More than 40,000 theses and dissertations produced at the University of Arizona are included in the UA Theses and Dissertations collections. These items are publicly available and full-text searchable. A small percentage of items are under embargo (restricted).

We have digitized the entire backfile of UA master's theses and doctoral dissertations that were held in the University of Arizona Libraries.

  • Submitting master's theses to the UA Libraries was optional for many decades; as a result, we do not have all master's theses that were written at the University of Arizona.
  • A small number of historical theses containing culturally sensitive material are not available online.
If you can't find the item you want in the repository and would like to check with us, please contact the Campus Repository team at repository@u.library.arizona.edu.

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Recent Submissions


    Garnar, Andrew; Della Valle, Brianna Salud Rose (The University of Arizona., 2023)
    Max Tegmark states in his Mathematical Universe Hypothesis that the external physical world is a mathematical structure, and proposes a supporting reality model split into three parts: external reality, consensus reality and internal reality. This reality model raises problems for phenomenological and feminist philosophies. These problems fall under the overall concern that Tegmark's reality model obfuscates human experience generally, and the lives of historically marginalized groups more specifically. This concern will initially be addressed by Husserlian phenomenology by proposing that a more rigorous reality model must take lived experience seriously. The concern will be further addressed by feminist standpoint theory which pushes the Husserlian critique into the realm of socially-situated marginalized lives.
  • Characterization of Small Molecule Inhibitors of CLKs and DYRKs

    Thorne, Curtis; Gonzalez, Lucia; Paek, Andrew; Wilson, Justin E. (The University of Arizona., 2023)
    Colorectal cancer (CRC) used to be known as a disease of old age, but now it is becoming a concern for younger adults. Researchers are unsure why, but they believe it may be due to environmental factors that lead to genetic changes in the colonic epithelium. These genetic changes affect essential signaling pathways, making them a crucial research focus. The Wnt signaling pathway is significant in maintaining digestive tract homeostasis but is often dysregulated in cancer. For this reason, researchers are working to identify proteins that affect Wnt signaling and target them with inhibitors. The CLK and DYRK kinase families are a group of proteins closely linked to the Wnt signaling pathway and implicated in disease. In this study, I tested 107 novel small molecules that are CLK/DYRK inhibitors in a dose-response curve with human colonic epithelial cells (HCECs). From this data, we identified six top compounds that were tested further in a cell viability assay to determine their efficacy against cancer cells. We also immunoblotted for CLKs' substrate to understand how the compounds work and obtained pharmacokinetic data to understand their biomechanics. Ultimately, two promising compounds emerged as potential candidates for further organoid profiling – DYR726 and DYR895. We are especially excited for DYR895 to be FDA-approved soon, but we will also further assess DYR726
  • Assessing the Potential for Hemp to be Used in the Bioremediation of Soils Containing Perfluoroalkyl Substances (PFAS)

    Recsetar, Matthew; Dusza, Nicholas Bernard; Farrell-Poe, Kitt; Babst-Kostecka, Alicja; Brusseau, Mark (The University of Arizona., 2023)
    Widespread industrial and commercial use of perfluoroalkyl substances (PFAS) has led to their accumulation in soil, groundwater, and freshwater supplies. The high stability of PFAS has rendered many traditional methods of remediation largely ineffective or too expensive to implement. This study seeks to quantify the efficacy of hemp as phytoremediator of soil contaminated by wastewater biosolid containing PFAS. Twenty hemp plants were cultivated using Arizona desert soil and mixed with biosolid contaminated with PFAS. The biosolid was incorporated into the soil at varying loading rates: 0%, 5%, 15%, and 30% biosolid by volume. Biosolid treatment groups consisted of five cannabis plants that were kept in a state of vegetative growth for 16 weeks. Initial soil samples were taken from the homogenized biosolid treatment mixtures before planting and compared with the final soil samples obtained from each plant to assess changes in PFAS levels. After harvest, plant tissue samples were taken from the roots, stems, and leaves for PFAS analysis. Plant growth metrics (height, stem diameter and number of axials) were recorded weekly for each plant. The plants grown in 5% biosolid by volume exhibited the greatest height and largest average stem diameter. The plants grown in 15% biosolid mixture appeared to be the healthiest and had greater biomass. The experiment unveiled significant translocation of PFOA and PFBS into various regions of the plants in all biosolid treatments. Specifically, within treatment #1 and treatment #2, 20.56% and 49.06% of the PFOA from the initial soil samples were translocated into the roots of plants, respectively. The types of PFAS that tend to be taken up by the plants are water soluble and tend to leach through soil. PFOS was found to be filtered out of samples by solid phase extraction ENV cartridges and were not translocated into the plants.
  • A Novel Kappa Opioid Receptor Antagonist with Prolonged Duration of Action

    Porreca, Frank; Navratilova, Edita; Redman, Paula; Kopruszinski, Carol (The University of Arizona., 2023)
    The history of opioid use traces its roots back to ancient civilizations, where substanceslike the opium poppy (Papaver somniferum) were harnessed for their remarkable analgesic properties. Today, the conventional analgesic option is opioids that target the mu opioid receptor (MOR), however, they are associated with deleterious effects, such as the development of dependence and respiratory depression. However, the kappa opioid receptor (KOR) subtype, found on the surface of cells particularly in the brain and spinal cord, promotes the negative affect of chronic pain and blockade of KOR signaling would be therapeutically desirable. KOR antagonists including CYM53093 (i.e., Navacaprant, former BTRX-335140 and NMRA-140) are in advanced clinical development for the treatment of severe depression, anxiety and anhedonia but require frequent dosing for beneficial effects due to their relatively short duration of action. This poses challenges for patient adherence and increases treatment costs. Developing longer- acting formulations is crucial to enhance convenience, adherence, and cost-effectiveness in managing conditions like generalized anxiety, major depressive disorder, pain and its comorbidities. This study pharmacologically evaluated the potential of longer-acting temporal profile for novel KOR antagonist, CYM3063, in mice.
  • Adapting the Differential Target Antenna Coupling (DTAC) Method to Commercial Geophysical Exploration Equipment

    Sternberg, Ben K.; Wang, Zida; Ferre, Paul A.; Heath, Gail (The University of Arizona., 2023)
    The Differential Target Antenna Coupling (DTAC) method is a newly developedelectromagnetic method that has been thoroughly studied using different array setups, such as horizontal array, vertical array, and fixed transmitter loop with moving receiver. However, all previous studies were conducted using laboratory equipment, which is not suitable for real-world survey’s needs. The primary objective of this paper is to adapt the DTAC method using equipment from Zonge International, a well-known geophysical equipment manufacturer worldwide. To achieve this goal and accommodate the limitations of a small-sized field crew used for this project, a newly designed compact version of the vertical array DTAC setup was built. This setup includes a 6m-by-6m transmitter loop and a 3-axis receiver coil. Field tests were conducted in a well-studied test site with a known target, along with numerical simulations using EMIGMA software as the benchmark. The results demonstrated that the DTAC method with Zonge International’s geophysical equipment offers significant advantages over conventional electromagnetic methods. This validates that the DTAC method is suitable for real-life exploration surveys. Additionally, this paper discusses a possible real-life field exploration setup and procedure that can be adapted for a larger field crew and a larger transmitter loop.
  • Alveolar Type 1 Epithelial Cell Deficiency in Pulmonary Hypertension

    Dai, Zhiyu; Hamid, Syed; Dai, Zhiyu; Gonzales, Rayna; Wang, Dong (The University of Arizona., 2023)
    Rationale: Pulmonary Arterial Hypertension (PAH) is a severe health condition that involvesan ongoing process of pulmonary vascular resistance and vascular remodeling. These changes can eventually cause right heart failure (RHF) and in severe cases and can eventually result in death. AT1 cells mediate gas exchange in the lung. However, the connection between AT1 cell dysfunction and the onset of pulmonary hypertension (PH) is still not well-understood. A better understanding of the mechanisms could help the improvement of treatment for PAH. Objectives: To investigate the role and underlying mechanisms of AT1 cell deficiency in the pathogenesis of PAH. Methods: To determine whether AT1 cells are deficient in the development of PAH, lung sections from idiopathic PAH (IPAH) and control donors, as well as lung tissues from PH mice model Egln1Tie2cre (CKO) mice and wild-type (WT) mice, were evaluated for the expression of AT1 cell markers. Reverse Transcription-quantitative PCR (RT-qPCR) was performed in mice samples, to determine the expression levels of AT1 cells markers (Ager, Aqp5, Hopx, Rtkn2) using lung tissues from CKO and WT mice. Western blot analysis was then performed to quantitatively evaluate AT1 cell marker protein levels (Ager, Hopx) in lungs from CKO and WT mice. Immunofluorescence staining was applied using HOPX in both mice lungs and human IPAH lungs. Additionally, the expression of VEGFA, AT1 derived factor, was determined using the RNAscope technique on human IPAH and control lungs. Results: The findings of this study showed the mRNA levels of AT1 markers including Hopx and Rtkn2 were downregulated in CKO mice. The expression levels of AT1 markers Ager but not Hopx was downregulated in CKO mice by Western Blot. A decrease of AT1 cells assessed by quantification of HOPX in the IPAH human samples and CKO mice was observed in Immunofluorescent staining. Lastly, upregulated VEGFA expression in IPAH human samples were recorded as revealed by the RNA scope. Conclusion: The findings of this study demonstrated that there is a deficiency of AT1 cells in PAH patients and PH mice. Deficient AT1 cells might lead to impaired regeneration of the pulmonary vasculature and the development of PAH. Our study might provide a novel concept to treat PAH patient via studying the AT1 cells and their underlying signaling.
  • Comparing Microbial Source Tracking Methods for Precision and Reliability

    An, Lingling; Kazemi, Mohadeseh; Watkins, Joseph C.; Zhang, Hao (The University of Arizona., 2023)
    Microbiome research has experienced remarkable growth in recent years, driven by advances in DNA or RNA sequencing technologies and our deepening understanding of the critical roles that microbiota play in diverse ecosystems, including the human body. The term "microbiome" refers to the entire collection of microorganisms in a given environment, whether that is the gut of a human, the soil in a forest, or the water in an ocean. These microorganisms encompass bacteria, viruses, fungi, and other microbes, all of which collectively influence the health and functioning of their host ecosystem. The complexity and diversity of microbiome data have led to the development of various decomposition methods, each tailored to tackle the specific challenges posed by different environments and research objectives. Numerous tools have been developed to estimate the proportion of different contamination sources within a mixture. In this study, we evaluate the accuracy of various source tracking methods using datasets from microbiome studies. In addition to assessing source tracking methods, we also incorporate two widely used cell type deconvolution methods, namely EPIC and PREDE, which are designed to identify missing cell types in a given dataset. Furthermore, we investigate the effectiveness of combined methods by integrating RAD, a source tracking method aimed at filtering out unimportant sources, with either EPIC or PREDE for enhanced accuracy in both source tracking and cell type deconvolution. This research represents a pioneering effort to examine the application of cell type deconvolution methods in source tracking and vice versa. Particularly noteworthy is our focus on scenarios involving missing sources or cell types in the reference data, shedding light on the intricate interplay between these two analytical domains.
  • Potential Role of Acetylpolyamines in the Prostatic Tumor Microenvironment

    Miranti, Cynthia; Cernyar, Brent; Pandey, Ritu; Gelmann, Edward (The University of Arizona., 2024)
    Prostate cancer is the most common cancer in men excluding non-melanoma skin cancer, and the second leading cause of cancer-related mortality after lung cancer. Early stages of prostate cancer are dependent on androgen for proliferation and survival, and can be curable with standard surgical or radiation treatment options. Unfortunately, recurrent and metastatic prostate cancer is highly refractory. Eventually the disease will develop castration resistance which is incurable with our currently available androgen deprivation therapies and chemotherapies. Initially, immunotherapy in preclinical trials showed promise in activating the innate and adaptive immune system to target prostate cancer cells. While sipuleucel-T and pembrolizumab have been approved by the FDA for the treatment of asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer patients, immunotherapies have overall shown only modest efficacy in clinical practice. Prostate tumors are heterogeneous and considered an immunologically “cold” tumor due to low expression of neoantigens and low tumor mutational burden, creating a significant obstacle to treatment with immunotherapy. In addition, the prostatic tumor microenvironment secretes factors that recruit an abundance of anti-inflammatory tumor associated macrophages (TAM), increases regulatory T cell infiltration, and activates immature myeloid cell differentiation to myeloid derived suppressor cells. These cells create an immunosuppressive barrier which inactivates cytotoxic T cells and prevents natural killer cell permeability. As of yet, we are unable to explain the abundance of infiltrating tumor associated macrophages associated with metastatic prostate cancer tumors. One factor may be acetylated polyamines released by prostate cancer cells into the tumor microenvironment. Classically, literature reports decreased total intracellular polyamine concentration with prostate cancer progression, suggesting polyamines have anti-tumorigenic properties. However, aggressive prostate cancer cells are shown to have a significant elevation in the message, protein, and activity of enzymes that direct polyamine metabolism. Interestingly, major studies that report decreased total polyamines levels in prostate cancer do not take into consideration the acetylated forms of these molecules, which is an alteration necessary for polyamine efflux and catabolism. Therefore, it would be reasonable to discuss how dysregulated polyamine metabolism in prostate cancer cells likely results in increased acetylpolyamines, as this may provide new insights into potential roles of these molecules in the prostatic tumor microenvironment. This review will focus on common mutations in prostate cancer that increase enzymes involved in polyamine synthesis and acetylation, reported impact polyamines have on varying mechanisms in immune cells that promote an immunosuppressive milieu, and highlight possible therapeutic targets that could increase the efficacy of currently available immunotherapies.
  • 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.
  • Oxygen and Glucose Therapy Improves Fetal Growth and β-cell Function in FGR Fetal Lambs

    Limesand, Sean W.; Varela, Mariangel; Craig, Zelieann; Goyal, Ravi (The University of Arizona., 2024)
    Babies born small for gestational age are more vulnerable to developing non-communicablediseases like glucose intolerance, obesity, and type-2 diabetes. Fetal growth restriction (FGR) occurs when the fetus is unable to grow to its full genetic potential and affects 3-7% of all pregnancies. FGR is often induced by placental insufficiency (PI-FGR) and accounts for a majority of babies born SGA. Placental insufficiency is characterized by poor placental transport of nutrients and oxygen to the fetus. In a previous study, we supplemented oxygen and glucose to PI-FGR fetal lambs in late gestation and showed improvements in their glucose homeostasis after 5-days but did not measure fetal and β-cell growth directly. In this study we supplemented glucose and oxygen for 10 days in PI-FGR sheep fetuses to determine whether raising glucose and oxygen concentrations to reverse the effects of PI could increase fetal and β-cell growth. Placental insufficiency was created with maternal heat stress during mid-gestation. For the experimental FGR fetuses supplemented with oxygen and glucose (FGR-OG), arterial oxygen and glucose were increased to near normal concentrations through maternal trachea insufflation of oxygen and an intravenous fetal glucose infusion. FGR-OG fetuses were compared to FGR fetuses receiving air and saline-infusions (FGR-AS) and control fetuses. Throughout treatment, thoracic circumference of each fetus was measured to visualize growth linear growth rates. After eight days of treatment, a square wave hyperglycemic clamp was performed to measure glucose stimulated insulin secretion (GSIS). At the end of treatment (day 10), fetal pancreata were collected and immunostained for insulin and phosphorylated Histone H3 to measure β-cell area and proliferation. After 24 hours of treatment, fetal thoracic circumference rates increase to rates comparable to control fetuses, which continued for the remainder of the treatment. As previously shown glucose stimulated insulin concentrations were low in FGR-AS fetuses but increased in FGR-OG fetuses to levels not different than control concentrations. In addition, β-cell proliferation rates also increased to rates not different than control β-cell proliferation rates. These findings show that continuously supplementing both oxygen and glucose to the FGR fetal lamb improved fetal and β-cell growth and insulin secretion responsiveness following the onset of PI-FG.
  • 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.

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