xxv, 468 p. : ill. (some col.) A print copy of this thesis is available through the UO Libraries. Search the library catalog for the location and call number. / 1,2-Dihydro-1,2-azaborine is a six-membered aromatic heterocycle that is related to the quintessential aromatic molecule, benzene, via the replacement of a CC fragment in benzene with an isoelectronic BN bond-pair. Like the benzene motif, 1,2-dihydro-1,2-azaborine derivatives could provide opportunities in fields ranging from medicine to materials. Recent breakthroughs in the synthesis of 1,2-dihydro-1,2-azaborine have led to a burgeoning interest in this relatively unexplored heterocycle. This dissertation describes the synthesis, characterization, and potential applications of novel 1,2-dihydro1,2-azaborines. Chapter I reviews the chemistry of monocyclic and polycyclic BN-heterocycles over the last fifty years. Chapter II introduces the synthesis of numerous boron-substituted 1,2-dihydro-1,2-azaborine derivatives from a versatile precursor. Chapter III discusses the first successful synthesis of the parent 1,2-dihydro-1,2-azaborine, which is isoelectronic with benzene itself. An examination of the chemistry of 1,2-dihydro-1,2-azaborine provides a direct comparison of its properties relative to benzene. Chapter IV discusses the synthesis and characterization of 1,2-dihydro-1,2-azaborines incorporated into phenylacetylenic scaffolds. Chapter V discusses unrelated work on nitrated lipids, which was performed under the guidance of Professor Bruce Branchaud. The chapter introduces the importance of nitrated lipids in a biological context and details the synthetic achievements in this field. This dissertation includes previously published and unpublished co-authored material. / Committee in charge: Michael Haley, Chairperson, Chemistry; Shih-Yuan Liu, Advisor, Chemistry; David Tyler, Member, Chemistry; Raghuveer Parthasarathy, Outside Member, Physics

No description available.

Nitrocellulose is the main component in many types of ammunition, propellants and explosives. The principles of production for nitrocellulose have not changed much since the 19th century when it started being industrially produced for this purpose. The character of the nitrocellulose has a large effect on the end products abilities. The aim of this study was to develop a method that would be able to characterise and distinguish between nitrocellulose from different manufacturers to be able to relate the character of the nitrocellulose to the properties of ammunition, propellants and explosives. Samples were dissolved in acetone and analysed by GC/MS and data were then analysed by multivariable statistics. FTIR was also used to characterise the nitrocellulose. Results from both methods showed very small differences when chromatograms and spectra were analysed. This study shows that GC/MS and FTIR are not suitable for this type of characterisation. The differences between the data were not sufficient to be able to separate the samples from each other. / Nitrocellulosa är den viktigaste komponenten i många typer av ammunition, drivmedel och sprängämnen. Principerna för produktionen av nitrocellulosa har inte förändrats mycket sedan det börjades produceras industriellt för detta ändamål på 1800 talet. Karaktären av nitrocellulosa har en stor inverkan på slutproduktens egenskaper. Syftet med denna studie var att utveckla en metod som skulle kunna karaktärisera och skilja mellan nitrocellulosa från olika tillverkare för att kunna relatera karaktären av nitrocellulosa till egenskaperna hos ammunition, drivmedel och sprängämnen. Proverna löstes i aceton och analyserades med GC/MS och data analyserades med multivariabel statistik. FTIR användes också för att karakterisera nitrocellulosan. Resultaten för båda proverna visade mycket små skillnader när kromatogram och spektra analyserades. Denna studie visar att GC/MS och FTIR inte är lämpliga för denna typ av karaktärisering. Skillnaderna i data var inte tillräckliga för att kunna skilja proverna från varandra.

Amyotrophic Lateral Sclerosis (ALS) is an always lethal motor neuron disease with unknown pathogenesis. Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) have limited neuroprotection in some models of motor neuron degeneration. However the direct effect of Hsp90 inhibition on motor neurons is unknown. Here we show that Hsp90 inhibition induced motor neuron death through activation of the P2X7 receptor. Motor neuron death required phosphatase and tensein homolog (PTEN)-mediated inhibition of the PI3K/AKT pathway leading to Fas receptor activation and caspase dependent death. The relevance of Hsp90 for motor neuron survival was investigated in mutant Cu/Zn superoxide dismutase (SOD) transgenic animal models for ALS. Nitrated Hsp90, a posttranslational modification known to induce cell death (Franco, Ye et al. 2013), was present in motor neurons after intracellular release of zinc deficient (Zn, D83S) and the SOD in which copper binding site was genetically ablated (Q) but not after copper deficient (Cu) wild type SOD. Zn deficient and Q mutant SOD induced motor neuron death in a peroxynitrite mediated and copper dependent mechanism. Nitrated Hsp90 was not detected in the spinal cord of transgenic animals for ALS-mutant SOD animal models until disease onset. Increased nitrated Hsp90 concentrations correlated with disease progression. Addition of Zn or Q SOD to nontransgenic brain homogenate treated with peroxynitrite led to an increase level of nitrotyrosine in comparison to wild type controls. However, in the same samples there was a 2 to 10 time increase in Hsp90 nitration as compared to nitrotyrosine. The selective increase is likely due to the binding of Hsp90 to Zn deficient and Q SOD as oppose to wild type SOD. These results suggest that Hsp90 nitration facilitated by mutant SOD may cause motor neuron degeneration in ALS. Targeted inhibition of nitrated Hsp90 may be a novel therapeutic approach for ALS. An alternative therapeutic strategy is to target the production of survival factors by glial cells. Riluzole is the only FDA approved drug for the treatment of ALS and it shows a small but significant increase in patient lifespan. Our results show that acute riluzole treatment stimulated trophic factor production by astrocytes and Schwann cells. However long-term exposure reversed and even inhibited the production of trophic factors, an observation that may explain the modest increase in patient survival in clinical trials. Discontinuous riluzole treatment can maintain elevated trophic factor levels and prevent trophic factor reduction in spinal cords of nontransgenic animals. These results suggest that discontinuous riluzole administration may improve ALS patient survival. In summary, we demonstrated that Hsp90 has an essential function in the regulation of motor neuron survival. We have also shown that Hsp90 was nitrated in the presence of mutant SOD and was present during symptom onset and increases as disease progresses, which may explain the toxic gain of function of mutant SOD. Finally we demonstrate a biphasic effect of riluzole on trophic factor production and propose changes in administration to improve effects in ALS patients.

No description available.

In recent years the nitrated polycyclic aromatic hydrocarbons (nitroPAH's) have been recognized as powerful mutagens in the Ames Salmonella test. Most nitroPAH’s are direct-acting mutagens in the Ames test i.e. they induce mutation in the absence of S9, and appear to be activated through nitroreduction by bacterial enzymes. Others, however, such as 3-nitroperylene, are indirect-acting mutagens and show maximum activity only when S9 is present. Studies using the Ames test have indicated that the cytochrome P-450-dependent mixed function oxidase system of S9 is responsible for the activation of 3-nitroperylene to mutagenic species. However, the pattern of P-450 isozymes involved in this process appears to be different from that involved in the conversion of most PAH's, such as the standard indirect-acting mutagen benzo(a)pyrene (B(a)P), to proximate mutagens. 6-NitroB(a)P, in contrast, behaves in an analogous manner to its parent hydrocarbon. Using appropriate Salmonella mutants, the activation of 3-nitroperylene was found to require bacterial involvement, although the nature of the bacterial contribution has yet to be determined. Studies with other mutants have indicated that nitroreduction, at least as a primary activation step, does not appear to be important. Incubation of 3-nitroperylene with high concentrations of S9 led to the formation of a number of metabolites, of which phenolic derivatives were prominent. In addition, S9-derived microsomes were able to catalyse the conversion of 3-nitroperylene to species which were able to bind to protein and DNA. Under the conditions employed in these binding studies, 3-nitroperylene appears to be acting like a simple PAH, and such experiments with very high concentrations of liver protein may be unrepresentative of the processes responsible for the mutagenesis of the compound. / Thesis / Master of Science (MSc)

2-Nitrofluorene is a model representative of nitrated polycyclic aromatic hydrocarbons (NPAH) which belongs to a group of mutagens and carcinogens. Interaction of DNA with genotoxic 2-nitrofluorene was monitored by an electrochemical DNA biosensor made of a glassy carbon electrode (GCE) and low molecular weight DNA from salmon sperm. Techniques used are electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV) and square-wave voltammetry (SWV). Using the EIS technique, no damage to DNA, which would cause strand breaks in DNA, was observed, whereas using the CV technique, the intercalation of NF to the structure of DNA was observed, leading to the formation of a NF-DNA complex. The intercalation results in a reduction of electroactive sites which can be oxidized. It was verified using the SWV technique, by which a decrease of the peak heights of adenosine and guanosine was observed. Because of the dangerous effect of NF on the structure of DNA, an electroanalytical method for its determination was developed. An applicability of the method was successfully tested on a model sample of sand. For the development of the technique, differential pulse voltammetry (DPV) was used in a mixture of the Britton-Robinson buffer of pH 7.0 and ethanol in a ratio of 7:3 (v/v) and with a periodic...

This Diploma Thesis is focused on investigation of the voltammetric behavior of the explosive penthrite (pentaerythritol tetranitrate) (PETN) and on searching for optimum conditions for its determination using differential pulse voltammetry (DPV) at a hanging mercury drop electrode (HMDE) (this part of the Diploma Thesis follows the topic investigated in the author's Bachelor Thesis; in this Diploma Thesis, the results of the Bachelor thesis are applied to the determination of PETN in environmental matrices) and at a mercury meniscus modified silver solid amalgam electrode (m-AgSAE) and on investigation of voltammetric behavior in real samples (deionized, drinking, and river water). For investigating the behavior of PETN in aqueous-methanolic media on the m-AgSAE, mixtures of Britton-Robinson buffers (BR-buffers) and methanol in various volume ratios were used. In non-aqueous media, methanolic solutions of tetramethylammonium bromide (TMAB), tetrabutylammonium iodide (TBAI), and tetrabutylammonium chloride (TBAC) were used as supporting electrolytes. Firstly, the influence of pH (in the range of 2 - 13) and methanol content (10 - 90 vol. %) on voltammetric responses of PETN was studied. The best response was obtained at each of those pH values at the volume ratio of BR-buffer - methanol of 1:9 or...

Lípides nitrados (NO2-FA) são apontados como uma nova classe de mediadores lipídicos, podendo atuar como reservatórios endógenos de óxido nítrico (&#8226NO) bem como moduladores pluripotentes de sinalização celular. Recentemente, tem sido sugerido que os doadores de &#8226NO estariam envolvidos na regulação da angiogênese. Evidências contundentes indicam ainda que o processo de neovascularização poderia contribuir para a patogênese de uma serie de condições clínicas, entre elas a aterosclerose. Contudo, apesar de diversos estudos terem explorado os efeitos biológicos dos NO2-FA, os efeitos destes compostos sobre o processo de angiogênese não haviam sido descritos. Dessa maneira, o presente trabalho investigou os efeitos dos NO2-FA (derivados da nitração do ácido linoléico e oléico) noprocesso de angiogênese. Demonstrou-se que os NO2-FA podem atuar como mediadores pró-angiogênicos. Este efeito foi caracterizado em células endoteliais humanas, assim como, em modelos ex vivo e in vivo. Nas células endoteliais, observou-se que os No2-FA não influenciaram a proliferação ou a viabilidade celular, ao passo que estimularam a migração. Demonstrou-se também que os NO2-FA podem modular o brotamento ex vivo de novos vasos, em cultura de anéis de aorta de rato, bem como o processo angiogênico in vivo observado na membrana corioalantóica de embrião de galinha. Adicionalmente, os NO2-FA induziram a expressão do fator de crescimento endotelial vascular (VEGF), que é o principal mediador do processo de angiogênese. Em relação ao mecanismo de ação, os achados sugerem que os efeitos demonstrados seriam via mecanismos dependentes de &#8226NO, uma vez que foram abolidos na presença de um seqüestrador de &#8226NO, enquanto concentrações equivalentes dos lípides precursores não demonstraram qualquer influência nas condições experimentais utilizadas neste estudo. Por fim, os efeitos pró-angiogênicos dos NO2-FA foram mediados pela estabilização da proteína do fator induzível por hipóxia -1α (HIF-1α), uma vez que estes compostos promoveram acúmulo desta proteína e falharam em demonstrar efeitos indutores em células knockdown para o gene HIF-1α. Em conjunto, estes resultados indicam que os NO2-FA podem modular a migração de células endoteliais e estimular o processo de angiogênese resultante da ativação de HIF-1a via mecanismo dependente de &#8226NO. / Nitrated lipids (NO2-FA) are described as a new class of Iipid mediators that are able to act as endogenously nitric oxide (&#8226NO) reservoirs as well as pluripotent cell signaling modulators. Furthermore, recent findings suggest that &#8226NO donors could be involved in the regulation of angiogenesis. Compelling evidence also indicate that the neovascularization process might contribute to the pathogenesis of many clinical conditions, such as atherosclerosis. However, although several studies have explored the NO2-FA biological properties, the effects of these compounds on the angiogenic process remain unknown. Hence, the present study investigated the effects of the NO2-FA (derivates from the nitration of Iinoleic and oleic acids at physiological concentrations) on angiogenesis processo It is demonstrated that the No2-FA could act as pro-angiogenic mediators. This effect was observed not only in human endothelial cells but also in ex vivo and in vivo models. Using endothelial cells, it is showed that NO2-FA failed to affect cell proliferation ar influence cellular viability, but significantly stimulated cell migration. It was also found that the NO2-FA might modulate the ex vivo sprouting of new vessels as well as the in vivo angiogenic process, while inducing the expression of the vascular endothelial growth factor, the main mediator of angiogenesis. The data are consistent with the hypothesis that the observed effects mediated by NO-dependent mechanisms, since the presence of a &#8226NO scavenger abrogated the induced effects, whereas equimolar concentrations of its precursors, showed no effect on angiogenesis under our experimental conditions. Finally, the pro-angiogenic effects of NOrFA were mediated by the stabilization of the hypoxia inducible factor-1α (HIF-1α) protein, because these compounds increased the protein amount and failed to show inductive effects in HIF-1α knockdown cells. Taken together, these findings indicated that NO2-FA might modulate the endothelial cell migration and stimulate the process of angiogenesis by the HIF-1α induction through a &#8226NO-dependent mechanism.

Lípides nitrados (NO2-FA) são apontados como uma nova classe de mediadores lipídicos, podendo atuar como reservatórios endógenos de óxido nítrico (&#8226NO) bem como moduladores pluripotentes de sinalização celular. Recentemente, tem sido sugerido que os doadores de &#8226NO estariam envolvidos na regulação da angiogênese. Evidências contundentes indicam ainda que o processo de neovascularização poderia contribuir para a patogênese de uma serie de condições clínicas, entre elas a aterosclerose. Contudo, apesar de diversos estudos terem explorado os efeitos biológicos dos NO2-FA, os efeitos destes compostos sobre o processo de angiogênese não haviam sido descritos. Dessa maneira, o presente trabalho investigou os efeitos dos NO2-FA (derivados da nitração do ácido linoléico e oléico) noprocesso de angiogênese. Demonstrou-se que os NO2-FA podem atuar como mediadores pró-angiogênicos. Este efeito foi caracterizado em células endoteliais humanas, assim como, em modelos ex vivo e in vivo. Nas células endoteliais, observou-se que os No2-FA não influenciaram a proliferação ou a viabilidade celular, ao passo que estimularam a migração. Demonstrou-se também que os NO2-FA podem modular o brotamento ex vivo de novos vasos, em cultura de anéis de aorta de rato, bem como o processo angiogênico in vivo observado na membrana corioalantóica de embrião de galinha. Adicionalmente, os NO2-FA induziram a expressão do fator de crescimento endotelial vascular (VEGF), que é o principal mediador do processo de angiogênese. Em relação ao mecanismo de ação, os achados sugerem que os efeitos demonstrados seriam via mecanismos dependentes de &#8226NO, uma vez que foram abolidos na presença de um seqüestrador de &#8226NO, enquanto concentrações equivalentes dos lípides precursores não demonstraram qualquer influência nas condições experimentais utilizadas neste estudo. Por fim, os efeitos pró-angiogênicos dos NO2-FA foram mediados pela estabilização da proteína do fator induzível por hipóxia -1α (HIF-1α), uma vez que estes compostos promoveram acúmulo desta proteína e falharam em demonstrar efeitos indutores em células knockdown para o gene HIF-1α. Em conjunto, estes resultados indicam que os NO2-FA podem modular a migração de células endoteliais e estimular o processo de angiogênese resultante da ativação de HIF-1a via mecanismo dependente de &#8226NO. / Nitrated lipids (NO2-FA) are described as a new class of Iipid mediators that are able to act as endogenously nitric oxide (&#8226NO) reservoirs as well as pluripotent cell signaling modulators. Furthermore, recent findings suggest that &#8226NO donors could be involved in the regulation of angiogenesis. Compelling evidence also indicate that the neovascularization process might contribute to the pathogenesis of many clinical conditions, such as atherosclerosis. However, although several studies have explored the NO2-FA biological properties, the effects of these compounds on the angiogenic process remain unknown. Hence, the present study investigated the effects of the NO2-FA (derivates from the nitration of Iinoleic and oleic acids at physiological concentrations) on angiogenesis processo It is demonstrated that the No2-FA could act as pro-angiogenic mediators. This effect was observed not only in human endothelial cells but also in ex vivo and in vivo models. Using endothelial cells, it is showed that NO2-FA failed to affect cell proliferation ar influence cellular viability, but significantly stimulated cell migration. It was also found that the NO2-FA might modulate the ex vivo sprouting of new vessels as well as the in vivo angiogenic process, while inducing the expression of the vascular endothelial growth factor, the main mediator of angiogenesis. The data are consistent with the hypothesis that the observed effects mediated by NO-dependent mechanisms, since the presence of a &#8226NO scavenger abrogated the induced effects, whereas equimolar concentrations of its precursors, showed no effect on angiogenesis under our experimental conditions. Finally, the pro-angiogenic effects of NOrFA were mediated by the stabilization of the hypoxia inducible factor-1α (HIF-1α) protein, because these compounds increased the protein amount and failed to show inductive effects in HIF-1α knockdown cells. Taken together, these findings indicated that NO2-FA might modulate the endothelial cell migration and stimulate the process of angiogenesis by the HIF-1α induction through a &#8226NO-dependent mechanism.