Matching Items (52)
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
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
There are problems in the breeding practices of miniature horses. This study seeks to determine the source of these detrimental outcomes based on an evaluation of primary attributes selected for by breeders and the lack of genetic information and understanding of these attributes. In order to do this a program model was created to test the effects of selection criteria on breeder behavior and the resultant foals of these crosses. Moving forwards this program will evolve into a database of the equine genome for different horses. This will allow breeders to input their horses and do faux crosses in order to decrease the incidence of negative and detrimental outcomes.
ContributorsDavis, Marissa Lynn (Author) / Oberle, Eric (Thesis director) / Martin, Thomas (Committee member) / College of Letters and Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
This project is to help Guatemalan youth immigrants by providing them with the information necessary to access support in the United States, and obtainin legal status in the United States. In order to produce a brochure with this information, it was necessary to research the political, economic, and social history of Guatemala in order to determine what struggles citizens are facing, and specifically what experiences youth in the country have prior to their journey to the United States. This research is culminated into a paper that discusses the history, the causes of emigration from Guatemala, and the status of youth immigrants before they leave Guatemala and once they arrive in the United States.
ContributorsMckay, Rachel Marie (Author) / Magaña, Lisa (Thesis director) / Elias, Olivia (Committee member) / School of Criminology and Criminal Justice (Contributor) / School of Politics and Global Studies (Contributor) / College of Letters and Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
This thesis examines the problems that occur when the politics and practices of social services, specifically maternal and prenatal care, are guided by a distorted understanding of immigration. It compares the politics and practice of this care across two international borders: the U.S.-Mexico and that within Hispaniola. In an ideal world, care would be extended to all individuals regardless of citizenship. However, since every welfare state has its limits at the national border, citizenship matters to both federal governments and medical professionals. Government-provided resources play an integral role in the current immigration debate, as these programs are a collective investment in which all individuals contribute in order to sustain it. The United States developed the welfare state in order to provide necessary resources to those who could not afford it. Its creators did not view these services as a handout, rather as a support for the future workforce of the country. However, health care was and still is not provided on this model of economic and social citizenship. Current U.S. healthcare policy dictates that no one can be turned away in an emergency situation because someone cannot pay their medical bill, including undocumented immigrants. But for immigrant mothers carrying children across the border, maternal and prenatal care does not qualify as an emergency and the federal government aid typically does not extend to them them as citizens. When care is extended to undocumented immigrants in the United States at all, it typically is provided to the child through Medicaid, who is by dint of the Fourteenth Amendment considered a citizen after birth. The relation between the Dominican Republic and Haiti offers a more complex situation, as the idea of birthright citizenship has recently been revoked. Following the Haitian Earthquake in 2010, the only healthcare to which many Haitians had access was across the Hispaniola border. Haitian women who give birth to children in the Dominican Republic are often not evaluated by a doctor until they are entering the delivery process, and even then health-care is complicated by or denied because of racial prejudice and unclear legal situation. In September of 2013, the Constitutional Court of the Dominican Republic issues a new ruling which declared that any immigrant born between 1929 and 2010 without documentation of their own or of their ancestors does not have citizenship, rendering many Haitians born in the Dominican Republic essentially stateless. To be born to a non-citizen mother typically means the child will likely be born with little or no prenatal care, and the mother will receive poor or inadequate care. Prenatal care is one of the most inexpensive elements of a care-model that carries huge returns relative to its costs. All governments would benefit from improved access to maternal and prenatal care because its future citizens who receive such care would be born healthier and have fewer expensive chronic illnesses. Fewer chronic illness among a population would have huge returns on the welfare state because fewer people would be utilizing it for expensive medical treatments. Though most medical professionals condemn the extreme act of denying care to pregnant women or infants (documented or not), the Dominican Republic and the United States have a popular politics that embraces this cruelty, despite the fact that both pride themselves on a multi-ethnic population. It is easy for policymakers to incriminate undocumented immigrants and claim that they are responsible for an illegitimate share of the consumption of the country's resources. Therefore, it seems likely that the host country's perceptions of immigrant natality and maternity help construct a negative image of the immigration "problem" in such a way that laws and policies are designed without accurate rationale. This thesis examines how the United States and the Dominican Republic might improve the relationship between the culture of healthcare and the role of the legal system for immigrants and their children. It seeks to understand the reasons, motivations, and consequences for denying immigrants services on the account of their citizenship status. The social, economic, and health consequences of being an undocumented citizen will be examined. Current legal policy and what political roadblocks and cultural prejudices must be overcome in order to implement a successful policy will be reviewed. Finally, the best practices prenatal care as a national investment will be discussed, as will the problem of cross-cultural perception of natality, maternity, and immigration.
ContributorsPrassas, Alexandra Rose (Author) / Oberle, Eric (Thesis director) / Vega, Sujey (Committee member) / Oberstein, Bruce (Committee member) / College of Letters and Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
Urbanization is a landscape-level alteration of habitat that can lead to habitat fragmentation, degradation, and the introduction of nonnative species. Due to their life history characteristics, mammalian predators are particularly vulnerable to these effects. The categorization of many species as synanthropic, benefiting from human development, has been difficult as species have a gradient of responses to urbanization. Although coyotes, gray foxes and bobcats have all been shown to benefit from light to moderate levels of urbanization, often due to the increase in food resources, they typically require access to natural areas as escape cover. Camera traps at varying distances were used to document mesopredator response to the urban edge of Gold Canyon, Arizona from November 2015 through March 2016. Coyote, gray fox and bobcat relative abundance did not vary with distance to urban edge during this time period. Although, negative trends suggest that a larger scale study may reveal a negative relationship between distance to urban edge and mesopredator abundance for all 3 of these species. The efficacy of different baits at increasing mesopredator detections was also tested, with insignificant results. However, coyotes seemed to be more likely to interact with Carman's Raccoon Lure No. 2 than coyote urine. Understanding the responses of mesopredators to urbanization will allow us to better coexist with these vulnerable species as land continues to be developed at high rates across the globe.
ContributorsEvans, Jacquelyn Diane (Author) / Cunningham, Stanley (Thesis director) / Allen, Daniel (Committee member) / College of Letters and Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
Dental caries also known as tooth decay is a bacterial infection that causes demineralization and destruction of enamel dentin and cementum in the tooth. This bacterium, Streprococcus mutans, feeds on the carbohydrates in the mouth and produces lactic acids that result in dental caries. This thesis discusses the use of plants to produce antibodies, Guy 13 and anti-GTFB to treat this dental disease. We believe these plant-derived antibodies will be effective to treat dental caries and economical to produce.
ContributorsSayegh, Luvenia Crystal (Author) / Chen, Qiang (Thesis director) / Garg, Vikas (Committee member) / Barrett, The Honors College (Contributor) / School of Letters and Sciences (Contributor)
Created2014-12
Description
This abstract is intended to explain the main ideas and thoughts pertaining to the author's experiences over time while attending Arizona State University and how certain course teachings have created a more positive outcome in life for the author. The goal of this Independent Study Thesis is to convey the great significance that the Information Measurement Theory (IMT) courses' ideas and teachings have contributed to the author's life and how they have increased the author's overall quality and outlook on life, not only from an academic standpoint and setting, but also in every facet. Based on this, the author's intention is to convey the new skills obtained regarding The Kashiwagi Solution Model (KSM) as they pertain to Information Measurement Theory (IMT), based on the author's own recent experiences in college with what he has learned, and to explain how they have helped tremendously. This is mainly comprised of information based on the external sources and writings of Dr. Dean Kashiwagi, and also direct resources and teachings by Dr. Dean Kashiwagi and Dr. Jacob Kashiwagi that have greatly contributed to the author's overall understanding of Information Measurement Theory (IMT), its revolutionary new ways of thinking, and the new skill sets developed from it as well. This will also focus on the benefits that can occur for anyone by applying the various aspects of The Kashiwagi Solution Model (KSM), through the use of the concepts of Information Measurement Theory (IMT), and to convey the author's findings pertinent to helping mitigate stress in life, while also being able to enter into any situation or event with a more positive mindset in order to help conclude that event successfully and with the increased potential for a more positive outcome. This idea of always striving to have a more positive mindset in order to complete a task, goal, or event in life in a more positive and successful way is exactly what the author will focus on, mostly pertaining to the author's own life experiences, referred to as Mind Over Matter with IMT. This Thesis idea of Mind Over Matter with IMT stems from some of the main aspects that the author found to be most impressive and significant in the honors courses offered at ASU by Dr. Dean Kashiwagi and Dr. Jacob Kashiwagi, mainly because of the fact that they inform students of some new ways to help mitigate stresses and anxieties in their lives and to more accurately predict the outcome of future events based on using deductive logic and expertise. This leads to focusing more on dominant information in order to obtain the key ideas and main points of any situation, rather than requiring additional and superfluous details, data, and minutia. The fact that the courses also focus on natural laws and initial conditions of events have proven to be extremely useful because of their significant importance to determining the final conditions and concluding outcome of events, of which many people tend to not even be aware at first when initially learning about Information Measurement Theory (IMT). Because of this, the Deductive Logic and Information Measurement Theory courses offered at ASU have proven to offer invaluable insight, great knowledge, unique ideas, and alternative ways of thinking to the author, which have contributed greatly to the author's increased success as a student enrolled at Arizona State University over these past years. Keywords: Kashiwagi Solution Model (KSM); Information Measurement Theory (IMT); Deductive Logic; initial conditions; final conditions; natural law; Mind Over Matter
ContributorsFranklin, Sean Donothan (Author) / Kashiwagi, Dean (Thesis director) / Kashiwagi, Jacob (Committee member) / College of Letters and Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2015-05