter 2 proposes a new fault location method based on sparse wide area measurements. One distinguishing feature of this method is its applicability to both transposed and untransposed transmission lines. In addition, the method is developed based on sparse-wide area measurement that may be taken far away from the faulted line. Shunt capacitances of transmission lines are also fully considered by the algorithm. Moreover, when synchronized measurements from multiple buses are available, an optimal estimator can be used to make the most use of measurements, and to detect and identify potential bad measurements. Most of the existing fault location literatures discuss common shunt faults, including single line-to-ground faults, line-to-line faults, line-to-line-to-ground faults, and three-phase faults. However, in addition to common shunt faults, some complex faults may also occur in power systems. Among these complex faults, evolving fault and inter-circuit fault are two typical examples. Chapter 3 extends the method developed in Chapter 2 to deal with evolving faults. The proposed wide-area fault location methods are immune to fault type evolution, and are applicable to both transposed and untransposed lines. Chapter 4 discusses location of inter-circuit faults. Inter-circuit fault is a type of simultaneous fault, and it is the most common simultaneous fault type. Inter-circuit faults between each circuit in a double-circuit line is the most common inter-circuit fault. A fault location method for inter-circuit faults on double-circuit lines are developed and evaluated in Chapter 4. Chapter 5 puts forward a fault location algorithm, which does not require line parameters information, for series-compensated transmission lines. Two-end synchronized voltage and current measurements are utilized. The proposed method is independent of source impedance and fully considers shunt capacitances of transmission lines.

<p>Thermodynamic stability measurements on proteins and protein-ligand complexes can offer insights not only into the fundamental properties of protein folding reactions and protein functions, but also into the development of protein-directed therapeutic agents to combat disease. Conventional calorimetric or spectroscopic approaches for measuring protein stability typically require large amounts of purified protein. This requirement has precluded their use in proteomic applications. Stability of Proteins from Rates of Oxidation (SPROX) is a recently developed mass spectrometry-based approach for proteome-wide thermodynamic stability analysis. Since the proteomic coverage of SPROX is fundamentally limited by the detection of methionine-containing peptides, the use of tryptophan-containing peptides was investigated in this dissertation. A new SPROX-like protocol was developed that measured protein folding free energies using the denaturant dependence of the rate at which globally protected tryptophan and methionine residues are modified with dimethyl (2-hydroxyl-5-nitrobenzyl) sulfonium bromide and hydrogen peroxide, respectively. This so-called Hybrid protocol was applied to proteins in yeast and MCF-7 cell lysates and achieved a ~50% increase in proteomic coverage compared to probing only methionine-containing peptides. Subsequently, the Hybrid protocol was successfully utilized to identify and quantify both known and novel protein-ligand interactions in cell lysates. The ligands under study included the well-known Hsp90 inhibitor geldanamycin and the less well-understood omeprazole sulfide that inhibits liver-stage malaria. In addition to protein-small molecule interactions, protein-protein interactions involving Puf6 were investigated using the SPROX technique in comparative thermodynamic analyses performed on wild-type and Puf6-deletion yeast strains. A total of 39 proteins were detected as Puf6 targets and 36 of these targets were previously unknown to interact with Puf6. Finally, to facilitate the SPROX/Hybrid data analysis process and minimize human errors, a Bayesian algorithm was developed for transition midpoint assignment. In summary, the work in this dissertation expanded the scope of SPROX and evaluated the use of SPROX/Hybrid protocols for characterizing protein-ligand interactions in complex biological mixtures.</p> / Dissertation

Gallium Oxide (Ga2O3) has emerged over the last decade as a new up-and-coming alternative to traditional wide bandgap semiconductors. It exists as five polymorphs (α-, β-, γ-, δ-, and ε-Ga2O3), of which β-Ga2O3 is the thermodynamically stable form, and the most extensively studied phase. β-Ga2O3 has a wide bandgap of ~4.8 eV and exhibits a superior figure-of-merit for power devices compared to other wide bandgap materials, such as SiC and GaN. These make β-Ga2O3 a promising candidate in a host of electronic and optoelectronic applications. Recent advances in β-Ga2O3 single crystals growth have also made inexpensive β-Ga2O3 single crystal grown from the melt a possibility in the near future. Despite the plethora of literature on β-Ga2O3-based devices, understanding of contacts to this material --- a device component that fundamentally determines device characteristics — remained lacking. For this research, ohmic and Schottky metal contacts to Sn-doped β-Ga2O3 (-201) single crystal substrates, unintentionally doped (UID) homoepitaxial β-Ga2O3 (010) on Sn-doped β-Ga2O3 grown by molecular beam epitaxy (MBE), and UID heteroepitaxial β-Ga2O3 (-201) epitaxial layers on c-plane sapphire by metal-organic chemical vapor deposition (MOCVD) were investigated. Each of the substrates was characterized for their structural, morphological, electrical, and optical properties, the results will be presented in the following document. Nine metals (Ti, In, Ag, Sn, W, Mo, Sc, Zn, and Zr) with low to moderate work functions were studied as possible ohmic contacts to β-Ga2O3. It was found that select metals displayed either ohmic (Ti and In) or pseudo-ohmic (Ag, Sn and Zr) behavior under certain conditions. However, the morphology was often a problem as many thin film metal contacts dewetted the substrate surface. Ti with a Au capping layer with post-metallization annealing treatment was the only consistently reliable ohmic contact to β-Ga2O3. It was concluded that metal work function is not a dominant factor in forming an ohmic contact to β-Ga2O3 and that limited interfacial reactions appear to play an important role. Prior to a systematic study of Schottky contacts to β-Ga2O3, a comparison of the effects of five different wet chemical surface treatments on the β-Ga2O3 Schottky diodes was made. It was established that a treatment with an organic solvent clean followed by HCl, H2O2 and a deionized water rinse following each step yielded the best results. Schottky diodes based on (-201) β-Ga2O3 substrates and (010) β-Ga2O3 homoepitaxial layers were formed using five different Schottky metals with moderate to high work functions: W, Cu, Ni, Ir, and Pt. Schottky barrier heights (SBHs) calculated from current-voltage (I-V) and capacitance-voltage (C-V) measurements of the five selected metals were typically in the range of 1.0 – 1.3 eV and 1.6 – 2.0 eV, respectively, and showed little dependence on the metal work function. Several diodes also displayed inhomogeneous Schottky barrier behavior at room temperature. The results indicate that bulk or near-surface defects and/or unpassivated surface states may have a more dominant effect on the electrical behavior of these diodes compared to the choice of Schottky metal and its work function. Lastly, working with collaborators at Structured Materials Industries (SMI) Inc., heteroepitaxial films of Ga2O3 were grown on c-plane sapphire (001) using a variety of vapor phase epitaxy methods, including MOVPE, and halide vapor phase epitaxy (HVPE). The stable phase β-Ga2O3 was observed when grown using MOVPE technique, regardless of precursor flow rates, at temperatures ranging between 500 – 850 °C. With HVPE growth techniques, instead of the stable β-phase, we observed the growth of the metastable α- and ε-phases, often a combination of the two. Cross-sectional transmission electron microscopy (TEM) shows the better lattice matched α-phase first growing semi-coherently on the c-plane sapphire substrate, followed by domain matched epitaxy of ε-Ga2O3 on top. Secondary ion mass spectrometry (SIMS) revealed that epilayers forming the ε-phase contain higher concentrations of chlorine, which suggests that compressive stress due to Cl- impurities may play a role in the growth of ε-Ga2O3 despite it being less than thermodynamically favorable.

<p>RNA binding proteins (RBPs) and non-coding RNAs orchestrate gene expression in part through the recognition specific sites in mRNA. Thus understanding the connection between binding to specific sites and regulation of the whole transcript is essential. Current methods to do this can either identify the binding sites or quantitate binding to whole transcripts, but not both. Furthermore reliance of binding site detection on ultraviolet crosslinking results in inefficient identification of binding sites, and insufficient data to assess binding strength at sites. I have overcome these limitations by combining aspects of current methods to develop a new method called DO-RIP-seq (digestion optimization RNA immunoprecipitations with deep sequencing) that can quantitate the binding strength of RBPs at sites in mRNA, and also relate binding sites to binding of the whole mRNA. DO-RIP-seq was developed using the well-studied RBP ELAVL1/HuR as a test case, and applied to the less well-studied RBP known as RBM38/RNPC1. The quantitative data from DO-RIP-seq out-performed current binding site methods at predicting other features of the binding sites of HuR and RBM38, for example the lack of RNA secondary structure, and preferences in binding to particular sub-motifs. My studies indicate that DO-RIP-seq will be useful in uncovering the determinants of RNA-protein interactions, and studying dynamic biological processes that could modulate these interactions.</p> / Dissertation