<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

No description available.

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.

Formula Student är en av de större tävlingarna för ingenjörs-studenter i världenoch går ut på att lag från olika universitet utvecklar samt bygger en racingbil somantingen drivs av en förbränningsmotor eller av eldrift. KTH Formula Studenttävlar i elbils-klassen och utvecklar just nu en ny bil för nästa års säsong. Dennabil skall vara fyrhjulsdriven med navmonterade motorer samt växellådor. Dessanya växellådor är av typen planetväxellådor på grund av det begränsade utrymmeti navet. Under detta arbete analyserades samt fastställdes det vilken konstruktionav dessa som skall väljas. Först fastställdes vilka krav som den nya växellådanskall uppnå samt vilka olika konstruktioner som skulle vara möjliga. Kraven somställdes var att växellådan skall ha en utväxling på 13.5 samt att den måste fårum i den 245 mm stora fälgen. De olika konstruktioner som analyserades var enenstegs-planetväxellåda (koncept 1), två seriekopplade enstegs-planetväxellådor(koncept 2) samt en Compound-planetväxellåda (koncept 3). Efter analys av dessatre koncept framkom det att koncept 3 bör väljas för vidareutveckling då dennauppfyller alla de krav som ställs på den. Skulle kraven kunna modifieras kan ävenkoncept 1 vara möjligt medans koncept 2 ansågs ej kunna uppfylla kraven.

The leptin receptor (Lepr) pathway is important for food intake regulation, energy expenditure, and body weight. Mutations in leptin and the Lepr have been shown to cause early-onset severe obesity in mice and humans. In studies with C57BL/6NCrl mice, we found a mouse with extreme obesity. To identify a putative spontaneous new form of monogenic obesity, we performed backcross studies with this mouse followed by a quantitative trait locus (QTL) analysis and sequencing of the selected chromosomal QTL region. We thereby identified a novel Lepr mutation (C57BL/6N-LeprL536Hfs*6-1NKB), which is located at chromosome 4, exon 11 within the CRH2-leptin-binding site. Compared with C57BL/6N mice, LeprL536Hfs*6 develop early onset obesity and their body weight exceeds that of Leprdb/db mice at an age of 30 weeks. Similar to Leprdb/db mice, the LeprL536Hfs*6 model is characterized by hyperphagia, obesity, lower energy expenditure and activity, hyperglycemia, and hyperinsulinemia compared with C57BL/6N mice. Crossing Leprdb/wt with LeprL536Hfs*6/wt mice results in compound heterozygous LeprL536Hfs*6/db mice, which develop even higher body weight and fat mass than both homozygous Leprdb/db and LeprL536Hfs*6 mice. Compound heterozygous Lepr deficiency affecting functionally different regions of the Lepr causes more severe obesity than the parental homozygous mutations.

[pt] Estuários são corpos de água costeiros semi-fechados que servem como receptores finais de matéria orgânica. Os contaminantes emergentes correspondem, na maioria dos casos, a contaminantes não regulamentados, que podem ser candidatos a regulamentação futura, dependendo da pesquisa sobre seus efeitos potenciais para a saúde e dados de monitoramento relativos à sua ocorrência. Este é o caso dos produtos farmacêuticos e de cuidados pessoais (PPCPs) que possuem origem da contaminação antropogênica pela liberação contínua em águas residuárias ou diretamente no meio ambiente (via excreção humana e animal) sendo frequentemente persistentes e bioacumuláveis com difícil avaliação precisa do impacto no meio ambiente pela infinidade de fontes de entrada no ambiente. Este trabalho visa então o monitoramento de PPCPs na Lagoa de Piratininga que se localiza a leste da Baía de Guanabara, a qual passa por um acelerado processo de expansão residencial e comercial. Visando a otimização de tempo e custo, a extração das amostras foi definida com base em testes de diferentes metodologias, como a extração em fase sólida (SPE), etapa necessária para purificação do extrato. A identificação e quantificação foi realizada por cromatografia gasosa acoplada a espectrometria de massas em modo de monitoramento seletivo de íons (SIM) por aliar sensibilidade à elevada seletividade. Para análise por cromatografia gasosa ambos os métodos, porém, necessitam de prévia derivatização para formação de composto volátil. Para avaliar a qualidade do método, foi confirmada a linearidade das curvas analíticas pelo valor do coeficiente de determinação (R2) e pelo teste F na análise da variância (ANOVA) da regressão. A homocedasticidade dos dados foi confirmada pelo teste de Breusch e Pagan. O Limite de Detecção (LD) variou de 0,11 a 0,52 ng g-1. A repetibilidade, expressa através do desvio padrão relativo (DPR) apresentou valores inferiores a 30 por cento. A recuperação média dos analitos variou de 60 por cento a 118 por cento. O método validado foi aplicado para a análise do sedimento da Lagoa de Piratininga e obteve resultados que indicam uma presença significativa dos fármacos bisfenol A, beta-estradiol e ibuprofeno. / [en] Estuaries are defined as a semi-enclosed water that serve as final receptors of organic matter. Emerging contaminants correspond, in most cases, to unregulated contaminants, which may be candidates for future regulation depending on research on their potential health efects and monitoring data regarding their occurrence. This is the case of the pharmaceuticals and personal care products (PPCPs) which the contamination origin is above all anthropogenic and continuously released in wastewater or directly in the environment (via human and animal excretion). They are more often persistent and bioaccumulable and the accurate assessment of PPCPs impact on the environment is as difficult as there is a multitude of input sources in environment. This work then aims to monitor PPCPs in the Piratininga lagoon which is located east of the Guanabara Bay, that is undergoing an accelerated process of residential and commercial expansion. In order to optimize time and cost, the sample extraction was defined based on tests of different methodologies, such as Solid Phase Extraction (SPE), a necessary step for extract purification. Identification and quantification were performed by gas chromatography coupled with mass spectrometry in Selected Ion Monitoring mode (SIM), combining sensitivity with high selectivity. For gas chromatography analysis, both methods, however, require prior derivatization to form a volatile compound. To assess the quality of the method, the linearity of the analytical curves was confirmed by the coefficient of determination (R2) value and by the F-test in the analysis of variance (ANOVA) of the regression. The homoscedasticity of the data was confirmed by the Breusch-Pagan test. The Limit of Detection (LOD) ranged from 0.11 to 0.52 ng g-1. Repeatability, expressed through the relative standard deviation (RSD), showed values below 30 percent. The average recovery of the analytes ranged from 59,8 percent to 100,7 percent. The validated method was applied to analyze sediment from Piratininga Lagoon and obtained results indicating a significant presence of the pharmaceuticals bisphenol A, beta-estradiol, and ibuprofen.