<p>The development of parallel syntheses that allow for rapid access to compound libraries is widely sought after in drug development and in the study of biological systems. These compound collections can be screened for biological activity and thereby provide useful structure-activity relationships (SAR) to help better understand the biological systems under investigation. This present thesis uses a small molecule library/SAR approach to probe a variety of biological problems such as: inhibiting the proliferation of breast cancer stem cells; inhibiting glutamine fructose-6-phosphate amidotransferase (GFAT, a key enzyme involved in Type II diabetes); and inhibiting aminoglycoside phosphotransferases (APHs, enzymes prevalent in antibiotic resistance). Specifically, synthetic protocols for the parallel preparation of libraries of 3-aryl-pyrimido[5,4-e][1,2,4]triazine-5,7-(1H,6H)-diones, 1-alkyl-3-aryl-<em>1</em>H-pyrazolo[3,4-d]pyrimidin-4-amines, 6-amino-1-alkyl-3-aryl-1<em>H</em>-pyrazolo[3,4-<em>d</em>]pyrimidin-4(5<em>H</em>)-ones, substituted 3-(4-chlorophenyl)-1-(-1<em>H</em>-1,2,3-triazol-4-yl)-1<em>H</em>-pyrazolo[3,4-<em>d</em>]pyrimidin-4-amines and substituted isoquinolines are described. In all cases, a robust synthetic approach was developed allowing for the generation of a library of heterocycles based on hit compounds from high throughput screening. The SARs gained from the assaying of the libraries generated are shown to help in the furthering of the biological understanding of each system.</p> / Doctor of Philosophy (PhD)

<p>Pages that are darker in colour were scanned one at a time to produce a high quality image.</p> / <p>Following a review of the gas nitriding process, of the Fe-N system and of the formation of the compound layer, this study investigates the interaction between the diffusing nitrogen and the material to be nitrided.</p> <p>The formation of the compound layer and diffusion case is discussed for pure iron. AISI 1070 low alloy steel is investigated using different microstructures and the resulting effect on the nitrided microstructure is presented. The interaction of a nitride forming element is studied with a Fe/Fe-5Cr diffusion couple specimen. The strengthening mechanisms resulting from the nitriding process for all these materials are discussed using standard models from the literature. The scale of the precipitates produced in pure iron as well as in the 1070 steel pearlitic and spheroidized microstructure is found to provide marginal hardening. The interaction between N and carbides obtained during the nitriding of the 1070 martensitic microstructure gives rise to a significant hardness increase up to 130HV. The most significant hardening effect (up to 900HV) is obtained with the formation of a high density of fine CrN precipitates in the Fe-Cr specimens.</p> / Master of Applied Science (MASc)

Quaternary ammonium compounds (QACs) have long served as lead disinfectants in residential, industrial, and hospital settings. Their simple yet effective amphiphilic nature makes them an ideal class of compounds through which to explore antibacterial activity. We have developed novel multiQAC scaffolds through simple and cost-efficient syntheses, yielding hundreds of diverse compounds strategically designed to examine various aspects of antibacterial and anti-biofilm activity, as well as toxicity. Many of these bis-, tris-, and tetraQACs display antibacterial activity 10 to 100 times greater than conventional monoQACs, and are among the most potent biofilm eradicators to date. Through analyzing their activity against several strains, we have uncovered and provided further evidence for key tenets of amphiphilic QAC bioactivity: a balance of hydrophobic side chains with cationic head groups generates optimal antibacterial activity, though toxicity to eukaryotic cells needs to be mitigated. Given their ubiquitous nature and chemical robustness, the overuse of QACs has led to the development of QAC resistance genes that are spreading throughout the microbial world at an alarming rate. These resistant strains, when found in bacterial biofilms, are able to persist in the presence of lead commercial QAC disinfectants, warranting the development of next-generation biocides. Several of our scaffolds were designed with QAC resistance machinery in mind; thus, we utilized these compounds not only as antibacterial agents but also as chemical probes to better understand and characterize QAC-resistance in methicillin-resistant Staphylococcus aureus (MRSA). Our findings support previous postulations that triscationic QACs would retain potency against QAC-resistant strains. Furthermore, we have identified monocationic and aromatic moieties, as well as conformational rigidity, as being more prone to recognition by the resistance machinery. Using our chemical toolbox comprised of QACs of various charge state and scaffold, we explored both the mechanism and scope of QAC-resistance by examining their structure-resistance relationship. Our holistic findings have allowed us to better understand the dynamics of this system towards the design and development of next-generation QACs that will: (1) allow us to better probe the resistance machinery, and (2) remain efficacious against a variety of microbial pathogens. / Chemistry

Indiana University-Purdue University Indianapolis (IUPUI) / Canines can detect different diseases simply by smelling different biological sample types, including urine, breath and sweat. This has led researchers to try and discovery unique volatile organic compound (VOC) biomarkers. The power of VOC biomarkers lies in the fact that one day they may be able to be utilized for noninvasive, rapid and accurate diagnostics at a point of care using miniaturized biosensors. However, the identity of the specific VOC biomarkers must be demonstrated before designing and fabricating sensing systems. Through an extensive series of experiments, VOCs in urine are profiled by solid phase microextraction (SPME) coupled to gas chromatography-mass spectrometry (GC-MS) to identify biomarkers for breast cancer using murine models. The results from these experiments indicated that unique classes of urinary VOCs, primarily terpene/terpenoids and carbonyls, are potential biomarkers of breast cancer. Through implementing chemometric approaches, unique panels of VOCs were identified for breast cancer detection, identifying tumor location, determining the efficacy of dopaminergic antitumor treatments, and tracking cancer progression. Other diseases, including COVID-19 and hypoglycemia (low blood sugar) were also probed to identify volatile biomarkers present in breath samples. VOC biomarker identification is an important step toward developing portable gas sensors, but another hurdle that exists is that current sensors lack selectivity toward specific VOCs of interest. Furthermore, testing sensors for sensitivity and selectivity is an extensive process as VOCs must be tested individually because the sensors do not have modes of chromatographic separation or compound identification. Another set of experiments is presented to demonstrate that SPME fibers can be coated with materials, used to extract standard solutions of VOCs, and analyzed by GC-MS to determine the performance of various gas sensing layers. In the first of these experiments, polyetherimide (PEI) was coated onto a SPME fiber and compared to commercial polyacrylate (PAA) fibers. The second experiment tuned the extraction efficiency of polyvinylidene fluoride (PVDF) - carbon black (CB) composites and showed that they had higher sensitivity for urinary VOC extraction relative to a polydimethylsiloxane (PDMS) SPME fiber. These results demonstrate SPME GC-MS can rapidly characterize and tune the VOC adsorption capabilities of gas sensing layers.

京都大学 / 新制・論文博士 / 博士(工学) / 乙第13457号 / 論工博第4197号 / 新制||工||1770(附属図書館) / (主査)教授 陰山 洋, 教授 安部 武志, 教授 江口 浩一 / 学位規則第4条第2項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

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What capacities are needed for effective response to compound events? And to what extent do these capacities exist within a selection of Swedish municipalities? Compound events are understood as when multiple crises occur simultaneously or in close succession within a geographic area. Scientists in the natural sciences emphasize that the occurrence of compound events will become more common in the future and request knowledge on how they should be managed. The identified capabilities considered particularly relevant to compound events are; awareness, collaboration, flexibility, planning, exercises, resources, and anchoring. The empirical study found that the capability most prevalent among the studied municipalities was awareness, 15 of 17 municipalities. 13 municipalities demonstrated anchoring, about half of the municipalities demonstrated collaboration, flexibility, planning and exercises, and resources was found in only one of the municipalities. Based on the policy cycle it can be observed that a majority of the municipalities are in the initial stage of the cycle, which is identifying the problem. The steps towards implementing and allocate resources to strengthen the necessary capabilities vary between the municipalities but have not been taken to any significant extent. Therefore, it can be concluded that the municipalities lack relevant capabilities to manage compound events, which becomes problematic due to the extensive disruptions and consequences they cause in the society. The contribution of this study is a theoretical framework containing relevant capabilities for managing compound events, as well as an empirical description of how these capabilities appear within the studied municipalities. The study concludes with suggestions for future research focusing specifically on a deeper understanding of the capabilities within the framework of the policy cycle.

Electrochemical energy storage has been widely used in various areas, including new energy sources, auto industry, and information technology. However, the performance of current electrochemical energy storage devices does not meet the requirements of these areas that include both high energy and power density, fast recharge time, and long lifetime. One solution to meet consumer demands is to discover new materials that can substantially enhance the performance of electrochemical energy storage devices. In this dissertation we report four transition metal materials systems with potential applications in electrochemical energy storage. Nanoscale and nanostructured materials are expected to play important roles in energy storage devices because of their enhanced and sometimes unique physical and chemical properties. Studied here is the comparative electrochemical cation insertion into a nanostructured vanadium oxide, a promising electrode material candidate, for the alkali metal ions Li+, Na+ and K+ and the organic ammonium ion, in aqueous electrolyte solutions. Observed are the distinctive insertion processes of the different ions, which yield a correlation between physical degradation of the material and a reduction of the calculated specific charge. The results reveal the potential of this nanostructured vanadium oxide material for energy storage. Vanadium based electrochemical systems are of general interest, and as models for vanadium based solid-state electrochemical processes, the solution state and the solid-state electrochemical properties of two cryolite-type compounds, (NH4)3VxGa1-xF6, and Na3VF6, are studied. The electrochemical behavior of (NH4)3VxGa1-xF6 explored the possibility of using this material as an electrolyte for solid state energy storage systems. Zeolite-like materials have large surface to volume ratios, with ions and neutral species located in the nanometer sized pores of the 3-dimensional framework, potentially yielding high energy density storage capabilities. Yet the insulating nature of known zeolite-like materials has limited their use for electrical energy storage. Studied here are two vanadium based zeolite-like structures, the oxo-vanadium arsenate [(As6V15O51)-9]∞, and the oxo-vanadium phosphate [(P6V15O51)-9]∞, where the former shows electronic conduction in the 3-dimensional framework. Mixed electronic and ionic conductivity, from the framework and from the cations located within the framework, respectively, is measured in the oxo-vanadium arsenate, and allows the use of this material in electrochemical double-layer capacitor configuration for energy storage. By contrast, the oxo-vanadium phosphate shows ionic conduction only. Lastly, a new strontium manganese vanadate with a layered structure exhibiting mixed protonic and electronic conductivity is studied. The various transition metal compounds and materials systems experimentally studied in this thesis showcase the importance of novel materials in future energy storage schemes. / Ph. D.

An open queueing network model (QNM) is proposed for wormhole-routed hypercubes with finite buffers and deterministic routing subject to a compound Poisson arrival process (CPP) with geometrically distributed batches or, equivalently, a generalised exponential (GE) interarrival time distribution. The GE/G/1/K queue and appropriate GE-type flow formulae are adopted, as cost-effective building blocks, in a queue-by-queue decomposition of the entire network. Consequently, analytic expressions for the channel holding time, buffering delay, contention blocking and mean message latency are determined. The validity of the analytic approximations is demonstrated against results obtained through simulation experiments. Moreover, it is shown that the wormholerouted hypercubes suffer progressive performance degradation with increasing traffic variability (burstiness).

This thesis is a study in the application of kinematics coupled with elastic body mechanics. Most studies in kinematics assume all mechanism links to be inelastic. Furthermore, the methods of kinematic synthesis have generally been developed to meet requirements of displacement, velocity and acceleration. The work presented in this thesis differs in two important aspects. First, one grounded link of a four-bar linkage is replaced by a cantilevered beam in flexure to produce a force generating mechanism. Second, the synthesis method presented here allows the generation of these mechanisms in closed form for prescribed force generation. A compound archery bow that incorporates four-bar linkages has been developed as an example. This design relies on the non-linear mechanical advantage of the four-bar linkage and the bow mechanics to provide a resistance curve that is more compatible with the human strength curve. In addition, by modifying the bow kinematics, more potential energy can be stored, and thus potentially more kinetic energy can be transferred to the arrow than with previous bows. / Master of Science