• The Comet Cipher: Understanding the Ultraviolet Emissions of Cometary Comae

      Harris, Walter M.; Noonan, John William; Reddy, Vishnu; Volk, Kathryn; Bodewits, Dennis; Asphaug, Erik (The University of Arizona., 2022)
      The study of cometary activity as a strategy to probe the icy planetesimals from early solar system formation is a relatively new endeavor. The effort began in earnest after observational confirmation in the late 1960's that the vast amounts of hydrogen and hydroxyl (OH) molecules in cometary comae are evidence of an icy object sublimating water into space. In the decades since, a key goal of solar system science has been to observe more comets with a wider array of techniques in order to constrain the initial molecular building blocks of our solar system, characterize composition patterns between comet types, and identify any peculiarities that may make our solar system more suitable for life than any other. However, cometary activity is an uncooperative partner in this investigation; at times the activity can be sporadic and weak, at other times explosive, and at far fewer times predictable. Understanding what processes can influence observations of cometary activity, specifically in the ultraviolet (UV) wavelengths of light, is the motivation for this Dissertation. Four projects are described in this work that probe how the UV emissions from two comets, 67P/Churyumov-Gerasimenko and 46P/Wirtanen, reflect the outgassing molecules from their surface and the processes that govern their emissions. Following an introduction about comet formation, dynamics, and observations, three chapters are dedicated to observations from the Alice UV spectrograph to investigate emission processes near (within 100s of km) the nucleus of 67P. The processes can range from outbursts of material from the cometary surface to outbursts of energetic plasma ejected from the Sun, revealing new science about the relevant scales for photon and collisional excitation mechanisms. The lessons learned from near-nucleus coma observations at 67P are then applied to 46P with a remote observing campaign using the Hubble Space Telescope to search for similar traces of the emission mechanism. Ultimately this Dissertation reflects on the implications of the work on the larger astrophysical community and lays out future directions for UV comet research.
    • Synthesis of Pharmaceutically Valued Molecules Enabled by Organophotoredox Catalysis

      Wang, Wei; Ji, Peng; Polt, Robin; Hulme, Christopher; Wondrak, Georg; Wang, Jun (The University of Arizona., 2022)
      Photoredox catalysis has emerged as the currently most powerful strategy to manipulatethe open-shell radicals for diverse chemical transformation that is impossible or difficult to accomplish using the conventional ionic pathways. This method is highlighted by the reaction mildness, biological compatibility, and broad substrates tolerance. Therefore, photoredox catalysis has been applied to total synthesis of nature products, modify the biomolecules (protein, DNA, saccharides, etc.), novel materials synthesis, etc. In the traditional polar strategy, a number of synthons such as organometal complexes are labile and/or less reactive, while the precursors of radicals (carboxylic acids, halogens, esters, amines, olefins, etc.) are usually bench stable, easily accessible, and the radicals are highly reactive, which demonstrate a quite distinct manner to construct the target molecules. Herein, we developed a series of novel approaches to constructing the pharmaceutically valued compounds using the photoredox catalysis. In the first effort, an approach for efficient synthesis of C-glycosyl amino acids is developed. Different from typical photoredox-catalyzed reactions of imines, the new process follows a pathway in which α-imino esters serve as electrophiles in chemoselective addition reactions with nucleophilic glycosyl radicals. The process is highlighted by the mild nature of the reaction conditions, the highly stereoselectivity attending C–C bond formation, and its applicability to C-glycosylation using both armed and disarmed pentose and hexose derivatives. In the second effort, a mild, versatile organophotoredox protocol has been developed for the preparation of diverse, enantioenriched α-deuterated α-amino acids. Distinct from the wellestablished two-electron transformations, this radical-based strategy offers the unrivaled capacity of the convergent unification of readily accessible feedstock carboxylic acids and a chiral methyleneoxazolidinone fragment and the simultaneous highly diastereo-, chemo-, and regioselective incorporation of deuterium. Furthermore, the approach has addressed the longstanding challenge of the installation of sterically demanding side chains into α-amino acids. While strategies involving a 2e− transfer pathway have dictated glycosylation development, the direct glycosylation of readily accessible glycosyl donors as radical precursors is particularly appealing because of high radical anomeric selectivity and atom- and step-economy. However, the development of the radical process has been challenging owing to notorious competing reduction, elimination and/or SN side reactions of commonly used, labile glycosyl donors. Toward this end,15 we introduce an organophotocatalytic strategy through which glycosyl bromides can be efficiently converted into corresponding anomeric radicals by photoredox mediated HAT catalysis without a transition metal or a directing group and achieve highly anomeric selectivity. The power of this platform has been demonstrated by the mild reaction conditions enabling the synthesis of challenging α-1,2-cis-thioglycosides, the tolerance of various functional groups and the broad substrate scope for both common pentoses and hexoses. Furthermore, this general approach is compatible with both sp2 and sp3 sulfur electrophiles and late-stage glycodiversification for a total of 50 substrates probed. Reactions that lead to destruction of aromatic ring systems often require harsh conditions and, thus, take place with poor selectivities. Selective partial dearomatization of fused arenes is even more challenging but it can be a strategic approach to creating versatile, complex polycyclic frameworks. We have developed a general organophotoredox approach for the chemo- and regioselective dearomatization of structurally diverse polycyclic aromatics, including quinolines, isoquinolines, quinoxalines, naphthalenes, anthracenes and phenanthrenes. The success of the new method for chemoselective oxidative rupture of aromatic moieties relies on precise manipulation of the electronic nature of the fused polycyclic arenes. Experimental and computational results show that the key to overcoming the intrinsic thermodynamic and kinetic unfavorability of the dearomatization process is an ultimate hydrogen atom transfer (HAT) step, which enables dearomatization to predominate over the otherwise favorable aromatization pathway. We show that this strategy can be applied to rapid synthesis of biologically valued targets and late-stage skeletal remodeling en route to complex structures.
    • Cleaning and Passivation of Germanium and Silicon Germanium Surfaces

      Muscat, Anthony; Monti, Oliver L.A.; Heslop, Stacy; Armstrong, Neal R.; Huxter, Vanessa M. (The University of Arizona., 2022)
      Germanium and silicon germanium are promising materials for the development offuture microelectronics as they exhibit higher carrier mobilities and smaller bandgaps which can be advantageous in the creation of faster devices. Before these materials can be integrated into current manufacturing, processes for cleaning, etching and passivation of the surface must be developed. Understanding and controlling these processes is critical as the surface plays a key role in device performance. Additionally, the development of liquid phase processes is important because they offer a simpler and less expensive method compared to in-situ methods. This work studies the effects of semiconductor cleaning and etching solutions on SiGe as well as the passivation of these surfaces. SiGe surfaces were treated in aqueous solutions of HCl, HF, and various combinations to determine the most effective strategy to remove oxides and limit carbon contamination. The most effective etching process is a combined solution of HF and HCl in a ratio of 1:3:300 v/v HF:HCl:H2O. The presence of HF is necessary to remove SiO2. Further cleaning studies were carried out on SiGe surfaces in solutions of (NH4)OH:H2O2:H2O at varying concentrations. The solution selectively etches Ge atoms and enriches the surface in Si atoms which are oxidized in solution. At high concentrations of (NH4)OH and H2O2 the selective etching of Si0:25Ge0:75 and Si0:15Ge0:85 can remove the entire SiGe film. The passivation of these surfaces with (NH4)2S and alkanethiols was studied. (NH4)2S deposits sulfur which reacts preferentially with the Ge atoms. The deposition of alkanethiol self-assembled monolayers (SAMs), particularly 1-eicosanethiol (ET, C20H42S) was studied on Ge with the goal of identifying the source of surface oxidation which occurs during the self-assembly process. Eliminating dissolved oxygen in solution and air exposure after the alkanethiol deposition resulted in the least oxidation as measured by XPS.
    • Protein Engineering Methods to Understand Kinase Signaling and Protein-Protein Interactions

      Ghosh, Indraneel; Amofah, Bismark; Charest, Pascale; Marty, Michael; Montfort, William R. (The University of Arizona., 2022)
      Tyrosine phosphorylation is one of the key covalent post-translational modifications through which multicellular organisms communicate. Phosphorylation of tyrosine residues on proteins can modulate enzymatic activity and can create binding sites for the recruitment of downstream signaling proteins. Conservation of enzyme structure across the human kinome makes it difficult to design small molecules to selectively modulate kinase activity, which can help elucidate their roles in signaling pathways and in diseases. To circumvent this limitation, we have developed a split-protein method to control the activity of individual kinases by utilizing chemical inducer of dimerization (CID) proteins. The split-protein approach relies on the identification of viable fragmentation sites in a protein that can be used to generate ligand-gated control of protein activity. The major focus of this dissertation is the identification of new kinase and firefly luciferase fragmentation sites for temporal control of a specific kinase and for the study of protein-protein interactions, respectively. With a sequence dissimilarity-based approach and structure-guided analysis, we successfully identified new split-Src sites, the first split-Syk site, the first split-Abl-1aFL, and new firefly luciferase fragmentation sites utilizing the CIDs of rapamycin and/or abscisic acid. Temporal control of split-Abl-1a coupled with quantitative phosphoproteomics analysis aided in the understanding of Abl-1 cellular signaling. Both known and novel substrates were identified, and validation of novel phosphotyrosine targets like AFDN, AMOT, DDX3X, NCAPH present opportunities for studying and understanding unanticipated functions of Abl-1. In summary, this work describes the split-protein approach to selectively control and dissect the complex signaling processes of specific protein tyrosine kinases (PTKs) and for monitoring PPIs. The new tools developed could potentially be used to rewire signaling pathways and aid in the development of novel therapeutic targets.
    • The Honey Bee Superorganism: Social Insect Life History and the Microbiome

      Duca, Frank A.; Copeland, Duan; Anderson, Kirk E.; McCarthy, Fiona M.; Schlenke, Todd A.; Stock, Patricia (The University of Arizona., 2022)
      Honey bee colonies are a complex society of individuals functioning to serve the collective group, colloquially known as a ‘superorganism.’ Their life history is intimately linked with their ability to separate reproduction, resource provisioning, defense, and offspring across thousands of individuals. Similarly, their gut microbiota also greatly influences their physiology and health. Here we explore the honey bee gut microbiota at pivotal moments during the honey bee life history. First we explore gut microbial succession and gene expression in freshly mated queens placed in colonies (high metabolic demand) or queen banks (low metabolic demand). We found differences in gut microbiota abundance between the two environments; colony queens were less diverse, while queen bank queens had microbiota similar to older queens who produce less eggs. We also found gene expression was similar between the two environments, suggesting post-mating had a stronger effect on gut gene expression. Our findings suggest that the queen gut microbiota experiences an extended period of microbial succession associated with post-mating development and colony assimilation. Next, we looked at the gut microbiota’s role in precocious forager midguts and ileums by determining if aging of the microbiota precedes or succeeds physiological aging. We found that social structure greatly influenced the absolute and relative abundance of midgut and ileum microbiota. We also performed immune and oxidative stress gene expression and found genes were explained by an interaction of both age and behavioral task. Our findings suggest that the physiological cost of early foraging is early senescence to the individual which can progress to population dwindling at the colony level. Finally, we conducted the first metaanalysis of the honey bee gut microbiota. We resolve the core microbiota and rare biosphere from over 3000 16S rRNA gene sequence libraries. We also highlight strain diversity and niche partitioning of the core microbiota. Collectively, we present the honey bee microbiota as a functional component of honey bee health from the novel perspectives of nascent queens, precocious foragers, and through a macro lens meta-analysis.
    • Conservation Genomic Analyses of the Endangered Masked Bobwhite Quail (Colinus Virginianus Ridgewayi)

      Culver, Melanie; Vargas, Karla Leonor; Gallery, Rachel; Badyaev, Alexander; Faircloth, Brant (The University of Arizona., 2022)
      The unparalleled rate at which biodiversity is disappearing around the globe has made conservation of imperiled populations an urgent but difficult task. Critical resources are increasingly limited, constraining effective conservation practices. Genetic distinctiveness is an important metric used to prioritize conservation efforts. The masked bobwhite (Colinus virginianus ridgwayi) is a peripheral population and genetically differentiated subspecies of the northern bobwhite. To generate data beneficial to conservation efforts for the endangered masked bobwhite, I used genomic sequencing methods to resolve fine scale evolutionary relationships among the masked bobwhite, Texas bobwhite, and Mexican subspecies of northern bobwhite. I analyzed thousands of single nucleotide polymorphisms (SNPs) to elucidate genetic diversity patterns and population structure among subspecies, and I applied a maximum entropy approach to generate species distribution models (SDMs) to assess climate variables that affect the geographic distributions, to examine similarity among key subspecies’ habitats, and to project potential habitat suitability of key subspecies under present-day and future climate change scenarios. The results from this study suggest that C. v. ridgwayi, C. v texanus, and C. v. graysoni are more closely related to each other than to other Mexican subspecies and support the genetic distinctiveness of C. v. ridgwayi. SNP analyses suggest some genetic distinction between contemporary and historical samples of the masked bobwhite, which should be further explored since results rely on only one successful historical sample. SDM analyses to estimate climatic variables most important to current and future habitat quality for northern bobwhite showed that specific climate variables that contribute to current and future potential distribution of the northern bobwhite differ when modeling distribution at the species- versus subspecies-level. Also, the distribution of C. v. ridgwayi and C. v. graysoni seemed to be determined by variables other than climate. SDM results suggest possible changes in habitat suitability over time, but the choice of variables and climate models could alter predictions, therefore, the SDM results should be used as a preliminary baseline to direct and build future model development for northern bobwhite. The results from this work could be used by managers for conservation planning and decision making and to aid the recovery efforts for the highly endangered masked bobwhite.
    • Mosquitoes in Paradise: An Interdisciplinary Approach To Explore the Adoption of Community-Based Mosquito Control Strategies for Aedes aegypti in Peñuelas, Puerto Rico

      Ernst, Kacey C.; Madera Garcia, Valerie; Jacobs, Elizabeth; Ellingson, Katherine; Walker, Kathleen R. (The University of Arizona., 2022)
      Background: Aedes (Ae.) aegypti, predominantly found in urban environments, oviposit in human-made containers in and around households, and is the primary vector of dengue, Zika, and chikungunya viruses in tropical and subtropical areas of the world. While the continental United States has had only sporadic outbreaks, dengue transmission has been intractable in Puerto Rico, where seasonal outbreaks have been recorded since 1915. Recent emergence of chikungunya and Zika further worsened health outcomes from mosquito-borne diseases in Puerto Rico. Prevention and reduction of arboviral diseases continue to depend on controlling mosquito populations. Vector control efforts have shown a minimal degree of success over the last 50 years in Puerto Rico. Evidence suggests that community mobilization is an essential component of successful and sustainable mosquito control efforts. Before implementing these interventions, it is imperative to obtain community-level information and input. The objectives of this interdisciplinary dissertation were to characterize the human and environmental factors associated with immature Ae. aegypti habitats in Peñuelas, Puerto Rico, explore the application of stated preferences methodologies in vector control research, and measure preferences for an Ae. aegypti mosquito control program in Peñuelas, Puerto Rico using a best-worst choice (BWC) approach. Methods: Outdoor house inspections were performed in the 69 selected houses from 10 neighborhoods of Peñuelas, and all containers were searched and inspected for water and mosquito immatures. Descriptive statistics were used to summarize demographics and human factors (i.e., knowledge about mosquito breeding sites) among the surveyed sample and to characterize containers, water-holding containers, and containers producing immature mosquitoes. Principal container analyses were used to quantify immature mosquito abundance in proportion to water-holding containers. Multiple regression models were used to examine the relationship between demographic and human factors (i.e., age, education) and containers, water-holding containers, and mosquito immature abundance. A PRISMA-guided scoping literature review was performed in August 2021 to synthesize and summarize the current use of stated preferences tools and vector control and provide recommendations to improve the application of these tools in the development and evaluation of vector control programming. A total of three databases (PubMed, Embase, PsycInfo) were searched for eligible studies, and data were extracted from studies meeting the eligibility criteria. Recommendations for improving the application of stated preferences tools to vector control programming were made. Finally, a total of 175 participants from Peñuelas were selected and surveyed face-to-face in July 2021 using a two-stage cluster design. Stated preferences toward various components of mosquito control programs were identified by implementing BWC in the participants from Peñuelas. Furthermore, willingness/unwillingness to participate in and willingness to pay for a mosquito control program was explored. A conditional logit analysis was used to estimate preferences and random effects logit was used to measure willingness to participate and willingness to pay. Results: A total of 4090 containers were identified and inspected during the outdoor inspections of 69 homes, from which 7.0% held water, 1.5% were larvae-positive, and 0.5% pupae-positive. Bromeliads were the most common water-holding container and were found to be responsible for 37.8% of the production of mosquito immatures in the surveyed houses. Higher education level was significantly negatively associated with container abundance and with lower odds of having mosquito immatures in their houses. Also, knowing at least one specific container that serves a breeding site was significantly associated with higher odds of mosquito immature infestation. In the scoping review, only 17 studies were included from the 686 articles screened. Most of the studies were conducted in sub-Saharan African countries (72.2%), focused on insecticide-treated nets (ITNs) for malaria prevention (52.9%), and used contingent valuation methods (82.4%). Studies were classified into reducing human-vector contact (64.7%), reducing mosquito abundance (29.4%), or both (5.9%). While demand exists for vector control programs, there were no consistent associations between demand and explanatory factors (i.e., demographics, etc.) in either human-vector studies or mosquito abundance studies. The BWC assessment indicates that the most important features of a mosquito control program were that it was applied at the neighborhood level, implemented by the local government, and focused specifically on reducing disease transmission instead of mosquito abundance (i.e., dengue). Programs targeting the reduction of disease transmission had a positive effect on willingness to participate in the program. Education was positively correlated with expressing willingness to participate in a mosquito control program. Our study results revealed that participants were willing to pay up to $72.00 to have a program targeting the reduction of diseases, such as dengue. Conclusion: The results of this dissertation provide evidence that bromeliads, the most common water-holding container and disproportionately productive, must be targeted in future mosquito control efforts. Conversely, having mosquito control strategies targeting large water storage containers might not be efficient at reducing mosquito indices in Peñuelas. The current literature on stated preferences and vector control is limited in the scope of vector control methods being investigated, the countries being studied, and the determinants of demand measured. Future research is needed to expand the application of stated preferences to measure demand and preferences for various vector control strategies, including newly developed and community-based methods. This dissertation demonstrated that reducing disease transmission is the highest priority and influences the likelihood of participation for the residents in Peñuelas. Individuals were willing to pay a considerable amount of money for a program with this focus. This finding suggests that a mosquito control program can specifically target Ae. aegypti mosquitoes, which transmit dengue, chikungunya, and Zika in the study area. The results of this dissertation can improve stakeholders’ decisions regarding mosquito control strategies implemented in Peñuelas, Puerto Rico. There is strong potential to incorporate community-based efforts with government-led efforts to decrease Ae. aegypti mosquito abundance and reduce the transmission of dengue in Peñuelas, Puerto Rico.
    • Utilizing Environmental Analytical Chemistry to Establish Culturally Appropriate Community Partnerships

      Briehl, Margaret; Ingram, Jani C.; Credo, Jonathan; Gachupin, Francine; Warneke, James (The University of Arizona., 2022)
      In the United States, minority communities are disproportionately exposed to environmental contaminants due to a combination of historically discriminatory based racial policies and a lack of social political capital. Within this demographic, American Indian/Alaskan Native (AI/AN) communities have additional factors that increase the likelihood of contaminant exposure. Some of these factors include the disparity of social, cultural, and political representation, differences in cultural understandings between AI/AN communities and western populations, and the unique history of tribal sovereignty in the US. Research from both private and federal organizations starting in the 1990s led to a change in research agendas that emphasized a push to conduct research with AI/AN communities. However, although many research pursuits may be rooted in beneficence, the rift in cultural upbringing can lead to negative outcomes as well as further isolation and misrepresentation of AI/AN communities. Arguably the most significant example of this breakdown is the Havasupai v Arizona Board of Regents case surrounding the misuse of Havasupai blood samples. The outcome of this case led to many Tribal Nations around the United States increasing their distrust of outsiders, regardless of their organizational affiliation. Despite this sobering example, collaborations with AI/AN communities need not be difficult or tempestuous. However, it does require a change in the existing western scientific approach to both community collaborations as well as how science is viewed. Simply put, researchers must work to overcome the initial distrust many Tribal Nations have towards outsiders, and this attitude must be maintained throughout the duration of the partnership. Some obstacles to collaboration include the amount of time and resource allocation as well as identifying the most culturally appropriate methodology while maintaining scientific rigor. Instead of viewing these hurdles as nuisances, western scientists should view them as challenges and the opportunity to adapt their approaches while still maintaining rigorous and reproducible science. An achievable change in heuristics is to approach these type of collaborations as if one is forging a healthy friendship with another individual. This dissertation exemplifies the benefits of adopting these approaches and outlines four years of effort to secure enough trust with two Tribal Nations, the Cocopah and the Colorado River Indian Tribes, to be allowed to conduct a pilot study within their Tribal lands in full collaboration with their governing body. As part of that four years, in addition to numerous in-person and virtual meetings, preliminary data was gathered to demonstrate the potential harm of environmental contaminants to the Tribal population. It should be noted, although there are similarities in the approved methodologies for the pilot grants with the Tribes, they are distinctly different but still address the underlying concerns of the Tribes. This versatility is one of the hallmark benefits of utilizing environmental analytical chemistry in this capacity. Specifically, it allows researchers numerous modalities to investigate the root causes of the environmental concerns a Tribal Nation may have and can be modified to be unique for each community.
    • TVET (Technical Vocational Education Training) Contributions toward Education Policy, Economic Sustainability, Development, and Poverty Abatement in a Globalized Economy: A Wicked Problem

      Koyama, Jill; Frick, Sumaya; Bosworth, Kris; Lee, Jenny (The University of Arizona., 2022)
      This dissertation is a study of policy stakeholders (N=24) in four countries within the regional Caribbean Community and Common Market (CARICOM) policy environment. The scope was to identify how they navigated and interpreted conceptualizations of TVET and general education, which have been explicitly tied to national and regional sustainability, development, poverty abatement and skilled labor migration initiatives. Despite variable levels of codified TVET policy, academic centric institutional frameworks, and political will, education policy stakeholders recognized the substantive impact of TVET on their nations and the region. Supported by networked regional knowledge exchanges that are informed by shared tenets central to the Ideal Caribbean Person, they strategically implemented nationally adapted blended TVET and academic education policy. As such, this policy environment has operationalized a rarely seen collaborative governance institutional design and learning system, quadruple-loop learning. At the national level, quadruple-learning principals conditioned calculated risk-taking and innovation, which productively informed regional knowledge exchanges and policy. As an effective tool to recognize, identify, and manage wicked problems, the outcome of this research is a new quadruple-loop learning policy model useful across different regions, national contexts, and connected institutional systems. Data was collected from interviews, policy documents, environmental scans, and public records. Analysis methods employed triangulating coded data, and network and policy analyses to produce modified comparative multi-site case studies and a comparative analysis of case study findings. Keywords: Caribbean, CARICOM, development, education policy, Ideal Caribbean Person, poverty abatement, networks, regional policy, skilled labor migration, social networks, sustainability, TVET, quadruple-loop learning, wicked problems
    • Chemical and Isotopic Characteristics of Sedimentary Basin Formation Waters for Evaluating Cross-Formational Mixing, Tracers of Contamination, and Li Resources

      McIntosh, Jennifer; Marza, Mohammad; Ferguson, Grant; Meixner, Thomas; Guo, Bo (The University of Arizona., 2022)
      Understanding the origin, diagenetic history, chemical composition, and migration pathways of saline fluids in sedimentary basins is important for extraction of subsurface resources (e.g., critical elements, such as Li), storage of alternative energy (e.g., H2) and saline produced waters, and long-term sequestration of anthropogenic CO2 and spent nuclear fuel. The presence of confining units, such as evaporites and shale, may impede basinal-scale fluid flow and can be a source of highly saline fluids to adjacent formations. Upward migration of saline fluids may contaminate surface waters or shallow aquifers. Identifying the source of saline fluids (e.g., fluids sourced from specific oil/gas reservoirs) through unique fluid isotopic signatures may help to remediate contamination. This issue is complicated by the fact that many subsurface reservoirs have been altered by extensive fluid injection activities (e.g., water flooding or disposal of produced, saline waters), which may modify original formation water chemistry. This dissertation aims to evaluate Sr isotopes as an adequate tracer for fingerprinting distinct sources of produced waters from overlapping oil/gas fields, influence of fluid surface storage and subsurface injection activities, and cross-formational fluid migration through evaporite confining units, combined with major ion, Br, and water stable isotope chemistry. Furthermore, this dissertation aims to explore the potential of Li production from sedimentary basin brines.To test the utility of Sr isotopes as a tracer of subsurface, saline fluid sources, Sr isotopes (87Sr/86Sr) of formation waters were evaluated from hydrocarbon reservoirs within three major oil/gas producing regions: the Williston, Appalachian, and Permian basins in North America. Based on a non-parametric statistical test, Sr isotope ratios of formation waters from multiple stacked oil and gas reservoirs within each basin have overlapping (i.e., non-unique) values. In regions where Sr isotope ratios of formation waters overlaps, Sr isotopes alone may not be a sensitive tracer of saline, produced water contamination in near surface environments, as previously proposed. Sr isotopes, along with major ion chemistry, Br, and water stable isotopes, were further applied to investigate the potential of fluid migration across a thick evaporite confining unit (Gotnia Formation) within the Kuwait Basin, as proposed by previous studies. Results indicate that the Pre-Gotnia (below the evaporites) and Post-Gotnia (above the evaporites) sections have distinct Sr isotopes signatures suggesting the Gotnia Formation impedes vertical fluid migration. These results are supported by major ion chemistry, Br, and water stable isotopes. The upward migration or downward leakage of saline water can deteriorate the quality of drinking water and modifies the formation waters chemical and isotopic signature. Interestingly, several of the subsurface reservoirs show extensive mixing with seawater, likely from water flooding activities for enhanced oil recovery. Replacement of formation waters by injection of different fluids may cause difficulties in fingerprinting sources of potential contamination, deteriorate the reservoir quality, lead to borehole scaling, and alter subsurface microbial activity. Li (and other critical elements) extraction from oil-field brines has been proposed, yet relatively little is known about the concentration of Li in various sedimentary basin fluids and potential extraction rates based on fluid fluxes. To address this issue, I investigated Li concentrations and potential Li extraction rates of formation waters from stacked oil/gas reservoirs in sedimentary basins across North America. Six of the basins contained [Li] above 65 mg/L, with the highest Li contents in the Smackover Formation in the Gulf Coast, E. Texas and Arkla basins (up to 1700 mg/L), which has been the focus of previous studies. The Paradox, Appalachian, Williston, Gulf Coast, East Texas, and Arkla basins also contained [Li] above 65 mg/L. In general, the highest Li concentrations are found in basinal brines sourced from highly evaporated seawater (halite to potash salt precipitation stage) from the geologic past. Li was then enriched by interaction with Li-rich rocks and minerals in the subsurface (e.g., detrital sediments, shales, and volcanic ash). Lithium concentrations and potential production rates are most promising in the Paradox Formation in the Paradox Basin, Clinton/Medina Groups in the Appalachian Basin, and Devonian section and Charles Formation in the Williston Basin. Results of this study show that basinal brines may be a competitive resource compared to more traditional continental brines for Li (and possibly other critical elements) production, worthy of further investigation.
    • From Sexual Objects to Sexual Survivors: Exploring the Cognitive Inconsistencies Within a Media Counter-Sexualization Script

      Stevens Aubrey, Jennifer; Terán, Larissa; Harwood, Jake; Rains, Stephen A. (The University of Arizona., 2022)
      Since the #MeToo movement of 2017, the modern media landscape reflects a set of two contradicting scripts in the media. The first is the dominant script where women are sexualized and encouraged to focus on their sexual appeal for men’s pleasure whereas men are encouraged to be sexual aggressors. The second is what I refer to as the Counter-Sexualization Script, wherein men are held accountable and punished for this same sexualization of women and women are valued outside of their sexualizing roles. Across three empirical studies, this dissertation investigated these cognitively inconsistent media messages. In Study 1, focus groups (n = 19) were conducted to conceptualize and develop items of the Counter-Sexualization Script. Three themes emerged in the focus groups: (1) Giving Women the Microphone, (2) Holding Predators Accountable, and (3) Consciousness Raising. These three themes served as the factors for the Counter-Sexualization Script measure. The identified themes informed 38 items for the Counter-Sexualization Script measure. In Study 2, I conducted factor analyses to examine if the Counter-Sexualization Script fit a three-factor structure with a separate sample of emerging adults (n = 605). Results indicated that the Counter-Sexualization Script fit a three-factor structure; 18 items were removed from the measure to improve model fit. The final Counter-Sexualization Script measure included 20 items and the three factors. Study 2 also established the convergent, predictive, and concurrent validity of the Counter-Sexualization Script measure. Results suggested that the Counter-Sexualization Script measure was uniquely distinct, yet negatively associated with similar concepts (e.g., self-objectification, sexism), demonstrated predictive ability with related concepts (e.g., heterosexual script endorsement, rape myth acceptance), and was positively associated with empathy towards rape victims; the Counter-Sexualization Script was not statistically associated with enjoyment of sexualization. Finally, individuals who had personal experience with sexual assault, sexual harassment, and were supporters of the #MeToo movement were the most likely to endorse the Counter-Sexualization Script. In Study 3, a 2 X 2 pre/post factorial experimental design (counter-sexualizing article and sexualizing article, sexualizing and neutral article, counter-sexualizing and neutral article, two neutral articles) was employed to investigate the effects of cognitively inconsistent media messages. Participants were recruited from Cloud Research and a large southwestern university (n = 308). Results exhibit that there are no significant direct effects from the message conditions on sexual aggression outcomes with one exception: There was a statistically significant interaction between media exposure to counter-sexualizing messages, endorsement in the Counter-Sexualization Script (pre-test score), and bystander intervention intentions. At low levels of endorsement in the Counter-Sexualization Script, participants who were exposed to a counter-sexualizing media message reported lower bystander intervention intentions. For the cognitive dissonance outcomes, there were no significant direct effects from the message conditions on psychological discomfort, counterarguing, or neglectful feelings towards the self with one exception: participants who were exposed to a sexualizing message versus those who were not reported greater psychological discomfort. Finally, mediation analyses exhibit that psychological discomfort mediated the relationships between the message conditions, neglectful feelings towards the self, and counterarguing. Results across the three studies have theoretical implications with sexual counter scripts and contradicting media messages. Also, results have implications for practitioners, media executives/producers, and parents regarding the affective and uncomfortable state produced by cognitively inconsistent media messages regarding sexualization.
    • Microcircuit Electrophysiological Functional Relationships in the Cortico-Basal Ganglia Network with Deep Brain Stimulation in Parkinson's Disease

      Greger, Bradley; Qiu, Shenfeng; Guest, Ashley Cerise; Mirzadeh, Zaman; Kruer, Michael; Anderson, Trent (The University of Arizona., 2022)
      Objective: This dissertation aims to learn about the neural networks involved with using deep brain stimulation (DBS) to treat Parkinson’s disease (PD) and increase our understanding of the mechanism of DBS. The particular focus is on examining network dynamics in the cortico-basal ganglia (BG) circuit and how DBS modulates functional connectivity in the cortico-BG circuit. The overarching hypothesis of this work is that DBS changes electrophysiological environments to alter the brain’s activity on a network level, examined here in the cortico-BG network in PD. Background: Deep brain stimulation (DBS) is the therapeutic use of chronic electrical stimulation of the brain via an implanted electrode and is a treatment for a variety of neurological disorders. The brain is an electrically active organ, containing neurons that communicate in circuits using action potentials (APs) and local field potentials (LFPs). We can infer information about how neurons communicate by studying these signals, how they behave in PD, and how they respond to DBS. PD is a neurodegenerative disease that manifests motor symptoms of bradykinesia, tremor, and rigidity, as well as a host of non-motor symptoms including cognitive impairment. It is characterized by a loss of dopamine (DA) neurons in the substantia nigra (SN), which has downstream effects on the function of the cortico-BG network. The cortico-BG network is an intricate web of connections between anatomical areas that regulates movement. DBS is used to treat the motor symptoms of PD with widespread success and has long-lasting efficacy. The DBS electrodes are placed into subcortical structures in the cortico-BG network, most commonly the subthalamic nucleus (STN) and the globus pallidus internus (GPi). There are many theories concerning how DBS works, and this project sought to provide increased mechanistic understanding. Empirical evidence attests to the effectiveness of DBS as a treatment for PD and how it must change some pathological activity to restore motor function. I hypothesized that rather than changing individual neuron properties, DBS acts on neuronal microcircuits embedded in the greater cortico-BG network as part of its neuromodulatory mechanism. Methods: Data was recorded during surgery for DBS electrode implantation from 2 sources: a microelectrode placed in the surgical target (STN or GPi) and a µ-electrocorticography (ECoG) grid placed on the motor association cortex. In one group of subjects, as the microelectrode was lowered along the surgical trajectory, we stopped at multiple sites with neuronal activity for periods of approximately 0.5-5 minutes. In another subset of subjects, DBS was applied across subtherapeutic, thereapeutic and supratherapeutic frequencies. The electrophysiological functional relationships between the STN or GPi and the cortex were studied using through examining APs and LFPs and their temporal and spatial connectivity. Additionally, I examined the DBS waveform and the relationship between the electromotive force (EMF) generated by DBS and distance to the recording electrode. Results: A subset of individual neurons in the STN has an electrophysiological functional relationship to the local electrical environment, and another subset of STN neurons has functional connectivity with the cortex as measured with the AP aligned average LFP. These electrophysiological connections have a high degree of spatial specificity, differing between neighboring neurons and within a few millimeters on the cortex. The effect of DBS on these microcircuits was an increase in LFP power in the alpha band (8-12 Hz) during 140 Hz stimulation. DBS modulated activity in the cortico-BG network at a therapeutically relevant frequency of 140 Hz, but not at subtherapeutic and supratherapeutic frequencies. The DBS waveform is attenuated as distance from the source of stimulation (the DBS lead) increases. Conclusions: The STN and the motor association cortex had an intricate and complex functional connectivity with a high degree of spatial specificity. The topographies of these functional connections varied across neurons and on a sub-centimeter scale on the cortex. When DBS was applied changes in these functional connections were seen with stimulation delivered at 140 Hz. These microcircuits are embedded within in the larger cortico-BG network and are affected by a therapeutically relevant frequency of DBS. The pathological activity in the cortico-BG network is modulated on fine temporal and spatial scales, which explains some of the short-latency effect of DBS on motor symptoms. Significance: We expect the outcomes of this project to be a better understanding of the electrophysiological mechanisms underlying the therapeutic effects of DBS. The broader implications of this research include improving DBS as an intervention and expanding its application to other neurological disorders. Examining the cortico-BG circuit is important in the effort to understand both normal and abnormal motor information processing and to improve neuromodulation therapies.
    • Much to Do about Non-Things: Exploring Agency and Responsibility Through Omissions

      Sartorio, Ana C.; Metz, Joseph William; McKenna, Michael; Turner, Jason; Horgan, Terence (The University of Arizona., 2022)
      This dissertation centers on agency and moral responsibility concerning actions and omissions, developing a unified account of responsibility for actions and omissions while still respecting the differences and asymmetries between them. This account is unified in that responsibility both for actions and omissions is based on the same type of ability – in particular a very weak type of ability. However, the relevant scope of the abilities required for responsibility differs for omissions and actions. Roughly, responsibility for omissions requires the ability to perform the omitted act, which therefore also requires the ability to do otherwise. Responsibility for actions does not require the ability to do otherwise. Much work has been done on actions, and some recent work has been done on omissions, but very little has been done that accommodates both, as well as their differences, into a single account. Particularly central to my project is accommodating and exploring the implications of the various asymmetries that arise between actions and omissions, which are relevant to causation, agency, responsibility, and luck. I discuss several practical applications of these asymmetries concerning how we should judge ourselves and others in virtue of our positive and negative agency, and concerning moral – and likely legal – responsibility as well.
    • Evaluating the Effect of Adenine Nucleotide Translocase-1 Acetylation on Mitochondrial Bioenergetics and Metabolic Inflexibility

      Mandarino, Lawrence J.; Barakati, Neusha; Willis, Wayne T.; Coletta, Dawn K.; Luo, Moulun; Zapata Bustos, Rocio (The University of Arizona., 2022)
      ANT1 in human mitochondria was previously identified as an acetylated protein and lysines 10, 23, and 92 of human ANT1 were noted to be acetylated in most of preparations of mitochondria isolated from human skeletal muscle biopsies. Lysine 23 contributes to a net overall positive charge in the nucleotide binding pocket of ANT1, molecular dynamics modeling showed that acetylation of lysine 23 reduced the positive charge and lowered the affinity of hANT1 from about 3 to 80 M [ADP]. Further computational modeling studies showed that if about 25% or higher of total ANT1 were acetylated, the apparent Km ADP for oxidative phosphorylation would be increased sufficiently to affect ANT1 function, with consequences for glycolysis and fuel selection.Based on previous findings, we decided to evaluate the involvement of altered acetylation of ANT 1 at lysine 23 in regulation of fuel selection and mitochondrial bioenergetics. This thesis consists of three chapters that describe the involvement of altered acetylation of ANT 1 at lysine 23 in regulation of fuel selection. The first chapter describes a luciferase-based assay to evaluate the ADP kinetic parameters of mitochondrial ATP production and the extent of control that ANT has in this pathway. The high sensitivity, reproducibility of this assay enabled to assess ADP kinetic parameters and ANT flux control in isolated mitochondria from skeletal muscle. It is confirmed that under the conditions used to study isolated mitochondria, the majority of flux control over oxidative phosphorylation resides at ANT. The second chapter deals with the question of relationship between acetylation of ANT1 and ANT1 content with metabolic flexibility during insulin stimulation or mild exercise. The findings from human skeletal muscle do not provide evidence that the extent of lysine 23 acetylation of ANT1 is a predictor of fuel selection at low [ADP]. Acetylation of lysine 23 of ANT1 is abundant and variable but perhaps too low to discernibly affect the sensitivity of mitochondria to the respiratory signal provided by [ADP] during conditions of insulin stimulation or mild muscle contraction. However, greater ANT1 content, either as a marker of greater mitochondrial abundance or higher specific abundance of ANT1 per mitochondrial mass, could result in changes in fuel selection by lowering the apparent K0.5ADP, driving skeletal muscle toward higher lipid oxidation during mild exercise. The participants in this study had normal or moderately abnormal glucose metabolism. It is conceivable that patients with more poorly controlled type 2 diabetes and more severe impairments in muscle fuel selection could have higher ANT acetylation. Consequently, it would be helpful to evaluate the extent and effect of ANT1 acetylation in this group. Finally, the last chapter provides actual experimental evidence whether loss of the positive charge at lysine 23 has any effect on the affinity of ANT for ADP. The cellular modeling experiments indicate that removing the positive charge of ANT1 at lysine 23 decreases the ability of ANT1 to bind ADP and result in a higher apparent KmADP for ATP production without changing the Vmax. Although it seems clear from modeling and simulation experiments that acetylation of lysine 23 of human ANT1 affects function, direct biochemical evidence is lacking regarding the extent of this effect. Experiments using ANT incorporated into artificial liposomes may help to answer this question.
    • Testing the Effects of an Affectionate Communication Intervention to Bolster Mental Health During the COVID-19 Pandemic

      Floyd, Kory; Woo, Nathan; Rains, Stephen A.; Pitts, Margaret J.; Hamann, Heidi A. (The University of Arizona., 2022)
      This study tested the efficacy of an affectionate communication intervention to help adults living in the United States bolster their mental health during the height of the COVID-19 pandemic. Ninety-eight married and cohabitating adults were randomly assigned to one of three groups: increased affectionate communication (treatment), increased thankfulness (comparison), or no change in behavior (control). The final sample contained 73 adults (ntreatment = 26, ncomparison = 24, ncontrol = 23) who completed the four-week intervention that started in September and concluded in October 2020. Although post-hoc analyses revealed that participants in the treatment group were, on average, less affection deprived, less depressed, less lonely, and less stressed than those in the comparison and the control groups halfway through the intervention and at the end of the intervention, these findings should be interpreted with caution due to a successful comparison manipulation, but a statistically nonsignificant treatment manipulation. Speculation as to why the intervention failed to reject the null hypotheses is presented in the discussion before providing methodological recommendations for future interventions in this area of research.
    • Reducing SARS-CoV-2 Vaccination Hesitancy in a Primary Care Setting

      Allison, Theresa; DeMello, Blythe; Pacheco, Christy; Locke, Sarah (The University of Arizona., 2022)
      Purpose: The purpose of this quality improvement project was to increase SARS-CoV-2 vaccination confidence and knowledge in adults who display reluctance or hesitancy through a brief educational discussion and a written pamphlet. Background: In recent history, the world was faced with an unprecedented challenge as a pandemic quickly encompassed the globe. In early 2020, this became commonly known and referred to as the COVID-19 pandemic. The severe health implications of this respiratory virus quickly overfilled hospitals and placed the health of communities at risk. To get ahead of further spread of COVID-19, it was pertinent to quickly develop an effective vaccine. Following rigorous clinical trials, two mRNA vaccines were approved by the United States (US) Food and Drug Administration (FDA). What seemed like a solution became a challenge within the US. The population of the US showed reluctance to participate in COVID-19 vaccination programs. Vaccine hesitancy related to COVID-19 mRNA vaccines prolonged communities achieving adequate herd immunity. Understanding why individuals were displaying vaccine hesitancy was pertinent for implementing strategies that would lead to increased mRNA COVID-19 vaccine compliance. Methods: Participants were recruited from Peak Family Practice in Colorado Springs, CO. A pre-survey was administered followed by a short one-on-one educational session reviewing a written pamphlet about mRNA vaccines and common misinformation related to COVID-19 vaccines. A post-survey was administered after the educational intervention. Each survey had the same five questions and assessed participant knowledge and confidence related to mRNA COVID-19 vaccines. Results: A total of 20 participants completed the pre- and post-survey responses, along with participating in the short educational session. No statistically significant differences were found, however, participants who changed their answers on post-survey showed an increase in confidence of mRNA vaccines as well as indicating they would be more likely to receive a COVID-19 vaccine. Conclusion: This educational intervention reviewing a written pamphlet of mRNA vaccine information was effective in increasing the confidence of mRNA COVID-19 vaccines in some participants. Participants who changed their post-survey answers indicated an increase in likeliness to receive COVID-19 vaccination and showed improvement in knowledge related to mRNA vaccines. Although there was evidence of clinical significance a larger sample size would be necessary to indicate true statistical significance.
    • Glyoxalase 1 as a Novel Molecular Marker of High-Grade Prostatic Intraepithelial Neoplasia and Causative Effector in the Progression of Prostate Cancer

      Wondrak, Georg T.; Rounds, Liliana; Nagle, Raymond B.; Chalasani, Pavani; Romagnolo, Donato; Roberts, Esteban; Riggs, Michael W. (The University of Arizona., 2022)
      The prostate is a male accessory sex gland that functions to produce many components of the seminal fluid including zinc and citrate, both of which are crucial to men fertility. The prostate gland has two main compartments: the stroma and the epithelium. Three cell types comprise the prostatic epithelium: secretory epithelial cells, basal/stem cells, and neuroendocrine cells. The prostatic epithelium is unique in that they are the only healthy human cells that produce energy by glycolysis rather than the Krebs cycle. Changes in the prostatic epithelium leading to malignant proliferation increase in incidence with age. Prostate carcinoma (PCa) is the leading malignancy and the second leading cause of cancer-associated deaths in the USA male population. PCa is a disease of the elderly and risk prediction becomes crucial. Most patients present low-risk, relatively indolent tumors; however, 20-30% of these men present tumor characteristics associated with high-risk PCa. High Grade Prostatic intraepithelial neoplasia (HGPIN) is the only widely accepted histological condition and precursor of invasive PCa. High glycolytic activity is an oncometabolic hallmark of cancer. Cancer cells turn to aerobic glycolysis for energy production in a process referred to as ‘the Warburg effect’ leading to accumulation of methylglyoxal (MG), a cytotoxic glycolytic byproduct responsible for the adduction of macromolecules, a process called advanced glycation end-products (AGEs) formation. Glyoxalase 1 (GLO1), also known as lactoylglutathione lyase (EC: 4.4.1.5), is part of the glyoxalase system, playing a crucial role in cellular detoxification of spontaneously formed MG. In a two-step reaction, GLO1 first catalyzes the conversion of highly reactive MG to S-D-lactoylgluthatione. The resulting thioester, in the case of MG, is then hydrolyzed by GLO2 to produce D-lactate and reformed glutathione (GSH). The cytoprotective glyoxalase system prevents formation of AGEs and promotes cell survival. GLO1 upregulation has been described in the context of metabolic and inflammatory stress in vitro and in vivo, serving as a cellular mechanism to detoxify high levels of MG, particularly in cancer, where high glycolytic rates as a result of the ‘Warburg effect’ are observed. Our laboratory has demonstrated GLO1 upregulation during tumor progression, observable in HGPIN and PCa versus normal prostatic tissue by immunohistochemistry in archival tumor samples. GLO1 upregulation was identified as a novel hallmark of HGPIN lesions. In PCa specimens, GLO1 expression correlated with intermediate–high risk Gleason grade but not with patient age, biochemical recurrence, or pathological stage. Using CRISPR/Cas9 we genetically engineered GLO1 knock-out isogenic clones from DU-145 prostate carcinoma cells to further examine the role of GLO1 in PCa. Interestingly, we showed upregulation of TXNIP (encoding the thioredoxin-interacting protein) in the DU-145-GLO1_KO as a function of GLO1 status. TXNIP is a master regulator of cellular energy metabolism and redox homeostasis, also considered a tumor suppressor. Furthermore, GLO1 elimination had a profound detrimental effect in the clonogenicity and invasiveness capacity. We also identified MMP-3 (encoding matrix metalloproteinase-3) and SPP1 (encoding secreted phosphoprotein 1) as the two genes displaying the most profound downregulation in response to GLO1 elimination. MMP-3 and SPP1 are two effectors implicated in the development of prostate cancer in the bone, tumor-associated inflammation, facilitating metastasis, and promoting drug resistance. Additionally, based on The Human Protein Atlas data, decreased survival probability correlated with high MMP-3 mRNA expression levels in tissue from prostate cancer patients suggesting that GLO1 expression status is a novel and underappreciated determinant of PCa invasiveness and patient survival. Our published GLO1 data generated some excitement in the private sector with a potential translational application for GLO1 in the clinical setting. Current studies performed at Roche Diagnostics seek to develop a methodology for the detection of malignant biochemical signatures in tissue by spectroscopic imaging. These signatures can be used as biomarkers of early prostate cancer associated with aggressive disease. GLO1 promises to be one of the targets of study. Our future goals seek to (a) have a better understanding of the molecular mechanisms underlining oncometabolic dysregulation in PCa, (b) an improved understanding of the molecular basis underlying early PCa with a focus on HGPIN lesions pursued in relevant murine models, (c) identify improved molecular therapeutics that allow early interventions targeting HGPIN and mPCa. Translationally, we seek to aid in the development of powerful prognostic and diagnostic biomarkers identifying HGPIN and PCa and the discovery and development of novel optics-based technologies for the antibody independent diagnosis and prediction of PCa grade and progression.
    • Developing Dithiocarbamate Derivatives as Copper-Dependent Antimicrobials Against S. pneumoniae and Other Pathogens

      Khanna, Rajesh; Johnson, Michael D. L.; Menghani, Sanjay Vijay; Knox, Kenneth S.; Shehab, Kareem W.; Tomat, Elisa (The University of Arizona., 2022)
      From the ancient Egyptians in 2500 BC using copper pots to prevent contamination of drinking water to the Greek physician Hippocrates writing about the application of dry copper powder on leg wounds to improve wound healing, humans have long known about the antimicrobial properties of copper. Mirroring the natural use of copper outside the human body, copper plays a role in innate immunity and host defenses. In the context of infection, it has been shown that the concentration of free copper ions within the blood increases 4-fold during infection. As it has been established that copper itself is antimicrobial, there has been a renewed effort to combine the efforts of copper with antimicrobials for synergistic biocidal effect. There is a growing body of evidence to use increased copper concentration to directly intoxicate intracellular pathogens within macrophages and other phagocytes as an antibiotic mechanism. In 2014, Festa et al. developed a copper-dependent antimicrobial against the fungus Cryptococcus neoformans that increases the efficiency of macrophage fungicidal activity. Following this model, we sought to identify small molecules with copper-dependent toxicity (CDT) through a targeted screen of compounds for antibiotic efficacy. From this targeted screen, we identified N,N-dimethyldithiocarbamate (DMDC) as a potent bactericidal copper-dependent antibiotic against Streptococcus pneumoniae in vitro with efficacy in significantly decreasing bacterial burden in vivo. DMDC was also proven to be antifungal against Coccidioides immitis, antiparasitic against Schistosoma mansoni, and antibacterial against Staphylococcus aureus. To provide mechanistic insights at the host-pathogen interface, we investigated DMDC’s interaction with innate immune phagocytes and found robust macrophage clearing of bacteria incubated with a combination of copper and DMDC. Zinc intoxication, hydrogen peroxide, and nitric oxide contribute to this rapid in vitro killing. Extending from the drug screening identifying DMDC, compounds derived from DMDC were screened and two compounds within the dithiocarbamate class were identified as copper-dependent bactericidal antibiotics with efficacy in vitro. One compound from the screen, TLA4, was an effective antibiotic in vivo. These findings identify and investigate copper-dependent antibiotics in the dithiocarbamate class, serving as a model for future development of similar compounds. Despite the successful clinical implementation of pneumococcal vaccines, the rise in disease caused by non-vaccine strains and antimicrobial resistance within S. pneumoniae are growing trends that exacerbate the impetus to develop novel antimicrobial strategies. The work detailed in this dissertation serves to contribute to this need.
    • Implementing and Evaluating Multiliteracies in College French: A Nested Case Study

      Smith, Blaine E.; Amgott, Natalie; Hellmich, Emily; Price, Joseph; Ferdinandt, Nicholas (The University of Arizona., 2022)
      In our globalizing world, language learners must navigate meaning across languages, audiences, and spaces to build multicultural and multilingual dialogues (Douglas Fir Group, 2016; New London Group, 1996). Second language (L2) researchers have responded to this multilingual paradigm by proposing multiliteracies curricula (Cope & Kalantzis, 2009; New London Group, 1996) to better equip language learners with the translingual and transcultural competencies necessary for interacting with other users of a language (Kern, 2003, 2004; MLA Report, 2007). Some scholars have further evaluated the implementation of such curricula to demonstrate the feasibility of innovative assessments (Byrnes, 2002; Van Gorp, 2018). While studies in language program evaluation and multiliteracies have contributed to the field of L2 teaching and learning, there is still little known about how stakeholders experience multiliteracies in L2 programs. To understand the tensions and opportunities fostered by multiliteracies, this three-article dissertation involved a nested case study (Thomas, 2011) of an undergraduate French program at a large university in the United States. Grounded in the overarching framework of complexity theory for L2 development (Larsen-Freeman, 2007), this design-based implementation research (DBIR) (Fishman et al., 2013) study explored the implementation and evaluation of multiliteracies at the macro, meso, and micro levels of an undergraduate French program. The first article, a language program evaluation grounded in complexity theory (Larsen-Freeman, 2007), examined the implementation of multiliteracies at the macro level of the French program by zooming in and out across the perspectives of 26 program stakeholders. Qualitative coding of program documents, 26 interviews, and 7 classroom observations revealed that multiliteracies provided opportunities to contextualize language learning and create social learning amongst multiliteracies instructors. Findings also indicated challenges for implementation such as the persistence of decontextualized “culture,” “language,” and “content.” At the meso level, the second article demonstrated how 185 undergraduate students enrolled in an Intermediate French II multiliteracies course experienced designing digital multimodal compositions. Grounded in multiliteracies, this qualitative analysis involved multimodal transcription (Flewitt et al., 2014) and open, axial, and selective coding (Strauss & Corbin, 1998) of 376 video reflections, 122 multimodal country presentations, 72 hypertext poetry projects, 32 multimodal presidential campaign projects, 39 final video projects, and 10 student interviews. Findings illustrated that digital multimodal composing helped students to develop critical literacy and a growth mindset while also creating a sense of community among classmates. The third article, a qualitative analysis grounded in multimodality (Kress, 2003; 2010), explored multiliteracies at the micro level by examining how seven undergraduate students from the United States leveraged multimodal composing to reflect on language, culture, and identity while studying French abroad in Paris, France. The study used multimodal transcription and open, axial, and selective coding to analyze 21 vlogs, 14 blogs, 21 video reflections, 7 final projects, and 7 design interviews. Findings elucidated how students developed their metalinguistic awareness and multilingual identities through their digital multimodal compositions. The examination of the macro, meso, and micro levels of the undergraduate French program holds important implications for conducting program evaluations, implementing multiliteracies curriculum for language learning, and applying multimodal composing in domestic and study abroad language learning programs for college students.
    • Resistive Robotic Gait Training to Restore Neuromuscular Function in Cerebral Palsy

      Lerner, Zachary F.; Kruer, Michael C.; Conner, Benjamin Charles; Schaefer, Sydney Y.; Duncan, Burris "Duke" (The University of Arizona., 2022)
      Individuals with cerebral palsy (CP) have deficits in strength and neuromuscular coordination, which contribute to a slow and inefficient gait pattern that makes walking difficult for an overwhelming majority of this population. Previous interventions seeking to address these aspects of gait dysfunction in CP have been unsuccessful to date in addressing both muscle weakness and motor control. In an effort to address this gap in clinical care, we developed and validated an adaptive control scheme in conjunction with an untethered ankle exoskeleton device to provide ankle plantar flexion resistance during walking that was responsive to user input. We found that compared to baseline, walking with adaptive plantar flexion resistance resulted in a 45 ± 35% increase in stance-phase plantar flexor activity (p = 0.02) and a 46 ± 25% reduction in stance-phase co-contraction at the ankle (p = 0.02) for children and young adults with CP. This modality was then applied in a pilot clinical trial in CP, whereby six pediatric participants completed ten, 20-minute training sessions with adaptive plantar flexion resistance over four weeks. We observed significant improvements in measures of strength (17 ± 8% increase in ankle plantar flexion strength, p = 0.02), preferred walking speed on a treadmill (39 ± 25% increase, p = 0.04), energetic efficiency (33 ± 9% reduction in metabolic cost of transport, p = 0.03), and measures of mobility (11 ± 9% improvement in timed up and go performance, p = 0.04; 13 ± 9% increase in six minute walk test distance, p = 0.04). These improvements in gross measures of performance were likely a result of observed improvements in neuromuscular control and mechanical efficiency, with training resulting in a 29 ± 11% decrease in co-contraction at the ankle (p = 0.02), a 33 ± 13% more typical soleus muscle activation profile (p = 0.01), a 7 ± 3% increase in neural control complexity (p < 0.01; measured via muscle synergy analysis), and a 58 ± 34% more mechanically efficient gait pattern (p < 0.05). Overall, this novel resistive robotic gait training paradigm demonstrated significant promise in improving strength and neuromuscular control at the ankle for improved mobility in children with CP. To further enhance the efficacy of this intervention, we developed an electrodeless audiovisual biofeedback system that utilized force sensitive resistors to display real-time plantar pressure to a user while walking. In validating this system against a soleus electromyography (EMG) biofeedback system in eight individuals with CP, which was considered the gold standard, we found comparable increases in mean soleus muscle activation relative to baseline (43 – 58%, p < 0.05), as well as mean (68 – 70%, p < 0.05) and peak (71 – 82%, p < 0.05) medial gastrocnemius activation, with strong relationships between the two systems for these outcome variables (R = 0.89 – 0.94). When this system was applied to our adaptive plantar flexion resistance scheme, it rapidly increased mean (36%, p < 0.05) and peak (46%, p < 0.05) soleus activation relative to resistance alone. The integration of this plantar pressure biofeedback system may help to improve active engagement with our resistive ankle exoskeleton scheme, reducing the necessity of constant verbal coaching or long acclimation periods. Finally, we aimed to better understand the underlying neuromuscular response to walking with our resistive ankle exoskeleton, as well as answer fundamental questions about reflex modulation in CP. We tested the effect of changes in motor task complexity, requiring varying levels of ankle stability, on soleus H-reflex excitability in this population. We found that individuals with CP displayed the typical decrease in soleus H-reflex excitability with increased standing task complexity (-26 ± 27%, p = 0.04). We also observed significant inverse relationships between soleus H-reflex amplitude and co-contraction at the ankle during both complex standing (R = -0.58, p < 0.01) and walking (R = -0.52, p < 0.01) tasks, suggesting the presence of reciprocal inhibition, which was previously thought to be absent in CP.