4 resultados para animal models, neutrophils, platelets, sheep, TRALI, two-event

em Digital Commons at Florida International University


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Free radicals have been implicated in various pathological conditions such as, stroke, aging and ischemic heart disease (IHD), as well as neurodegenerative diseases like Alzheimer’s, Parkinson’s, and Huntington’s disease. The role of antioxidants in protection from the harmful effects of free radicals has long been recognized. Trapping extremely reactive free radicals and eliminating them from circulation has been shown to be effective in animal models. Nitrone-based free radical traps have been extensively explored in biological systems. Examples include nitrones such as PBN, NXY-059, MDL-101,002, DMPO and EMPO. However, these nitrones have extremely high oxidation potentials as compared to natural antioxidants such as Vitamin E (α-tocopherol), and glutathione. Becker et al. (1995) synthesized novel azulenyl nitrones, which were shown to have oxidation potentials much lower than that of any of the previously reported nitrone based spin traps. Another azulenyl nitrone derivative, stilbazulenyl nitrone (STAZN), was shown to have an even lower oxidation potential within the range of natural antioxidants. STAZN, a second generation free radical trap, was found to be markedly superior than the two most studied nitrones, PBN and NXY-059, in animal models of cerebral ischemia and in an in vitro assay of lipid peroxidation. In this study, a third generation azulenyl nitrone was synthesized with an electron donating group on the previously synthesized STAZN derivative with the aim to lower the oxidation potential even more. Pseudoazulenes, because of the presence of an annular heteroatom, have been reported to possess even lower oxidation potential than that of the azulenyl counterpart. Therefore, pseudoazulenyl nitrones were synthesized for the first time by extracting and elaborating valtrate from the roots of Centranthus ruber (Red valerian or Jupiter’s beard). Several pseudoazulenyl nitrones were synthesized by using a facile experimental protocol. The physical and biological properties of these pseudoazulenyl nitrones can be easily modified by simply changing the substituent on the heteroatom. Cyclic voltammetry experiments have shown that these pseudoazulenyl nitrones do indeed have low oxidation potentials. The oxidation potential of these nitrones was lowered even more by preparing derivatives bearing an electron donating group at the 3-position of the five membered ring of the pseudoazulenyl nitrone.

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Concurrent software executes multiple threads or processes to achieve high performance. However, concurrency results in a huge number of different system behaviors that are difficult to test and verify. The aim of this dissertation is to develop new methods and tools for modeling and analyzing concurrent software systems at design and code levels. This dissertation consists of several related results. First, a formal model of Mondex, an electronic purse system, is built using Petri nets from user requirements, which is formally verified using model checking. Second, Petri nets models are automatically mined from the event traces generated from scientific workflows. Third, partial order models are automatically extracted from some instrumented concurrent program execution, and potential atomicity violation bugs are automatically verified based on the partial order models using model checking. Our formal specification and verification of Mondex have contributed to the world wide effort in developing a verified software repository. Our method to mine Petri net models automatically from provenance offers a new approach to build scientific workflows. Our dynamic prediction tool, named McPatom, can predict several known bugs in real world systems including one that evades several other existing tools. McPatom is efficient and scalable as it takes advantage of the nature of atomicity violations and considers only a pair of threads and accesses to a single shared variable at one time. However, predictive tools need to consider the tradeoffs between precision and coverage. Based on McPatom, this dissertation presents two methods for improving the coverage and precision of atomicity violation predictions: 1) a post-prediction analysis method to increase coverage while ensuring precision; 2) a follow-up replaying method to further increase coverage. Both methods are implemented in a completely automatic tool.

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Free radicals have been implicated in various pathological conditions such as, stroke, aging and ischemic heart disease (IHD), as well as neurodegenerative diseases like Alzheimer’s, Parkinson’s, and Huntington’s disease. The role of antioxidants in protection from the harmful effects of free radicals has long been recognized. Trapping extremely reactive free radicals and eliminating them from circulation has been shown to be effective in animal models. Nitrone-based free radical traps have been extensively explored in biological systems. Examples include nitrones such as PBN, NXY-059, MDL-101,002, DMPO and EMPO. However, these nitrones have extremely high oxidation potentials as compared to natural antioxidants such as Vitamin E (á-tocopherol), and glutathione. Becker et al. (1995) synthesized novel azulenyl nitrones, which were shown to have oxidation potentials much lower than that of any of the previously reported nitrone based spin traps. Another azulenyl nitrone derivative, stilbazulenyl nitrone (STAZN), was shown to have an even lower oxidation potential within the range of natural antioxidants. STAZN, a second generation free radical trap, was found to be markedly superior than the two most studied nitrones, PBN and NXY-059, in animal models of cerebral ischemia and in an in vitro assay of lipid peroxidation. In this study, a third generation azulenyl nitrone was synthesized with an electron donating group on the previously synthesized STAZN derivative with the aim to lower the oxidation potential even more. Pseudoazulenes, because of the presence of an annular heteroatom, have been reported to possess even lower oxidation potential than that of the azulenyl counterpart. Therefore, pseudoazulenyl nitrones were synthesized for the first time by extracting and elaborating valtrate from the roots of Centranthus ruber (Red valerian or Jupiter’s beard). Several pseudoazulenyl nitrones were synthesized by using a facile experimental protocol. The physical and biological properties of these pseudoazulenyl nitrones can be easily modified by simply changing the substituent on the heteroatom. Cyclic voltammetry experiments have shown that these pseudoazulenyl nitrones do indeed have low oxidation potentials. The oxidation potential of these nitrones was lowered even more by preparing derivatives bearing an electron donating group at the 3-position of the five membered ring of the pseudoazulenyl nitrone.

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Concurrent software executes multiple threads or processes to achieve high performance. However, concurrency results in a huge number of different system behaviors that are difficult to test and verify. The aim of this dissertation is to develop new methods and tools for modeling and analyzing concurrent software systems at design and code levels. This dissertation consists of several related results. First, a formal model of Mondex, an electronic purse system, is built using Petri nets from user requirements, which is formally verified using model checking. Second, Petri nets models are automatically mined from the event traces generated from scientific workflows. Third, partial order models are automatically extracted from some instrumented concurrent program execution, and potential atomicity violation bugs are automatically verified based on the partial order models using model checking. Our formal specification and verification of Mondex have contributed to the world wide effort in developing a verified software repository. Our method to mine Petri net models automatically from provenance offers a new approach to build scientific workflows. Our dynamic prediction tool, named McPatom, can predict several known bugs in real world systems including one that evades several other existing tools. McPatom is efficient and scalable as it takes advantage of the nature of atomicity violations and considers only a pair of threads and accesses to a single shared variable at one time. However, predictive tools need to consider the tradeoffs between precision and coverage. Based on McPatom, this dissertation presents two methods for improving the coverage and precision of atomicity violation predictions: 1) a post-prediction analysis method to increase coverage while ensuring precision; 2) a follow-up replaying method to further increase coverage. Both methods are implemented in a completely automatic tool.