published_or_final_version / abstract / Pharmacology / Doctoral / Doctor of Philosophy

The Comprehensive Nuclear Test Ban Treaty verification regime mandates atmospheric monitoring for the four radioxenon isotopes that are produced in high abundance in a nuclear explosion: [superscript 131m]Xe, [superscript 133m]Xe, [superscript 133g]Xe, and [superscript 135g]Xe. This mandate has driven the development of improved xenon detectors, including a phoswich detector, which has potential to replace the ARSA detector in the International Monitoring System. In this experiment, the four relevant radioxenon isotopes were produced through neutron activation and the phoswich detector was used to attain spectra from the gas. Spectral characteristics and resolution of the phoswich spectra were compared to an ARSA-type [beta]-[gamma] coincidence detector to perform an overall evaluation of the phoswich detector. The results indicated that spectral characteristics and resolutions for the phoswich were comparable to the ARSA-type detector, with slightly improved beta detection. As an additional test of the new detector's capabilities, a tailored spectrum designed to mimic a nuclear explosion signature was produced and analyzed with the detector. / text

A novel type of model substrates, i.e. immobilized p-aminophenyl-β-D-cellooligosaccharides, was developed and used in the study of exocellulases. The two major cellobiohydrolases from Trichoderma reesei, CBH I and CBH II were used as representative enzymes. p-Aminophenyl derivatives of cellobiose (PAPG₂), cellotriose (PAPG₃), and cellotetraose (PAPG₄) were synthesized from the reaction of p-nitrophenol and peracetylated glycosyl bromide of the corresponding cellooligosaccharides under the phase-transfer catalyzed conditions, followed by deacetylation and catalytic hydrogenation. p-Aminophenyl cellooligosaccharides were then tethered via their amino functional groups to N-hydroxy succinimide-activated agarose. The ability of CBH I and CBH II to associate with and catalyze the hydrolysis of reducing end tethered cellooligosaccharides was tested. CBH I catalyzed the hydrolysis of free PAPG₂ but CBH II did not. Both CBH I and CBH II reversibly bound, but did not hydrolyze, immobilized PAPG₂. Hence, the immobilized PAPG₂ was tested for the affinity chromatographic application. PAPG₂ is shown to be an effective ligand for the chromato graphic fractionation of cellobiohydrolases (CBHs). The PAPG₂-derivatized agarose specifically retained the CBH component of relatively complex cellulase mixtures. The purity of the resulting CBH preparation was comparable to that of corresponding enzyme preparations obtained using more traditional thioglycoside-based affinity ligands. The application of PAPG₂ as an affinity ligand suggests that the immobilized reducing end-blocked ligand associate with the T. reesei CBHs in a catalytically nonproductive mode. The catalytic activity for the hydrolysis of free and immobilized arylcellodextrins by the CBH I and CBH II were determined. CBH II attacked free and immobilized PAPG₃ and PAPG₄ in a typical exo manner in which cellobiose is a major hydrolytic product released from the nonreducing end. The rate of hydrolysis increases with increasing chain length suggesting the extended binding sites (at least 4 binding sites). Like CBH II, CBH I preferentially cleaved immobilized PAPG₃ and PAPG₄ at a second glycosidic linkage from the nonreducing end; the rate of hydrolysis increases as a function of chain length. However, it attacked free aryl-cellodextrins in a random manner. The rate of hydrolysis increases only from PAPG₂ to PAPG₃ and significantly drops in PAPG₄. This suggests that CBH I interacts with free and immobilized substrates in different modes. / Graduation date: 1999

This document is a project document based on finding a more economical way to use buttermilk at Synlait Milk Ltd. Buttermilk is a by-product from the Anhydrous Milk Fat (AMF), which is the concentration of cream. It is a problem for many dairy companies in New Zealand, including Synlait. the problems arise due to the opportunity cost of using it. It is a low value product, but made in substantial quantities at a ratio of 55% buttermilk to 45% AMF. This feasibility study contains an analysis on buttermilk at Synlait, including opportunity costs and benefits with processing buttermilk into buttermilk powder. It provides insight into the feasibility of implementing a ‘washed cream’ process at Synlait which would provide an alternative method for using buttermilk. The feasibility of separating buttermilk components for separate use is also examined. Overall, this project provides a more economical solution for buttermilk use at Synlait Milk Ltd.

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The provitamin A carotenoid β-carotene is an attractive candidate for the prevention of cancer. Indeed, abundant evidence suggests that β-carotene inhibits carcinogenesis. β-Carotene is thought to inhibit carcinogenesis by scavenging free radicals involved in tumor formation. However, there is no direct evidence that β-carotene traps radicals under conditions where it inhibits carcinogenesis. The overall objective of this dissertation research was to identify β-carotene oxidation products from β-carotene antioxidant reactions in model systems. Identification of such products will enable the direct measurement of β-carotene antioxidant activity in systems where it inhibits neoplastic transformation. In hexane solution, β-carotene was oxidized by peroxyl radicals to 5,6-epoxy-β, β-carotene, 15,15'-epoxy-β, β-carotene, a previously unreported product, and several unidentified polar products. Studies on the kinetics of product formation suggested that polar products are formed by both epoxide-dependent and -independent pathways. Because β-carotene may be localized within lipid bilayers in vivo, peroxyl radical oxidation of β-carotene in model membranes was examined. In soy phosphatidylcholine liposomes, β-carotene was oxidized by peroxyl radicals to the 5,6-epoxide and to unidentified polar products. β-Carotene antioxidant activity in the liposome system was the same at 15 torr and 160 torr O₂ and decreased at 760 torr O₂. These results suggest that β-carotene provides equal antioxidant protection in all tissues in vivo. The relative rates of product formation and β-carotene oxidation at different pO₂ suggested that β-carotene antioxidant activity is governed by the relative proportions of β-carotene radical trapping and autoxidation reactions, which do not contribute to radical trapping. Therefore, the loss of β-carotene antioxidant action at 760 torr O₂ may result from an increase in β-carotene oxidation by autoxidation pathways. The 5,6-epoxide was formed during both antioxidant reactions and autoxidation reactions and may be marker for the peroxyl radical oxidation of β-carotene. Attempts to study β-carotene antioxidant reactions in biological membranes were only partially successful. In vitro incorporation of β-carotene into microsomes was attempted by several methods. However, these efforts resulted in only modest β-carotene antioxidant activity in microsomes. These studies provide a basic understanding of β-carotene antioxidant chemistry in model systems. Their results will enable further investigation of β-carotene antioxidant action in biological systems.

Two investigations were conducted to examine the influence of beta-adrenergic blockade on cardiovascular, respiratory, metabolic, and thermoregulatory responses to maximal and submaximal exercise in both highly trained and untrained subjects. In both studies, subjects received randomized and double-blind oral medication with atenolol (100 mg/day), propranolol (160 mg/day), and placebo. In the first study significant reductions in HR max and ‘VO₂ max resulted during the atenolol and propranolol treatments in both the trained and untrained subjects. However, the reductions in ‘VO₂ max were significantly greater in the trained subjects and both groups experienced their greatest reduction during the propranolol treatment. In all subjects, the magnitude of reduction in HR max was significantly greater than the concomitant decrease in ‘VO₂ max. It is concluded that untrained subjects have a greater compensatory reserve than do trained subjects during maximal exercise while under beta-adrenergic blockade. In addition, significant advantages were found with the use of a selective compared to a non-selective beta blocker. Thermoregulation during prolonged exercise in the heat with beta blockade was studied in fourteen subjects. Subjects performed 90-minute cycle ergometer rides at a workload equivalent to 40% of the subjects' unblocked ‘VO₂ max. Rectal temperature was slightly higher during the atenolol trial compared to the placebo but was not different during the propranolol trial compared to the placebo. Skin blood flow was significantly lower during the propranolol trial compared to both the atenolol and placebo trials, but it did not differ significantly between the atenolol and placebo trials. Maintenance of rectal temperatures appeared to be achieved through changes in sweat rate, skin blood flow, and a reduced heat production, i.e., lower ‘VO₂ during the propranolol trial. The decrease in cutaneous blood flow reported during the propranolol trial is likely associated with the associated increase in TPR. This increase in TPR would help to compensate for the lower ‘Q and, hence, help maintain mean arterial pressure. Changes in substrate utilization, i.e., decreased lipolysis, during the beta-blocked trials may also be indicated. Lastly, the inability of two subjects to complete the 90-minute ride, the elevated RPE values, and the additional side effects reported during the propranolol trial would indicate an advantage for the use of a selective blocker.

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