A combined experimental and analytical approach is used to study damage initiation and evolution in three-dimensional second phase particle fields. A three-dimensional formulation of a damage percolation model is developed to predict damage nucleation and propagation through random-clustered second phase particle fields. The proposed approach is capable of capturing the three-dimensional character of damage phenomena and the three stages of ductile fracture, namely void nucleation, growth, and coalescence, at the level of discrete particles. The experimental work focuses on the acquisition of second phase particle field data and measurement of damage development during plastic deformation. Two methods of acquisition of three-dimensional second phase particle fields are considered. The first method utilizes three-dimensional X-ray tomography for the acquisition of real microstructural data. The second method involves statistical stereological reconstruction of second phase particle fields from two orthogonal metallographic sections of the as-received material. The reconstruction method is also used to introduce parametric variation of key microstructural parameters to support a study of the effect of particle clustering and second phase constituent content on formability. An in situ tensile test with X-ray tomography is utilized to quantify material damage during deformation in terms of the number of nucleated voids and porosity. The results of this experiment are used for both the development of a clustering-sensitive nucleation criterion and the validation of the damage percolation predictions. The three-dimensional damage percolation model is developed based on the acquired second phase particle fields and the damage evolution characterization using the results of the in situ tensile test. Void nucleation, growth, and coalescence are modelled within the considered second phase particle field. The damage percolation model is coupled with a commercial finite element code, LS-DYNA. The damage percolation model is applied to simulate the in situ tensile test as well as to study bendability. In particular, the effect of second phase particle field parameters on formability is examined. The volume fraction of Fe-rich and Mg2Si particles is shown to be of critical importance in controlling the formability of aluminum alloy AA5182. This study of microstructural heterogeneity using the damage percolation model has resulted in a more fundamental understanding of the processes of material degradation during deformation in the presence of second phase particles. The results of the study indicate a significant effect of second phase content on formability and provide practical recommendations to improve material formability in future alloy designs.

A combined experimental and analytical approach is used to study damage initiation and evolution in three-dimensional second phase particle fields. A three-dimensional formulation of a damage percolation model is developed to predict damage nucleation and propagation through random-clustered second phase particle fields. The proposed approach is capable of capturing the three-dimensional character of damage phenomena and the three stages of ductile fracture, namely void nucleation, growth, and coalescence, at the level of discrete particles. The experimental work focuses on the acquisition of second phase particle field data and measurement of damage development during plastic deformation. Two methods of acquisition of three-dimensional second phase particle fields are considered. The first method utilizes three-dimensional X-ray tomography for the acquisition of real microstructural data. The second method involves statistical stereological reconstruction of second phase particle fields from two orthogonal metallographic sections of the as-received material. The reconstruction method is also used to introduce parametric variation of key microstructural parameters to support a study of the effect of particle clustering and second phase constituent content on formability. An in situ tensile test with X-ray tomography is utilized to quantify material damage during deformation in terms of the number of nucleated voids and porosity. The results of this experiment are used for both the development of a clustering-sensitive nucleation criterion and the validation of the damage percolation predictions. The three-dimensional damage percolation model is developed based on the acquired second phase particle fields and the damage evolution characterization using the results of the in situ tensile test. Void nucleation, growth, and coalescence are modelled within the considered second phase particle field. The damage percolation model is coupled with a commercial finite element code, LS-DYNA. The damage percolation model is applied to simulate the in situ tensile test as well as to study bendability. In particular, the effect of second phase particle field parameters on formability is examined. The volume fraction of Fe-rich and Mg2Si particles is shown to be of critical importance in controlling the formability of aluminum alloy AA5182. This study of microstructural heterogeneity using the damage percolation model has resulted in a more fundamental understanding of the processes of material degradation during deformation in the presence of second phase particles. The results of the study indicate a significant effect of second phase content on formability and provide practical recommendations to improve material formability in future alloy designs.

DNA is the carrier of biological information and damage to DNA has been believed to be responsible for many diseases including aging and cancer. One electron oxidation by charge migration through DNA is one of the processes that lead to DNA damage. It is known that the guanine N1 imino proton can be transferred to the N3 of cytidine that is hydrogen bonded to it. Some reports have implication that this proton transfer and radical cation migration are coupled to each other. We have incorporated 5-fluoro-2 -deoxycytidine (F5dC) in place of normal dC in DNA duplexes. Although, the lower pKa of F5dC should perturb the proton transfer process from the guanine to it, we do not see any change in the charge migration ability compared to the strands having normal cytidines. However, there is a considerable decrease in the guanine damage, when there is F5dC opposite to it. These results indicate that the charge migration is not coupled with proton transfer process, but the change in basicity affects the reactivity of the guanine radical cation. We have also reported a systematic study on the charge migration through adenine (A) and thymidine (T) containing DNA strands. The damage has predominantly seen in thymidine, although from oxidation potentials reaction at adenine was expected. The thymidine reaction has been analyzed thoroughly. It has similar distance dependence property as the well known guanine damage. Study of thymidine damage in presence of radical scavengers, replacement of thymidines by Uracil and HPLC-MS study point toward reactions involving tandem lesion. On the basis of these information and molecular modeling study we have proposed a possible pathway leading to one-electron oxidation at the thymidines.

The deleterious effect of moisture on the structural integrity of asphalt mixtures has been recognized as one of the main causes of early deterioration of asphalt pavements. This phenomenon, usually referred to as moisture damage, is defined as the progressive loss of structural integrity of the mixture that is primarily caused by the presence of moisture in liquid or vapor state. Moisture damage is associated with the development of different physical, mechanical, and chemical processes occurring within the microstructure of the mixture at different intensities and rates. Although there have been important advancements in identifying and characterizing this phenomenon, there is still a lack of understanding of the damage mechanisms occurring at the microscopic level. This situation has motivated the research work reported in this dissertation. The main objective of this dissertation is to formulate and apply a numerical micromechanical model of moisture-induced damage in asphalt mixtures. The model focuses on coupling the effects of moisture diffusion—one of the three main modes of moisture transport within asphalt mixtures—with the mechanical performance of the microstructure. Specifically, the model aims to account for the effect of moisture diffusion on the degradation of the viscoelastic bulk matrix of the mixture (i.e., cohesive degradation) and on the gradual deterioration of the adhesive bonds between the aggregates and the asphalt matrix (i.e., adhesive degradation). The micromechanical model was applied to study the role of some physical and mechanical properties of the constitutive phases of the mixtures on the susceptibility of the mixture to moisture damage. The results from this analysis suggest that the diffusion coefficients of the asphalt matrix and aggregates, as well as the bond strength of the aggregate-matrix interface, have the most influence on the moisture susceptibility of the mixtures. The micromechanical model was further used to investigate the influence of the void phase of asphalt mixtures on the generation of moisture-related deterioration processes. Two different probabilistic-based approaches were used to accomplish this objective. In the first approach, a volumetric distribution of air voids sizes measured using X-Ray Computed Tomography in a dense-graded asphalt mixture was used to generate probable void structures in a microstructure of an asphalt mixture. In the second approach, a stochastic modeling technique based on random field theory was used to generate probable air voids distributions of the mixture. In this second approach, the influence of the air voids was accounted for by making the physical and mechanical properties of the asphalt matrix dependent on probable voids distributions. Although both approaches take into consideration the characteristics of the air void phase on the mechanical response of the mixtures subjected to moist environments, the former explicitly introduces the air phase within the microstructure while the latter indirectly includes its effects by modifying the material properties of the bulk matrix. The results from these simulations demonstrated that the amount, variability and location of air voids are decisive in determining the moisture-dependent performance of asphalt mixtures. The results from this dissertation provide new information on the kinetics of moisture damage mechanisms in asphalt mixtures. In particular, the results obtained from applying the micromechanical model permitted identification of the relative influence of the characteristics of the constitutive phases of a mixture on its moisture-related mechanical performance. This information can be used as part of design methodologies of asphalt mixtures, and/or as an input in life-cycle analysis models and maintenance programs of road infrastructure.

Here the ciliate protozoa Tetrahymena thermophila was used as a model system to study the DNA damage response. Tetrahymena enclose nuclear dimorphism, a polyploid somatic macronucleus (MAC), which is transcriptionally active and maintains vegetative growth, and a diploid germline micronucleus (MIC) responsible for the transmition of genetic information during conjugation. Previous studies have identified Tif1p, a novel protein involved in the regulation of rDNA replication in Tetrahymena. TIF1 hypomorphic strains acquire spontaneous DNA damage during vegetative cell cycle and are hypersensitive to DNA damaging agents. TIF1-deficient strains acquire DNA damage in both nuclear compartments, suggesting a global role of Tif1p in the maintenance of genomic stability. In my dissertation research, I studied the role of Tif1p during the cell cycle progression. To this end, I generated tagged-Tif1p strains, which revealed that the subcellular localization of Tif1p is dynamic throughout the cell cycle. However, the addition of epitope tag to this protein generated phenotypes analogous to ones observed in a TIF1-deficient strain. This suggested that the addition of epitope tag to Tif1p severely affects the properties of Tif1p and hence the overall integrity of the cell. To overcome these limitations, a peptide antibody specific to Tif1p was generated to study the endogenous protein. This work revealed that the abundance of Tif1p protein is not cell cycle regulated and that Tif1p is absent in starved cells. Furthermore, the specific binding of TIf1p to rDNA minichromosome was studied during vegetative cell cycles. Chromatin immunoprecipitation studies revealed that the specific binding of Tif1p extends beyond the cis-acting determinant of replication present at the rDNA origin and promoter. This suggests that coding regions may be targeted for the binding of Tif1p to previously uncharacterized sequences, and that Tif1p preferentially localizes on the rDNA minichromosome. I also studied the induction of DNA damage response, demonstrating that Tetrahymena activates a checkpoint response mediated by an ATR-like pathway. Studies with a hypomorphic TIF1 strain revealed that Tif1p mediates proper activation of the DNA damage response. Further characterization of the response to genotoxic agents showed that Tetrahymena is able to activate a G1/S and intra-S phase DNA damage response. The results presented here suggest that a caffeine-dependent checkpoint activator protein modulates the response to DNA damage. In addition, a subunit of the replicative helicase, Mcm6p, is directly affected by the induction of DNA damage. This suggests that Tetrahymena uses a novel mechanism to halt the progression of DNA replication forks during genotoxic stress through degradation of Mcm6p.

Burn-induced intestinal barrier failure has been proposed to be a potential cause of subsequent multiple organ failure after burn. Studies have shown that the increased iNOS activity is closely related to intestinal and pulmonary damage in rats after burn. Expression of iNOS and MMP-9 is regulated by nuclear factor NF-£eB activation, which is frequently a result of MAPKs pathway activation. This study was to investigate the role of ERKs in intestinal and pulmonary damage induced by burn in rats. In experiments, SD rats underwent 30 ~ 35 % TBSA burn. At various times after burn, intestinal mucosa and pulmonary proteins were assayed for ERKs and p38 phosphorylation by immunoblotting, nuclear extracts were assayed for NF-£eB activation by EMSA, intestinal and pulmonary iNOS, MMP-9 expressions were evaluated by RT-PCR, the FITC-dextran permeability was determined to assess the intestinal barrier function and the pulmonary microvascular dysfunction was quantitated by measuring the extravasation of Evans blue dye. The results show that burn induced ERKs and p38 phosphorylation, the expression of iNOS, and NF-£eB activation in intestinal mucosa and lung, but the expression of MMP-9 was attenuated. Treatment with MEK1/2 inhibitors, PD98059 (10 mg/kg i.p.) or U0126 (5 mg/kg i.p.) immediately after burn, attenuated the phosphorylation of intestinal mucosa and pulmonary ERKs, the activation of NF-£eB, the increase in intestinal permeability, and pulmonary microvascular dysfunction. Interestingly, the expression of iNOS in intestinal mucosa and pulmonary tissues was induced by PD98059 administration, but the expression of MMP-9 in intestinal mucosa was attenuated by PD98059 administration. These results suggest that the tissue damage is regulated by NF-£eB activation and the activation of NF-£eB is primarily mediated by signal pathway of ERKs in burn-injured rats, so the signal transduction pathway may involve ERKs and p38, NF-£eB, iNOS or MMP-9, then causes tissue damage. Further, burn-induced intestinal mucosa and pulmonary ERKs have different degree of activation. The p38 and ERKs phosphorylation showed a two-step activation in intestinal mucosa and pulmonary tissues after burn. Inhibition of intestinal and pulmonary ERKs in vivo afforded significant protection against burn-induced barrier failure. However, the data showed that iNOS may not play a major role in the burn-induced intestinal and pulmonary damage, and MMP-9 may have more affect on tissues damage.

This research investigates the performance of an existing structural damage detection method (SDIM) when only experimentally-obtained measurement information can be used to calculate the frequency response functions used to detect damage. The development of a SDIM that can accurately identify damage while processing measurements containing realistic noise levels and overcoming experimental modeling errors would provide a robust method for identifying damage in the larger, more complex structures found in practice. The existing SDIM program, GaDamDet, uses an advanced genetic algorithm, along with a two-dimensional finite element model of the structure, to identify the location and the severity of damage using the linear vibration information contained in frequency response functions (FRF) as response signatures. Datagen is a Matlab program that simulates the three-dimensional dynamic response of the four-story, two-bay by two-bay UBC test structure built at the University of British Columbia. The dynamic response of the structure can be obtained for a range of preset damage cases or for any user-defined damage case. Datagen can be used to provide the FRF measurement information for the three-dimensional test structure. Therefore, using the FRF measurements obtained from the UBC test structure allows for a more realistic evaluation of the performance of the SDIM provided by GaDamDet as the impact on performance of more realistic noise and model errors can be investigated. Previous studies evaluated the performance of the SDIM using only simulated FRF measurements obtained from a two-dimensional structural model. In addition, the disparity between the two-dimensional model used by the SDIM used to identify damage and the measurements obtained from the three-dimensional test structure is analyzed. The research results indicate that the SDIM is able to accurately detect structural damage to individually damaged members or to within a damaged floor, with few false damages identified. The SDIM provides an easy to use, visual, and accurate algorithm and its performance compares favorably to performance of the various damage detection algorithms that have been proposed by researchers to detect damage in the three-dimensional structural benchmark problem.

Thesis (Ph. D.)--York University, 2000. Graduate Programme in Psychology. / Typescript. Includes bibliographical references (leaves 112-127). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://wwwlib.umi.com/cr/yorku/fullcit?pNQ59153.

Thesis (M.S. in biochemistry)--Washington State University, December 2009. / Title from PDF title page (viewed on Jan. 20, 2010). "School of Molecular Biosciences." Includes bibliographical references.

Thesis (Ph. D.)--University of Texas at Austin, 1999. / Vita. Includes bibliographical references (leaves 202-222). Available also in a digital version from Dissertation Abstracts.