• Mind the Gap: Gender Differences in Alcohol Consumption and Protective Behavioral Strategies at a Large Public University, 2002 - 2016

      Schachter, Kenneth; Salafsky, David B.; Harris, Robin; Yuan, Nicole; Hsu, Chiu-Hsieh (The University of Arizona., 2019)
      Alcohol use among college students is a persistent and far-reaching public health issue. While some measures of alcohol use within the college population appear to have improved, questions remain as to whether the alcohol use gender gap has been stable or is in a period of change. Protective behavioral strategies (PBS), harm reduction approaches commonly used to address high-risk alcohol use among college students, were also assessed, to determine their relationship with several key alcohol consumption measures for both males and females. Methods: This research summarizes alcohol-related consumption measures based on annual, cross-sectional survey data collected between 2002 - 2016 at a large, public university. Linear regression models as well as descriptive statistics were used to explain overall trends and gender-specific patterns of use over time. In addition, an analysis based on pooled data between 2013 – 2016 was conducted to determine the association between protective behavioral strategies and key alcohol consumption measures, to inform programming that uses these strategies to reduce high risk alcohol use among students, and determine which strategies may be more likely to benefit either males and females for the following alcohol measures: binge drinking in the past two weeks, average drinks when partying and the number of drinks last time consumed alcohol. Both logistic and linear regression models were used to describe these relationships. Results: The results of the 15-year trend analysis revealed significant and meaningful declines among all students in past 30-day alcohol use, average number of drink consumed in the past week, average number of nights students “party” each week, and reductions in the frequency of binge drinking. Looking at the gender gap specifically, these results showed a declining gender gap (i.e. where the difference between male and female use decreased) most notably in average number of drinks consumed in the past week, estimated BAC last time students drank, and past 30 day alcohol use. Based on recent survey results, women showed slightly higher past 30-day alcohol use and reported a higher estimated BAC last time they drank, compared to men. For the second aim of the study, which was based on pooled data collected between 2013 - 2016, most PBS that were expected to moderate alcohol use showed clear and strong protective effects, with a few exceptions. Top strategies for females that were associated with lower alcohol consumption included stopping alcohol use 1-2 hours before going home, avoiding pre-partying and avoiding hard liquor. For men, these included setting a limit on drinks, avoiding pre-parting, and avoiding hard liquor. Conclusion: A number of alcohol measures improved during the study period, and for these, male university students showed greater declines, on average, than females – resulting in a shrinking gender gap. Decreases in the frequency of drinking occasions likely influenced overall declines in average drinks per week and the frequency of binge drinking. Male and female students showed considerable overlap with respect to protective behavioral strategies that were negatively associated with alcohol use and identified a few strategies that may have limited effectiveness. These results highlight evolving trends in alcohol use among college students and point to specific strategies which can help address this longstanding public health issue. Policy and program recommendations, informed by these findings, are detailed in its conclusion.
    • Improving Use of Opioid Safety in Primary Care

      Prettyman, Allen; Fisher, Kristen; Allison, Theresa; Kiviat, Joy (The University of Arizona., 2019)
      With an increase in opioid prescription rates, opioid misuse, abuse and overdose deaths have increased in parallel. Primary care providers are responsible for the majority of the system’s pain management but may lack proper training. The purpose of this project was to implement an educational module designed to improve primary care providers’ knowledge about unnecessary opioid prescriptions, safe pain management and opioid related disorders. This project implemented an educational module to familiarize primary care providers with evidence based guidelines for prescribing opioids for chronic pain management. This project used a pretest-posttest design to evaluate if the educational module was effective in increasing provider knowledge. Provider knowledge was assessed using the KnowPain-12 tool and an eight-item survey based on the Center for Disease Control (CDC) guidelines for opioid prescribing. Six providers participated in the educational intervention and responded to the pre and post-survey. For the KnowPain-12 survey, three providers had a higher score following the intervention, one provider’s score stayed the same and two had lower scores. The KnowPain-12 survey score ranges from 0-60, average score of the pre-intervention survey was 39.33 and the average score of the post-intervention survey was 39.50. For the knowledge assessment of the CDC guidelines, one point was awarded to each correct response for a total of eight points possible. Overall scores were high, with an average score of 6.83 before the intervention and 7.5 after the intervention. Findings suggest that there may be an educational gap in chronic pain management for primary care providers. There needs to be further research to evaluate opioid prescribing practices in the primary care setting and to identify educational gaps. Educational interventions should be implemented to improve provider knowledge of chronic pain management.
    • Compassion Fatigue among Pediatric Oncology Nurses

      Peek, Gloanna J.; Cooper, Jessica; Moore, Ida M.; Lee-Miller, Cathy A. (The University of Arizona., 2019)
      Purpose: To conduct an educational intervention to improve knowledge about compassion fatigue among pediatric oncology nurses at Phoenix Children’s Hospital (PCH). Background: Burnout, secondary traumatic stress, and decreased compassion satisfaction contribute to compassion fatigue. Pediatric oncology nurses face stressful situations based on the unique care demands of children battling cancer such as complex treatment regimens, managing professional boundaries, providing emotional support. grief, and bereavement. Compassion fatigue is a progressive process that can impact a nurse’s quality of life and contributes to decreased job satisfaction, performance, patient satisfaction, and turnover. Methods: A 20-minute educational PowerPoint presentation was presented on compassion fatigue to highlight what compassion fatigue is, signs and symptoms, and common triggers. There was also a handout provided with available resources at PCH that could be utilized to help with compassion fatigue. The Professional Quality of Life (ProQOL) scale was used to measure compassion fatigue and compassion satisfaction levels and a pre- and post-test was completed to measure if an educational intervention improves nurse’s knowledge about compassion fatigue. Findings: The results showed that participants (n=30) knowledge significantly improved after the 20-minute educational intervention (p=0.001) with a mean score of 76.2% on the pre-test and a mean score of 95.4% on the post-test. In addition, nurses had a significant increase (p=0.0001) in the utilization of resources; prior to the intervention only seven participants (23.3%) utilized some of the available resources offered by PCH compared to 24 participants (80%) one-month post-intervention. However, there were no statistically significant changes in raw scores for the pre- and one-month post ProQOL survey (p > 0.05). Overall the participants viewed the class worthwhile and had positive things to say about the class. Implications: The results of this study showed that an educational intervention on compassion fatigue improved nurses knowledge about compassion fatigue, symptoms, common triggers, and available resources with improved utilization of available resources. Even with improved knowledge and utilization of resources, there was not a statistically significant difference in pre- and one-month post survey scores on compassion satisfaction, burnout, and secondary traumatic stress. Future research could benefit from analyzing the long-term effects improved knowledge of compassion fatigue and the utilization of resources has on compassion satisfaction and fatigue.
    • Evaluating Healthcare Providers’ Utilization of Social Support for COPD Patients

      Love, Rene; Nguyen, Thiennga; Carrington, Jane M.; Downs, Charles A. (The University of Arizona., 2019)
      Background: Currently, most primary healthcare providers manage chronic obstructive pulmonary disease (COPD) through pharmacological treatments, often lacking assessment of the patient’s social support. A lack of social support negatively impacts the quality of life (QOL) of individuals with COPD resulting in increased morbidity, hospital readmissions and excessive costs (Metting, van der Molen, & Kocks, 2016). A comprehensive approach extends beyond pharmacological management to include ways that improve patients’ disease knowledge and self-efficacy, resulting in better disease management and improved QOL. Aim: The purpose of this quality improvement (QI) project is to increase healthcare providers’ understanding of the importance of adding a social support referral as part of a comprehensive treatment for patients with COPD. Methods: The QI project was conducted at Banner Desert Medical Center in Mesa, Arizona. The targeted participants were registered nurses, case managers, social workers, and any other care providers in telemetry units, where most COPD patients are treated. The project included a pre- and post-test survey questionnaire and a brief PowerPoint educational presentation. The presentation showed the positive role of social support groups for COPD patients based on multiple evidence-based studies and introduced several options of social support groups to the participants. Results: Total number of participants who completed the project were 42 (n=42), and included registered nurses, one case manager, and one social worker. Most of the participants were not aware of the existence of any social support group before the educational presentation. After the presentation, the collected data demonstrated increased participants’ knowledge and attitudes about the social support groups and the participants’ willingness to utilize the social support referral as part of a comprehensive education and treatment for COPD patients. Conclusion: The referral of social support program is a cost-effective intervention. As shown in several evidence-based studies, the benefits are endless when integrating the referral of a social support group, such as the Better Breathers Club, into COPD patients’ education and discharge planning, so that the patients themselves can connect, share their experiences, learn to better cope with the disease, improve their knowledge and self-care and reduce their depression, exacerbation, and hospital readmissions.
    • Secure and Reliable Communications over Free-space Optical Channels

      Djordjevic, Ivan B.; Sun, Xiaole; Bilgin, Ali; Kilper, Daniel (The University of Arizona., 2019)
      Free-space optical (FSO) communication provides a promising alternative solution to the traditional radio frequency (RF) communications. Compared to the RF technology, there are many advantages of FSO communications, such as ultra-high bandwidth, license-free spectrum, low inter-channel interference, and energy-efficient transmission. The potential applications for FSO communication include the last-one-mile access link from the fiber-based backbone network, low earth orbit (LEO) satellite communications, high-altitude base station platforms or vehicles, deep-space communications, and in-building automation connections. As the FSO technology becomes mature and increasingly involved, the security and reliability requirements of such applications also become crucial. Regarding the security issues, although the FSO communication is inherently more secure than the RF counterpart due to high directivity of its line-of-sight (LOS) link, it can still suffer from optical wire-tapping attack. There are many different application schemes that an eavesdropper can still probe the FSO link. Traditionally, to protect the communication, many works have been done on encryption layer and upper network layer, such as computationally intensive cryptographic algorithms and message exchanging protocols. In recent years, physical-layer security (PLS) has been getting more attentions as it provides an extra layer of security against eavesdropping. The PLS schemes, in general can be categorized into two main categories: classical PLS and quantum key distribution (QKD) protocols. The classical PLS is based on the information theoretic security analysis, while the QKD security is guaranteed by the quantum mechanics laws. Both techniques have been studied for FSO channels. In the first half of this dissertation, we study the PLS in a LOS FSO channel using orbital angular momentum (OAM) multiplexing and show that higher secrecy capacity can be achieved using OAM multiplexing technology in the presence of atmospheric turbulence effects. Then, we proposed an adaptation scheme for QKD system over FSO channel with different QKD protocols, i.e. BB84 and decoy state protocols. By adapting the source brightness based on the channel condition, we optimized the secret key rate (SKR) of the QKD system. Furthermore, we proposed a multiple spatial modes-based QKD system with backpropagation method to increase the total SKR through parallel channels. Regarding the reliability of an optical communication system as well as information reconciliation for both PLS and QKD schemes, the forward error correction (FEC) becomes an essential technique to enable high-speed transmission. The FEC with low-density parity-check (LDPC) codes has been studied for decades from LDPC block codes to the most recent spatially-coupled (SC) LDPC codes. For FSO communications, due to the time-varying nature of FSO channels, the capability of rate adaptation is important to achieve a consistent reliable transmission. In the second half of this dissertation, we proposed unified FPGA-based architecture to implement both quasi-cyclic (QC) LDPC codes and SC-LDPC codes with rate adaptation capability. The performance is verified through FPGA emulation to show good error floor properties. To further validate the rate adaptation capability, we have built a spatial light modulator (SLM)-based FSO channel emulator to test the adaptive coding scheme. Furthermore, we have conducted a fiber-based experiment with our rate adaptative coding scheme to show that the proposed adaptive coding scheme can be also used in dynamic fiber-based networks.
    • Examining the Comprehensiveness of Psychological Services Provided to Students with Cancer Upon School Reentry

      Wodrich, David L.; Tesoro, Andrew; Sulkowski, Michael L.; Yoon, Jina (The University of Arizona., 2019)
      With advancements in medicine, childhood cancer survival rates have increased in recent years. Consequently, many of these children return to school post-treatment at risk for cognitive, academic, and social-emotional difficulties, as a result of cancer and its treatment effects. During the re-entry process, school psychologists have a unique skill set that would allow them to identify educational needs and create interventions to help these students readapt to school and thrive both socially and academically. However, the existing literature is scarce concerning school psychologists' specific role during the school re-entry process and the factors that may influence the provision of re-entry services. This study concerns school psychologists and the factors that influence their likelihood of providing comprehensive re-entry services to students returning from cancer treatment. It investigates the effect of targeted cancer information on the provision of services, as well as the impact of demographic and cancer experience variables. In this study, 176 school psychologists were randomly assigned to one of two conditions: cancer information group (received facts on brain tumors and its educational impact) and no cancer information group (received no fact sheet). After being randomly assigned, participants were then directed to the following information: Demographic Questionnaire, Study Instructions and Hypothetical Case, Summary of Record Review, The Facts About Brain Tumors and Schooling (only Cancer Information group), Comprehensiveness of Psychological Reentry services for Children with Cancer Survey, and Experience with Cancer Questionnaire. There were three predictions: 1) school psychologists receiving cancer information will endorse more comprehensive re-entry services compared to school psychologists not receiving cancer information, 2) school psychologists’ demographic information will predict comprehensiveness of re-entry services, and 3) cancer knowledge and cancer experiences will predict comprehensiveness of re-entry services. The first prediction was analyzed using ANOVA, and the other predictions were analyzed separately using multiple regression. Findings from the ANOVA suggest that cancer information results in more re-entry services, albeit with a small effect size. Moreover, the multiple regression analysis for demographic variables did not predict the provision of re-entry services, whereas cancer-experience variables did predict re-entry services. The perceived importance of cancer knowledge was the best predictor of re-entry services among cancer-experience variables. Study limitations, implications for practice, and future directions for research are discussed.
    • Bradley Ellingboe’s Requiem: Influences and Analysis for Performance

      Chamberlain, Bruce; Robison, Brett Patrick; Schauer, Elizabeth; Brobeck, John (The University of Arizona., 2019)
      Bradley Ellingboe (b. 1956) is an American composer who resides in Albuquerque, New Mexico. Ellingboe has over one hundred and twenty choral compositions and four larger choral-orchestral works in print. Requiem, composed in 2001, was Ellingboe’s first major work for choir and orchestra. Bradley Ellingboe’s study of the music of Edvard Grieg (1843-1907) and his prolonged exposure to Norwegian folk song and Lutheranism have influenced his melodic, textual, and formal choices in his Requiem. An understanding of these influences will aid conductors in creating stylistically appropriate performances of Requiem. Bradley Ellingboe was raised in a Norwegian-American family in Lakeville, Minnesota. To give further context, a brief biography of the composer and highlights of the history of requiem mass are included in this document. In this document, I discuss the importance of the inclusion of the folk tune, Jeg lagde mig saa silde and a recurring cello solo that serves as a Leitmotif throughout Requiem. Through motivic analysis the influence of Norwegian folk music and the music of Edvard Grieg are further revealed. The discussion of the architecture, text choices, and the emotional progression in Requiem reveal the influence of Ellingboe’s Lutheran faith. This document also includes a chapter that provides rehearsal and performance suggestions for conductors.
    • A Society of Individuals: Worker Differentiation and Collective Behavior in Social Insects

      Dornhaus, Anna; Leitner, Nicole Elise; Gronenberg, Wulfila; Bronstein, Judith; Duckworth, Renee (The University of Arizona., 2019)
      Individuals are not identical. Organisms of the same species usually exhibit diverse phenotypes, a phenomenon that extends not only to physical characteristics but to behavior as well. Indeed, consistent differences in behavior across individuals are now well cited across the animal kingdom and have been shown to be an integral part of the ecology and evolution of an organism. Yet, the proximate, physiological mechanisms upon which natural selection might act to either favor or eliminate variation is often not known. Here, I use social insect division of labor – essentially an exaggerated form of behavioral variation in which nestmate workers specialize in different tasks – as a study system for exploring potential neural mechanisms of inter-individual behavioral variation. This investigation also led me to test and review one of the most widely accepted hypotheses for division of labor, the results of which provide new and important insights into how and why social insect workers choose different tasks. In my first chapter I explored variation among Temnothorax rugatulus ant workers in their peripheral sensory organs, a potentially important, but often overlooked, source of behavioral variation (or, in the context of social insects, task specialization). The idea for this study was based on the popular “response threshold” mechanism for division of labor, whereby workers become specialized in tasks because they vary in their response (often assumed to be ‘sensitivity’) to task-associated stimuli. Potentially, variation in worker sensory organs might influence a worker’s ability to detect such work-associated stimuli. Though workers showed considerable variation in the number of antennal sensory structures, this variation was not related to variation in worker behavior. This led to my second chapter, in which I directly tested the response threshold hypothesis in T. rugatulus ants. Here, I found no evidence for individual variation in response thresholds to three different putative task stimuli, calling into question the ubiquity of this mechanism as a general driver of social insect division of labor. To follow up on this idea, in my third chapter I performed a comprehensive review of the response threshold hypothesis in the social insect literature and found that the empirical evidence for it is not as strong as is commonly assumed. This chapter also provides guidelines for how to test response thresholds, with the goal of becoming a valuable reference work for those studying both social insects and self-organization in complex systems in general. My last chapter scaled up to the colony level. I explored plasticity and constraint in task reallocation by challenging colonies of T. rugatulus with different types of perturbations. By considering multiple types of tasks, this study provided novel insight into how the variety of tasks a colony performs are regulated quite differently. Here, I found that colonies were able to achieve considerable flexibility through the use of two different strategies. Which strategy the colony used was task-dependent. In addition, colonies appeared to have two types of reserve workers upon which to draw when task needs increased, dependent on task type.
    • Modern Contraceptive Use among Women in Sub-Saharan Africa: Individual, Interpersonal, and Healthcare System Indicators

      Ehiri, John E.; Asaolu, Ibitola; Ernst, Kacey; Nuno, Velia; Taren, Douglas (The University of Arizona., 2019)
      Background: Contraceptives promote maternal and child health by reducing the prevalence of: unintended pregnancies, unsafe abortions, maternal deaths, low birth weight infants, preterm birth, and infant mortality. Despite its benefits, the uptake of contraceptives among women of childbearing age remains low in sub-Saharan Africa. In sub-Saharan Africa, the prevalence of contraceptive use among women in a union is 28%. To advance maternal and child health in this region, it is imperative to identify various individual, interpersonal, cultural, and healthcare system factors that affect the adoption of modern contraceptives. Objective: This project assesses individual, interpersonal, and healthcare systems indicators of modern contraceptive use among women in sub-Saharan Africa. Methods: Quantitative insight into the determinants of modern contraceptive use was obtained through analyses of multiple Demographic and Health Surveys (DHS) and Performance Monitoring and Accountability (PMA) 2020 data. The quantitative research studies were limited to women with a need for contraception, i.e. respondents who want to limit or space childbirth. Multivariable logistic regression models assessed the relationship between modern contraceptive use and: a) individual; b) interpersonal; and c) healthcare system factors. To further explore the barriers and facilitators of modern contraceptive use, this project employed focus group discussions and semi-structured interviews of healthcare providers in Calabar, Nigeria. Data from focus group discussions and interviews were analyzed using the thematic analysis approach. Results: The prevalence of modern contraceptives ranged from 7.8% in Gambia to 68.9% in Kenya among women. Several factors were positively associated with modern contraceptives use. Evidence from the DHS revealed that two domains of women’s empowerment—labor force participation and education—were most consistently associated with increased rates of modern contraceptive use. Results from analysis of the PMA2020 data identified four healthcare factors associated with women’s use of modern contraceptives. Health worker home-visits, adolescent reproductive health services, and polyclinic/hospitals were associated with modern contraceptive use in Ghana, Kenya, and Nigeria. Evidence from focus group discussions showed that women mostly used condoms, emergency contraceptives pills, fertility awareness (rhythm), and folkloric methods of contraception. In addition, myths about contraceptives prevented participants from using certain forms of modern contraception. For instance, participants cited that pills, injectables, and implants caused infertility and diseases among women who use these methods. Conclusion: Modern contraceptive use among sub-Saharan African women can be increased by promoting the health-worker visits, empowering women through education and labor force participation, and correcting myths about the side effects of modern contraceptives. By addressing individual, interpersonal, and healthcare correlates of contraceptive use, findings from this research can inform the design of comprehensive and more effective contraceptive interventions. Therefore, findings from this research can inform the design and implementation of interventions that acknowledge multiple correlates of contraceptive use.
    • Novel Host Targets in Respiratory Viral Illnesses

      Chen, Yin; Zhou, Xu; Wang, Jun; Wang, Ting; Lantz, Robert C. (The University of Arizona., 2019)
      Rhinovirus (RV) and influenza virus infections are the leading causes of airway tract problems that lead to cold and flu and exacerbated asthma, chronic obstructive pulmonary disease (COPD), and other respiratory illnesses. This dissertational study investigated the effects of host factors in these viral infections. Chapter 2 and chapter 3 are related research about rhinovirus, and chapter 4 is research about influenza virus. Human rhinovirus (RV) is the major cause of common cold and it also plays a significant role in asthma and asthma exacerbation. Airway epithelium is the primary site of RV infection and production. In contrast, monocytic cells (e.g., monocytes and macrophages) are believed to be non-permissive for RV replication. Instead, RV has been shown to modulate inflammatory gene expressions in these cells via a replication-independent mechanism. However, Johnston et al. firstly reported a low-grade productive replication of RV9 in monocytes and also showed the RV16 replication in monocytes in following studies. In the present study, we generated the epithelial cell- monocyte coculture system. RV16 (a major-group RV) replication was found to be significantly enhanced in monocytes when co-cultivated with airway epithelial cells. This effect appeared to be mediated by secretory components from epithelial cells, which stimulated RV16 replication and significantly elevated the expression of a number of proinflammatory cytokines. The lack of such effect with RV1A, a minor-group RV that enters the cell by a different receptor, suggests that ICAM1, the receptor for major-group RVs, may be involved. Conditioned media from epithelial cells significantly increased ICAM1 expression in monocytes. Consistently, ICAM1 overexpression and ICAM1 knockdown enhanced and blocked RV production, confirming the role of ICAM1 in this process. In addition, we isolated secretory components from the epithelial conditioned medium and further determined their function. Alpha-Heremans Schmid Glycoprotein (AHSG) is the top matched secretory protein to induce the ICAM1 expression. High AHSG expression is closely related to asthma in mice models and human patients. Thus, we demonstrated that airway epithelial cells direct significant RV16 replication in monocytic cells via an ICAM1-dependent mechanism. This is the first time we demonstrated that AHSG expression is related to asthma. Influenza virus is the major cause of influenza (or the flu). Pandemic flu killed tens of millions of people and seasonal flu yearly outbreak also caused severe illness and hundreds of thousands of deaths. Current options for preventing or treating influenza are either limited (e.g., vaccine) or becoming ineffective due to the emergence of drug resistant strains (e.g., M2 blockers). Thus, new treatments for influenza viral infection are urgently needed. Host targets are relatively stable, so the drugs have high barrier when they are targeting on the host factors. To develop drugs targeting the host, it is important to understand the influenza related pathway in the host cells. In the present study, we generated an influenza infectious model on human airway epithelial cells, which are primary sites for the virus’ infections. We serendipitously found that a small-molecule inhibitor (AG1478), previously used for epidermal growth factor receptor (EGFR) inhibition, demonstrated a potent and broad-spectrum activity against influenza. Surprisingly, the antiviral effect of AG1478 was not mediated by its EGFR inhibitory activity, as influenza was insensitive to EGFR blockade by other EGFR inhibitors or by the knockdown using a small interference RNA against EGFR. Additionally, interferons are the major anti-viral proteins in the cells, its effect has to be considered when we research on the anti-viral activity. A knockout approach using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) further demonstrated that this antiviral activity was also interferon independent. AG1478 was found to target on Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1- ADP ribosylation factor 1 (GBF1-ARF1). AG1478 reversibly inhibit GBF1 activity and disrupted its Golgi-cytoplasmic trafficking. Compared to the two existing GBF1 inhibitors, AG1478 demonstrated lower cellular toxicity and better preservation of Golgi structure, suggesting its antiviral activity may not originate from a non-specific disruption of intracellular vesicle trafficking regulated by GBF1. GBF1 was found to interact with a specific set of viral proteins including M1, NP and PA. AG1478-elicited spatial alternation of GBF1 distribution disrupted these interactions. Because host factors are more genetically stable than viral proteins, host-targeting antivirals might have a higher genetic barrier to drug resistance than direct-acting antivirals. In conclusion, the host factors are crucial for these respiratory viral illnesses, and drugs targeting host factors are a new direction for treating infectious illnesses. 1) For rhinovirus, we demonstrate that epithelial secretions, especially AHSG, direct robust RV replication in monocytes via significantly increased ICAM1. This new information will advance our understanding of the interaction between airway epithelium and inflammatory cells in the context of RV infection and RV-induced disease exacerbation. Blocking ICAM1 or decreasing AHSG expression will be a new direction in treating rhinovirus infections. This finding will open a new venue for the study of RV infection in airway disease and its exacerbation. 2) For influenza virus, through a serendipitous finding, we have discovered a potent and broad-spectrum anti-influenza drug candidate-AG1478. Its antiviral activity is mediated by targeting GBF1.The treatment of AG1478 disrupted this interaction and potentially impaired vRNP transport leading to markedly decreased IAV production. It is a new direction to develop the drugs targeting GBF1. Further development on this candidate target will lead to novel anti-influenza therapy.
    • Combined Model Approach to the Problem of Ranking

      Lin, Wei-Hua; Lee, Alexander S.; Son, Young-Jun; Valerdi, Ricardo; Valacich, Joseph (The University of Arizona., 2019)
      Ranking can be defined in many ways and has been applied in many areas. Over the past years, many research studies have been conducted on ranking methods for decision-making. The issue is that results pertaining to ranking entities are based only on one method, which can be subjective and prone to biases. As a result, results vary from method to method. To resolve this issue, a combined model approach is proposed, in which multiple methods are taken into account. The goals of the combined model are to rank entities more objectively and obtain more reliable results. The combined model has both qualitative and quantitative elements, where the qualitative element is the ranking and clustering, while the quantitative element is comprised of the scores. Since ranking is based on the scores of the entities, it takes into account the distribution of scores. In some scenarios, closely ranked entities can have similar scores, while in other scenarios, their scores can be relatively different even though they are ranked close to one another. The score distribution leads to clustering analysis, where entities are divided into clusters based on the spread of the scores. Hence, the combined model takes into account not only the ranks but also the scores of the entities. The proposed combined model is applied to three areas for this dissertation research. The first is identifying and ranking road hotspots and predicting the number of traffic crashes in road segments using the Empirical Bayesian (EB) enhanced by the Proportion Discordance Ratio (PDR) metric. The effectiveness of the Enhanced EB method is tested and demonstrated through a case study that is conducted in one of the major highways in Phoenix, Arizona. The second is ranking major US metropolitan areas in traffic congestion using unsupervised learning based on the Normalized Scoring Method (NSM), Principal Component Analysis (PCA), and the PDR similarity matrix. In 2015, TomTom ranked Tucson as the 21st most congested metropolitan area in the US, and the unsupervised learning combined model is applied to assess TomTom’s traffic congestion ranking of the metropolitan areas in order to determine if Tucson is highly congested based on the proposed model. The third is ranking and assessing the Hall of Fame (HOF) worthiness of retired Major League Baseball players based on their performance statistics through supervised learning based on Support Vector Machines (SVM) and Neural Networks (NN). Players are considered for the HOF through a voting procedure, where voters are comprised of members of the media, but there is a possibility of voting bias that can favor or go against certain players. Results from all three scenarios show that the proposed combined models are more reliable and can more objectively rank entities in order to correct biases based on previous methodologies.
    • Regulation of Antibody Responses against West Nile Virus by the Innate Signaling Adaptor MAVS

      Schenten, Dominik; Kuhns, Michael; O'Ketch, Marvin; Purdy, John; Bhattacharya, Deepta; Nikolich-Zugich, Janko (The University of Arizona., 2019)
      The activation of pattern recognition receptors (PRRs) is a major regulatory checkpoint for the generation of adaptive immunity. Rig-I-like Receptors (RLRs) comprise a PRR family that includes the RNA helicases RIG-I and MDA-5, which recognize microbial RNA in the cytosol. RLR activation induces antiviral effector programs in infected cells and lead to the release of proinflammatory cytokines and interferons. RLRs are therefore important mediators of the innate immune response to many viral infections. However, the role of RLRs in the regulation of adaptive immunity is still poorly understood. Infection of mice deficient in MAVS, the essential signaling adaptor of RLRs, with West Nile Virus (WNV) results in a defective adaptive immune response. While this finding suggests a role for RLRs in the control of adaptive immunity to WNV, it is difficult to interpret due to high WNV titers in the absence of a MAVS-dependent innate immune response. In order to overcome this caveat, we have infected MAVSKO mice with a replication-incompetent mutant of WNV. Here, we report a defect in the neutralizing antibody response to WNV in the absence of MAVS despite the presence of normal WNV-specific antibody titers. This defect was accompanied by an increased number of Tfh cells and an enlarged germinal center (GC) B cell compartment in the draining lymph nodes. Our data show that the epitope specificity of the antibody response to WNV is unchanged in MAVSKO mice and instead implicate the presence of low avidity antibodies as the cause for the inefficient neutralization of WNV. Together, our findings suggest that RLR -dependent signals regulate humoral immunity to WNV infection.
    • I. Causes of Multiple Diffusing Populations of Fluorescently Labeled Probes in Lipid Membranes II. Evaluation of Phospholipid Membranes Incorporating the Polymerizable Lipid Bis-Denpc (16, 16) and Suitability as Ultra-Stable Platforms for Ion Channel Based Sensors

      Saavedra, S. Scott; Smith, Christopher M.; Aspinwall, Craig A.; Pemberton, Jeanne E.; Denton, Bonner; Brown, Michael F. (The University of Arizona., 2019)
      This dissertation is composed of two major projects, though some capabilities and findings from the first project were applied to the second. Project I focuses on advancements made in the understanding of the chemical interactions of a number of commonly used fluorescently labeled phospholipid probes. These probes are used for a variety of studies, including labeling of cellular or artificial membranes, examining transport and communication between different membranes, and determining membrane fluidity. Understanding the chemical behavior and interactions of these probes in membranes can be key for the proper interpretation of experimental data. Utilizing fluorescent recovery after photobleaching (FRAP), in combination with other spectroscopic techniques, multiple diffusing populations of commonly used probes in various artificial lipid membrane formats were identified, as were the causes for these populations. This allows for a fuller description of the fluidity of lipid membranes. These findings are the focus of Chapters 3 and 4 while the hardware developed that enabled critical measurements is the focus of Chapter 2. Project II focuses on addressing key limitations in developing ion channel (IC) based biosensors utilizing artificial lipid membranes. Among these limitations are the weak mechanical, chemical, and electrical stabilities of artificial lipid bilayers due to the weak noncovalent interactions involved in the membrane. To address these limitations, the polymerizable lipid bis-dienoyl phosphatidylcholine (bis-DenPC(16, 16)) was characterized for its ability to form ultra-stable membranes suitable for IC based sensors using the model IC gramicidin A (gA). Special attention was given to determining the membrane fluidity given the requirement of gA that two subunits must laterally diffuse to converge and dimerize to form a conductive pore. These studies are the focus of Chapters 5 and 6.
    • Examining the Role of Top-Down Signaling and Tegmental Activity in Nucleus Accumbens Dopamine Release

      Cowen, Stephen L.; Hill, Daniel; Heien, Michael L.; Fuglevand, Andrew; Navratilova, Edita (The University of Arizona., 2019)
      The capacity to assess the value of future outcomes based on current context is critical for learning, adaptive decision making, and motivation. In the brain this requires the integration of many complex signals from multiple brain regions into a unitary value signal. Midbrain dopamine neurons are among the most notable neural substrates associated with outcome valuation and have been shown to be essential for economic decision making, motivation, and error-driven learning. The mechanisms by which complex behavioral and environmental stimuli are distilled down to value signals by dopamine neurons and their afferents remain incompletely understood. This work seeks to better understand the patterns of top-down input and local control that give rise to phasic dopamine release. To examine how cortical input influences phasic dopamine release, we used fast-scan cyclic voltammetry (FSCV) to measure dopamine release evoked by varying frequencies of electrical stimulation in the medial prefrontal cortex. We found that there is a non-linear response to frequency such that 20 Hz stimulation optimizes dopamine release in the nucleus accumbens (NAc) even when controlling for stimulus duration. These data suggest that specific frequencies of cortical activation preferentially activate dopamine neurons and may have implications for cortical control of dopamine release in circumstances when value encoding must be optimized (e.g., during cognitively demanding tasks involving working memory and attention). Though electrical and optogenetic stimulation are valuable tools for dissecting functional circuits, they modulate activity in ways that are not physiological and therefore, they cannot be used to assess how endogenous patterns of neural activity influence dopamine release. To address this, we developed a novel instrument capable of simultaneous measurement of dopamine release (FSCV) and neural activity (electrophysiology). This system was validated in vitro and in vivo to show reliable recovery of single-unit activity and local field oscillations while recording changes in phasic dopamine. The real-time correlation of these signals enables the investigation of patterns of activity that drive dopamine release and how dopamine entrains cell assemblies in downstream structures. Though the relationship between dopamine neuron activity and dopamine release is seemingly intuitive, technological limitations have limited the capacity to measure these signals simultaneously. To better understand how tegmental activity gives rise to changes in dopamine release, we implemented the instrument described above to record FSCV in the nucleus accumbens and single-unit activity in the VTA. As expected, we observed changes in firing rate of putative dopaminergic neurons associated with the onset of phasic dopamine release events. We also observed a number of non-dopaminergic neurons with reliable peri-event changes in firing. Although we expected the majority of non-dopaminergic cells to decrease their activity preceding dopamine release events, the majority increased, suggesting that local mechanisms other than disinhibition of dopamine neurons contribute to phasic dopamine release. We also anticipated that changes in firing rate of putative dopamine neurons would be directly correlated with release. Instead, the majority of dopamine neurons increased firing at the onset of dopamine release, returned to baseline, and then increased again at the peak of dopamine release. Taken together, these data suggest that the dopamine neuron activity is not perfectly correlated with dopamine release and that processing within the VTA and RMTg may involve an intricate network of non-dopaminergic neurons that facilitate dopamine cell activity and dopamine release.
    • Effects of Plant Invasions on Birds Breeding In Desert Grasslands

      Steidl, Robert; Andersen, Erik; Archer, Steven; Bronstein, Judith; Mannan, William (The University of Arizona., 2019)
      Over the past 150 years, encroachment by woody plants and invasions by nonnative grasses have altered the structure and composition of plant communities that once dominated desert and semidesert grasslands. These plant invasions have reduced the quantity and quality of habitat for many grassland-associated species, including grassland birds, which have declined more rapidly across North America than any other group of birds. Along gradients in cover of woody plants and nonnative grasses in semidesert grasslands of southeastern Arizona, we evaluated how these plant invasions affected species richness, density, habitat selection, and arthropod prey of breeding birds between 2013 and 2015. Encroachment by woody plants influenced breeding birds strongly, with distributions and densities of most grassland obligates decreasing sharply as woody cover increased. As encroachment by woody plants progressed, overall density of birds increased as shrub-associated species were recruited to the community. Bird species richness also increased along the encroachment gradient and plateaued when woody cover reached ~20%, the point at which losses of grassland-associated species equaled gains in shrub-associated species. Invasions by nonnative grasses altered settlement patterns and distributions of breeding bird species differentially, with variation among species reflecting the interplay between the plasticity of habitat preferences and the structural similarity between the invading plants and the native plants with which they evolved. These patterns reveal the importance of the role of habitat selection by individual species as a mechanism to explain broad-scale responses of birds that express at population and community scales. Additionally, invasions by nonnative grasses altered populations and communities of arthropods, the primary prey of grassland birds during their nesting period. For every 10% increase in nonnative-grass dominance, richness of arthropods decreased by 2% and total abundance decreased by 7%. Responses of arthropods varied among taxa and functional groups. Abundances of most predators and specialist herbivores decreased as dominance of nonnative grasses increased, whereas abundances of most generalist herbivores were lowest at intermediate points of nonnative dominance. These changes in the arthropod community can alter broad-scale ecological processes and reduce food resources for insectivores, which can have adverse, cascading effects on imperiled grassland ecosystems. As woody plants and nonnative grasses continue to proliferate in desert grassland ecosystems and threaten native species, monitoring the effects on species of conservation concern reliably will become increasingly important. We evaluated the influence of population attributes (animal density, availability, detection probability, and magnitude of trend) and sampling design features (number of sites, number of repeat surveys, and survey-year interval) on statistical power to detect trends in abundance within a distance-sampling framework. For a range of values common to monitoring studies for breeding grassland birds, power to detect trends in abundance was highest when the number of sites surveyed was maximized, sites were surveyed only once per year, and the interval between survey years was long, a pattern independent of density or detectability of the target species. Our results provide general guidance to help ensure that monitoring programs will have sufficient power to meet objectives effectively and efficiently.
    • Examination of Latinx Bullying Victimization and Depressive Symptoms through a Social-Ecological Framework

      Carvajal, Scott; Lutrick, Karen; Bauman, Sheri; Yuan, Nicole; Leybas Nuno, Velia; Peskin, Melissa (The University of Arizona., 2019)
      BACKGROUND: Bullying victimization is correlated with depressive symptoms in adolescents. While the literature is extensive, there has been little focus on racial/ethnic minorities, specifically Latinx youth. In the United States, there is some evidence that Latinx adolescents experience bullying victimization and depressive symptoms at higher rates than their non-Hispanic white (NHW) peers. OBJECTIVES: This dissertation is composed of three studies that work together to identify factors of influence in the development of depressive symptoms within Latinx adolescents that experience peer violence: 1) a synthesis of the bullying/depression literature to evaluate Latinx representation and Latinx-specific factors; 2) identification of the interaction between racial/ethnic discrimination and bullying victimization on depressive symptoms; and 3) examination of the role of family and social support as a protective factor in the relationship between bullying victimization and depressive symptoms three years after victimization. METHODS: A systematic review was conducted for research aim one following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. For research aims two and three, secondary data analysis was conducted utilizing the Healthy Passages national and longitudinal dataset with permission from the publication committee. Hierarchal regression analyses were conducted for research aims two and three. RESULTS: For research aim one, of 957 studies identified, 17 included a Latinx population of 25% or more. They all identified a relationship between bullying and depression, with nine examining factors related to race/ethnicity or unique to the Latinx population. For aims two and three, a sample of 1,666 Latinx adolescents (grade 7) reported bullying victimization rates of 60% within the previous year. For aim two specifically, 15.7% reported racial/ethnic discrimination and 14.4% reported bullying and discrimination victimization in the previous year. All forms of victimization were found to be significantly related to depressive symptoms, including the interaction between bullying and discrimination victimization (p<.001 for immediate effect, p<.05 three years later). For research aim three, parent/child connectedness had a moderation effect (p<.001, b=-.061; p=.011, b=.006), reducing the likelihood of depressive symptoms three years after victimization. Social support reduced the relationship to depressive symptoms (p<.001, b=.025) but was not a moderator, and global parental monitoring had no significant effect. CONCLUSIONS: The Latinx community is the fastest growing racial/ethnic minority population in the United States, but they are underrepresented in the bullying literature. Studies that included variables unique to Latinx communities such as acculturation and unique family factors found a stronger relationship between bullying victimization and depression. In a Latinx sample, this dissertation identified an increased likelihood of depressive symptoms when bullying and racial/ethnic discrimination were experienced. Additionally, this work found that strong family relationships and strong social support reduced the likelihood of depressive symptoms of bullying victimization even three years after victimization occurred. These two findings identify potential future directions for bullying research and practice. At a minimum, they illustrate a need for an expanded social-ecological lens when measuring victimization as well as the inclusion of family and the development of strong family relationships in bullying interventions.
    • Incentives, Livelihoods, and Forest Ecology: Payments for Ecosystem Services in Guatemala’s Western Highlands

      Osborne, Tracey; VonHedemann, Nicolena; Liverman, Diana; Barron-Gafford, Greg; Oglesby, Elizabeth (The University of Arizona., 2019)
      Payments for Ecosystem Services (PES) programs are a form of environmental governance that offers compensation to land owners or managers who provide ecosystem services such as carbon sequestration, water filtration, or erosion control. Guatemala has three national forestry incentive programs, a form of PES, that grant payments to private landowners and communal forest managers for existing forest preservation, reforestation, and agroforestry. Participants receive annual payments for 5-10 years for completing activities deemed to be good forestry practices that are assumed to provide ecosystem services. While this form of PES is not tied to ecosystem service markets, it does act as a new form of neoliberal conservation in that the programs aim to shape individuals’ behavior and instill responsibility for conservation through offering incentives. This dissertation examines the social and environmental impacts of this form of PES through assessing Guatemala’s national forestry incentive programs that began over 20 years ago but have received little scholarly attention to date. In particular, I explore (1) how marginalized groups use PES as a “surface of engagement” to make demands on the state and, to a certain degree, successfully modify and reframe PES programs; (2) how incentive payments and land tenure affect the ecosystem service of carbon sequestration; and (3) how successfully PES can change forest management behaviors among those who choose to participate. I utilize a mixed methods approach of participant observation, semi-structured interviews, and carbon forestry plots in order to explore these questions in a truly interdisciplinary way. I find that PES in Guatemala has been used as a tool for political organization by smallholders and indigenous communal forest managers, creating advocacy around forests in ways that have not been seen before. These groups have been successful at shaping PES in Guatemala towards their own needs, but still remain constrained by preexisting land inequalities and power asymmetries. I also find that (1) land tenure is a much larger determining factor of the size of standing carbon stocks than the presence or absence of an incentive payment and (2) incentives have the potential to help prevent localized forest degradation because the most heavily utilized plots are enrolled first. Additionally, I demonstrate how management plans written by forestry experts and annual reviews act as technologies of governance that can slightly change forest management behaviors, although participation in the programs is limited to those who own relatively larger amounts of land. The incentives provide an opportunity for political organization, encourage attention to forest management, and provide a small supplemental income. They face challenges, however, in their continued ties to unequal systems of land tenure and lack the ability to change more fundamental causes of poverty and forest degradation.
    • Targeting Organic Anion Transporting Polypeptide 1A4 (Oatp1a4) for Effective Drug Delivery at the Blood-Brain Barrier

      Ronaldson, Patrick; Abdullahi, Wazir; Wright, Stephen; Lynch, Ronald; Largent-Milnes, Tally; Streicher, John (The University of Arizona., 2019)
      Drug delivery to the central nervous system (CNS) is greatly limited by the blood-brain barrier (BBB). Physical and biochemical properties of the BBB have rendered treatment of CNS diseases extremely difficult. Targeting endogenous BBB transporters from the ATP-binding cassette (ABC) superfamily (i.e., P-glycoprotein (P-gp)) or from the solute carrier (SLC) family (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents)) have been investigated as strategies that can improve blood-to-brain drug transport and optimize treatment of CNS diseases. Indeed, direct pharmacological inhibition of P-gp using small molecules or selective regulation by targeting intracellular signaling pathways has been extensively explored; however, these approaches have been largely unsuccessful due to toxicity concerns and unpredictable pharmacokinetics. Therefore, our laboratory has proposed that optimization of CNS drug delivery, particularly for treatment of diseases with hypoxia-reoxygenation (H/R) component such as ischemic stroke, can be achieved by targeting of endogenous BBB transporters that mediate blood-to-brain uptake of their substrates. We have focused our work on organic anion transporting polypeptide 1a4 (Oatp1a4), the primary drug transporting Oatp isoform at the BBB. Oatp1a4 has demonstrated blood-to-brain transport of drugs with neuroprotective properties such as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins). Development of Oatp1a4 as a transporter target that can be exploited for improved treatment of neurological diseases requires a rigorous characterization of the “molecular machinery” that controls its functional expression at the BBB. Here, we show that activation of activin receptor-like kinase 1 (ALK1), a critical component of the transforming growth factor-β (TGF-β) pathway, using the selective agonist Bone Morphogenetic Protein (BMP)-9 increases Oatp1a4 protein expression in rat brain microvessels in vivo. Additionally, we demonstrate that BMP-9 treatment increases blood-to-brain transport and brain exposure of established Oatp transport substrates (i.e., taurocholate, atorvastatin, pravastatin). Of particular significance, we have elucidated that BMP-9 activates the canonical TGF-β/ALK1 signaling pathway in brain microvessels as indicated by increased nuclear translocation of specific Smad proteins associated with signaling mediated by the ALK1 receptor (i.e., pSmad1/5/8). Furthermore, we report for the first time that an activated Smad protein complex comprised of phosphorylated Smad1/5/8 and Smad4 is formed following BMP-9 treatment and directly binds to the promoter of the Slco1a4 gene (i.e., the gene that encodes Oatp1a4). This signaling mechanism causes increased expression of Slco1a4 mRNA. Additionally, BMP-9 treatment did not alter expression of tight junction proteins (i.e., occludin, claudin-5) or paracellular “leak” of the vascular marker sucrose, indicating that targeting TGF-β/ALK1 signaling does not adversely affect BBB integrity. Overall, our work provides novel evidence that Oatp1a4 transport activity at the BBB is regulated by TGF-β/ALK1 signaling and indicates that this pathway can be targeted for control of CNS delivery of Oatp substrate drugs. Overall, our results point toward a unique opportunity to optimize drug delivery and improve pharmacotherapy for CNS diseases.
    • Mechanisms that Promote Adhesion Defects and Genomic Instability to Produce Invasive Prostate Cancer

      Cress, Anne E.; Rogers, Greg C.; Wang, Mengdie; Mouneimn, Ghassan; Nagle, Raymond B. (The University of Arizona., 2019)
      Localized prostate cancer (PCa) display instabilities in both tissue homeostasis and genome. Normal human prostate epithelium consists of two cell layers. Basal cells localize outsize the glands, adherent to extracellular matrix (ECM) through integrins, and providing contextual cues for ordered repopulation of the luminal cell layer. To date, histological and cytological differentiation of prostate tissue are the primary cues used clinically to diagnose prostate cancer. Prostate cancer arises from high-grade prostatic intraepithelial neoplasia (HG-PIN). Early HG-PIN and localized prostate cancer are characterized by loss of basal cell layer, luminal layer expansion, enlarged nuclei/nucleoli, and large-scale genomic instability while lacking recurrent specific driver mutations. Yet, the molecular bases for how the instabilities arise that result in loss of tissue architecture and large-scale genomic alterations during cancer is unknown. In this study, we explored the mechanisms promoting instabilities in tissue homeostasis through adhesion defects and genomic instability during prostate cancer initiation and progression. A model summarizing this study is provided below (Figure 0 1). In normal prostate glands, β4 integrin and its variant β4E, which heterodimerize with α6 integrin, function in forming strong cell-ECM adhesion structures to maintain homeostasis of normal prostate tissue architecture. During prostate cancer initiation and progression, α6β4 and basal cells are lost early, generating instability in tissue homeostasis and loss of tissue architecture. Meanwhile, the major microtubule organizing centers in the cell, called centrosomes, were significantly lost during localized prostate cancer progression. Centrosome number is critical in maintaining a stable genome in normal cells. Loss of centrosome generated large-scale genomic instabilities in non-tumorigenic cells and transformed them to display invasive PCa phenotype in vitro and in vivo. Together, defects in α6β4 integrin mediated adhesions generate instability in tissue homeostasis and centrosome loss give rise to an unstable genome. These instabilities promote the formation of invasive prostate cancer. A model for the study is summarized below in Figure 0 1. Integrin α6β4 and α6β1 are essential, dynamic adhesion receptors for laminin 332 found on epithelial cells. Integrin α6β4 is required for formation of strong cell-ECM adhesion structures and induced migration, which are coordinated by regions of the β4C cytoplasmic domain. Integrin β4E, a unique splice variant of β4, expressed in normal tissue, contains a cytoplasmic domain of 231 amino acids with a unique 114 amino acids sequence instead of β4C’s canonical 1089 amino acids. We determined the distribution of α6β4E protein within normal human glandular epithelium and its regulation and effect on cellular biophysical properties. We found α6β4E was localized within a subset of luminal cells. α6β4E expression was induced by 3D hanging drop culture conditions. Induced expression of β4E by a doxycycline inducible system activated Src. During induced migration, α6β4E expression was restricted to a subset of follower cells with increased cell-cell and cell-ECM resistance properties. α6β4E was present in ring-like patterns measuring ~ 1.75 x 0.72 microns containing actin and CD9 at a cell-ECM location. In contrast, α6β4C was found only within hemidesmosome-like structures containing BP180. We showed that Integrin α6β4E is an inducible, dynamic adhesion isoform in normal epithelial cells that can alter biophysical properties of cell-cell and cell-ECM interactions. HG-PIN markers include loss of α6β4 integrin or its ligand, laminin-332, and budding of tumor clusters into laminin-511 rich stroma. In a 3D culture condition, normal human, stable isogenic prostate epithelial cell lines formed spheroids representative as normal prostate glands, while the reduction of α6β4C integrin modeled the invasive budding phenotype in spheroids formed from. Normal cells continuously spin in 3D culture, forming multicellular spheroids containing an outer laminin-332 layer, basal cells, and luminal cells that secrete PSA. Basal cells were optimally positioned relative to the laminin-332 layer. α6β4C defective spheroids contained a discontinuous laminin-332 layer corresponding to regions of abnormal budding. The centrosome is the major microtubule-organizing center in cells and is crucial in defining mitotic spindle poles and forming cilia. To understand mechanisms of early molecular alterations that resulted large scale genomic instability independent of driver mutations, we investigated centrosome number alterations during localized prostate cancer progression. We established a method to quantify centrosomes at a single-cell level in different types of human tissue samples. Using this method, we found centrosome loss - which has not been described in human cancer - was associated with PCa progression. Centrosome alteration can be induced by microenvironment conditions like hypoxia. Non-transformed basal cells display centrosome loss under hypoxia condition, while non-transformed luminal cells or cancer cells had centrosome amplification under the same condition. Centrosome loss in non-tumorigenic prostate epithelial cells, generated either by a small molecule inhibitor or genetically knockout of the essential centrosomal gene Plk4, resulted in mitotic error, and gave rise to aneuploid and multinucleated progeny. In addition, centrosome loss produced invasive budding with luminal differentiation in the 3D model described above. Consistent with our integrin β4 study, centrosome loss disrupted β4 distribution, generating spheroids with β4 localized intracellular instead of outside with cell-ECM. Furthermore, both transient or chronic centrosome loss transformed prostate epithelial cells which produced highly proliferative and poorly differentiated invasive tumors in mice. Our findings suggest that centrosome loss could create a cellular crisis with oncogenic potential in prostate epithelial cells.
    • Culturally Sensitive Education for Mental Health Providers Treating African American Adults with Major Depression

      Kahn-John, Michelle; Azode, Christian Maduabuchi; Love, Rene; Pace,, Thaddeus W. (The University of Arizona., 2019)
      Background: African Americans (AAs) or Blacks in America are over-represented in groups or populations that are at risk for mental illness. About 20% of AAs are more likely to report serious psychological problems than their Caucasian counterparts. Urban AAs in the United States currently engage in medication therapy and psychotherapy for treatment resistant depression (TRD) however, they minimally engage in the use of electroconvulsive therapy (ECT) as a treatment option. Significance: AAs may be limiting their treatment options by opting out of ECT for the treatment of TRD. Culture may play a role in the decision-making process for AAs seeking treatment for TRD. Purpose: The purpose of this quality improvement project (QI) was to explore cultural influences of health-related decision-making among AA adults. Upon determination of cultural factors that may impact AA health-related decision-making, a culturally sensitive education session was developed and offered to mental health (MH) providers who care for patients with TRD at a Phoenix, AZ, clinic. Methods: This is a descriptive study design. Cultural factors influencing health-related decision-making among AA adults in their selection of treatment modalities for severe depression were explored in this QI project. Aim 1: AA adults with TRD receiving care at an urban mental health clinic in Arizona were administered a self-administered questionnaire (SAQ) on how culture impacts treatment related decision making. Aim 2: Responses from the questionnaire were analyzed and compiled. Aim 3: A culturally sensitive education session was developed with a goal of educating Nurse Practitioners and Physicians at the Phoenix, AZ, clinic who care for AA adults with TRD. Analysis: Univariate descriptive statistics were utilized to analyze responses from the structured SAQ. Thematic commonalities were used to analyze six qualitative/open-ended questions to obtain a description of the categorical thematic responses. Implications for Nursing: Findings from this QI will offer contributions to the scientific nursing database and offer a resource to inform ECT providers on how culture impacts decision making among AA adults with TRD.