ASU Electronic Theses and Dissertations
This collection includes most of the ASU Theses and Dissertations from 2011 to present. ASU Theses and Dissertations are available in downloadable PDF format; however, a small percentage of items are under embargo. Information about the dissertations/theses includes degree information, committee members, an abstract, supporting data or media.
In addition to the electronic theses found in the ASU Digital Repository, ASU Theses and Dissertations can be found in the ASU Library Catalog.
Dissertations and Theses granted by Arizona State University are archived and made available through a joint effort of the ASU Graduate College and the ASU Libraries. For more information or questions about this collection contact or visit the Digital Repository ETD Library Guide or contact the ASU Graduate College at gradformat@asu.edu.
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Description
Infectious diseases have emerged as a significant threat to wildlife. Environmental change is often implicated as an underlying factor driving this emergence. With this recent rise in disease emergence and the acceleration of environmental change, it is important to identify the environmental factors that alter host-pathogen dynamics and their underlying mechanisms. The emerging pathogen Batrachochytrium dendrobatidis (Bd) is a clear example of the negative effects infectious diseases can have on wildlife. Bd is linked to global declines in amphibian diversity and abundance. However, there is considerable variation in population-level responses to Bd, with some hosts experiencing marked declines while others persist. Environmental factors may play a role in this variation. This research used populations of pond-breeding chorus frogs (Pseudacris maculata) in Arizona to test if three rapidly changing environmental factors nitrogen (N), phosphorus (P), and temperature influence the presence, prevalence, and severity of Bd infections. I evaluated the reliability of a new technique for detecting Bd in water samples and combined this technique with animal sampling to monitor Bd in wild chorus frogs. Monitoring from 20 frog populations found high Bd presence and prevalence during breeding. A laboratory experiment found 85% adult mortality as a result of Bd infection; however, estimated chorus frog densities in wild populations increased significantly over two years of sampling despite high Bd prevalence. Presence, prevalence, and severity of Bd infections were not correlated with aqueous concentrations of N or P. There was, however, support for an annual temperature-induced reduction in Bd prevalence in newly metamorphosed larvae. A simple mathematical model suggests that this annual temperature-induced reduction of Bd infections in larvae in combination with rapid host maturation may help chorus frog populations persist despite high adult mortality. These results demonstrate that Bd can persist across a wide range of environmental conditions, providing little support for the influence of N and P on Bd dynamics, and show that water temperature may play an important role in altering Bd dynamics, enabling chorus frogs to persist with this pathogen. These findings demonstrate the importance of environmental context and host life history for the outcome of host-pathogen interactions.
ContributorsHyman, Oliver J. (Author) / Collins, James P. (Thesis advisor) / Davidson, Elizabeth W. (Committee member) / Anderies, John M. (Committee member) / Elser, James J. (Committee member) / Escalante, Ananias (Committee member) / Arizona State University (Publisher)
Created2012
Description
The complex life cycle and widespread range of infection of Plasmodium parasites, the causal agent of malaria in humans, makes them the perfect organism for the study of various evolutionary mechanisms. In particular, multigene families are considered one of the main sources for genome adaptability and innovation. Within Plasmodium, numerous species- and clade-specific multigene families have major functions in the development and maintenance of infection. Nonetheless, while the evolutionary mechanisms predominant on many species- and clade-specific multigene families have been previously studied, there are far less studies dedicated to analyzing genus common multigene families (GCMFs). I studied the patterns of natural selection and recombination in 90 GCMFs with diverse numbers of gene gain/loss events. I found that the majority of GCMFs are formed by duplications events that predate speciation of mammal Plasmodium species, with many paralogs being neutrally maintained thereafter. In general, multigene families involved in immune evasion and host cell invasion commonly showed signs of positive selection and species-specific gain/loss events; particularly, on Plasmodium species is the simian and rodent clades. A particular multigene family: the merozoite surface protein-7 (msp7) family, is found in all Plasmodium species and has functions related to the erythrocyte invasion. Within Plasmodium vivax, differences in the number of paralogs in this multigene family has been previously explained, at least in part, as potential adaptations to the human host. To investigate this I studied msp7 orthologs in closely related non-human primate parasites where homology was evident. I also estimated paralogs’ evolutionary history and genetic polymorphism. The emerging patterns where compared with those of Plasmodium falciparum. I found that the evolution of the msp7 multigene family is consistent with a Birth-and-Death model where duplications, pseudogenization and gene lost events are common. In order to study additional aspects in the evolution of Plasmodium, I evaluated the trends of long term and short term evolution and the putative effects of vertebrate- host’s immune pressure of gametocytes across various Plasmodium species. Gametocytes, represent the only sexual stage within the Plasmodium life cycle, and are also the transition stages from the vertebrate to the mosquito vector. I found that, while male and female gametocytes showed different levels of immunogenicity, signs of positive selection were not entirely related to the location and presence of immune epitope regions. Overall, these studies further highlight the complex evolutionary patterns observed in Plasmodium.
ContributorsCastillo Siri, Andreina I (Author) / Rosenberg, Michael (Thesis advisor) / Escalante, Ananias (Committee member) / Taylor, Jesse (Committee member) / Collins, James (Committee member) / Arizona State University (Publisher)
Created2016
Description
Emerging pathogens present several challenges to medical diagnostics. Primarily, the exponential spread of a novel pathogen through naïve populations require a rapid and overwhelming diagnostic response at the site of outbreak. While point-of-care (PoC) platforms have been developed for detection of antigens, serologic responses, and pathogenic genomes, only nucleic acid diagnostics currently have the potential to be developed and manufactured within weeks of an outbreak owing to the speed of next-generation sequencing and custom DNA synthesis. Among nucleic acid diagnostics, isothermal amplification strategies are uniquely suited for PoC implementation due to their simple instrumentation and lack of thermocycling requirement. Unfortunately, isothermal strategies are currently prone to spurious nonspecific amplification, hindering their specificity and necessitating extensive empirical design pipelines that are both time and resource intensive. In this work, isothermal amplification strategies are extensively compared for their feasibility of implementation in outbreak response scenarios. One such technology, Loop-mediated Amplification (LAMP), is identified as having high-potential for rapid development and PoC deployment. Various approaches to abrogating nonspecific amplification are described including a novel in silico design tool based on coarse-grained simulation of interactions between thermophilic DNA polymerase and DNA strands in isothermal reaction conditions. Nonspecific amplification is shown to be due to stabilization of primer secondary structures by high concentrations of Bst DNA polymerase and a mechanism of micro-complement-mediated cross-priming is demonstrated as causal via nanopore sequencing of nonspecific reaction products. The resulting computational model predicts primer set background in 64% of 67 test assays and its usefulness is illustrated further by determining problematic primers in a West Nile Virus-specific LAMP primer set and optimizing primer 3’ nucleotides to eliminate micro-complements within the reaction, resulting in inhibition of background accumulation. Finally, the emergence of Orthopox monkeypox (MPXV) as a recurring threat is discussed and SimCycle is utilized to develop a novel technique for clade-specific discrimination of MPXV based on bridging viral genomic rearrangements (Bridging LAMP). Bridging LAMP is implemented in a 4-plex microfluidic format and demonstrates 100% sensitivity in detection of 100 copies of viral lysates and 45 crude MPXV-positive patient samples collected during the 2022 Clade IIb outbreak.
ContributorsKnappenberger, Mark Daniel (Author) / Anderson, Karen S (Thesis advisor) / LaBaer, Joshua (Committee member) / Roberson, Robert (Committee member) / Lindsay, Stuart (Committee member) / Arizona State University (Publisher)
Created2023
Description
According to the World Health Organization, cancer is one of the leading causes of death around the world. Although early diagnostics using biomarkers and improved treatments with targeted therapy have reduced the rate of cancer related mortalities, there remain many unknowns regarding the contributions of the tumor microenvironment to cancer progression and therapeutic resistance. The tumor microenvironment plays a significant role by manipulating the progression of cancer cells through biochemical and biophysical signals from the surrounding stromal cells along with the extracellular matrix. As such, there is a critical need to understand how the tumor microenvironment influences the molecular mechanisms underlying cancer metastasis to facilitate the discovery of better therapies. This thesis described the development of microfluidic technologies to study the interplay of cancer cells with their surrounding microenvironment. The microfluidic model was used to assess how exposure to chemoattractant, epidermal growth factor (EGF), impacted 3D breast cancer cell invasion and enhanced cell motility speed was noted in the presence of EGF validating physiological cell behavior. Additionally, breast cancer and patient-derived cancer-associated fibroblast (CAF) cells were co-cultured to study cell-cell crosstalk and how it affected cancer invasion. GPNMB was identified as a novel gene of interest and it was shown that CAFs enhanced breast cancer invasion by up-regulating the expression of GPNMB on breast cancer cells resulting in increased migration speed. Lastly, this thesis described the design, biological validation, and use of this microfluidic platform as a new in vitro 3D organotypic model to study mechanisms of glioma stem cell (GSC) invasion in the context of a vascular niche. It was confirmed that CXCL12-CXCR4 signaling is involved in promoting GSC invasion in a 3D vascular microenvironment, while also demonstrating the effectiveness of the microfluidic as a drug screening assay. Taken together, the broader impacts of the microfluidic model developed in this dissertation include, a possible alternative platform to animal testing that is focused on mimicking human physiology, a potential ex vivo platform using patient-derived cells for studying the interplay of cancer cells with its surrounding microenvironment, and development of future therapeutic strategies tailored toward disrupting key molecular pathways involved in regulatory mechanisms of cancer invasion.
ContributorsTruong, Danh, Ph.D (Author) / Nikkhah, Mehdi (Thesis advisor) / LaBaer, Joshua (Committee member) / Smith, Barbara (Committee member) / Mouneimne, Ghassan (Committee member) / Vernon, Brent (Committee member) / Arizona State University (Publisher)
Created2018
Description
Transient Receptor Potential Vanilloid-1 (TRPV1) is an integral membrane polymodal cation channel involved in various essential biological functions, including thermosensing, thermoregulation, and nociception. Discrete TRPV1 activation modes such as ligand, heat, and proton have been challenging to disentangle. However, dissecting the polymodal nature of TRPV1 is essential for therapeutic development. The human TRPV1 (hTRPV1) voltage-sensing like domain (VSLD; transmembrane helices S1-S4) contains the canonical vanilloid ligand binding site and significantly contributes to thermosensing. Nuclear magnetic resonance (NMR)-detected studies probe the role of the hTRPV1-VSLD in TRPV1 polymodal function. The hTRPV1-VSLD is identified as an allosteric hub for all three primary TRPV1 activation modes and demonstrates plasticity in chemical ligand modulation. The presented results underscore molecular features in the VSLD that dictate TRPV1 function, highlighting important considerations for future therapeutic design.
ContributorsOwens, Aerial M. (Author) / Van Horn, Wade D. (Thesis advisor) / Levitus, Marcia (Committee member) / LaBaer, Joshua (Committee member) / Arizona State University (Publisher)
Created2023