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Description
Flavivirus infections are emerging as significant threats to human health around the globe. Among them West Nile(WNV) and Dengue Virus (DV) are the most prevalent in causing human disease with WNV outbreaks occurring in all areas around the world and DV epidemics in more than 100 countries. WNV is a neurotropic virus capable of causing meningitis and encephalitis in humans. Currently, there are no therapeutic treatments or vaccines available. The expanding epidemic of WNV demands studies that develop efficacious therapeutics and vaccines and produce them rapidly and inexpensively. In response, our lab developed a plant-derived monoclonal antibody (mAb) (pHu-E16) against DIII (WNV antigen) that is able to neutralize and prevent mice from lethal infection. However, this drug has a short window of efficacy due to pHu-E16's inability to cross the Blood Brain Barrier (BBB) and enter the brain. Here, we constructed a bifunctional diabody, which couples the neutralizing activity of E16 and BBB penetrating activity of 8D3 mAb. We also produced a plant-derived E16 scFv-CH1-3 variant with equivalent specific binding as the full pHu-E16 mAb, but only requiring one gene construct for production. Furthermore, a WNV vaccine based on plant-derived DIII was developed showing proper folding and potentially protective immune response in mice. DV causes severe hemorrhaging diseases especially in people exposed to secondary DV infection from a heterotypic strain. It is hypothesized that sub-neutralizing cross-reactive antibodies from the first exposure aid the second infection in a process called antibody-dependent enhancement (ADE). ADE depends on the ability of mAb to bind Fc receptors (FcγRs), and has become a major roadblock for developing mAb-based therapeutics against DV. We aim to produce an anti-Dengue mAb (E60) in different glycoengineered plant lines that exhibit reduced/differential binding to FcγRs, therefore, reducing or eliminating ADE. We have successfully cloned the molecular constructs of E60, and expressed it in two plant lines with different glycosylation patterns. We demonstrated that both plant-derived E60 mAb glycoforms retained specific recognition and neutralization activity against DV. Overall, our study demonstrates great strives to develop efficacious therapeutics and potent vaccine candidates against Flaviviruses in plant expression systems.
ContributorsHurtado, Jonathan (Author) / Chen, Qiang (Thesis advisor) / Huffman, Holly A (Committee member) / Steele, Kelly P (Committee member) / Arizona State University (Publisher)
Created2014
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
One necessary condition for the two-pass risk premium estimator to be consistent and asymptotically normal is that the rank of the beta matrix in a proposed linear asset pricing model is full column. I first investigate the asymptotic properties of the risk premium estimators and the related t-test and Wald test statistics when the full rank condition fails. I show that the beta risk of useless factors or multiple proxy factors for a true factor are priced more often than they should be at the nominal size in the asset pricing models omitting some true factors. While under the null hypothesis that the risk premiums of the true factors are equal to zero, the beta risk of the true factors are priced less often than the nominal size. The simulation results are consistent with the theoretical findings. Hence, the factor selection in a proposed factor model should not be made solely based on their estimated risk premiums. In response to this problem, I propose an alternative estimation of the underlying factor structure. Specifically, I propose to use the linear combination of factors weighted by the eigenvectors of the inner product of estimated beta matrix. I further propose a new method to estimate the rank of the beta matrix in a factor model. For this method, the idiosyncratic components of asset returns are allowed to be correlated both over different cross-sectional units and over different time periods. The estimator I propose is easy to use because it is computed with the eigenvalues of the inner product of an estimated beta matrix. Simulation results show that the proposed method works well even in small samples. The analysis of US individual stock returns suggests that there are six common risk factors in US individual stock returns among the thirteen factor candidates used. The analysis of portfolio returns reveals that the estimated number of common factors changes depending on how the portfolios are constructed. The number of risk sources found from the analysis of portfolio returns is generally smaller than the number found in individual stock returns.
ContributorsWang, Na (Author) / Ahn, Seung C. (Thesis advisor) / Kallberg, Jarl G. (Committee member) / Liu, Crocker H. (Committee member) / Arizona State University (Publisher)
Created2011
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
Antibodies are naturally occurring proteins that protect a host during infection through direct neutralization and/or recruitment of the innate immune system. Unfortunately, in some infections, antibodies present unique hurdles that must be overcome for a safer and more efficacious antibody-based therapeutic (e.g., antibody dependent viral enhancement (ADE) and inflammatory pathology). This dissertation describes the utilization of plant expression systems to produce N-glycan specific antibody-based therapeutics for Dengue Virus (DENV) and Chikungunya Virus (CHIKV). The Fc region of an antibody interacts with Fcγ Receptors (FcγRs) on immune cells and components of the innate immune system. Each class of immune cells has a distinct action of neutralization (e.g., antibody dependent cell-mediated cytotoxicity (ADCC) and antibody dependent cell-mediated phagocytosis (ADCP)). Therefore, structural alteration of the Fc region results in novel immune pathways of protection. One approach is to modulate the N-glycosylation in the Fc region of the antibody. Of scientific significance, is the plant’s capacity to express human antibodies with homogenous plant and humanized N-glycosylation (WT and GnGn, respectively). This allows to study how specific glycovariants interact with other components of the immune system to clear an infection, producing a tailor-made antibody for distinct diseases. In the first section, plant-produced glycovariants were explored for reduced interactions with specific FcγRs for the overall reduction in ADE for DENV infections. The results demonstrate a reduction in ADE of our plant-produced monoclonal antibodies in in vitro experiments, which led to a greater survival in vivo of immunodeficient mice challenged with lethal doses of DENV and a sub-lethal dose of DENV in ADE conditions. In the second section, plant-produced glycovariants were explored for increased interaction with specific FcγRs to improve ADCC in the treatment of the highly inflammatory CHIKV. The results demonstrate an increase ADCC activity in in vitro experiments and a reduction in CHIKV-associated inflammation in in vivo mouse models. Overall, the significance of this dissertation is that it can provide a treatment for DENV and CHIKV; but equally importantly, give insight to the role of N-glycosylation in antibody effector functions, which has a broader implication for therapeutic development for other viral infections.
ContributorsHurtado, Jonathan (Author) / Chen, Qiang (Thesis advisor) / Arntzen, Charles (Committee member) / Borges, Chad (Committee member) / Lake, Douglas (Committee member) / Arizona State University (Publisher)
Created2019
Description
The advertising agency, in its variety of forms, is one of the most powerful forces in the modern world. Its products are seen globally through various multimedia outlets and they strongly impact culture and economy. Since its conception in 1843 by Volney Palmer, the advertising agency has evolved into the recognizable—and unrecognizable—firms scattered around the world today. In the United States alone, there are roughly 13.4 thousand agencies, many of which also have branches in other countries. The evolution of the modern advertising agency coincided with, and even preceded, some of the major inflection points in history. Understanding how and why changes in advertising agencies affected these inflection points provides a glimpse of understanding into the relationship between advertising, business, and societal values.
In the pages ahead we will explore the future of the advertising industry. We will analyze our research to uncover the underlying trends pointing towards what is to come and work to apply those explanations to our understanding of advertising in the future.
In the pages ahead we will explore the future of the advertising industry. We will analyze our research to uncover the underlying trends pointing towards what is to come and work to apply those explanations to our understanding of advertising in the future.
ContributorsHarris, Chase (Co-author) / Potthoff, Zachary (Co-author) / Gray, Nancy (Thesis director) / Samper, Adriana (Committee member) / Department of Information Systems (Contributor) / Department of Marketing (Contributor) / Herberger Institute for Design and the Arts (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
This research compares shifts in a SuperSpec titanium nitride (TiN) kinetic inductance detector's (KID's) resonant frequency with accepted models for other KIDs. SuperSpec, which is being developed at the University of Colorado Boulder, is an on-chip spectrometer designed with a multiplexed readout with multiple KIDs that is set up for a broadband transmission of these measurements. It is useful for detecting radiation in the mm and sub mm wavelengths which is significant since absorption and reemission of photons by dust causes radiation from distant objects to reach us in infrared and far-infrared bands. In preparation for testing, our team installed stages designed previously by Paul Abers and his group into our cryostat and designed and installed other parts necessary for the cryostat to be able to test devices on the 250 mK stage. This work included the design and construction of additional parts, a new setup for the wiring in the cryostat, the assembly, testing, and installation of several stainless steel coaxial cables for the measurements through the devices, and other cryogenic and low pressure considerations. The SuperSpec KID was successfully tested on this 250 mK stage thus confirming that the new setup is functional. Our results are in agreement with existing models which suggest that the breaking of cooper pairs in the detector's superconductor which occurs in response to temperature, optical load, and readout power will decrease the resonant frequencies. A negative linear relationship in our results appears, as expected, since the parameters are varied only slightly so that a linear approximation is appropriate. We compared the rate at which the resonant frequency responded to temperature and found it to be close to the expected value.
ContributorsDiaz, Heriberto Chacon (Author) / Mauskopf, Philip (Thesis director) / McCartney, Martha (Committee member) / Department of Physics (Contributor) / School of Mathematical and Statistical Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
This study estimates the capitalization effect of golf courses in Maricopa County using the hedonic pricing method. It draws upon a dataset of 574,989 residential transactions from 2000 to 2006 to examine how the aesthetic, non-golf benefits of golf courses capitalize across a gradient of proximity measures. The measures for amenity value extend beyond home adjacency and include considerations for homes within a range of discrete walkability buffers of golf courses. The models also distinguish between public and private golf courses as a proxy for the level of golf course access perceived by non-golfers. Unobserved spatial characteristics of the neighborhoods around golf courses are controlled for by increasing the extent of spatial fixed effects from city, to census tract, and finally to 2000 meter golf course ‘neighborhoods.’ The estimation results support two primary conclusions. First, golf course proximity is found to be highly valued for adjacent homes and homes up to 50 meters way from a course, still evident but minimal between 50 and 150 meters, and insignificant at all other distance ranges. Second, private golf courses do not command a higher proximity premia compared to public courses with the exception of homes within 25 to 50 meters of a course, indicating that the non-golf benefits of courses capitalize similarly, regardless of course type. The results of this study motivate further investigation into golf course features that signal access or add value to homes in the range of capitalization, particularly for near-adjacent homes between 50 and 150 meters thought previously not to capitalize.
ContributorsJoiner, Emily (Author) / Abbott, Joshua (Thesis director) / Smith, Kerry (Committee member) / Economics Program in CLAS (Contributor) / School of Sustainability (Contributor) / School of Mathematical and Statistical Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
The objective of this paper is to provide an educational diagnostic into the technology of blockchain and its application for the supply chain. Education on the topic is important to prevent misinformation on the capabilities of blockchain. Blockchain as a new technology can be confusing to grasp given the wide possibilities it can provide. This can convolute the topic by being too broad when defined. Instead, the focus will be maintained on explaining the technical details about how and why this technology works in improving the supply chain. The scope of explanation will not be limited to the solutions, but will also detail current problems. Both public and private blockchain networks will be explained and solutions they provide in supply chains. In addition, other non-blockchain systems will be described that provide important pieces in supply chain operations that blockchain cannot provide. Blockchain when applied to the supply chain provides improved consumer transparency, management of resources, logistics, trade finance, and liquidity.
ContributorsKrukar, Joel Michael (Author) / Oke, Adegoke (Thesis director) / Duarte, Brett (Committee member) / Hahn, Richard (Committee member) / School of Mathematical and Statistical Sciences (Contributor) / Department of Economics (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
The town of Guadalupe, Arizona has a long history of divided residents and high poverty rates. The high levels of poverty in the town can be attributed to numerous factors, most notably high rates of drug abuse, low high school graduation rates, and teen pregnancy. The town has named one of its most pressing issues of today to be youth disengagement. There are currently a handful of residents and community members passionate about finding a solution to this issue. After working with Guadalupe's Ending Hunger Task Force and resident youth, I set out to create a program design for a Guadalupe Youth Council. This council will contribute to combating youth disengagement. The program design will assist the task force in creating a standing youth council and deciding on the structure and role the council has in the town. I will offer learning outcomes and suggestions to the Task Force, youth council staff, and the youth of the youth council. This study contains an analysis of relevant literature, youth focus group results and data, and how the information gathered has contributed to the design of the youth council. The results of this study contain recommendations about four themes within the program design of a youth council: size, recruitment, activities and engagement, and adult support. The results also explore how the youth council will impact the power, policy, and behavior of Guadalupe youth.
ContributorsBalderas, Erica Theresa (Author) / Wang, Lili (Thesis director) / Avalos, Francisco (Committee member) / School of Community Resources and Development (Contributor) / Department of Information Systems (Contributor) / W.P. Carey School of Business (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05