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Reciprocating-piston expanders are being considered for a range of clean-energy applications, including small- to medium-scale organic Rankine cycle (ORC) engines for conversion of low-grade heat to power, and compressed air and pumped thermal energy storage (CAES, PTES) to help integrate intermittent renewables. At large scale, turbines remain the dominant technology, but at scales of 10 - 100s of kilowatts, reciprocating-piston expanders can offer high efficiency at large pressure ratios, robust part-load performance, and affordable manufacture. Further advantages are available in compressed air energy storage applications, where the potential exists to operate a single reciprocating-piston machine as both compressor and expander. Although there is a wealth of experience in reciprocating-piston machines for internal combustion engines and compressors, quantitative understanding of the particular loss mechanisms which influence reciprocating expanders is less well-established, as a consequence of operating without combustion, and at different temperatures and valve timings. This thesis describes the development and validation of a lumped-mass piston expander model by means of experimental data and computational fluid dynamics (CFD) simulations. The model replicates the cylinder pressure and temperature to a high degree of accuracy, and captures trends in gas-wall heat transfer, though with slight discrepancies in instantaneous magnitudes. The model accounts for frictional losses, and a time-resolved exergy calculation has been introduced to attribute losses to particular thermodynamic and mechanical processes occurring within the device, at both design conditions and part-load operation. Surrogate-model-based optimisation approaches have been demonstrated to optimise an expander geometry and valve timings. By considering a broad range of possible operating conditions and geometries, a set of performance maps are developed to provide insights into the relative magnitudes of the different loss mechanisms that should be considered within the design process. The role of piston expanders in ORC systems is investigated here in multiple waste heat recovery applications, such as recovering heat from stationary internal combustion engines. The piston expander is compared to and contrasted with screw expanders for a broad range of possible ORC working fluids. Unlike previous studies, the expansion device and working fluid selection are carried out simultaneously by means of an integrated optimisation process, ensuring that performance interactions between the expansion device and working fluid properties are captured. When capturing heat from the exhaust gas of the stationary internal combustion engine, a two-stage screw expander is found to provide the highest power output and efficiency, with acetone found to be the optimal working fluid, while a single-stage piston expander offers the lowest specific investment cost and payback time. The relative merits of piston expanders and small-scale radial-inflow turbines for a fluctuating heat source are also assessed, for low-temperature (<100 °C) and high-temperature (400-600 °C) waste heat. At low temperatures, radial-inflow turbines are found to offer both higher isentropic efficiency and lower cost per unit power, while at high temperatures the reciprocating-piston expander is found to be the more economical option, demonstrating lower specific costs as well as a greater robustness to part-load conditions. Building on this finding, an in-depth assessment is carried out into two competing configurations of stationary internal combustion engines paired with ORC engines for building heat and power needs, using reciprocating-piston expanders for the ORC engine in each case. As current ORC engines are limited to small-scale production and tend to face high integration costs due to the custom nature of each installation, building energy consumption data from a set of thirty supermarkets is used to explore the economic feasibility of a common internal combustion and ORC engine design that could offer greater economies of scale. In the first configuration considered, the ORC engine recovers heat from both the exhaust gas and cooling jacket water of the stationary engine, while in the second, heat is extracted only from the exhaust gases, with the condensing temperature of the ORC engine deliberately raised well above ambient in order to allow heat to be rejected from the ORC engine's condenser to the building heating system. The former is found to offer considerably higher power and lower specific investment costs, but the economic returns are inconsistent across the set of buildings, while the second configuration demonstrates favourable payback periods of 3.5-7.5 years for all thirty of the buildings considered, offering much greater scope for larger manufacturing volumes and associated reductions in the unit price and competitiveness of these systems. The design and optimisation of a set of reciprocating-piston engines for small-scale CAES systems is performed. An initial feasibility study identifies two overall architectures for the CAES system as being of particular interest, and these are assessed from a technoeconomic standpoint. The on- and off-design performance of appropriately sized reciprocating-piston machines are simulated in order to quantify the realistic technical and commercial performance of these systems. Valve timing strategies are proposed for efficient charging and discharging of the preferred system configuration in fixed- and variable-speed operation, with variable-speed part-load operation found to deliver higher efficiency than fixed-speed even with fully variable valve timing. Consideration is given to mitigation of the main loss mechanisms within the system and the piston machines in particular, with a strong sensitivity to piston ring leakage identified for high-pressure stages. Based on broad parameter space exploration and specific case studies of piston expander operation, this work aims to highlight favourable opportunities for high-efficiency reciprocating machines and demonstrates the use of a lumped-mass model for determining relevant loss mechanisms and identifying optimal designs at component- and system-level, with a view to accelerating appropriate deployment of these machines for selected clean-energy applications.

Software simulation is vitally important in a number of industries. It allows engineers to test new products before they leave the drawing board and enables tests that would otherwise be difficult or impossible to perform. Traditional engineering simulations use sophisticated numerical methods to produce models that are highly accurate, but computationally expensive and time-consuming to use. This accuracy is essential in the latter stages of the design process, but can make the early stages - which often involve frequent, iterative design changes - a lengthy and frustrating process. Additionally, the scope of such simulations is often limited by their complexity. An attempt has been made to produce an alternative, real-time simulation tool, developed using software and development practices from the video games industry, which are designed to simulate and render virtual environments efficiently in real-time. In particular, this tool makes use of real-time physics engines; iterative, constraint-based solver systems that use rigid body dynamics to approximate the movements and interactions of physical entities. This has enabled the near-real-time simulation of multi-vehicle trains, and is capable of producing reasonably realistic results, within an acceptably small error bound, for situations in which a real-time simulation would be used as an alternative to existing methods. This thesis presents the design, development and evaluation of this simulation tool, which is based on NVidia's PhysX Engine. The aim was to determine the suitability of a physics engine-based tool for simulating various aspects of rail dynamics. This thesis intends to demonstrate that such a tool, if configured and augmented appropriately, can produce results that approach those produced by traditional methods and is capable of simulating aspects of rail dynamics that are otherwise prohibitively expensive or beyond the capabilities of existing solutions, and may therefore be a useful supplement to the existing tolls used in the rail industry.

Atom transfer cyclisation has been demonstrated as a valuable route to produce cyclic structures incorporating sites for further functionalisation. However, the current methods available to carry out this type of reaction are limited by various aspects, including the use of toxic reagents, the need for anhydrous reaction conditions, or the requirement to use a two-step protocol involving a-iodination prior to atom transfer cyclisation.

The one step hydrohydroxymethylation which can be used to transform C[sub]n alkenes into C [sub](n+1) alcohols has been explored for functionalised alkenes. The catalyst system used for this study was generated in situ from [Rh2(OAc)4], Pet3, CO/ H2 and ethanol. The main alkene investigated was 2-propen-1-ol, because of the potential to produce 1,4-butanediol by a novel route, which it indeed does in reasonable yield. Of interest the branched chain product was not the expected 2-methyl-1,3-propanediol, but 2-methylpropan-1-ol. 1,4-butanediol and 2-methylpropan-1-ol make up the majority of the final products, no aldehydic intermediates from the possible hydroformylation reaction were detected. A mechanism is proposed for the formation of 2-methylpropan-1-ol, the key steps of which are; protonation of a metal acyl species (on the acyl oxygen) to form a metal hydroxycarbene intermediate, dehydration of the hydroxycarbene species (conjugation being the driving force for this step), oxidative addition of hydrogen to the metal centre, a single hydrogen atom transfer to the carbene carbon, a sigma-pi allylic rearrangement of the substrate based ligand, followed by reductive elimination of a vinyl alcohol. This rapidly rearranges to 2-methylpropanal, which is hydrogenated by this system to give 2-methylpropan-1-ol. The mechanism was studied using 'black box' studies, recently developed deuterium labelling techniques (in one experiment 18 different isotopomers were formed, this technique could quantify them all) and some model studies. The effect on product distribution was examined by systematic variation of the reaction conditions and ligands. The reaction was expanded to other substrates such as propenyl halide, propenyl ethers, propenyl cyanide and ketones. Propenyl ethers gave similar reaction products to 2-propen-1-ol, whilst propenyl halides gave esters and ethers.

Scope and Method of Study: Qualitative research to collect data from two sources: (1) Face-to-face interviews with school board members representing four Oklahoma School Districts; (2) Newspaper articles. Findings and Conclusions: Data from the study indicate that time availability and personnel expertise are determining factors in the decision to select a search consultant. The consultant advised each board about issues of employment law and appropriate interviewing practices. Despite the assistance of an outside person with expertise, the process involved more work and much greater time than anticipated. Superintendents in the sample were selected from the available candidate pool, but no evidence existed that they were recruited; selections were from a pool of candidates who submitted applications. Results supported school districts desiring to hire an internal candidate do not need the services of a search consultant if a quality candidate is available. Board members believed the presence of a consultant in the process provided connections to improve the candidate pool while also bringing credibility to the process. All board members indicated they would support the use of a consultant again in the event of a superintendent vacancy. The decision making models of Wayne Hoy and John Tarter guided the theoretical framework of the study. The Satisficing Theory of the Administrative Model of decision making along with the Shared Decision Making model were relevant to this study. Satisficing Theory looks for satisfactory solutions to a problem; final selections were limited to candidates who showed interest in the position through submitting an application; final selections were the best of the satisfactory options. Each school district had a component of involvement for the board, staff or community based on needs identified by the board. Boards shared a segment of their decision making process with an appropriate group. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]

Aspects of the host parasite relationships which exist between larvae of the filarial nematode Brugia patei and two mosquito intermediate hosts are explored with the aid of an autoradiographic technique and selected histochemical staining methods. In Aedes togoi normal development of the worm occurs following a blood meal taken from a domestic cat infected with microfilariae of Brugia patei. Conversely Anopheles labranchiae atroparvus is refractory to infection with Brugia patei and it has been established previously that in the latter mosquito the parasite exhibits a number of abnormalities in its pattern of growth, and it rarely develops successfully to the second larval stage. The present study therefore concentrates largely on the principal histological events which take place in both the parasite and its two mosquito hosts during this early critical period of development. The results describe the incorporation of [H3]-labelled nucleosides, amino acids and carbohydrates in normal and abnormal worms and include autoradiographic and histochemical features of the host reaction elicited by Brugia patei when parasitic in Anopheles labranchiae atroparvus. Autoradiographic observations are also recorded for both host mosquitoes. Particular emphasis is given to the alimentary canal, fat body, heart, pericardial cells and female reproductive tract during the period when the mosquito is parasitised by the nematode. Differences between parasitised individuals and uninfected controls are noted. These findings are discussed in relation to our general understanding of host parasite relationships in insects and entomophilic nematodes.

Nephrotic syndrome (NS) is a rare kidney disease resulting from malfunction of the primary ultra-filtration unit in the kidney, the renal glomerulus, leading to excessive leak of protein into urine. NS has an annual incidence of 2 and 7 per 100,000 children and adults, and a prevalence of 1 to 15 per 100,000 depending on the ethnicity; NS is more common in African and South Asian populations. However, despite its rare disease status, it remains one of the most common kidney diseases to affect children and adults. It has a devastating impact on the health of affected individuals, with around 20% of cases developing end stage kidney failure and 60% of the severe group experiencing disease recurrence post kidney transplant. Mendelian inheritance appears only to explain around 30% of cases. Inheritance may be autosomal recessive or dominant with variable penetrance and more recently Xlinked has also been described. To date, causal genetic variants have been identified in 67 genes in NS patients. However, the molecular genetic mechanisms underlying the remaining 70% remain poorly understood and are likely to fall into a complex genetic category. The aim of this study was to identify causal genetic variation of NS, focusing on the 70% of cases currently unexplained by single mutations in previously established nephrotic syndrome genes. A cohort of 485 deeply phenotyped patients was available for analysis; all have undergone whole exome sequencing or whole genome sequencing. Data was analysed by applying computational approaches including linkage and association analyses. Based on this, a link with HLA was identified, confirming that despite a lack of typical inflammatory markers, NS in both children and adults falls into the category of an autoimmune disease.

Abstract: The fructose-fed rat is an animal model of metabolic syndrome, which includes the development of hypertension. In other animal models of hypertension, an increase in the amount catecholamine released from chromaffin cells was reported. Employing carbon fibre amperometry, I tested the hypothesis that fructose feeding causes an increase in the amount of catecholamine released from individual adrenal chromaffin cells. When I stimulated chromaffin cells from fructose-fed rats with a non-selective acetylcholine agonist, they secreted more catecholamine than cells from age-matched control rats, although the amplitude of the rise in intracellular Ca2+ (measured by fura-2) was not increased. Fructose feeding also increased the amount of catecholamine released from individual secretory granules. These changes in catecholamine release were not reproduced when the cells were stimulated by elevating the extracellular concentration of K+. My findings suggest that fructose feeding may alter the expression or function of muscarinic acetylcholine receptors in chromaffin cells.

The inferior alveolar nerve (IAN) block is the most frequently used mandibular injection technique for achieving local anesthesia for endodontic treatment. However, the inferior alveolar nerve block does not always result in successful pulpal anesthesia. Previous studies have suggested that preoperative medication may increase the success rate of the IAN block, particularly a combination of preoperative ibuprofen and acetaminophen. Recent clinical studies found that giving only ibuprofen preoperatively did not significantly improve the success rate of the IAN block in patients with irreversible pulpitis. The purpose of this prospective, randomized, double-blind, placebo-controlled study was to determine the effect of the administration of both preoperative ibuprofen and acetaminophen on the efficacy of the IAN block in patients with irreversible pulpitis. One hundred emergency patients diagnosed with irreversible pulpitis of a mandibular posterior tooth randomly received (in a double-blind manner) identical capsules of either 800 mg ibuprofen and 1000 mg acetaminophen or a placebo 45 minutes before the administration of a conventional IAN block. Access was begun 15 minutes after completion of the IAN block, and all patients had profound lip numbness. Success was defined as no or mild pain (visual analog scale recordings) on access or instrumentation. The success rate for the IAN block was 32% with the ibuprofen and acetaminophen group and 24% with the placebo group, with no significant difference (p = 0.37) between the 2 groups. In conclusion, for mandibular posterior teeth, a preoperative dose of 800 mg of ibuprofen and 1000 mg of acetaminophen did not result in a statistically significant increase in success of the IAN block in patients with irreversible pulpitis.

With the sequencing of the genomes of individuals with rare Mendelian disease becoming routine, there is an emerging challenge in identifying and quantifying similarity between individual's phenotypes to assist in the identification of commonalities in the genetic variation contributing to disease. Whilst it is relatively easy to assess genetic similarities between individuals, it is less trivial to assess phenotypic similarity due to the complexity of phenotypic information. One route to systematically estimate similarity between phenotypes utilises computational approaches applied to standardised machine-readable phenotypic descriptors, such as those in the Human Phenotype Ontology (HPO) or structured patient questionnaires. This thesis describes advances in the representation of clinical phenotypes in machine-readable controlled vocabulary within the context of genetic studies of both the diagnosis of monogenic disease patients, and common variant association analysis of severe acne subtypes. When using genome sequencing for the genetic diagnosis of individuals with rare Mendelian diseases, a virtual gene panel approach is often taken wherein only a curated list of genes suspected to cause a phenotype are considered. With the number of known monogenic disease-gene pairs exceeding 5,000, manual curation of personalised gene panels based on the entire human phenotypic spectrum is challenging. Methods have previously been developed that formalise the approach using the patient phenotype to generate candidate genes, requiring both patients and known disorders to be defined in standardised machine-readable terms. Work in this project has investigated the ways by which established phenotypic descriptions (OMIM free-text) can be further leveraged using simple quantification of disease terms to gain a more nuanced description of known phenotypes with HPO terms, and how this helps to more efficiently generate candidate gene panels in real patient datasets. This project also examines the utility of extensive patient questionnaire records in patients with severe acne, enabling the identification of questionnaire response stratified subtypes of acne for use in downstream investigations seeking to identify new genetic determinants of the disease.

Frontal fibrosing alopecia (FFA), a clinical variant of follicular lichen planus, is a highly distressing inflammatory and scarring dermatosis of unknown pathobiology that affects almost exclusively post-menopausal women. Since FFA was first described in 1994, there has been rapid increase in reported incidence, culminating in speculation about likely environmental triggers. There is substantial evidence for an inherited component in the aetiology of FFA, as demonstrated by elevated incidence in first-degree relatives. To test the hypothesis that rare large effect size alleles underlie FFA, whole exome sequencing (WES) was utilised to identify variants shared by affected individuals within each of 12 FFA families of presumed Mendelian inheritance. To investigate the contribution of common genetic variation to disease susceptibility, a two-phase genome-wide association study (GWAS) was performed in a UK and a Spanish cohort in a total of 1,016 cases and 4,145 controls. Scalp skin RNA-seq was undertaken to define the FFA transcriptome. A case-control metabolomic analysis was performed to probe the relevance of xenobiotic processing in disease pathogenesis. Significant association with FFA was observed at genomic loci 2p22.2 (CYP1B1) and 6p21.1 (HLA-B), highlighting the role of xenobiotic and hormone metabolism and autoimmunity in the pathogenesis of FFA respectively. Transcriptomic analysis of affected skin implicated both innate and adaptive immune mechanisms. In short, this study provides insight into the genetic basis of FFA by characterising the condition as a complex immuno-inflammatory trait.

The present study answers the question: If a community loses their language, culture. and environment how are they still able to preserve and maintain their Identity? In the first chapter the rationale, justification, purpose, and methodology are presented. The Hanis-Miluk, or Coos community, which traditionally inhabited the Coos Bay area of the southern Oregon coast, is Introduced, and the thesis and schema regarding their survival and how to best study their systemic processes are elaborated. Chapter Two presents the historical background of the Coos people; Including geographic and ecological systems, prehistory of the human population and their cultural makeup, and a detailed description of the Coos lifestyle from prehistoric to modern times. Chapter Three examines the experience of the Coos culture previous to contact with the Anglo-Europeans and subsequent developments which have influenced cultural identity in historic times. Also considered are the means whereby the community preserved some of Its past and adapted to the demands of modern existence, and how the foundational elements of Coos identity Interact in such a way as to produce the present-day community. Chapter Four presents the conclusions and implications of this study regarding methodology, the Coos community's place In modern America, and intercultural understanding.

Ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) are clinically undetectable forms of non-invasive breast cancer. DCIS is considered a non-obligate precursor of invasive ductal carcinoma (IDC). LCIS shares many of the same genetic aberrations as invasive lobular breast cancer (ILC), which accounts for 10-15% of all invasive breast cancer. With the advent of screening mammography, the diagnosis of pure DCIS (with no invasive component) and LCIS has become more common, and approximately 20% of screen detected tumours are pure DCIS. The aim of this project is to test the hypothesis that breast cancer is a heterogeneous disease and that by focusing on specific histological subtypes we can increase the power to detect genetic variants that predispose to DCIS/LCIS/ILC. We also exploited the extreme phenotype hypothesis, having focused on cases with a severe phenotype such as early-onset or bilateral disease. During this PhD we assessed the role of rare coding variants using next generation sequencing approaches. We also interrogated data on 211,000 SNPs, genotyped on the iCOGS platform in 3,000 DCIS cases 2500 LCIS/ILC and 5000 controls, to evaluate common variants that predispose to these subtypes of breast cancer. Some of the key findings include the excess of CDH1 protein truncating variants in cases with bilateral lobular lesions (8%), and the identification of a novel lobular specific locus on 7q34. We were also able to estimate the prevalence of rare variants predisposing to breast cancer in the context of sporadic cases with DCIS/LCIS/ILC. Further analyses and validation is required in order to assess any of the novel putative genes can be linked with ILC development. Once such variants have been validated they can be used to predict which women are at high risk of developing DCIS/LCIS/ILC and such women can be offered intensive screening or chemoprevention.

Myoclonic astatic epilepsy (MAE) is a rare generalised childhood epilepsy with variable but poorly described neurodevelopmental outcome. Family studies suggest a major genetic influence as up to two thirds of relatives have seizures, or electroencephalographic (EEG) abnormalities. MAE is associated with 10 different genes, yet these genes account for less than 20% of the genetic aetiology of MAE leaving the majority unexplained. The aims of this thesis were (1) describe the epilepsy and neurodevelopmental phenotype of MAE cases, (2) perform EEG studies on first degree family members for familial EEG abnormalities and compare occurrence of epileptiform features to population prevalence and (3) to collect DNA and identify MAE causative genetic variants through exome sequencing. I assembled the largest MAE cohort (n=123) to date. The epilepsy phenotype is remarkably similar to previously published cohorts. I identified a severe neurodevelopmental phenotype: intellectual disability was reported in 64.9%, autism spectrum disorder in 21.3% and attention deficit hyperactivity symptoms in 41.0%. Additionally, extremely low adaptive behavioural scores were identified in 69.4% of cases. I performed EEG studies on 38 first-degree relatives of 13 MAE families, and found an excess of epileptiform EEG features in adults (>16 years), compared to controls (P=0.05, RR 6.82). I identified likely pathogenic or candidate variants in 11 of 109 cases. This comprised known genes associated with MAE: CHD2 n=1, SYNGAP1 n=2, SLC6A1 n=1, KIAA2022 n=1; epilepsy associated genes novel for MAE: KCNB1 n=1, MECP2 n=1, KCNH5 n=1, and three new candidate genes; SMARCA2 n=1, ASH1L n=1 and CHD4 n=1. Lastly, I highlight phenotypic features which help correlate with known and novel specific gene associations, discuss that MAE is a phenotypic and genetic nosological bridge between genetic generalised epilepsy and epileptic encephalopathy, and discussion applications and future directions leading on from this project.

Next generation sequencing generates a large quantity of sequence data which has the potential to be highly informative when evaluated using appropriate analytical methods. One of the key aims of human genetic disease studies is to use such methods to help identify sequence variants having some phenotypic effect. In the past few years, whole exome sequencing in particular has been used to identify single variants that cause many monogenic diseases. However, monogenic diseases in which genetic heterogeneity plays a role present a more difficult problem because different affected individuals in a study may not carry disease-causing mutations in the same gene. A major focus of my work is to develop and implement algorithms to identify disease-causing variants in such diseases. In particular I make use of functional information, such as that encoded by interaction networks, to prioritise genes for follow-up analysis. In this thesis I present two different analysis tools designed for this purpose. Simulated datasets are constructed to demonstrate the utility of these tools and test their performance under varying conditions. The tools are applied to a whole exome sequencing study for a genetically-heterogeneous monogenic disease (Adams-Oliver syndrome) with the aim of generating novel hypotheses regarding disease aetiology. This work also allows comparison and exploration of the challenges facing network-based methods in practice. The tools are also applied to a study of families exhibiting atypically strong recurrence of a complex disorder (Crohn’s disease), testing the hypothesis that one or a small number of rare highly-penetrant variants might be implicated in each family. In this way it is proposed that the application of network-based methods to next generation sequencing data can help to describe disease mechanisms that move beyond monogenic diseases and towards more complex genetic architectures.