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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- All Subjects: Biology
- Creators: Chang, Yung
- Creators: Fenichel, Eli
Description
Consideration of both biological and human-use dynamics in coupled social-ecological systems is essential for the success of interventions such as marine reserves. As purely human institutions, marine reserves have no direct effects on ecological systems. Consequently, the success of a marine reserve depends on managers` ability to alter human behavior in the direction and magnitude that supports reserve objectives. Further, a marine reserve is just one component in a larger coupled social-ecological system. The social, economic, political, and biological landscape all determine the social acceptability of a reserve, conflicts that arise, how the reserve interacts with existing fisheries management, accuracy of reserve monitoring, and whether the reserve is ultimately able to meet conservation and fishery enhancement goals. Just as the social-ecological landscape is critical at all stages for marine reserve, from initial establishment to maintenance, the reserve in turn interacts with biological and human use dynamics beyond its borders. Those interactions can lead to the failure of a reserve to meet management goals, or compromise management goals outside the reserve. I use a bio-economic model of a fishery in a spatially patchy environment to demonstrate how the pre-reserve fisheries management strategy determines the pattern of fishing effort displacement once the reserve is established, and discuss the social, political, and biological consequences of different patterns for the reserve and the fishery. Using a stochastic bio-economic model, I demonstrate how biological and human use connectivity can confound the accurate detection of reserve effects by violating assumptions in the quasi-experimental framework. Finally, I examine data on recreational fishing site selection to investigate changes in response to the announcement of enforcement of a marine reserve in the Gulf of California, Mexico. I generate a scale of fines that would fully or partially protect the reserve, providing a data-driven way for managers to balance biological and socio-economic goals. I suggest that natural resource managers consider human use dynamics with the same frequency, rigor, and tools as they do biological stocks.
ContributorsFujitani, Marie (Author) / Abbott, Joshua (Thesis advisor) / Fenichel, Eli (Thesis advisor) / Gerber, Leah (Committee member) / Anderies, John (Committee member) / Arizona State University (Publisher)
Created2014
Description
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by progressive autoimmune destruction of insulin-producing pancreatic β-cells. Genetic, immunological and environmental factors contribute to T1D development. The focus of this dissertation is to track the humoral immune response in T1D by profiling autoantibodies (AAbs) and anti-viral antibodies using an innovative protein array platform called Nucleic Acid Programmable Protein Array (NAPPA).
AAbs provide value in identifying individuals at risk, stratifying patients with different clinical courses, improving our understanding of autoimmune destructions, identifying antigens for cellular immune response and providing candidates for prevention trials in T1D. A two-stage serological AAb screening against 6,000 human proteins was performed. A dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) was validated with 36% sensitivity at 98% specificity by an orthogonal immunoassay. This is the first systematic screening for novel AAbs against large number of human proteins by protein arrays in T1D. A more comprehensive search for novel AAbs was performed using a knowledge-based approach by ELISA and a screening-based approach against 10,000 human proteins by NAPPA. Six AAbs were identified and validated with sensitivities ranged from 16% to 27% at 95% specificity. These two studies enriched the T1D “autoantigenome” and provided insights into T1D pathophysiology in an unprecedented breadth and width.
The rapid rise of T1D incidence suggests the potential involvement of environmental factors including viral infections. Sero-reactivity to 646 viral antigens was assessed in new-onset T1D patients. Antibody positive rate of EBV was significantly higher in cases than controls that suggested a potential role of EBV in T1D development. A high density-NAPPA platform was demonstrated with high reproducibility and sensitivity in profiling anti-viral antibodies.
This dissertation shows the power of a protein-array based immunoproteomics approach to characterize humoral immunoprofile against human and viral proteomes. The identification of novel T1D-specific AAbs and T1D-associated viruses will help to connect the nodes in T1D etiology and provide better understanding of T1D pathophysiology.
AAbs provide value in identifying individuals at risk, stratifying patients with different clinical courses, improving our understanding of autoimmune destructions, identifying antigens for cellular immune response and providing candidates for prevention trials in T1D. A two-stage serological AAb screening against 6,000 human proteins was performed. A dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) was validated with 36% sensitivity at 98% specificity by an orthogonal immunoassay. This is the first systematic screening for novel AAbs against large number of human proteins by protein arrays in T1D. A more comprehensive search for novel AAbs was performed using a knowledge-based approach by ELISA and a screening-based approach against 10,000 human proteins by NAPPA. Six AAbs were identified and validated with sensitivities ranged from 16% to 27% at 95% specificity. These two studies enriched the T1D “autoantigenome” and provided insights into T1D pathophysiology in an unprecedented breadth and width.
The rapid rise of T1D incidence suggests the potential involvement of environmental factors including viral infections. Sero-reactivity to 646 viral antigens was assessed in new-onset T1D patients. Antibody positive rate of EBV was significantly higher in cases than controls that suggested a potential role of EBV in T1D development. A high density-NAPPA platform was demonstrated with high reproducibility and sensitivity in profiling anti-viral antibodies.
This dissertation shows the power of a protein-array based immunoproteomics approach to characterize humoral immunoprofile against human and viral proteomes. The identification of novel T1D-specific AAbs and T1D-associated viruses will help to connect the nodes in T1D etiology and provide better understanding of T1D pathophysiology.
ContributorsBian, Xiaofang (Author) / LaBaer, Joshua (Thesis advisor) / Mandarino, Lawrence (Committee member) / Chang, Yung (Committee member) / Arizona State University (Publisher)
Created2015
Description
Infections caused by the Hepatitis C Virus (HCV) are very common worldwide, affecting up to 3% of the population. Chronic infection of HCV may develop into liver cirrhosis and liver cancer which is among the top five of the most common cancers. Therefore, vaccines against HCV are under intense study in order to prevent HCV from harming people's health. The envelope protein 2 (E2) of HCV is thought to be a promising vaccine candidate because it can directly bind to a human cell receptor and plays a role in viral entry. However, the E2 protein production in cells is inefficient due to its complicated matured structure. Folding of E2 in the endoplasmic reticulum (ER) is often error-prone, resulting in production of aggregates and misfolded proteins. These incorrect forms of E2 are not functional because they are not able to bind to human cells and stimulate antibody response to inhibit this binding. This study is aimed to overcome the difficulties of HCV E2 production in plant system. Protein folding in the ER requires great assistance from molecular chaperones. Thus, in this study, two molecular chaperones in the ER, calreticulin and calnexin, were transiently overexpressed in plant leaves in order to facilitate E2 folding and production. Both of them showed benefits in increasing the yield of E2 and improving the quality of E2. In addition, poorly folded E2 accumulated in the ER may cause stress in the ER and trigger transcriptional activation of ER molecular chaperones. Therefore, a transcription factor involved in this pathway, named bZIP60, was also overexpressed in plant leaves, aiming at up-regulating a major family of molecular chaperones called BiP to assist protein folding. However, our results showed that BiP mRNA levels were not up-regulated by bZIP60, but they increased in response to E2 expression. The Western blot analysis also showed that overexpression of bZIP60 had a small effect on promoting E2 folding. Overall, this study suggested that increasing the level of specific ER molecular chaperones was an effective way to promote HCV E2 protein production and maturation.
ContributorsHong, Fan (Author) / Mason, Hugh (Thesis advisor) / Gaxiola, Roberto (Committee member) / Chang, Yung (Committee member) / Chen, Qiang (Committee member) / Arizona State University (Publisher)
Created2011
Description
Conditions during development can shape the expression of traits at adulthood, a phenomenon called developmental plasticity. In this context, factors such as nutrition or health state during development can affect current and subsequent physiology, body size, brain structure, ornamentation, and behavior. However, many of the links between developmental and adult phenotype are poorly understood. I performed a series of experiments using a common molecular currency - carotenoid pigments - to track somatic and reproductive investments through development and into adulthood. Carotenoids are red, orange, or yellow pigments that: (a) animals must acquire from their diets, (b) can be physiologically beneficial, acting as antioxidants or immunostimulants, and (c) color the sexually attractive features (e.g., feathers, scales) of many animals. I studied how carotenoid nutrition and immune challenges during ontogeny impacted ornamental coloration and immune function of adult male mallard ducks (Anas platyrhynchos). Male mallards use carotenoids to pigment their yellow beak, and males with more beaks that are more yellow are preferred as mates, have increased immune function, and have higher quality sperm. In my dissertation work, I established a natural context for the role that carotenoids and body condition play in the formation of the adult phenotype and examined how early-life experiences, including immune challenges and dietary access to carotenoids, affect adult immune function and ornamental coloration. Evidence from mallard ducklings in the field showed that variation in circulating carotenoid levels at hatch are likely driven by maternal allocation of carotenoids, but that carotenoid physiology shifts during the subsequent few weeks to reflect individual foraging habits. In the lab, adult beak color expression and immune function were more tightly correlated with body condition during growth than body condition during subsequent stages of development or adulthood. Immune challenges during development affected adult immune function and interacted with carotenoid physiology during adulthood, but did not affect adult beak coloration. Dietary access to carotenoids during development, but not adulthood, also affected adult immune function. Taken together, these results highlight the importance of the developmental stage in shaping certain survival-related traits (i.e., immune function), and lead to further questions regarding the development of ornamental traits.
ContributorsButler, Michael (Author) / McGraw, Kevin J. (Thesis advisor) / Chang, Yung (Committee member) / Deviche, Pierre (Committee member) / DeNardo, Dale (Committee member) / Rutowski, Ronald (Committee member) / Arizona State University (Publisher)
Created2012
Description
Many studies over the past two decades examined the link between climate patterns and discharge, but few have attempted to study the effects of the El Niño Southern Oscillation (ENSO) on localized and watershed specific processes such as nutrient loading in the Southwestern United States. The Multivariate ENSO Index (MEI) is used to describe the state of the ENSO, with positive (negative) values referring to an El Niño condition (La Niña condition). This study examined the connection between the MEI and precipitation, discharge, and total nitrogen (TN) and total phosphorus (TP) concentrations in the Upper Salt River Watershed in Arizona. Unrestricted regression models (UMs) and restricted regression models (RMs) were used to investigate the relationship between the discharges in Tonto Creek and the Salt River as functions of the magnitude of the MEI, precipitation, and season (winter/summer). The results suggest that in addition to precipitation, the MEI/season relationship is an important factor for predicting discharge. Additionally, high discharge events were associated with high magnitude ENSO events, both El Niño and La Niña. An UM including discharge and season, and a RM (restricting the seasonal factor to zero), were applied to TN and TP concentrations in the Salt River. Discharge and seasonality were significant factors describing the variability in TN in the Salt River while discharge alone was the significant factor describing TP. TN and TP in Roosevelt Lake were evaluated as functions of both discharge and MEI. Some significant correlations were found but internal nutrient cycling as well as seasonal stratification of the water column of the lake likely masks the true relationships. Based on these results, the MEI is a useful predictor of discharge, as well as nutrient loading in the Salt River Watershed through the Salt River and Tonto Creek. A predictive model investigating the effect of ENSO on nutrient loading through discharge can illustrate the effects of large scale climate patterns on smaller systems.
ContributorsSversvold, Darren (Author) / Neuer, Susanne (Thesis advisor) / Elser, James (Committee member) / Fenichel, Eli (Committee member) / Arizona State University (Publisher)
Created2012
Description
The southwestern willow flycatcher (Empidonax traillii extimus) is listed as an endangered species throughout its range in the southwestern United States. Little is known about its sub-population spatial structure and how this impacts its population viability. In conjunction with being listed as endangered, a recovery plan was produced by the US Fish and Wildlife Service, with recovery units (sub-populations) roughly based on major river drainages. In the interest of examining this configuration of sub-populations and their impact on the measured population viability, I applied a multivariate auto-regressive state-space model to a spatially extensive time series of abundance data for the southwestern willow flycatcher over the period spanning 1995-2010 estimating critical growth parameters, correlation in environmental stochasticity or "synchronicity" between sub-populations (recovery units) and extinction risk of the sub-populations and the whole. The model estimates two parameters, the mean and variance of annual growth rate. Of the models I tested, I found the strongest support for a population model in which three of the recovery units were grouped (the Lower Colorado, Gila Basin, and Rio Grande recovery units) while keeping all others separate. This configuration has 6.6 times more support for the observed data than a configuration assigning each recovery unit to a separate sub-population, which is how they are circumscribed in the recovery plan. Given the best model, the mean growth rate is -0.0234 (CI95 -0.0939, 0.0412) with a variance of 0.0597 (CI95 0.0115, 0.1134). This growth rate is not significantly different from zero and this is reflected in the low potential for quasi-extinction. The cumulative probability of the population experiencing at least an 80% decline from current levels within 15 years for some sub-populations were much higher (range: 0.129-0.396 for an 80% decline). These results suggest that the rangewide population has a low risk of extinction in the next 15 years and that the formal recovery units specified by the original recovery plan do not correspond to proper sub-population units as defined by population synchrony.
ContributorsDockens, Patrick E. T. (Author) / Sabo, John (Thesis advisor) / Stromberg, Juliet (Committee member) / Fenichel, Eli (Committee member) / Arizona State University (Publisher)
Created2012
Description
Over the past decade, several high-value proteins have been produced using plant-based transient expression systems. However, these studies exposed some limitations that must be overcome to allow plant expression systems to reach their full potential. These limitations are the low level of recombinant protein accumulation achieved in some cases, and lack of efficient co-expression vectors for the production of multi-protein complexes. This study report that tobacco Extensin (Ext) gene 3' untranslated region (UTR) can be broadly used to enhance recombinant protein expression in plants. Extensin is the hydroxyproline-rich glycoprotein that constitutes the major protein component of cell walls. Using transient expression, it was found that the Ext 3' UTR increases recombinant protein expression up to 13.5- and 6-fold in non-replicating and replicating vector systems, respectively, compared to previously established terminators. Enhanced protein accumulation was correlated with increased mRNA levels associated with reduction in read-through transcription. Regions of Ext 3' UTR essential for maximum gene expression included a poly-purine sequence used as a major poly-adenylation site. Furthermore, modified bean yellow dwarf virus (BeYDV)-based vectors designed to allow co-expression of multiple recombinant genes were constructed and tested for their performance in driving transient expression in plants. Robust co-expression and assembly of heavy and light chains of the anti-Ebola virus monoclonal antibody 6D8, as well as E. coli heat-labile toxin (LT) were achieved with the modified vectors. The simultaneous co-expression of three fluoroproteins using the single replicon, triple cassette is demonstrated by confocal microscopy. In conclusion, this study provides an excellent tool for rapid, cost-effective, large-scale manufacturing of recombinant proteins for use in medicine and industry.
ContributorsRosenthal, Sun Hee (Author) / Mason, Hugh (Thesis advisor) / Mor, Tsafrir (Committee member) / Chang, Yung (Committee member) / Arntzen, Charles (Committee member) / Arizona State University (Publisher)
Created2012
Description
Immunotherapy has been revitalized with the advent of immune checkpoint blockade
treatments, and neo-antigens are the targets of immune system in cancer patients who
respond to the treatments. The cancer vaccine field is focused on using neo-antigens from
unique point mutations of genomic sequence in the cancer patient for making
personalized cancer vaccines. However, we choose a different path to find frameshift
neo-antigens at the mRNA level and develop broadly effective cancer vaccines based on
frameshift antigens.
In this dissertation, I have summarized and characterized all the potential frameshift
antigens from microsatellite regions in human, dog and mouse. A list of frameshift
antigens was validated by PCR in tumor samples and the mutation rate was calculated for
one candidate – SEC62. I develop a method to screen the antibody response against
frameshift antigens in human and dog cancer patients by using frameshift peptide arrays.
Frameshift antigens selected by positive antibody response in cancer patients or by MHC
predictions show protection in different mouse tumor models. A dog version of the
cancer vaccine based on frameshift antigens was developed and tested in a small safety
trial. The results demonstrate that the vaccine is safe and it can induce strong B and T cell
immune responses. Further, I built the human exon junction frameshift database which
includes all possible frameshift antigens from mis-splicing events in exon junctions, and I
develop a method to find potential frameshift antigens from large cancer
immunosignature dataset with these databases. In addition, I test the idea of ‘early cancer
diagnosis, early treatment’ in a transgenic mouse cancer model. The results show that
ii
early treatment gives significantly better protection than late treatment and the correct
time point for treatment is crucial to give the best clinical benefit. A model for early
treatment is developed with these results.
Frameshift neo-antigens from microsatellite regions and mis-splicing events are
abundant at mRNA level and they are better antigens than neo-antigens from point
mutations in the genomic sequences of cancer patients in terms of high immunogenicity,
low probability to cause autoimmune diseases and low cost to develop a broadly effective
vaccine. This dissertation demonstrates the feasibility of using frameshift antigens for
cancer vaccine development.
treatments, and neo-antigens are the targets of immune system in cancer patients who
respond to the treatments. The cancer vaccine field is focused on using neo-antigens from
unique point mutations of genomic sequence in the cancer patient for making
personalized cancer vaccines. However, we choose a different path to find frameshift
neo-antigens at the mRNA level and develop broadly effective cancer vaccines based on
frameshift antigens.
In this dissertation, I have summarized and characterized all the potential frameshift
antigens from microsatellite regions in human, dog and mouse. A list of frameshift
antigens was validated by PCR in tumor samples and the mutation rate was calculated for
one candidate – SEC62. I develop a method to screen the antibody response against
frameshift antigens in human and dog cancer patients by using frameshift peptide arrays.
Frameshift antigens selected by positive antibody response in cancer patients or by MHC
predictions show protection in different mouse tumor models. A dog version of the
cancer vaccine based on frameshift antigens was developed and tested in a small safety
trial. The results demonstrate that the vaccine is safe and it can induce strong B and T cell
immune responses. Further, I built the human exon junction frameshift database which
includes all possible frameshift antigens from mis-splicing events in exon junctions, and I
develop a method to find potential frameshift antigens from large cancer
immunosignature dataset with these databases. In addition, I test the idea of ‘early cancer
diagnosis, early treatment’ in a transgenic mouse cancer model. The results show that
ii
early treatment gives significantly better protection than late treatment and the correct
time point for treatment is crucial to give the best clinical benefit. A model for early
treatment is developed with these results.
Frameshift neo-antigens from microsatellite regions and mis-splicing events are
abundant at mRNA level and they are better antigens than neo-antigens from point
mutations in the genomic sequences of cancer patients in terms of high immunogenicity,
low probability to cause autoimmune diseases and low cost to develop a broadly effective
vaccine. This dissertation demonstrates the feasibility of using frameshift antigens for
cancer vaccine development.
ContributorsZhang, Jian (Author) / Johnston, Stephen Albert (Thesis advisor) / Chang, Yung (Committee member) / Stafford, Phillip (Committee member) / Chen, Qiang (Committee member) / Arizona State University (Publisher)
Created2018
Description
The closer integration of the world economy has yielded many positive benefits including the worldwide diffusion of innovative technologies and efficiency gains following the widening of international markets. However, closer integration also has negative consequences. Specifically, I focus on the ecology and economics of the spread of species and pathogens. I approach the problem using theoretical and applied models in ecology and economics. First, I use a multi-species theoretical network model to evaluate the ability of dispersal to maintain system-level biodiversity and productivity. I then extend this analysis to consider the effects of dispersal in a coupled social-ecological system where people derive benefits from species. Finally, I estimate an empirical model of the foot and mouth disease risks of trade. By combining outbreak and trade data I estimate the disease risks associated with the international trade in live animals while controlling for the biosecurity measures in place in importing countries and the presence of wild reservoirs. I find that the risks associated with the spread and dispersal of species may be positive or negative, but that this relationship depends on the ecological and economic components of the system and the interactions between them.
ContributorsShanafelt, David William (Author) / Perrings, Charles (Thesis advisor) / Fenichel, Eli (Committee member) / Richards, Timorthy (Committee member) / Janssen, Marco (Committee member) / Collins, James (Committee member) / Arizona State University (Publisher)
Created2016
Description
The properties of adjuvants to stimulate an immune response to treat cancer has sparked a major area of research in the field of immunotherapy. Given the presence of multiple RNA sensors in mammalian host cells for eliciting innate immunity, synthetic RNA nanostructures present a unique opportunity for adjuvant exploration. While RNA nanostructures are organic and biocompatible in nature than other adjuvants, they could be tailored to have desired structural stability and functional diversity for in vivo application. In this study, a rectangular RNA origami nanostructure was designed to contain double-stranded RNA motifs and possess high structural stability. Using in vitro assays, RNA origami was shown to stimulate the toll-like receptor 3 (TLR3) signaling pathway, which has been reported to activate antigen presenting cells (APCs), natural killer (NK) cells, cluster of differentiation 8 (CD8) T-cells, and the secretion of proinflammatory cytokines. To explore RNA origami as an adjuvant for cancer immunotherapy, intraperitoneal administration of a murine colon cancer cell line (CT26) was used as a model system to mimic peritoneal metastasis (PM), in which RNA origami was investigated for its activities in mitigating PM tumor microenvironment and improving anti-tumor immunity. Given the poor outcome of the patients with PM and urgent need for new interventions, this study aims to translate the adjuvant activities of RNA origami demonstrated in vitro into potent anti-cancer immunotherapeutics. Here, it was shown that multiple intraperitoneal injections of RNA origami could inhibit tumor growth, leading to a significant delay and/or regression of metastatic tumor growth in the peritoneum. Furthermore, tumor-free mice, after being treated with RNA origami, were also resistant to a second challenge of tumor cells, indicating the development of the adaptive anti-tumor immunity. This immunity is dependent on T-cells since nude mice succumbed to tumor growth with or without RNA origami treatment. Thus, RNA-origami can function as an adjuvant to activate the innate immunity and subsequently the adaptive anti-tumor immunity, leading to tumor regression. Conceivably, RNA origami could be explored as an immunotherapeutic agent to improve the disease outcome of patients with peritoneal metastasis and peritoneal carcinogenesis.
ContributorsRodriguez del Villar, Ryan Luis (Author) / Chang, Yung (Thesis advisor) / Liu, Xiaowei (Committee member) / Qi, Xiaodong (Committee member) / Arizona State University (Publisher)
Created2018