The UA Dissertations Collection provides open access to dissertations produced at the University of Arizona, including dissertations submitted online from 2005-present, and dissertations from 1924-2006 that were digitized from paper and microfilm holdings.

We have digitized the entire backfile of master's theses and doctoral dissertations that have been submitted to the University of Arizona Libraries - since 1895! If you can't find the item you want in the repository and would like to check its digitization status, please contact us.


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Recent Submissions

  • Automated Localization of Dynamic Code Generation Bugs in Just-in-Time Compilers

    Debray, Saumya; Lim, HeuiChan; Collberg, Christian; Kobourov, Stephen; Rahaman, Sazzadur (The University of Arizona., 2024)
    This dissertation presents a new approach to the automatic localization of dynamic code generation bugs in Just-in-Time (JIT) compilers. JIT compilers are widely utilized to improve the performance of interpreted code. However, incorrect code generated by JIT compilers may pose significant security risks or raise a reliability concern. Therefore, addressing bugs quickly is essential to mitigate potential security concerns and improve code quality. Existing bug localization approaches for ordinary software or traditional compilers often fall short when applied to JIT compilers. The approaches overlook essential features of JIT compilers, including their size and complexity, dynamic code generation, and the absence of debugging information. The core approach proposed in this dissertation is to model the execution behavior of the JIT compiler explicitly. These models are system independent, meaning that the approach can be used to construct models for different JIT compilers, such as Google’s TurboFan and Mozilla’s IonMonkey. The approach focuses on modeling two key JIT compiler behaviors: The optimization of the optimizer’s intermediate representation (IR) and the manipulation of the back-end representation for code generation. By carefully examining the modeled representations, the approach aims to identify sections of representations that are manipulated incorrectly. Then, by analyzing the memory accesses within the models, the approach identifies the buggy location in the JIT compiler source code (i.e., functions). The approach is based on two key insights: (1) the constructed model should be an abstract representation of concrete JIT compiler representations, i.e., the model should hold information that are common to multiple JIT compiler representations, and (2) the difference between a model constructed from a buggy execution and a model constructed from a non-buggy execution should contain information about the bug. Another critical technique to improve the bug localization accuracy proposed in this work is automated test program generation, as the characteristics of the input test programs can significantly impact bug localization performance. The following two key insights motivated the approach: (1) the generated test programs should contain both passing inputs (which do not trigger the bug) and failing inputs (which trigger the bug), and (2) the passing inputs should be as similar as possible to the initial seed input, while the failing programs should be as different as possible from it. Experimental results using a prototype implementation on two widely used JavaScript JIT compilers, namely Google’s V8 TurboFan and Mozilla’s IonMonkey demonstrates that the proposed approach achieves a higher accuracy in identifying suspicious functions related to dynamic code generation bugs compared to existing approaches
  • Accountability Rhetoric in Language Policies: First Year Composition Teachers and Culturally Sustaining Pedagogies

    Baca, Damián; Carter, Tamara; Ramirez, Cristina; Smith, William; Lanehart, Sonja (The University of Arizona., 2023)
    This paper examines how Graduate Teaching Assistants (GTAs) at Pacific Conference (Pac-12) universities are trained to teach First-Year Composition (FYC) and introductory writing skills that meet the learning needs of diverse student populations. It also analyzes how the online institution's rhetoric and English department policies fail to address the accountability of teachers for culturally sustaining pedagogy and curricula that include students' linguistic rights. The project presents two different analyses to confront the urgency of training GTAs in antiracist pedagogy and curriculum before they teach an FYC or introductory writing course. It also aims to restructure education policies to support diversity and inclusion classroom practices and the linguistic rights of students of color. The primary findings of the analyses are as follows: 1) Most FYC and introductory writing courses are taught by graduate students, 2) Nationally, most GTAs receive no training in teaching students of color. However, at Pac-12 institutions, GTAs receive formal or informal training on how to teach writing skills across racial differences, identify alternative grading assessments, conduct regular self-assessments utilized to complete a yearly report on their teaching strengths and weaknesses, and receive department evaluations on their classroom practices, 3) The University of Arizona and Arizona State University, the only Hispanic Serving Institutes (HSIs) in the conference, receive numerous grievances for racial discrimination and injustices on their campuses, 4) In recent years, Pac-12 institutions have made diversity and inclusion the focus of current initiatives, 5) There is enough evidence to support scholarly arguments (e.g., April Baker-Bell, Asao Inoue, Vershawn Young, Stacey Perryman-Clark) for students' language rights and institutional policy reform reflecting the needs of marginalized students.
  • Measuring White Matter Changes in Alzheimer’s Disease Using a Novel Technique

    Su, Yi; Lifshitz, Jonathan; Bhargava, Vedanshi; Reiman, Eric; Chen, Kewei; Kiehlbaugh, Kasi (The University of Arizona., 2024)
    White Matter Hyperintensities (WMHs), defined as areas of increased signal intensity within white matter in T2-weighted MRIs, were once classified as “incidental findings” associated with aging. Recently, WMHs have been increasingly shown to be relevant in various diseases including Alzheimer’s disease (AD). Although MRI is commonly used to detect and measure WMHs, MRIs cannot provide us with a biological understanding of WMH. On the other hand, PET tracers can provide us with physiological information by binding to a specific molecule. In this thesis, we ask the question, are amyloid PET tracers measuring white matter changes associated with the core biomarkers of AD? Does this myelin-specific measure give us more information about white matter changes in AD? Briefly, we find that amyloid PET tracer Florbetapir (FBP) uptake in white matter is associated with various multimodal biomarkers of AD including amyloid, tau, and neurodegeneration. WMHs were only found to be associated with measures of amyloid and neurodegeneration. In sum, we provide evidence in support of the use of amyloid PET tracers for tracking white matter changes in the AD brain and evidence for their relevance in AD pathology.
  • An Optical Atomic Clock based on Frequency Comb Spectroscopy

    Jones, Ronald J.; Erickson, Seth E.; Anderson, Brian P.; Wilson, Dalziel J. (The University of Arizona., 2024)
    Doppler free two-photon spectroscopy of 87Rb is a leading candidate for a portable frequency standard with instability comparable to a hydrogen maser. The required 778 nm light has been achieved through second-harmonic generation of continuous wave (cw) lasers, due to the availability of compact, narrow linewidth, fiber-coupled telecom diodes at 1556 nm. The cw laser was then compared to a frequency comb to convert the optical frequency into a radio frequency. It is alternatively possible to excite the same transition directly with a frequency comb, removing the need for the cw laser and increasing the efficiency of second-harmonic generation. Previous efforts to utilize direct comb spectroscopy as a frequency standard have shown larger instability than their cw counterparts, due in large part to residual Doppler broadening from pulses lasting less than one ps. Herein are discussed the relevant considerations to make direct comb spectroscopy perform equivalently to cw two-photon spectroscopy, most importantly, narrowly filtering the optical bandwidth. The leading sources of instability are explained and methods for compensation are implemented. Features which distinguish direct comb spectroscopy from cw two-photon spectroscopy, such as spectral aliasing, pulse overlap volume, and the residual Stark shift, are evaluated theoretically and experimentally. Direct comb spectroscopy is shown to be capable of resolving the two photon transitions with equivalent linewidth and equivalent ac-Stark shift compared to cw two-photon spectroscopy, with total fluorescence capture of up to 60%. By recording relative frequency deviations between two nearly identical direct comb clocks, instability rivaling the state-of-the-art compact optical frequency standard is shown, with fractional frequency Allan deviation at 1.7×10−13 at one second averaging down to 3×10−14 at 1000 s before drifting in longer timescales. The drift at times longer than an hour is shown to correlate with room temperature, offering some explanation for its source and solution. Efforts towards miniaturization and packaging and future directions for research are discussed.
  • Synthesis of Bioactive Molecules Enabled by Photoredox Catalysis

    Wang, Wei; Dong, Yue; Wondrak, Georg; Chapman, Eli; Mash, Eugene (The University of Arizona., 2023)
    Photoredox catalysis stands out as the foremost strategy for manipulating open-shell radicals in a diverse range of chemical transformations. These are often impossible or challenging to achieve using conventional ionic pathways. This method is distinguished by its gentle reaction conditions, compatibility with biological systems, and wide tolerance for various substrates. Consequently, photoredox catalysis has found applications in total synthesis of natural products, modification of biomolecules (such as proteins, DNA, and saccharides), as well as the synthesis of novel materials. In contrast to the traditional polar strategy, where certain synthons like organometal complexes may be less reactive and labile, the radicals' precursors like carboxylic acids, halogens, esters, amines, olefins, etc. are typically stable on the bench, readily available, and the radicals themselves are highly reactive. This leads to a markedly distinct approach in construction of target molecules. In this context, we have developed a series of innovative methods for synthesis of utilizing photoredox catalysis. In the first effort, a mild organophotoredox synthetic protocol for forming a Csp3−S/Se bond by reacting widespread redox-active esters with thio/selenosulfonates has been developed. The mild process serves as a viable strategy for the synthesis of both alkyl−alkyl and alkyl−aryl sulfides with outstanding functional group tolerance. Furthermore, an unrivaled feature of the process is to employ the feedstock carboxylic-acid-derived RAEs as radical progenitors, and an unprecedented broad substrate scope is achieved. These merits make this protocol a promising strategy for the construction of C−S bonds in widespread applications within organic synthesis. In the second effort, a mild metal- and oxidant-free visible-light photoredox mediated selective C3-formylation of indoles is developed. The newly uncovered process is synthetically sustainable by using readily accessible indoles and feedstock glyoxylic acid as the formylation reagent, molecular oxygen (air) as the terminal oxidant, and visible light without requiring an external PC or additional amine catalyst. A new self-activation mode by the generation of byproduct isatin as PC was found. The synthetic strategy has been successfully adopted for the practical synthesis of C1-deuterated 3-formylindoles. A cost-effective deuterated glyoxylic acid as a new formyl deuteration reagent has been developed for this demand. The mild, operationally simple protocol serves as a general powerful method for the practical synthesis of structurally diverse C1-deuerated 3-formylindoles with broad functional group tolerance and late-stage deuteration of complex structures at high level (95−99%).. In the third effort, a mild, versatile photoredox protocol for the efficient incorporation of aromatic and alkyl side chains and deuterium into (S)-methyleneoxazolidinone is developed. The method delivers structurally diverse chiral α-deuterated α-amino acid derivatives in good yields with excellent diastereoselectivity and uniformly high levels of deuterium incorporation. The employment of readily available starting materials, inexpensive and safe D2O as a deuterium reagent, mild reaction conditions, and operational simplicity makes the method practical in synthesis. Notably, the approach has significantly expanded the scope for accessing both aryl and alkyl side chain-containing α-amino acids. It is expected that the synthetic method and the valued deuterated amino acid building blocks will find broad applications in organic and medicinal chemistry.
  • High-Dimensional Data Analytics Based on Spatial-Temporal Decomposition

    Liu, Jian; Zhang, Yinwei; Fan, Neng; An, Lingling (The University of Arizona., 2023)
    In the last decade, significant progress in sensing and data storage technologies has ushered in a new era of spatiotemporal data analysis. This progress has dramatically increased the availability and scale of spatiotemporal data, presenting both exciting opportunities and complex challenges in this field. Spatiotemporal data from various sources exhibit unique patterns, but they share two common characteristics: (i) anomalies in spatiotemporal data are typically sparse, meaning that the number of anomalies is significantly less than the number of normal data, and (ii) anomalies cause deviations from the normal patterns of the data. To illustrate the practical application of these principles, consider a water distribution system (WDS). A sudden burst in the system can lead to a substantial drop in water pressure compared to normal conditions. To efficiently detect such anomalies, a penalized regression model based on basis expansion is introduced. This model effectively captures the features of hydraulic measurements through basis coefficients. It encourages sparsity in the anomalies (such as bursts) by applying an $L_1$ penalty. Furthermore, it encourages normal measurements to align closely with the sample mean through an $L_2$ regularization term. The model is solved using an optimization algorithm, and its performance is evaluated through a simulated case study. In the context of additive manufacturing, where images capture the manufacturing process, the profile of objects being produced must be extracted accurately. This is particularly challenging due to variations in pixel intensities between the cured profile and the background, which are caused by differences in optical properties. To address this, a tensor decomposition-based method is introduced. Difference matrices are employed to penalize variations in pixel intensities both vertically and horizontally, promoting smoothness in the background. Simultaneously, an $L_1$ regularization term enforces sparsity in the cured profile. The optimization model is solved to estimate the profile, with the effectiveness of this approach demonstrated through both simulated and real-world case studies. In the context of a surveillance system, the primary goal is to detect moving targets, especially when dealing with a moving camera. To achieve this, a novel optical flow-based method is proposed. Beyond considerations for background smoothness and foreground sparsity, this method introduces a total-variance regularization mechanism based on patches. This ensures that the optical flow associated with the foreground moves consistently. Real-world case studies are used to validate the proposed model's performance in detecting moving objects.
  • The Role and Regulation of the Mechanistic Target of Rapamycin Complex 2 and Ras in Non-Small Cell Lung Cancer Cell Migration

    Charest, Pascale G.; Werner, Alyssa Nicole; Mouneimne, Ghassan; Schwartz, Jacob; Montfort, William (The University of Arizona., 2023)
    Cell migration is vital in normal cellular functions, such as development and immune responses. However, in the case of cancer cells, abnormal regulation of the signaling pathways that govern cell migration can lead to cancer metastasis, the cause of 90% of cancer-related deaths. The mechanistic Target of Rapamycin Complex 2 (mTORC2) is increasingly implicated as a regulator of cell migration, however its activation and potential signaling mechanisms are incompletely understood. Lung cancer is the leading cause of cancer-related death in both the US and the world and 70% of lung cancers are metastatic at diagnosis. Therefore, we utilized the A549 Non-Small Cell Lung Cancer (NSCLC) cell line to investigate mTORC2 signaling and mTORC2-mediated migration in lung cancer cells. We investigated two potentially implicated membrane receptors, CXC-motif Receptor 4 (CXCR4) and Epidermal Growth Factor Receptor (EGFR) and found that both could activate mTORC2 and mTORC2-mediated migration. Interestingly, we found that when the receptors were activated in combination, the mTORC2 downstream substrate AKT was robustly phosphorylated, but migration was not significantly increased. Therefore, we propose a feedback mechanism between mTORC1 and mTORC2, modulated through AKT activity. We also identified PI3K and Src as signaling partners of mTORC2 leading to AKT activation. Furthermore, Ras GTPases and their oncogenic mutations have recently been linked directly to mTORC2 activation. Therefore, we used a CRISPR/Cas9-based gene knock-in approach to determine a role for oncogenic Ras versus wild-type Ras proteins in mTORC2 activity and cell migration. Interestingly, we found that in A549 cells, neither oncogenic Ras nor wild-type Ras contributes to mTORC2 or mTORC2-mediated cell migration, but we do highlight a role for wild-type Ras proteins in the proliferation of A549 cells. Taken together, our work defines novel mTORC2 signaling mechanisms in A549 NSCLC cells.
  • Advancement of FDM 3D Printable Materials Through Epoxy and Benzoxazine Chemistry

    Loy, Douglas A.; Peiris, Edirisinghe Arachchige Dineshi Anupama; Mash, Eugene; Jewett, John; Muralidharan, Krishna (The University of Arizona., 2024)
    The field of additive manufacturing (AM) continues to capture significant interest from both academic and industrial sectors. In order to expand its usage across a broader range of applications, there exists a persistent desire to develop novel materials that are compatible with diverse AM technologies. This dissertation offers a comprehensive exploration of thermoset 3D printing, with the goal of expanding the material options available and enhancing the potential of Fused Deposition Modeling (FDM). The first chapter provides a thorough review of recent advancements in thermoset 3D printing technologies, analyzing material formulations, printing processes, and post-curing methodologies. The second chapter addresses the limitations of FDM due to the restricted availability of commercial materials with reactive functionalities and introduces a new di-telechelic epoxy polymer thermoplastic filament. This filament demonstrates excellent printability in FDM, offering a promising avenue to diversify material options for various applications. Moreover, the dissertation investigates the challenge of associating FDM 3D printing with thermosets, a relatively underexplored area. In Chapter 3, an epoxy-polybenzoxazine-based composite filament is introduced, formulated using the di-telechelic epoxy polymer from Chapter 2, and a benzoxazine monomer to print thermosets. The low-temperature filament extrusion and successful printing, followed by high-temperature post-curing, resulted in an epoxy-polybenzoxazine thermoset with almost 100% thermoset content and excellent thermal properties. Furthermore, the dissertation delves into the synthesis and characterization of main chain benzoxazine polymers incorporating Diels-Alder moieties (DA-MCBPs) in Chapter 4, to be used in FDM 3D printing low shrinkage thermosets. This includes the successful synthesis of monomeric precursors, including furan-functionalized benzoxazine precursors (BA-FBz and BS-FBz) and Bismaleimides (BMIs), followed by DA-MCBP polymer synthesis. The thermal characterization of DA-MCBPs provides valuable insights into selecting suitable DA-MCBPs for further studies and post-curing parameters for FDM 3D printing. This research establishes a foundation for employing DA-MCBPs in unconventional FDM 3D printing, opening avenues for producing thermosets with enhanced thermal properties. Finally, Chapter 5 provides an overview of potential future work for the projects discussed in Chapters 2, 3, and 4.
  • Molecular Determinants of Diffuse Midline Glioma of the Pons Vulnerability to the Histone Deacetylase Inhibitor, Quisinostat

    Berens, Michael; Paine, Danyelle; Sharma, Shalini; Mouneimne, Ghassan; Katsanis, Emmanuel (The University of Arizona., 2023)
    Diffuse Midline Glioma of the Pons (DMG/Pons) represents a highly aggressive pediatric high-grade glioma, standing as a predominant cause of brain tumor-related fatalities in children. Despite persistent efforts over the last four decades, no clinically approved therapy has emerged, leaving fractionated focal radiation as the sole standard of care. Genomic and molecular scrutiny has unraveled pivotal mutations in histone-encoding genes, genetic drivers, and alterations in DNA methylation patterns within DMGs, offering critical insights into tumorigenic mechanisms. The concurrent development of in vitro and in vivo DMG models has opened avenues for investigating novel therapeutic interventions. Notably, treatment-naive patient-derived xenograft (PDX) models, characterized by their untreated status, provide a unique opportunity to explore the natural state of DMGs before any intervention. The hallmark epigenetic anomaly in DMGs involves a histone H3 mutation, specifically a substitution of lysine with methionine at residue 27 (H3K27M). This mutation instigates profound reprogramming and alterations in the tumor microenvironment. Histone deacetylase inhibitors (HDACi), exemplified by Quisinostat, have exhibited clinical efficacy across various cancer types, inducing apoptosis, growth arrest, and regression of oncogenic phenotypes. Our study sets out to probe the effects of Quisinostat on DMGs, with a keen focus on its influence on the genome, transcriptome, and patterns of cell-free DNA fragmentation. In our investigation, two DMG models, PBT-22 and PBT-29, both carrying H3K27M and TP53 mutations, displayed a remarkable 30-fold difference in response to Quisinostat treatment. Western blot analysis showcased heightened protein expression of H3K27ac and H3K27me3, while H3K27M expression remained largely unchanged in both cell lines. RNA sequencing further delineated distinct gene expression profiles for each cell line, featuring commonalities and differences. Upregulated genes orchestrated cell signaling cascades, cell growth, collagen production, stemness, chromatin remodeling, and transcription. Conversely, downregulated genes were associated with chromatin remodeling, lysine and DNA methyltransferases, cell cycle, apoptosis, ATP-binding cassette, and immune response. Validation experiments with additional cell lines affirmed these findings. Crucially, examination of cell-free DNA fragmentation patterns pre- and post-Quisinostat treatment disclosed discernible differences in fragment lengths. Treated groups exhibited shorter fragments than controls, with the most resistant cell line, PBT-29, displaying the shortest fragment lengths. In summary, this comprehensive study delves into the multifaceted impact of Quisinostat on DMGs, unraveling alterations at the genomic, transcriptomic, and cell-free DNA fragmentation levels. These revelations furnish crucial insights into potential therapeutic avenues for addressing the complexities of this formidable and aggressive brain tumor.
  • Advancing the Biological Insights of Chromatin Accessibility Profiling: Improved Methodologies Spanning From Bulk Populations Down to Single-Cell Resolution

    Cusanovich, Darren; Romanoski, Casey; Zhang, Hao; Romanoski, Casey; Cusanovich, Darren; Wilson, Jean; Paek, Andrew (The University of Arizona., 2023)
    Chromatin accessibility profiling is a cornerstone in epigenomic exploration, providing insights into the regulatory mechanisms that orchestrate gene expression. Understanding these mechanisms is critical as they establish the nexus between genotype and phenotype, influencing cellular identity, fate determination, and responses to environmental cues. Genome-wide methods relying on high-throughput sequencing, such as ATAC-seq (Assay for Transposase Accessible Chromatin sequencing), have emerged as powerful tools in this domain, enabling the identification of open chromatin regions where transcription factors and other regulatory proteins interact with DNA to modulate gene activity. In this dissertation, we present significant improvements in the measurement of chromatin accessibility by optimizing bulk ATAC-seq protocols for both native and fixed samples and developing a large-scale single-cell ATAC-seq method. For bulk protocol optimization, we performed a thorough analysis of 24 experimental conditions, testing all possible combinations of three reaction buffers, two enzymatic temperatures, and two enzyme sources on different nuclear preparations. This systematic evaluation, conducted on a well-characterized cell line and extended to primary mouse lung tissue, reveals intricate dependencies between protocol choices and data quality, particularly highlighting the sensitivity of chromatin accessibility data to enzymatic reaction temperatures and the physical state of nuclei. Our findings underscore the need for a multi-faceted evaluation of ATAC-seq data to mitigate protocol-driven biases and accurately represent the functional genomic elements, thereby enhancing the fidelity of chromatin profiling. Advancing beyond protocol refinement, we develop a massive-scale single-cell ATAC-seq method called txci-ATAC-seq (Ten(10)X-compatible Combinatorial Indexing ATAC Sequencing) by incorporating combinatorial indexing into a droplet-based microfluidic system. This approach substantially increases the scalability and flexibility of current single-cell assays, enabling the indexing of up to 200,000 nuclei in a single emulsion reaction across multiple samples. To improve the multiplexing capabilities of this new technique, we further develop a “phased” protocol variant (Phased-txci-ATAC-seq) that effectively decouples sample processing from library preparation, allowing for simultaneous profiling of up to 96 samples. In the proof-of-concept study, we benchmark txci-ATAC-seq across diverse biological systems, yielding an atlas of chromatin accessibility for 449,953 nuclei from different species, tissues, and genetic backgrounds. In addition, the application of txci-ATAC-seq to a CC16 knockout mouse model uncovers previously underappreciated technical artifacts derived from unintended residual genetic material introduced by gene targeting strategies, resulting in profound cell type-specific changes in chromatin landscape. The findings and methodologies established in this work expand the toolkit for epigenomic research, facilitating an in-depth examination of the intricacies of the chromatin accessibility landscape and its regulatory network.
  • PNA5: A Novel Therapy for Heart Failure Induced Vascular Dementia

    Konhilas, John P.; Hoyer-Kimura, Christina Helen; Hay, Meredith; Pires, Paulo W.; Duca, Frank (The University of Arizona., 2023)
    Decreased brain blood flow, increased reactive oxygen species production (ROS), and pro-inflammatory mechanisms contribute to cognitive impairment and neurodegenerative disease progress, including vascular contributions to cognitive impairment and dementia (VCID). However, the specific mechanisms that underlie heart failure (HF)-induced VCID are not clearly elucidated. Hence, in this work of experiments to identify biomarkers and test PNA5 treatment in HF-induced VCID, we also needed to establish the mechanisms for HF-induced VCID as a unique disease model that in itself is able to be identified and treated.This present study aims to 1) establish the pathophysiology associated with the progression/development of HF-induced VCID and establish biomarkers to predict HF individuals at risk for developing VCID and 2) advance our novel pluripotent peptide, PNA5. We hypothesize that 1) PNA5 will improve cognitive outcomes in HF-induced VCID via neuroprotective effects by decreasing neuronal damage, inflammation, blood-brain barrier (BBB) permeability, and neurovascular coupling (NVC) function, and 2) that NfL is a biomarker for cognitive impairment in HF individuals and that NfL will increase with increased cognitive impairment as HF severity progresses. To answer our hypothesis, we measured PNA5 neuroprotective effects in our HF-induced VCID mouse model. VCID was induced via myocardial infarction (MI). Mice were treated for 24 days with subcutaneous injections of PNA5 (500 mcg/kg/day or 50 mcg/kg/day) or saline (as control) five weeks after the MI. Cognitive function was assessed following the treatment protocol, and NVC was analyzed. NfL and cytokine levels were measured from blood collected at death. Brains were either homogenized to analyze brain cytokine levels or total hemisphere BBB permeability or sectioned and stained to analyze microglia morphology and regional BBB permeability. Biomarkers in the clinical studies, including NfL and pTau181, were measured from individuals (ages <50) with HF. HF individuals also underwent a battery of neuropsychological tests to assess cognitive performance. We observed that HF-induced VCID mice had increased intracerebral inflammatory responses, NVU dysregulation, and BBB leakage. PNA5 mitigated this mechanism and decreased markers for neuronal damage/death, thereby rescuing cognitive function independent of changes in heart function. These results are reflected in our clinical results, showing that NfL and pTau181 both negatively correlated to cognitive impairment and positively correlated to HF severity. Further, our results indicate that NfL may be a sensitive predictive biomarker for cognitive impairment in HF individuals and that PNA5 protects against cognitive impairment potentially through intervening in these neurotoxic mechanisms. Using an ischemic reperfusion injury mouse model, we also showed that PNA5 can improve heart function and decrease infarct size and fibrosis when treated immediately after reperfusion. These results indicate that PNA5 improves cognitive outcomes via neuroprotective effects on inflammation and vascular changes. Our work has further defined HF-induced VCID and made efforts to establish a biomarker panel to indicate disease progression.
  • Phototransformation of Trace Organic Compounds in Effluent-Receiving Waters: Exploring the Significance of Singlet Oxygen

    Sáez, A. Eduardo; Lee, Doorae; Arnold, Robert G.; Quanrud, David M.; Hickenbottom, Kerri (The University of Arizona., 2024)
    With ongoing climate change, economic growth and urbanization, a water crisis arises from both decreasing water resources and increasing water demands. Municipal wastewater effluent is now considered a potential potable water resource, particularly in semi-arid and arid regions. Indirect potable reuse employs an environmental buffer to polish the quality of treated wastewater. Natural attenuation processes may mitigate wastewater-derived pollutants, including recalcitrant trace organic compounds (TOrCs), in effluent-receiving environmental buffers. Photolysis is amongst natural processes that may contribute to attenuating the presence of such organic contaminants. In photolysis reactions, singlet oxygen (1O2) production can be an important mechanism leading to TOrC attenuation.Here, the significance of photolysis in the attenuation of TOrCs is evaluated in effluent-receiving waters, with particular attention to the role of 1O2. Quantitative kinetic parameters of 1O2, depicting its formation and reaction with TOrCs, are determined. Properties of effluent organic matter (EfOM) responsible for 1O2 formation are suggested, and the contribution of photolysis to the in-stream attenuation of TOrCs is examined in an effluent-dependent river. Primary findings include apparent quantum yields for 1O2 formation in effluent-receiving waters and second-order rate constants for the reaction of 1O2 with TOrCs. A subset of measured optical parameters and molecular-level components from EfOM is correlated with 1O2 formation. Photolysis plays a significant role in attenuating a range of TOrCs in a sunlit stream. Results provide essentials for incorporating the 1O2-involving light-driven natural process into engineered multi-process treatments for water reuse systems.
  • Neoantigen-Specific T Cells in a Novel Cutaneous Squamous Cell Carcinoma Model

    Hastings, Karen T.; Adams, Anngela Christina; Katsanis, Emmanuel; Dickinson, Sally E.; Hale, Taben M. (The University of Arizona., 2024)
    Non-melanoma skin cancer, which includes cutaneous squamous cell carcinoma (cSCC), is the most common cancer. In the US, there are more than a million cases of cSCC diagnosed annually. Although most early stage cSCC are successfully treated with excision, cSCC results in significant morbidity, and approximately 4% of cSCC patients develop metastases and 2% die. Immune checkpoint inhibitors and other immunotherapies are becoming increasingly important in treating multiple cancer types, including cSCC, but only a fraction of patients respond. Yet, there is a paucity of clinically relevant cSCC murine models that can be used to study neoantigen-specific T cell responses. Outbred SKH-1 mice are highly susceptible to solar UV light-induced cSCC. However, an outbred strain limits the ability to evaluate MHC-restricted, antigen-specific T cell responses and perform studies with genetically engineered mice. To address this need, solar UV light was used to induce tumors in inbred FVB/N, BALB/c, and C57BL/6 mice. Solar UV light reliably induced tumors in FVB/N and BALB/c mice. In contrast, C57BL/6 mice were relatively resistant to tumor formation. Most tumors were histologically diagnosed as actinic keratosis, cSCC in situ, or invasive cSCC. Histologically confirmed solar UV-induced invasive cSCC tumors were used to create clonal cSCC cell lines on the BALB/c background. The cSCC cell lines recapitulate the high mutational burden, mutational profile, and driver mutations observed in human disease. These cSCC cell lines constitutively express MHC class I, and thus, can be targeted for destruction by CD8 T cells. T cells constrain the cSCC cell lines, as cSCC tumors grew faster in athymic mice, which lack mature T cells, compared to wild-type mice. In vivo depletion of CD8 and CD4 T cells demonstrated a major role for CD8 T cells and a supportive role for CD4 T cells in controlling cSCC growth. Vaccination with irradiated cSCC cells completely protected mice from tumor challenge, and this response was dependent on CD8 T cells. This supports that MHC class I neoantigens in the cSCC model can mediate tumor destruction. To identify tumor-rejecting MHC class I neoantigens, mutations were prioritized based on the predicted neoantigen: MHC interaction and mRNA expression. ELISPOT was used to evaluate the immunogenicity of the prioritized neoantigens, and IFN-γ-secreting CD8 T cells that recognize mutant Kars and mutant Picalm.2 were identified. Prophylactic vaccination with mutant Kars or mutant Picalm.2 constrained cSCC tumor growth, demonstrating that both mutant Kars and mutant Picalm.2 are tumor-rejecting neoantigens. To identify characteristics that distinguish tumor-rejecting neoantigens, we evaluated the non-immunogenic neoantigens from in the cSCC model and tumor-rejecting neoantigens from the cSCC model and other murine cancer models. Among neoantigens with a low differential agretopic index (DAI), tumor-rejecting neoantigens had a greater solvent accessible surface area (SASA) of the mutated residue compared to non-immunogenic neoantigens. Thus, SASA of the mutated residue may be an important characteristic to consider when prioritizing neoantigens that do not have a large difference in MHC binding compared to the wild-type sequence. As this cSCC model recapitulates human disease, future work using this model may provide insights into the neoantigens to target in neoantigen-based immunotherapy that can improve therapeutic outcomes for patients with cSCC and other high mutational burden cancers.
  • The Gut Microbiome as an Outcome Measure of Dietary Therapy Efficacy After Traumatic Brain Injury (TBI)

    Lifshitz, Jonathan; Rojas Valencia, Luisa Maria; Cope, Emily K.; Rowe, Rachel K.; Lybarger, Lonnie P.; Bibb, James A. (The University of Arizona., 2023)
    TBI is caused by a physical impact on the brain that results in cellular damage and pathological processes that lead to the enduring symptoms observed in the patients. The cellular damage observed after TBI induces the release of proinflammatory signals locally (neuroinflammation) and in the periphery (peripheral inflammatory response). The proinflammatory signals flow from the brain to the bloodstream and activate a peripheral inflammatory response, causing damage to other organs, including the gut. Gut dysfunction is commonly observed after TBI and can lead to gut microbiome alterations. The gut microbiome is the collection of bacteria, fungi, viruses, and protozoa in the gut. After brain injury, peripheral inflammation has been associated with gut microbiome disbalance. Furthermore, gut dysfunction and gut microbiome alterations advance neurological disease. This is due to the bidirectional relationship between the gut microbiome and the brain, known as the microbiota-gut-brain axis. This leads us to hypothesize that interventions that modulate the gut microbiome, such as dietary therapies, have the potential to reduce peripheral inflammation and, ultimately, brain inflammation. Dietary therapies are modifications of regular diet to fit the nutritional needs of the patients. Dietary therapies like probiotics modulate the gut microbiome and reduce inflammation in the gut and peripheral blood. On the other hand, there is a need for monitoring outcome measures that can inform disease progression and treatment effectiveness. Here, we asked if the microbiota-gut-brain axis could be used as an outcome measure of the efficacy of dietary therapy after traumatic brain injury. To answer that question, we first determined the effects of brain injury on the gut microbiome diversity and composition in Chapter 2. We observed an initial change in fecal microbiome diversity at 1 DPI in the female group. We also evaluated changes in gut microbiome composition after brain injury and found that members of the phylum Firmicutes were enriched in the injury group at different time points while other members of the same phylum decreased. In Chapter 2, we studied the interaction between peripheral inflammation and the gut microbiome, as it is a communication mechanism in the microbiota-gut-brain axis. We identify that the level of neutrophils interacts with the rate of change in beta diversity over time according to injury group and sex. In Chapter 3, we studied two probiotic administration regimens (dietary therapy). We evaluated the effects of probiotic pretreatment and treatment after brain injury on the gut microbiome. In the pretreatment experiment, we observed that gut microbiome diversity and composition changes were related to probiotic dose. The pretreatment with probiotics had an effect on the interaction between the neutrophil populations and gut microbiome diversity. Then, we evaluated the effect of a probiotic treatment post-injury on the gut microbiome diversity and composition. In the treatment experiment, we observed that gut microbiome diversity can discriminate probiotic treatment groups from water control or sham. We also identified bacterial genera that increased with probiotic administration and the ones that decreased after brain injury. Interestingly, most of the bacterial taxa that change with probiotic administration belong to the Phylum Firmicutes, a phylum that produces metabolic intermediaries that reduce the inflammatory response in the gut. Our combined results from Chapters 2 and 3 indicate that gut microbiome diversity and composition can discriminate between injury vs sham, probiotic doses, and probiotic treatment. Our results also suggest that the effect of probiotic therapy is through modulation of gut microbiome composition. Furthermore, we observed an interaction between the gut microbiome diversity, inflammatory markers, and sex that is time point-specific (Chapters 2 and 3). We conclude that the gut microbiome diversity and composition (and microbiota-gut-brain axis) are promising translational outcome measures of dietary therapy efficacy after brain injury. At a higher level of discussion, we will include data science principles and practices applied during this research. As those principles and practices improved and advanced, the analysis of the results.
  • An Analysis and Performance Guide of Chinese Representative Viola Works by Qingwu Guan, Nian Liu, and Bright Sheng

    Gebrian, Molly; Dong, Xiaochen; Kantor, Timothy; Traut, Don (The University of Arizona., 2024)
    This document delves into five Chinese representative viola pieces: The Sound of the Mongolian Grassland (Caoyuan Zhige 草原之歌) by Qingwu Guan , First Suite for Solo Viola by Nian Liu, and Three Chinese Love Songs, Angel Fire Duo, and The Stream Flows by Bright Sheng. These works contain numerous uniquely Chinese musical elements including pitch collections, folk song melodies, viola performance techniques. By incorporating such Chinese elements and folk melodies into their compositions, these composers have bridged cultural gaps between China and Western countries, thereby instilling a deeper appreciation of Chinese musical heritage on a global scale. Their shared contributions to the incorporation of Chinese compositional elements into viola music has helped to foster the development of Chinese viola repertoire.
  • Exploring Indigeneity in English Language Teaching Through Turi Aisa Ya With Indigenous Miskitu Teachers of English

    Nicholas, Sheilah E.; Mejia Mayorga, Jaime Fabricio; Tardy, Christine M.; Combs, Mary Carol (The University of Arizona., 2024)
    This dissertation explored the aspect of Indigeneity as a significant consideration in English Language Teaching (ELT); and thus makes a critical contribution to the literature in ELT/TESOL and applied linguistics. This body of knowledge benefits from privileging Indigenous ways and Indigenous knowledge in research practices, making explicit understandings on language use and language teaching and learning from Indigenous knowledge systems, Indigenous and postcolonial sites, and incorporating ethical approaches to research that empower all parties involved (Norton and Tohey, 2011; Pennycook & Makoni, 2020; Sterling & De Costa, 2018). As such, this dissertation was informed by Indigenous and decolonizing research methodologies that contribute to decoloniality and the advancement of Indigenous knowledge in academia. The exploration of the aspect of Indigeneity in ELT was conducted by investigating the stories and experiences of two Indigenous Miskitu teachers of English from Honduras. Additionally, the exploration includes a prologue in which the principal researcher narrates the awareness of his Indigeneity as Indigenous Chorotega in storying his life history. Consequently, I define Indigeneity as a quality of being Indigenous encompassing: as embracing Indigenous worldviews, paradigms, and ways of being, doing, knowing, and thinking (Garroutte, 2006; Huaman, 2022; Peltier, 2021); as the self-identification as Indigenous; as the awareness and interest on one’s spirituality and well-being; as the use in, interest on, and passion for one’s Indigenous language and culture (Huaman, 2022; Peltier, 2021); as the connection to Indigenous people by blood, kinship, or ancestry (Garroutte, 2006; Simpson, 2011) as well as to one’s Indigenous land, place, and community (Absolon, 2011; Sarivaara et al., 2013). The study investigated the stories and experiences of two Indigenous Miskitu teachers of English as former students of an ELT program in Honduras and current teachers of English in the public education system of Honduras. It sheds light in understanding how the Indigeneity of these Indigenous Miskitu teachers of English intersected with their preparation and professionalization as English language teachers and how their Indigeneity informs and impacts their teaching praxis. The study used turi aisa ya, an Indigenous Miskitu methodology, for data collection (Smith, 2012). Turi aisa ya is a space for sharing and the exchange of information and experiences; it requires sitting down and listening with humbleness and intention—listening to hear. Turi aisa ya is also a social activity in which participants engage in laughing, thinking together, crying, worrying, and coming up with solutions. It is imagining, experiencing vicariously, and feeling. In a similar manner to sharing circles (Lavallée, 2009), turi aisa ya is an approach “used to capture people’s experiences [and is] comparable to focus groups in qualitative research” (p. 28). In addition to turi aisa ya, the participants engaged in storywork as we were storying our intersecting lived experiences as a way of making and gaining insights from our life stories (Archibald, 2008). Engaging in turi aisa ya and storywork created the space for dialoguing about their beliefs on education merging traditional Miskitu worldviews with English language learning, English language teaching, and their lived experiences teaching in the Honduran public education system as Indigenous Miskitu teachers of English. Findings shows that the Indigeneity of the Indigenous Miskitu teachers of English, who were co-researchers on this study, was important and influential in their becoming teachers of English. First, their Indigeneity is understood as anchored in intergenerational relations as well as family and community relations, thus informed their desires to become teachers of English. Secondly, their awareness and consciousness towards the English language informed their becoming as teachers of English. Such awareness and consciousness served as a reminder on why pursuing a bachelor’s degree in ELT was relevant to them. Third, their personal traits of hard-work, resolution, commitment, and determination, aspects of their Indigeneity, intersected with their becoming as teachers of English. Said personal traits ensured that both Zoila and Wesley negotiated and navigated newer spaces and situations as they moved to new locations to pursue higher education and invested themselves in mastering English as their third language --a language that for them served community-oriented, professional, and academic purposes. Moreover, the dialogues held during the turi aisa ya sessions helped identify the ways in which their Indigeneity manifests in their teaching praxis. Their Indigeneity is manifested in their teaching praxis as reciprocity in the classroom, through the centering of well-being through a pedagogy of kindness and care, via culturally responsive teaching, and in the use of storytelling as a pedagogical tool. While these are some of the ways in which their Indigeneity is manifested in their teaching praxis, they are not the only ones considering that, as Zoila stated, “[their] Indigeneity is present in everything [they] do” (Zoila, Turi aisa ya session # 4 with Zoila. Jan, 13, 2023). Furthermore, the curricular innovations to the ELT teacher education program in Honduras, that emerge from their stories and experiences, include: (a) a class to learn about Indigenous Miskitu ways, (b) English language [pre-service] teachers learning about the linguistic diversity of Honduras, (c) representation in faculty and instructors, (d) additional preparation for students in the ELT program to teach in the public education system of Honduras, (e) formal academic and educational spaces to learn about the current state of Indigenous communities in Honduras, and (f) training students in the ELT program under the paradigm of Teaching English as a Global Language from an Indigenous relational paradigm. Key conclusions and implications for ELT teacher education in Honduras and beyond are: a) English should be taught as an additional language, b) multilingualism is as an aspect of our identities as we might be trilingual individuals (users of three languages or users of two languages and heritage speakers of an Indigenous language), and c) the ways teachers of English are educated should be innovated by a new paradigm that is encompassing of multilingual education and the fact that English is a global language. Noteworthy to identify are the limitations that impacted this study. These include a lack of Indigenous knowledge in the fields of ELT/TESOL and applied linguistics, the realities exacerbated by COVID-19 even post-pandemic, and the small number of Indigenous Miskitu teachers of English. The possibilities for future research suggest that this study could be replicated with the collaboration of more Indigenous Miskitu teachers of English as well as other teachers of English who belong to other ‘ethnic’ communities such as the Garifuna and Islanders. Also, further research could instigate other critical dialogues to gain insights into the multilingual realities of all these individuals. Furthermore, this study could be replicated to learn how other Indigenous teachers of English throughout the world teach this language as informed by their Indigeneity. Lastly, further research that builds from this dissertation could investigate how the teaching of languages such as English could look like if informed by an Indigenous relational paradigm. Keywords: Indigeneity, Indigenous Knowledge, Miskitu, Honduras, English Language Teaching, TESOL, Applied Linguistics, Global Englishes, teacher education.
  • Clinician Education: Optimizing Music Choices for Ketamine-Assisted Psychotherapy

    Velo, Jamie R.; Chenette, Christie Iliana; Young, Janay R.; Edmund, Sara J.; Reed, James R. (The University of Arizona., 2024)
    Purpose:The purpose of this quality improvement project was to increase clinician knowledge regarding evidence-based music selections for ketamine-assisted psychotherapy at a local clinic. Background: Ketamine is used to treat a variety of mental health issues. Set and setting have been identified as important variables that support the tolerability and efficacy of ketamine. Music is one key variable that clinicians can utilize to optimize the therapeutic experience; however, not every provider is knowledgeable regarding how to best do this. Methods: This quality improvement project was delivered as an educational presentation for clinicians at Tucson Counseling Associates. The presentation was created based on published literature and evidence provided as a multi-media PowerPoint lecture including examples of appropriate music choices and a case study. Data was collected through a pre- and post-survey questionnaire, which was used to assess baseline knowledge and knowledge gained after the lecture. The surveys utilized a five-item Likert scale and short-answer format questions. A number was assigned to each Likert scale rating (strongly disagree = 1, disagree = 2, neutral = 3, agree = 4, strongly agree = 5) and thenumber of responses for each item on the scale was factored in. Free text responses were reviewed for major themes. 12 Results:Participant perception of current clinic practices indicated that clinicians agreed that music was intentionally selected at Tucson Counseling Associates with an average Likert-scale score of 4.43. Clinicians agreed that they understood why certain music is used for patients. The post-survey results indicated a statistically significant improvement in knowledge gain compared to the pre-survey results. Participants strongly agreed that they learned valuable information during the presentation and that they intend to use the information in their future practice. The free-response questions indicated six unique ways in which participants intend to use this new information in their clinical practice and provided insights on how to improve the intervention moving forward. Conclusions: Results suggest the efficacy of an interactive multi-media PowerPoint lecture with an incorporated case study in increasing clinician understanding and confidence in choosing appropriate music choices for KAP sessions to help optimize the patient experience.
  • The Cahuilla Research Agenda Model: Using Indigenous Methods and Cahuilla Traditional Knowledge in Research

    Trosper, Ronald L.; Lewis, Larea Mae; Reader, Tristan; Ferguson, T.J.; Tatum, Melissa L. (The University of Arizona., 2023)
    Years of settler colonialism, annihilation, and assimilation caused our tribal communities to lose precious traditional knowledge in cultural traditions and our relationships to land. The relationships between people and land are significant because we create physical and cultural identities based on our life experiences while living on the landscape. We create realities that explain our presence and we make meaning of our surrounding environments. As a culture, we pass the knowledge down to our future generations, so they know where they come from and how to give respect and thanks to our Ancestors and our Creators. In return, our Ancestors give us the gifts of life. To disturb our relationship with the land is to disturb our culture and our identity. In efforts to preserve culture, researchers throughout time have documented traditional knowledge in Cahuilla language, history, traditions, and stories. Oral stories, language and traditions have also been recorded by Cahuilla Elders in books, phonographic records, and tapes. Although Cahuilla cultural studies continues with the use of these sources, it is not common practice for researchers to engage with Cahuilla communities to help with the research. Their research also does not fully accomplish the goal of directly reconnecting us to our culture or our relationships to our traditional land. In this research, I engage with my community to change the narrative and bring forth their voice in helping us reach those goals. I apply Indigenous methodologies which are methods of research that are guided by traditional knowledge systems and worldviews. Applying these methods changes the course in how knowledge is shared between the researcher and the community and how we reach researcher and community goals. Furthermore, using these methods requires us to create a research framework that includes tribal ethics, tribal sovereignty, and worldview. In this research, we explore Indigenous research methods and engage with the Agua Caliente Band of Cahuilla Indian tribe to create a research agenda model that can be used in further research studies on their culture. As an example, we explore how the Cahuilla Research Agenda model is used by applying its research methods to an ongoing research project that studies the traditional use of plants, the Cahuilla Plant Database Project. Our goal is to reconnect the Agua Caliente Band of Cahuilla Indians to their traditional homelands and revitalize cultural ways of life by doing research by, with, and for the community.
  • Moving Beyond the Decolonization Framework: Indigenous Research, Collaboration, and Decision-Making in Mi’kma’ki

    Trosper, Ronald L.; Starks, Rachel Rose; Gonzales, Patrisia; Begay, Jr, Manley A.; Tatum, Melissa (The University of Arizona., 2024)
    This dissertation is divided into three parts. Part I addresses the researchquestion, literature review, and methodologies. Part II is a treatment of original research that took place at Membertou Mi’kmaq Band between 2010 and 2013. The community centered research model is described in detail, which is followed by new analysis of data that was collected during that community-centered research. Part III discusses the context of Mi’kmaq Nation action over the last several decades. This action is influenced by the experience of Donald Marshall, Jr. in two major legal cases: 1) Marshall’s wrongful conviction and incarceration for murder, and then exoneration; and 2) Marshall’s arrest for violating provincial fishing laws, leading to a landmark decision on Mi’kmaw land, hunting and fishing, and commerce rights. Both these cases, along with evolving standards for Aboriginal rights, consultation, and accommodation, and changing institutional arrangements at Mi’kmaq led to the collaborative governance regime, the Made in Nova Scotia Process.
  • Voices of Mexican Army Wives

    Beezley, William; Marquez Sandoval, Maria Concepcion; Mooney, Jadwiga Pieper; Senseney, John R. (The University of Arizona., 2024)
    Voices of Mexican Amy Wives is a study about the inner world of the army, a traditionally secluded institution with a primordial role in the history of Mexico. It focuses on a group usually absent in army studies, seeking to contribute to understanding their roles, behavior, and influence. It presents written and oral testimonies of army wives chronologically from the first years of the Revolution, 1910-1924, the Social Revolution 1925- 1950s, and the Contemporary times 1960s-2016. Studying them over three periods allows readers to see changes and continuities while providing a better understanding of the institution that they are part of, showing that army wives are not passive and invisible companions and contribute significantly to the institution and their country.

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