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Novel biological strategies for cancer therapy have recently been able to generate antitumor effects in the clinic. Of these new advancements, oncolytic virotherapy seems to be a promising strategy through a dual mechanism of oncolysis and immunogenicity of the host to the target cells. Myxoma virus (MYXV) is an oncolytic poxvirus that has a natural tropism for European rabbits, being nonpathogenic in humans and all other known vertebrates. MYXV is able to infect cancer cells which, due to mutations, have defects in many signaling pathways, notably pathways involved in antiviral responses. While MYXV alone elicits lysis of cancer cells, recombinant techniques allow for the implementation of transgenes, which have the potential of ‘arming’ the virus to enhance its potential as an oncolytic virus. The implementation of certain transgenes allow for the promotion of robust anti-tumor immune responses. To investigate the potential of immune-inducing transgenes in MYXV, in vitro experiments were performed with several armed recombinant MYXVs as well as unarmed wild-type and rabbit-attenuated MYXV. As recent studies have shown the ability of MYXV to uniquely target malignant human hematopoietic stem cells, the potential of oncolytic MYXV armed with immune-inducing transgenes was investigated through in vitro killing analysis using human acute myeloid leukemia (AML) and multiple myeloma (MM) cell lines. Furthermore, in vitro experiments were also performed using primary bone marrow (BM) cells obtained from human patients diagnosed with MM. In this study, armed MYXV-infected human AML and MM cells resulted in increased cell death relative to unarmed MYXV-infected cells, suggesting enhanced killing via induced mechanisms of cell death from the immune-inducing transgenes. Furthermore, increased killing of primary BM cells with multiple myeloma was seen in armed MYXV-infected primary cells relative to unarmed MYXV-infected primary cells.
ContributorsMamola, Joseph (Author) / McFadden, Grant (Thesis director) / Jacobs, Bertram (Committee member) / Blattman, Joseph (Committee member) / School of Life Sciences (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
Description
Brought on by extended survival due to Highly Active Anti-Retroviral Therapy and increased incidence among older adults, the demographic profile of the HIV epidemic has begun to shift towards the aging population. As people living with HIV (PLWH) begin to age and develop multiple comorbidities, their needs are no longer limited to HIV treatment and disease management; they may require aging services similar to those with a negative HIV status. Increased attention has been placed on HIV and aging to assess the unique needs of older PLWH, however, limited research exists on the preparedness of aging services to provide adequate care to this population. This study aims to assess HIV and aging within Maricopa County, where individuals aged 50 years and older account for nearly half the reported HIV/AIDS cases in the county, and 30% of cases in Arizona. Two focus groups – one with older PLWH and another with aging service professionals – were conducted to gather information about existing aging services and the perspectives of older PLWH regarding their growing needs. Older PLWH were found to experience challenges similar to those that have been well-documented in previous studies: most notably, PTSD and other mental health conditions; fear of the future and isolation; HIV status disclosure and stigma; and economics and financial security. An anonymous survey was developed in conjunction with Aunt Rita’s Foundation to evaluate Maricopa County aging services; it was discovered that providers lack experience with HIV and admit deficiencies in their preparation to address the age-related concerns of older PLWH. The results show that the majority of providers were supportive of offering care to older PLWH and expressed interest in improving their preparedness. Future research is necessary to obtain perspectives from additional aging services in Maricopa County and word towards the development of an aging services directory to connect older PLWH to care.
ContributorsLayon, Sarah (Author) / Jacobs, Bertram (Thesis director) / Coon, David (Committee member) / Spencer, Glen (Committee member) / School of Life Sciences (Contributor) / School of Human Evolution & Social Change (Contributor) / School of Art (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
Description
Programmed cell death plays an important role in a variety of processes that promote the survival of the host organism. Necroptosis, a form of programmed cell death, occurs through a signaling pathway involving the protein kinase RIPK3. In response to vaccinia virus infection, necroptosis acts through RIPK3 and the adaptor protein DAI to inhibit further viral replication in host cells. Stress granules are accumulations of mRNAs that have stalled in translation due to cellular stress. The toxin arsenite is a canonical inducer of stress granule formation and can cause necroptosis. By initiating necroptosis with arsenite and vaccinia virus, this research project investigated the roles of necroptosis proteins and their localizations into stress granules. The two aims of this research project were to determine if stress granules are important for arsenite-induced necroptosis, and whether the proteins DAI, RIPK3, MLKL, and G3BP localize into stress granules. The first aim was investigated by establishing a DAI and RIPK3 expression system in U2OS cells; arsenite was then used to treat the U2OS cells as well as U2OSΔG3BP cells, which are not able to form stress granules. The second aim was carried out by designing fluorescent tagging for the necroptosis proteins in order to visualize protein localization with fluorescent microscopy. The results showed that arsenite induces DAI-dependent necroptosis in U2OS cells and that this arsenite-induced necroptosis requires stress granules. In addition, it was determined that vaccinia virus induces DAI-dependent necroptosis that also requires stress granules. This project contributes to a greater understanding of the roles of DAI and RIPK3 in necroptosis, as well as the roles of stress granules in necroptosis, both of which are important in research regarding viral infection and cellular stress.
ContributorsGogerty, Carolina (Author) / Jacobs, Bertram (Thesis director) / Langland, Jeffrey (Committee member) / Jentarra, Garilyn (Committee member) / School of Life Sciences (Contributor, Contributor) / School of Music (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
Human Immunodeficiency Virus, or HIV, is a global epidemic, costing over 9.51 million individuals their lives since 2000. There are different modes of transmission of HIV, one such mode being from an HIV positive woman to her child before, during, or after delivery (SIC Curriculum, 2006). Though a global epidemic, not all countries have the same prevalence of mother to child, or MTC, transmission of HIV. In 2016, over 160,000 children under the age of five were newly infected with HIV in sub-Saharan Africa. That is compared to the United States of America, where it is estimated that fewer than 150 new infant HIV infections occur yearly (Glaser Foundation, 2020). Those differences exist despite both countries having access to preventative medication as of 1998.
Additionally, the World Health Organization, or WHO, developed three treatment plans for prevention of MTC transmission of HIV, globally available as of 2010 (WHO, 2010). The goal of the WHO was to globally standardize care of HIV-positive pregnant women and their infants in order to decrease the global prevalence of HIV. The first plan was called Option A, then came Option B, and lastly Option B+. While preventative medication has been available for over twenty years and at least one of these theoretically effective treatment plans has been implemented and is readily available in each country of sub-Saharan Africa, the overall prevalence of MTC transmission of HIV in sub-Saharan Africa has continued to be notably high compared to other countries. Thus, the aim of this thesis is to explore some of the significant obstacles to implementation of the WHO’s treatment plans in sub-Saharan Africa that contribute to that high prevalence. I also suggest possible solutions to those barriers in order to effectively decrease the prevalence of MTC transmission of HIV.
Additionally, the World Health Organization, or WHO, developed three treatment plans for prevention of MTC transmission of HIV, globally available as of 2010 (WHO, 2010). The goal of the WHO was to globally standardize care of HIV-positive pregnant women and their infants in order to decrease the global prevalence of HIV. The first plan was called Option A, then came Option B, and lastly Option B+. While preventative medication has been available for over twenty years and at least one of these theoretically effective treatment plans has been implemented and is readily available in each country of sub-Saharan Africa, the overall prevalence of MTC transmission of HIV in sub-Saharan Africa has continued to be notably high compared to other countries. Thus, the aim of this thesis is to explore some of the significant obstacles to implementation of the WHO’s treatment plans in sub-Saharan Africa that contribute to that high prevalence. I also suggest possible solutions to those barriers in order to effectively decrease the prevalence of MTC transmission of HIV.
ContributorsJones, Sierra Hope (Author) / Jacobs, Bertram (Thesis director) / Maienschein, Jane (Committee member) / School of Molecular Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
The concept of “good” research is concrete in terms of technique, but complex in theory. As technology advances, the complexity of problems we must solve also grows. Research is facing an ethical dilemma—which projects, applied or basic, should be funded. Research is no longer an isolated sector in society, and the decisions made inside of the laboratory are affecting the general public more directly than ever before. While there is no correct answer to what the future of research should be, it is clear that good research can no longer be only defined by the current classification system, which is rooted in antiquated, yet ingrained, social status distinctions.
Differences between basic and applied research were explored through a wet-lab case study. Vaccinia virus (VACV) infections are a prime model of the competition between a virus and its host. VACV contains a gene that is highly evasive of the host immune system, gene E3L. The protein encoded by E3L is E3, which contains two highly conserved regions, a C-terminus, and a N-terminus. While the C-terminus is well-understood, the mechanism by which the N-terminus grants IFN resistance was previously unknown. This project demonstrated that the N-terminus prevents the initiation of programmed necrosis through host-encoded cellular proteins RIP3 and DAI. These findings provide insight into the function of the N-terminus of E3, as well as the unique functions of induced programmed necrosis.
This project was an example of “basic” research. However, it highlights the interconnectivity of basic and applied research and the danger in isolating both projects and perspectives. It points to the difficult decisions that must be made in science, and the need for a better research classification system that considers what makes science “good” outside of antiquated social class ideologies that have shaped science since ancient Greece. While there are no easy answers to determine what makes research “good,” thinking critically about the types of research projects that will be pursued, and the effects that research has on both science and society, will raise awareness, initiate new conversations, and encourage more dialogue about science in the 21st century.
Differences between basic and applied research were explored through a wet-lab case study. Vaccinia virus (VACV) infections are a prime model of the competition between a virus and its host. VACV contains a gene that is highly evasive of the host immune system, gene E3L. The protein encoded by E3L is E3, which contains two highly conserved regions, a C-terminus, and a N-terminus. While the C-terminus is well-understood, the mechanism by which the N-terminus grants IFN resistance was previously unknown. This project demonstrated that the N-terminus prevents the initiation of programmed necrosis through host-encoded cellular proteins RIP3 and DAI. These findings provide insight into the function of the N-terminus of E3, as well as the unique functions of induced programmed necrosis.
This project was an example of “basic” research. However, it highlights the interconnectivity of basic and applied research and the danger in isolating both projects and perspectives. It points to the difficult decisions that must be made in science, and the need for a better research classification system that considers what makes science “good” outside of antiquated social class ideologies that have shaped science since ancient Greece. While there are no easy answers to determine what makes research “good,” thinking critically about the types of research projects that will be pursued, and the effects that research has on both science and society, will raise awareness, initiate new conversations, and encourage more dialogue about science in the 21st century.
ContributorsSnyder, Caroline Jane (Author) / Jacobs, Bertram (Thesis director) / Hurlbut, Ben (Committee member) / Mateusz, Szczerba (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
The purpose of this study was to evaluate the efficacy and quality of HEAL International's HIV/AIDS education prevention program for secondary school students in the Arusha region of Tanzania during the summer of 2016 using a cross-cultural teaching team. Basic HIV/AIDS knowledge and attitudes concerning risk reduction behaviors as well as towards people living with HIV/AIDS were studied among Form 1 and Form 3 students from two secondary schools in rural Tanzania. The intervention program aimed to increase knowledge and positive attitudes related to HIV/AIDS in order to motivate healthy behavior change. 211 Form 1 students and 156 Form 3 students received the intervention and completed both pre- and post-evaluation surveys. At the post-evaluation, all students showed increases in basic HIV/AIDS knowledge levels as well as positive attitudes concerning HIV/AIDS risk reduction and about people living with HIV/AIDS. Students' levels of uncertainty when answering the survey questions were also decreased. Overall, the study findings indicate that HEAL's program had a positive impact on HIV/AIDS related knowledge and attitudes of secondary school students in Arusha, Tanzania. While this study had many limitations, it also offers areas of improvement for future HEAL International volunteer programs.
ContributorsPrynn, Tory Ayn (Author) / Jacobs, Bertram (Thesis director) / Maupin, Jonathan (Committee member) / School of Human Evolution and Social Change (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
The growing urban heat island (UHI) phenomenon is having detrimental effects on urban populations and the environment, and therefore, must be addressed. The purpose of this research is to investigate possible strategies that could be utilized to reduce the effects of the urban heat island for the city of Phoenix. Current strategies, case studies, and the ENVI-Met modeling software were used to finalize conclusions and suggestions to further progress Phoenix's goals in combating its urban heat island. Results from the studies found that there is much potential in reducing daytime and evening temperatures through improving infrastructure by means of increased vegetation in the forms of green roofs and walls, reducing anthropogenic heat release, improving artificial surface coverage, and implementing lasting policies for further development. Results from the ENVI-met microclimate program shows areas for further research in urban heat island mitigation strategies.
ContributorsShqalsi, Ema (Author) / Pijawka, David (Thesis director) / Middel, Ariane (Committee member) / Civil, Environmental and Sustainable Engineering Programs (Contributor) / School of Geographical Sciences and Urban Planning (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
Vaccinia virus is a cytoplasmic, double-stranded DNA orthopoxvirus. Unlike mammalian cells, vaccinia virus produces double-stranded RNA (dsRNA) during its viral life cycle. The protein kinase R, PKR, is one of the principal host defense mechanisms against orthopoxvirus infection. PKR can bind double-stranded RNA and phosphorylate eukaryotic translation initiation factor, eIF2α, shutting down protein synthesis and halting the viral life cycle. To combat host defenses, vaccinia virus encodes E3, a potent inhibitor of the cellular anti-viral eIF2α kinase, PKR. The E3 protein contains a C-terminal dsRNA-binding motif that sequesters dsRNA and inhibits PKR activation. We demonstrate that E3 also interacts with PKR by co-immunoprecipitation. This interaction is independent of the presence of dsRNA and dsRNA-binding by E3, indicating that the interaction is not due to dsRNA-bridging.
PKR interaction mapped to a region within the dsRNA-binding domain of E3 and overlapped with sequences in the C-terminus of this domain that are necessary for binding to dsRNA. Point mutants of E3 were generated and screened for PKR inhibition and direct interaction. Analysis of these mutants demonstrates that dsRNA-binding but not PKR interaction plays a critical role in the broad host range of VACV. Nonetheless, full inhibition of PKR in cells in culture requires both dsRNA-binding and PKR interaction. Because E3 is highly conserved among orthopoxviruses, understanding the mechanisms that E3 uses to inhibit PKR can give insight into host range pathogenesis of dsRNA producing viruses.
PKR interaction mapped to a region within the dsRNA-binding domain of E3 and overlapped with sequences in the C-terminus of this domain that are necessary for binding to dsRNA. Point mutants of E3 were generated and screened for PKR inhibition and direct interaction. Analysis of these mutants demonstrates that dsRNA-binding but not PKR interaction plays a critical role in the broad host range of VACV. Nonetheless, full inhibition of PKR in cells in culture requires both dsRNA-binding and PKR interaction. Because E3 is highly conserved among orthopoxviruses, understanding the mechanisms that E3 uses to inhibit PKR can give insight into host range pathogenesis of dsRNA producing viruses.
ContributorsFoster, Clayton (Co-author) / Alattar, Hamed (Co-author) / Jacobs, Bertram (Thesis director) / Blattman, Joseph (Committee member) / McFadden, Grant (Committee member) / School of Life Sciences (Contributor) / W. P. Carey School of Business (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
Description
In the years following the HIV epidemic, much has changed in the way of public health, the social epidemic of stigma has remained. It is the assertion of the authors that stigma can be combatted through the propagation of accurate education and exposure to the lasting negative impacts of social stigma on persons living with HIV in the United States at present. Although individuals who are not apart of this community cannot truly understand the impacts of HIV-related stigma on those directly impacted by it, a sense of understanding and compassion may be elicited through the breakdown of social stigma into comprehensible components and the provision of stigma-inspired artwork. In addition to providing a background on the scientific basis of Human immunodeficiency virus and its spread, the authors have elected to utilize public engagement by means of an anonymous survey as well as personal interactions with HIV advocates to synthesize paintings. Responses were collected from approximately 300 survey participants via social media with no demographic information collected. It was the hope of the authors that the lack of identifying questions may prompt participants to answer freely and honestly to improve overall understanding of social perceptions of HIV and its related stigma. These paintings and resources deemed appropriate based on the results of the aforementioned survey are to be displayed on a webpage for easier access and engagement with a broader audience.Moreover, this webpage is intended to be maintained and utilized beyond the timeframe of this Undergraduate Honors Thesis for the intended purpose of promoting stigma-free HIV advocacy and education.
ContributorsRidgley, Nathan Laurence (Co-author) / Luigs, Stephanie (Co-author) / Jacobs, Bertram (Thesis director) / Salamone, Damien (Committee member) / Spencer, Glen (Committee member) / School of Molecular Sciences (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Obesity and related health disparities including type 2 diabetes disproportionately impact Latino youth. These health disparities may be the result of gene-environment interactions, but limited research has examined these interactions in the pediatric age group. Lifestyle intervention is the cornerstone for preventing diabetes among high-risk populations and epigenetic and genetic factors may help explain the biological mechanisms underlying diabetes risk reduction following lifestyle changes. MicroRNAs (miRNAs) are small, non-coding RNA’s that regulate gene expression and have emerged as potential biomarkers for predicting type 2 diabetes risk in adults but have yet to be applied to youth. Therefore, the purpose of this study was to identify changes in miRNA expression among Latino youth with prediabetes (4 female/2 male, ages 14-16, BMI percentile 99 ±.2) who participated in a 12-week lifestyle intervention focused on increasing physical activity and improving nutrition-related behaviors.
ContributorsKarch, Jamie (Co-author) / Day, Samantha (Co-author) / Shaibi, Gabriel (Thesis director) / Coletta, Dawn (Committee member) / Arizona State University. College of Nursing & Healthcare Innovation (Contributor) / College of Integrative Sciences and Arts (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05