• Partial Nitritation/Anammox Applications for Sidestream Nitrogen Removal: Experience from a Pilot-Scale Reactor

      Field, Jim; Sierra, Reyes; McMurray, Mallory; Karanikola, Vasiliki (The University of Arizona., 2020)
      Wastewater streams containing high ammonium and low organic carbon concentrations present challenges for safe and effective wastewater recycling or discharge. Traditionally, ammonium is removed through biological nutrient removal (BNR) processes such as nitrification/denitrification (N/DN). In recent years, an alternative biological process, anaerobic ammonium oxidation (Anammox), has become more widely researched, due to the advantages of the Anammox metabolism that allows ammonium and nitrite to be converted directly to nitrogen gas. This process is an attractive alternative to conventional N/DN methods. Anammox applied as a technology with limited aeration to partially convert ammonium to nitrite, known as partial nitritation/Anammox (PN/A), requires less aeration and the need for an electron donor is eliminated. This allows for a more sustainable process, as less chemicals and energy are required when compared to N/DN. One of the most popular applications of Anammox is in nitrogen removal of sidestream municipal wastewater. This thesis analyzes the performance of a pilot-scale expanded granular sludge bed (EGSB) Anammox bioreactor. This reactor was monitored over the course of approximately 18 months to examine the removal efficiency of ammonium from sidestream sludge digestion centrate. The performance of the reactor, quantified as nitrogen removal efficiency and Anammox activity, varied over its operational lifetime, with nitrogen removal efficiencies ranging from 18.4% - 90.9%. Ultimately, it was found that Anammox bacteria within the EGSB reactor were sensitive to nitrogen (N) inhibition at concentrations of 2100 mg N L-1 or higher, which caused severe disruption in reactor performance (up to 75.9% loss in nitrogen removal efficiency) when operated as an Anammox only process. When operated as a combined PN/A process, fluctuation in performance was also investigated due to potential toxicity of constituents present in centrate. Laboratory scale activity assays conducted to measure the specific Anammox activity (SAA) showed a 56% reduction in SAA when Anammox were exposed to centrate as opposed to synthetic wastewater of the same nitrogen concentration. It was also observed that reactor pH of 5.7 or below, or 8.9 and above led to nitrogen removal efficiency to decrease by a factor of 63.9% and 63.2%, respectively. However, the reactor was able to recover any removal efficiency and Anammox activity lost due to nitrogen or pH shocks within 5 – 10 days given remediation of the issue. Ultimately, further experimentation will be needed to more definitively determine whether Anammox is a feasible solution for the removal of sidestream ammonium in wastewater treatment plants in Pima County, Arizona.
    • Differential Remodeling of Multivesicular Bodies by Human Cytomegalovirus (HCMV) in Endothelial Cells and Fibroblasts

      Wilson, Jean M.; Momtaz, Samina; Goodrum, Felicia D.; Purdy, John G. (The University of Arizona., 2020)
      Human cytomegalovirus (HCMV) is a prevalent and opportunistic pathogen. HCMV has many modes of cellular entry and egress, depending upon the cell type. How the virus uses host cell machinery to exit different cell types is poorly understood. Previous studies found that viral tegument proteins affect the multivesicular body (MVB) formation and viral maturation differently in fibroblasts and endothelial cells, providing a possible mechanism for the distinct cellular tropisms. We hypothesize that HCMV infection induces cell-type specific remodeling of the MVBs in endothelial cells (EC) and fibroblasts to facilitate viral egress. To define the nature of infection-induced MVBs, we infected cells with HCMV that had been engineered to express a fusion protein containing the tegument protein pp150 (gene UL32) fused in frame with green fluorescent protein (GFP). Four days after infection, cells were fixed and labeled with antibodies against subcellular compartment markers and imaged using confocal and super-resolution microscopy. In fibroblasts, we find that the UL32/GFP- positive vesicles colocalize with CD63 and lysobisphosphatidic acid (LBPA), both classical MVB markers, as well as the coat protein, clathrin. In endothelial cells, UL32/GFP- positive vesicles colocalized with clathrin, GM130 (cis-Golgi marker), LAMP1 (lysosomal marker), and Rab27a (associated with exocytosis of lysosome related organelles), but not with classical late endosome (LE) marker, CD63 and LBPA. These findings suggest that virus containing MVBs in fibroblasts are derived from the endocytic pathway whereas those in endothelial cells are derived from the early biosynthetic pathway. We propose that fibroblasts use the classical MVB/exosome pathway to facilitate viral egress whereas endothelial cells exploit a less characterized early Golgi/LAMP1 associated secretory granule pathway for egress.
    • Cost-Effectiveness and Value of Perfect Information Analyses for Bruton's Tyrosine Kinase Inhibitors for Patients with Relapsed or Refractory Mantle Cell Lymphoma in the United States

      Abraham, Ivo; Al Rawashdh, Neda; Slack, Marion; McBride, Ali (The University of Arizona., 2020)
      Objectives: This study aimed to (1) evaluate the cost-effectiveness of second-generation Bruton’s tyrosine kinase (BTK) inhibitors, including acalabrutinib and zanubrutinib, compared with the first-generation BTK inhibitor (ibrutinib) in treating patients with relapsed or refractory mantle cell lymphoma (R/R MCL) using existing evidence from phase I/II clinical trials for second-generation BTK inhibitors; (2) assess the value of additional information analyses to identify the gap and uncertainty of the current evidence and to prioritize future studies to resolve uncertainty; (3) compare the expected value of additional evidence with expected opportunity costs for performing additional studies. Methods and Materials: A Markov model with two health states (progression-free [PF] and progression or death) was established, comparing acalabrutinib or zanubrutinib with ibrutinib from the United States (US) payer perspective. To simulate health outcomes for each treatment regimen, transition probabilities between the two health states were derived from parametric distributions fitted to Kaplan–Meier (KM) curves based on PF survival (PFS) curves from the phase III clinical trial reported by Dreyling et al. (Lancet 2016) for ibrutinib, the phase II clinical trial reported by Wang et al. (Lancet 2018) for acalabrutinib, and the phase I/II clinical trial reported by Tam et al. (Blood 2019) for zanubrutinib. The analysis was conducted over a lifetime horizon, and health utility outcomes and costs were discounted at 3.5% per year. The PFS life years (LYs) and PFS quality-adjusted LYs (QALYs) for each treatment, the incremental PFS LYs and PFS QALYs gained with acalabrutinib or zanubrutinib over ibrutinib, and the incremental cost-effectiveness ratio (ICER) and cost-utility ratio (ICUR) were estimated in both base and probabilistic sensitivity analyses (PSA; 100,000 simulations). The expected value of perfect information (EVPI) was calculated from the net monetary benefit (NMB) and net health benefit (NHB) that are forgone, by comparing the overall optimal treatment resulting from the PSA ICURs with the optimal strategy in each of 100,000 PSA simulations. Results: Treatment with acalabrutinib resulted in incremental PFS LYs and PFS QALYs of (3.40, 2.66) while zanubrutinib was associated with incremental PFS LYs and PFS QALYs of (2.21, 1.71) when compared with ibrutinib. The incremental costs per PFS QALY gained when comparing acalabrutinib and zanubrutinib with ibrutinib were $41,744 and $37,813, respectively. For a willingness to pay (WTP) value of $100,000, the probabilities of acalabrutinib, zanubrutinib, and ibrutinib being cost-effective are 50%, 34%, and 16%, respectively. Using the available evidence regarding clinical efficacy, costs, and utility outcomes as inputs for the model, an uncertainty cost of $92,473 (NHB=0.93 QALYs is forgone) per patient was obtained, which implies a need for additional research. The uncertainty costs of effectiveness for acalabrutinib, zanubrutinib, and ibrutinib were $66,709, $53,916, and $984, respectively, while the health-related quality of life (HRQoL) (disutility values) of adverse events was associated with an uncertainty cost of $85,949. Conclusions: The results demonstrate that acalabrutinib is more cost-effective compared with ibrutinib and zanubrutinib and greatly improves health outcomes in R/R MCL patients. However, decisions based on this analysis, which used phase I/II trials, are associated with a high level of uncertainty in terms of health benefits that may be forgone for some populations if acalabrutinib is adopted by health insurance companies. Future studies that compare the efficacy and HRQoL of these agents are recommended.
    • Mixed Two-Factor Benchmark-Dose Risk Assessment in Biomedicine

      Piegorsch, Walter W.; Sans-Fuentes, Maria Assumpció; Billheimer, Dean; Zhang, Hao H. (The University of Arizona., 2020)
      Benchmark analysis is a general risk estimation strategy for identifying the benchmark dose (BMD), past which the risk of exhibiting the adverse response exceeds a fixed value of benchmark response (BMR). The BMD has traditionally been applied in toxicological stimulus-response settings; the adverse outcomes have included cancer, birth defects, environmental toxicity, neurological damage, etc. For this context, risk is defined as the probability that a subject exhibits the adverse effect when exposed to a quantifiable dose level of the hazardous stimulus or agent. Such settings often involve binary or proportion responses—called quantal data—where the observations are taken as independent binomial variates at each exposure, input, or dose level. The estimation of BMD and its lower confident limit (BMDL) is well understood for the case of an adverse response to a single stimulus. However, in many situations one or more additional, secondary, qualitative factor(s) may collude to affect the risk, such that the risk changes with differential levels of the secondary factor. While the BMD is highly effective at integrating information over a single stimulus-response curve into the risk estimation problem, no dedicated methodology exists for modifying it to accommodate such secondary qualitative factors. Extending the translational capabilities of the BMD approach, this research is motivated by problems in childhood development, where early-age levels of some markers in blood, such as immunoglobulin E (IgE), may be useful in predicting future asthma diagnoses. A complicating factor here is that childhood obesity (a qualitative variable) often affects future asthma status, leading to differential asthma risk/response in children. In this framework, the goal of this research is to develop modern benchmark methods that can produce effective estimates of joint risk and from these, reliable inferences on BMD with mixed-factors and quantal-response data. Using as a dose-response function the logistic model, we derived the expressions for BMD and BMDL (ζ ̂(u) and ζ_L (u)). Four different approaches were used to derive the BMDL: i) Wald lower confidence limit (WALD), ii) Bivariate Normal lower confidence limit (BVN), iii) Wald lower limit on the log-transformation of the BMD (WALD-log), and iv) Bivariate Normal lower confidence limit on the log-transformation of the BMD (BVN-log). Using Monte Carlo simulations, we studied the performance of the four confidence limits described by examining their conditional coverage properties. We found that the conditional coverages were affected by the and ζ_L (u) construct, the ratio of individuals between the two levels of the qualitative variable, the level of the background response, and the underlying characteristics of the dose variable. In brief, WALD and BVN performed better than WALD-log and BVN-log. Moreover, the methodology worked better when the background response level was higher and when the ratio of individuals between the two levels of the qualitative variable was closer to one. Finally, skewness of the data also affected performance; higher coverages were obtained when the skewness was lower. The theory developed in this dissertation can be further extended to additional qualitative factors and/or to use other models as a risk function, such as the probit or quantal-linear model. Nevertheless, additional research is required to study whether our methods can translate effectively to other link functions for mixed-factor dose-response modeling.
    • Optimizing NBA Lineups

      Watkins, Joesph; Spector, Jason; Bedrick, Edward; Zhou, Jin (The University of Arizona., 2020)
      The goal of every NBA coach is to put the best lineup on the floor against the given opposition. A coach will pick individual players to form a lineup from a variety of factors with the end goal of scoring more points than the opposing lineup. This paper aims to analyze and assess NBA lineup creation from individual statistics using various forms of machine learning. We started by web- scraping individual player statistics and five-man lineup data from basketballreference.com. Then the general box score and advanced statistics of the individual players were joined to the players in the lineup. The lineup data was used to train a linear regression model, a random forest, a support vector machine, an extreme gradient boosted model, and a neural network. All models were evaluated on their mean absolute error with the final goal of getting as close to the points the lineup actually scored. None of the models created a conclusive algorithm to accurately portray the lineup capabilities from individual statistics. This was due to the fact that individual per game statistics do not hold enough information about how combinations of players might perform together or if the performance by the player would be above or below their expected individual statistics. Furthermore, the models often overfit the data, having the ability to understand the patterns of the training data well but not able to generalize. Because of this our focus shifted to creating simpler models with fewer features. Fewer features caused a slight increase in performance but not by much. Finally, we repeated the process with a classification of bad, average, and great offensive or defensive ability as the output in hopes of at least being able to classify a good offensive or defensive lineup. Both classification networks were only slightly better than random guessing however.
    • Improving Children’s Lead Risk Modelling in a Rural and Active Mining Community and an Evaluation of Risk Communication in a Rural Mining Community

      Ramirez-Andreotta, Monica; Heusinkveld, Dominika; Brusseau, Mark; Schwalbe, Carol (The University of Arizona., 2020)
      Lead exposure has been shown to be harmful to humans in various settings. Lead is particularly harmful to children, in whom it can cause neurological problems, low IQ, developmental delay, and other health issues. There are no safe levels of blood lead in children. At the ASARCO Alternative Superfund site in Hayden-Winkelman, Arizona, lead exceedances in air and soil have been measured in the past 20 years. An important question is whether these lead levels can be expected to affect the health of children in the community, since those age seven and under are particularly vulnerable to the effects of lead. Over 140 children under age 11 live in Hayden and Winkelman. The majority live within a quarter mile of the smelter. In the main portion of the thesis, I used the U.S. Environmental Protection Agency’s Integrated Exposure Uptake Biokinetic (IEUBK) model to estimate Hayden-Winkelman children’s (age 6 months--7 years) blood lead levels using site-specific lead concentrations measured in indoor and outdoor air, soil, indoor dust, and water. Values used by the Arizona Department of Environmental Quality’s airborne lead risk forecast were also evaluated in the IEUBK model to determine whether their forecasting program is useful in determining risk for children in the community when coupled with other measured lead exposures on the site. The results demonstrate that lead in dust is the major contributor to estimated blood lead levels in a simulated population of children at this site, while lead in the air does not contribute greatly to risk. In the second portion of the thesis, an analysis of the Arizona Department of Environmental Quality ’s Air Lead Risk Forecast as a risk communication was performed and suggestions for further evaluation were given.
    • New High Throughput Approaches for Culturing Soil Microbes from Shallow Subsurface Soils

      Carini, Paul; Custer, Joy; Neilson, Julia; Tfaily, Malak (The University of Arizona., 2020)
      The majority of soil microbial biodiversity is uncultured in the laboratory. In part, the inability to cultivate many microbial lineages may be because these uncultured microbes are oligotrophic and do not grow on typical high-nutrient growth media. While there are several microbial cultivation methods designed to isolate microbes inhabiting oligotrophic marine environments, these methods are challenging to implement in soil. My thesis research directly addresses the need for new microbial cultivation methods for soil oligotrophs. I developed a cell separation protocol to extract viable microbes from shallow subsurface soils and used the extracted cells for high-throughput dilution-to-extinction. We reported the impacts of substrate concentration on culturability of microbes inhabiting a shallow subsurface soil in a conifer forest in Tucson, AZ. Substrate concentration significantly influenced the culturability of Actinobacteria from these locations. Our results indicate that the dilution-to-extinction method, combined with the optimized method for separating viable cells from soil, is suitable for the isolation of oligotrophic microbes from shallow subsurface soils.
    • International Law: Russia's Instrument for Acquiring State Interests

      Lucey, Colleen; Korns, Samantha; Klimanova, Liudmila; Puig, Sergio (The University of Arizona., 2020)
      Over the last decade research has shown that the stability of international law has been threatened by Russia’s actions including the annexation of Crimea, breaches of airspace, and the approval of the “Sovereign Internet” law. This thesis seeks to examine Russia’s utilization of international law as an instrument to pursue national interests. Expanding on existing research of Russia’s international law violations, it asks: what are the long-term ramifications if Russia’s actions continue to go unpunished? In this context international law violations refer to Russia’s divergence from agreements that it previously consented to. Based on a literature review of international legal documents and Russia’s state first ideology, the following research analyzes three case studies on Russia’s violations of sovereignty and internationally recognized human rights. The case studies indicate that Russia’s violations of international law will only escalate as it attempts to assert itself as a global superpower. Further research is needed to identify what factors might align Russia’s approach to international legal practices with democratic values.
    • Exploring Black and White Differences in Cardiovascular Health in Pre- and Post-Spousal Bereavement

      O'Connor, Mary- Frances; Wilson, Damere Tianna; Allen, John J.B; Ruiz, John (The University of Arizona., 2020)
      Research has shown that bereavement is associated with excess risk of mortality, especially in the early weeks and months after loss. However, the lack of representation of Black people in bereavement and grief research has led to a lack of understanding of how the effects of grief may be different in this population. The current study assesses whether the cardiovascular effects of grief differ for Black individuals versus non-Hispanic Whites, using archival data from a national prospective study of widowhood. The current study analyzes data from the Changing Lives of Older Couples (CLOC) study is a multi-wave prospective study of 1,532 married individuals from the Detroit metropolitan area recruited using two-stage area probability sampling. The study included self-reported measures of hypertension and heart disease. Systolic and Diastolic blood pressure was also measured for a subset of the study participants. Time-points included for the current study include baseline and W1(6- months post spousal loss). We failed to confirm the hypothesis that Black participants would have higher pre-loss (i.e., baseline) incidence of hypertension and heart disease. Analysis of longitudinal data revealed that systolic BP at wave 1 was only significantly predicted by average systolic BP at baseline The present study provided some evidence that Black people are at increased risk of developing hypertension and heart disease following the loss of a loved one. However, further research is needed to understand the potential role of race in accounting for post-loss risk of poor cardiovascular health.
    • Rasch Analysis of the Student Refractive Error and Eyeglass Questionnaire-R in Myopic School-Aged Children/Children and Young People in London

      Warholak, Terri; Marupuru, Srujitha; Slack, Marion; Dahlmann-Noor, Annegret; Crescioni, Mabel (The University of Arizona., 2020)
      BACKGROUND: Multiple vision-related quality of life (VRQoL) instruments exist, but questionnaires designed specifically for myopic children that are appropriate for assessing the impact of refractive error are rare. The aim of the study is to assess SREEQ-R validity and to determine if this instrument is appropriate to measure VRQoL related to spectacle utilization in school-aged children sample with myopia in London. METHODS: This study, which utilized prospective questionnaire methodology, was conducted in London. Children up to the age of 18 years who presented for an eye examination with current or previous reported use of eyeglasses and who met the study requirements for spectacle prescription were included. SREEQ consists of 20 specific items divided into two parts with 3 response categories. WithoutGlasses relates to perceptions of uncorrected vision/not wearing glasses and WithGlasses relates to perceptions of corrected vision/wearing glasses followed by demographic and clinician details. Rasch analysis was used to explore the psychometric performance of the questionnaire and scale using WINSTEPS software. Results: A total of 125 eligible children completed the SREEQ-R, with mean age of 12.7±2.9. All items fit the Rasch model and were retained and the scale was unidimensional (as indicated by principal-components analysis of the residuals). All children and item Infit and Outfit MNSQs fell within recommended fit criteria. Without Glasses the item that students were bothered least by was “feeling dizzy” and in contrast the item that affected respondents most was “problems seeing the board, at the movies or other things far away”. While With Glasses, students found the same item “feeling dizzy” to be the least bothering item and “I get headache, or my head or eyes hurt when I read” to be the most problematic symptom. As per the Rasch analysis, person reliability coefficient for the Without Glasses version was 0.84 and 0.91 for the With Glasses version. The item reliability for Without Glasses version was 0.99 and 0.80 for the With Glasses version. Conclusions: The SREEQ-R had satisfactory psychometric properties and Rasch analysis further supported the construct validity of the scale to measure the impact of uncorrected and corrected refractive error on VRQoL in myopic school-aged children in London. The SREEQ-R could be used in future studies to evaluate improvement in VRQoL.
    • Compact Heterodyne Interferometer for High Precision Displacement Measurements

      Guzman, Felipe; Clark, Erin; Kim, Dae Wook; Schwiegerling, Jim (The University of Arizona., 2020)
      The Laser Interferometer Gravitational-Wave Observatory (LIGO) and the Laser Interferometer Space Antenna (LISA) both utilize displacement measuring interferometers to obtain high precision measurements of linear motion. Displacement measuring interferometers are among the most sensitive devices for tracking linear motion. High precision measurements are primarily limited by periodic errors, also known as nonlinear errors, which arise from frequency mixing, polarization mixing, and ghost reflections. These errors can be mitigated by spatially separating the beams in the interferometer and through purposeful misalignment of the optics. It was determined that the compact heterodyne interferometer designed and built through this research shows achievable picometer level displacement sensitivity in air, has no detectable periodic errors, and was found to be twice as thermally stable as other highly stable commercial interferometers, enabling high precision displacement measurements over long distances.
    • Observer-Driven Texture Analysis in CT Imaging

      Kupinski, Matthew A.; Garrett, Zachary Taylor; Furenlid, Lars R.; Clarkson, Eric W. (The University of Arizona., 2020)
      We have created a faster, less computationally intensive method of estimating human observer performance when tasked with detecting a signal in CT images. This is achieved by using a set of images to train the model observer, extract the “most useful” textures in detecting the input signal, and applying those textures to a new set of images and extracting an SNR2-equivalent metric. This is validated by comparing to the Channelized Hotelling Observer (CHO), the field standard for modeling human observer performance, as well as testing on data with known relative performance, which will be elaborated on in the results section. A large merit in this project is that it can be used to help find appropriate radiation dosing per tissue texture to achieve the best differentiation between a signal (such as cancer) and noise or tissue texture, as well as CT image reconstruction algorithm optimization.
    • Multiplexing Holographic Waveguide Couplers in Photopolymer Material

      Kostuk, Raymond K.; Nguyen, Jilian; Blanche, Pierre-Alexandre; Hua, Hong (The University of Arizona., 2020)
      Augmented Reality headsets that are viable for the consumer market still face many optical challenges, including a limited field of view and complexity of the headset. The well-known current architectures such as HoloLens and Magic Leap employ surface relief grating coupler waveguides to produce images for the user. These waveguides are limited in FOV and can add bulk to the overall system. Volume holograms as waveguide couplers can be another solution to produce images for the user. This thesis discusses the theory behind volume holograms for use in augmented reality waveguide optical applications. Current generation AR solutions are discussed and the potential of photopolymer hologram material to match current optical specifications is simulated. For scalability and ease of manufacturing, the recording of such holograms should be at least as efficient and as costly as SRG couplers. A method to monitor the material response for better control of diffraction efficiency is described and used to experimentally verify the recording of a transmission hologram coupler for a waveguide. The same method is used to record a multiplexed transmission hologram coupler which verified simulations for multiplexed gratings. Expanded FOV is demonstrated with the multiplexed transmission hologram coupler. The capabilities and limitations of a commercially available photopolymer recording material are discussed along with techniques for future studies that can improve the performance of volume hologram couplers.
    • Low-Cost, Near-Infrared, Scan-Less Portable Confocal Microscope

      Kang, Dongkyun; Gong, Cheng; Barton, Jennifer K.; Liang, Rongguang (The University of Arizona., 2020)
      Reflectance confocal microscope (RCM) is a diagnostic tool for various skin diseases, but the application of that is hampered by its high cost. In this thesis, we developed two versions of the low-cost, near-infrared scan-less portable confocal microscope. 1) High- speed RCM. We have used 840 nm central wavelength superluminescent LED as the light source. A confocal detection optics has been developed to maintain high lateral resolution even when a relatively large slit width was used. The material cost of the NIR RCM device was low as $5,200. The lateral resolution was 1.1 μm and 1.3 μm, along with the vertical and horizontal directions, respectively. Axial resolution was measured as 11.2 μm. In vivo confocal images of human forearm skin obtained at the imaging speed of 203 frames/sec clearly visualized characteristic epidermal and dermal cellular features of the human skin. 2) Speckle-free RCM. We have developed a portable confocal microscope (PCM) that uses a near-infrared (NIR) LED as the light source, and the speckle noise on the image was reduced due to the used of the spatially incoherent light source. The material cost of it is still low as ~$5,000 and weighed 1kg. The lateral resolution was measured as 1.6 μm, and axial resolution as 6.0 μm. The PCM device could visualize characteristic cellular features of human skin in vivo in a range from the stratum corneum to the superficial dermis. This capability is expected to facilitate the evaluation and clinical adoption of this low-cost diagnostic imaging tool. Dynamic imaging of blood flow in vivo was also demonstrated.
    • Understanding the Mechanism of Cancer Therapeutic SAH5-EJ1 in Targeting Breast Cancer Metastasis

      Schroeder, Joyce A.; Soyfer, Eli Michael; Paek, Andrew L.; McEvoy, Justina D. (The University of Arizona., 2020)
      While many breast cancer subtypes overexpress members of the ERBB family of receptor tyrosine kinases (including the Epidermal Growth Factor Receptor/EGFR, HER2, ERBB3 and ERBB4), only HER2 has been effectively targeted. Evidence indicates that established therapeutics against EGFR targeting either the extracellular domain or the kinase domain fail due to unique biological activities of the receptor in breast cancer. In light of this, a stapled peptide mimicking the EGFR juxtamembrane domain (SAH5-EJ1) was developed and found to induce complete tumor regression in a model of inflammatory breast cancer (SUM149/NODSCID). SAH5-EJ1 was found to induce both necrosis and apoptosis through calcium and ROSdependent mechanisms, but the mechanism by which this was achieved was unknown. In the current study, we have evaluated EGFR-dependent calcium signaling as a means to promote cell death. We have discovered that SAH5-EJ1-induced cell death is dependent upon expression of both EGFR and the TRPV1 (transient receptor potential cation channel subfamily V member 1) calcium channel located on the plasma membrane. Mechanistically, SAH5-EJ1induces the activation of TRPV1, resulting in a dramatic influx of extracellular calcium. This is followed by a sharp rise in cellular reactive oxygen species (ROS) into the cell and induction of cell death. These data demonstrate a reliance of EGFR on calcium signaling in breast cancer survival, one which can be effectively targeted in breast cancer.
    • A Brazilian-Muslim Identity in the Land of the Holy Cross: The Assimilation of Muslim Immigrants in Curitiba, Brazil (2001-2020)

      Clancy-Smith, Julia A.; Spinder, Nathan; Fortna, Benjamin C.; Hudson, Leila (The University of Arizona., 2020)
      Scholarship on the Muslim diaspora in Brazil is still relatively scarce. There is an abundance of English and Portuguese academic research focused mainly on Arab Christian immigrants, who arrived in the late nineteenth century, in large measure because of the estimated twelve million Syro-Lebanese descendants now calling the country home. Nevertheless, Muslim communities have deep roots in Brazil, stretching back to the slave trade. Thus, Muslim immigrants have played a significant role in the evolution of a Brazilian society. This thesis investigates the assimilation of Muslim immigrants in Curitiba, the capital of the southern state of Paraná, mainly during the latest period of the diaspora, from 2001-2020. I chose the city of Curitiba for my fieldwork because of the strong assimilation (Birgit Meyer, 1999) of the Muslim community into society and the hyphenated Brazilian-Muslim identity (Jeffrey Lesser, 1999) there. However, my fieldwork revealed that instead of being a united ummah (Vanessa Souza-Lima, 2016), Shi’i and Sunni Muslims in Curitiba currently compete in order to create a more ample social space in society for themselves. To explain this competition, I lay out the historical background, the physical, non-physical and virtual spaces in which these immigrants have created a Brazilian-Muslim identity, and the forces that have led to exclusion and discrimination. This thesis identifies a Brazilian-Muslim identity and argues that acculturation is not merely or simply a one-sided process but that both Muslim and non-Muslim immigrants in Brazil have adapted to some aspects of Brazilian culture, norms, and social expectations, and distancing themselves from others.
    • The Expansion of Christianity in the Pre-Islamic Middle East: From Edessa to 'Uman

      Talattof, Kamran; Atchison-Day, Susan Lynn; Peterson, John E.; Noorani, Yaseen; Hudson, Leila (The University of Arizona., 2020)
      The purpose of this descriptive study was to examine the expansion of Christianity in the pre-Islamic Middle East, from Edessa to Mazun/'Uman on the southeastern corner of the Arabian Peninsula. This area today would include the peninsula occupied by Oman and the United Arab Emirates. Its name in the Pahlavi language was Mazun, but the Arab tribe first migrating there called it 'Uman. The study also introduced and discussed various influences that may have contributed to the disappearance of the church of Mazun from history in the late seventh century. The first bishop from Bet Mazunaye, the name for the ecclesiastical unit in Mazun, appeared first in history in 424, as a signator to the synod procedings of the Church of the East in that year; the last was in 676. The literature suggests three sources of Christians in 'Uman: converts or descendants of these converts, who were made by early missionaries;. refugees, who had fled persecution and prisoners of war taken then relocated by the Persians; and, finally, converts who resulted from the mingling of non-Christian tribes with those that were partially or totally Christianized. This last trail began at Ma'rib in Himyar with the migration of the Azd tribe to 'Uman, led by the semi-legendary figure Malik ibn Fahm. One legend has him continuing onward to Bahrain, then still further north where he formed an alliance with the Tanukh and, through marriage, merged the two tribes, giving birth to the Lakhmid Empire. These trails were recreated by examining and blending historical, documentary, and archaeological evidence, with information drawn from hagiographies, legends, traditions, and sacred texts into three somewhat overlapping narratives. Included is a list of suggestions for potentially fruitful investigation in the future, and a call for scholars to study Aramaic, Syriac, Pahlavi and Arabic to enable the expansion of available sources to future researchers.
    • Cardioplegic Solution Provides Myocardial Protection via Activation of NRF2

      Wong, Raymond; Diao, Hongting; Chen, Qin; Fox, Kenneth A. (The University of Arizona., 2020)
      Open heart surgery is often an unavoidable procedure for treatment of cardiovascular disease. Myocardial Ischemia-Reperfusion Injury (MIRI) can occur as a result of cardiopulmonary bypass which is required in open heart surgery. The multifaceted mechanisms of MIRI involve the generation of pro-inflammatory mediators and increase in reactive oxygen species (ROS), resulting in damage to proteins, lipids, and DNA, ultimately impacting postoperative cardiac performance and complications. Nf-E2 related factor-2 (NRF2), a basic leucine zipper transcription factor, is regarded as one of the most important regulators in antioxidant pathways. NRF2 binds to and activates the Antioxidant Response Element (ARE) in the promoters of many antioxidant and detoxification genes. Mechanism of NRF2 activation involves de novo protein translation, or protein stabilization due to dissociation from KEAP1 and other alternative mechanisms. We addressed whether or not cardioplegic solutions induce the activation of NRF2, therefore serving to protect the myocardium from MIRI. We next investigated the specific components of cardioplegic solution playing critical roles in NRF2 activation and the precise underlying mechanism. We used adult cardiomyocytes in culture to test whether or not five different types of cardioplegic solutions and their key ingredients induce NRF2. We tested routine laboratory cell culture at 37C. Our data showed that Del Nido and High K cardioplegic solution caused increases in NRF2 protein levels under cell culture. We found that the combination of K+ and Ca2+ included in those cardioplegic solutions play an essential role in induction of NRF2. ARE luciferase reporter assay confirmed NRF2 activation as a transcription factor by the cardioplegic solutions and K+ in the presence of Ca2+. Our data supports that cardioplegic solutions can be cardiac protective via the activation of NRF2 and the results also indicate among cardioplegic solution compositions, K+ and Ca2+ play an essential role in activation of NRF2.
    • Extracellular Mitochondria in Sepsis-Induced Acute Respiratory Distress Syndrome

      Wong, Raymond K.; Satterlee, Taylor; Fox, Kenneth A.; Chen, Qin M. (The University of Arizona., 2020)
      Sepsis-induced acute respiratory distress syndrome (ARDS) is a life threatening disease that is associated with high mortality rates, and high hospital costs. The body’s widespread and aggressive inflammatory response to infection plays a central role in this condition, as it results from a rampant generation of inflammatory cytokines and reactive oxygen species in response to pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs). Despite the seriousness of this condition, successful treatment strategies and effective biomarkers remain elusive. Here we aim to mimic a state of sepsis-induced ARDS in vitro and examine the response of extracellular mitochondria under these conditions. Additionally we aim to examine the proteomic profile of the extracellular mitochondrial pellet in a state of oxidative stress compared to control. Finally we aim to demonstrate that extracellular mitochondria are present in an in vivo model of sepsis-induced ARDS using a porcine model. From this work we are able to conclude that cells release mitochondrial DNA in response to both lipopolysaccharide and hydrogen peroxide treatments, however the mechanism by which this occurs remains unclear. Extracellular mitochondrial DNA is also present in an in vivo porcine sepsis-induced ARDS model. From proteomic analysis of the extracellular mitochondrial pellet by liquid chromatography - mass spectrometry, we found 16 proteins to be significantly (P<0.10) up-regulated and 2 proteins to be significantly down-regulated. We hope to apply the profile of extracellular mitochondria we have built to eventually identify a novel biomarker of sepsis-induced ARDS.
    • Study of Swirling Jets on an Impingement Surface

      Shkarayev, Sergey V.; Stoner, Ryan Michael; Zohar, Yitshak; Thanga, Jekan (The University of Arizona., 2020)
      There has been extensive research performed on the turbulent jet stream flow including unimpeded and impinged flow. Vortex jet streams however has not been studied in as great of detail. Some researchers have focused on the development of vortex flow as well as axial and azimuthal velocity profiles generated from these jet streams. The need for better control over aircraft carries and decrease the wait time between landing aircraft at airports has driven a need for further research into these vortex flows. If an impingement surface is introduced into these example environments at which angle should it be positioned to quickly dissipate the flow? This research will validate a blower jet stream system, develop vortex nozzles, validate the tripped nozzle and characterize the vortex flow on an impingement surface. To start, an existing converging/diverging blower motor system was utilized for all the experiments performed. A tripped nozzle configuration was used to confirm that the results generated matched those of pervious experiment published. This confirmed not only the physical setup but also the data acquisition methods. Next varying nozzle configuration were designed, printed and tested to determine their functionality. The results confirmed that the nozzles generated increasing levels of vortex flow ranging from low, medium and high azimuthal axis components. After all the nozzles were characterized in the unimpeded configuration the impingement wall was introduced. The tripped nozzle was used as a baseline for this setup since the results for this configuration are well defined. Next each of the vortex nozzles went through the same series of tests. This involved varying speeds of the jet flow as well as three different impingement wall angles. The results showed that at low swirl numbers the jet stream profile match the tripped nozzle setup closely. As the swirl number increase the flow became harder to dissipate. This resulted in the wall needing to be positioned at a steeper angle. Another interesting observation was at the higher vortex flows there was as axial vortex generated that was not seen in any of the other setups. Overall, it was determine that vortex flow required a near vertical wall to effectively impede the flow.