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Extrinsic and Intrinsic Properties of ssDNA Packaging in Mircrovirdae
No full textViral systems across genera have evolved diverse mechanisms that ensure successful encapsidation and organization within virions. Genome packaging requires coordination between trans-acting elements that transport and package the genome; and cis-acting genetic elements that aid in genetic regulation but may also assist in folding and organization. My dissertation focuses on elements that regulate packaging within the øX174-like, G4-like and ⍺3-like microvirus clades.Chapter 1 is a literature review of diverse packaging mechanisms amongst bacteriophage and eukaryotic viruses. Chapter 2 focuses on the genome organization function of the ssDNA binding protein J, that guides and organizes the genome within capsids. Analysis of mutants that have interchanged J genes between clades, display altered genome organization that leads to various packaging defects. Results demonstrate that mutants produced fully packaged uninfectious particles unable to attach to host-cells. Thus, internal organization of the genome can affect properties of the surface of the virion necessary for attachment and penetration. Chapter 3 focuses on the genetic diversification of ⍺3-like microviruses that impacts packaging, such as genome length and temperature sensitivity. Although, capsid volumes are comparable in size between øX174-like, G4-like and ⍺3-like viruses, ⍺3 has the largest genome and is the most cold-sensitive. Due to temperature influencing DNA persistence length, it was hypothesized that ⍺3 is more prone to packaging errors at low temperature. Mutations that expanded the temperature growth limit were isolated and characterized. The results are consistent with this hypothesis, demonstrating that low-temperature adaptation can lead to species diversification. Chapter 4 focuses on periodic sequences in the øX174 genome hypothesized to regulate ssDNA organization within virions. The hypothesis was tested by tracking DNA replication and packaging in a co-infection, between a mutant with modified periodic sequences and wild-type øX174. Results showed that DNA replication was comparable to wild-type. However, at low temperature the mutant produced significantly less progeny virions. This indicates the genome has innate properties that regulate packaging. Together, this work furthers our understanding of ssDNA microvirus packaging regulation. The work reported herein, provides insight into the impact of genome organization on the biophysical properties of the microvirus virion. As well as, insights into the varying role of protein A* protein between microvirus clades; and lastly, ssDNA packaging is under cis-acting regulation which was previously unknown and may be reflected in other ssDNA virus systems
Development of Small Molecule Kinase Inhibitors: A Multi-Target Therapeutic Strategy for Cancer Treatment
No full textDual-specificity tyrosine-regulated kinases (DYRKs) and CDC-like kinases (CLKs) play essential roles in oncogenic signaling, RNA splicing, and cancer stemness, particularly in aggressive malignancies such as colorectal cancer (CRC), glioblastoma (GBM), and acute myeloid leukemia (AML). This dissertation describes the design, synthesis, and biological evaluation of a diverse portfolio of small-molecule inhibitors and targeted degraders, guided by structure-based drug design, SAR exploration, and pharmacological profiling. Beginning with a selective DYRK1A inhibitor (DYR533), iterative medicinal chemistry efforts led to the development of pan-DYRK/CLK inhibitors (e.g., DYR747), with expanded kinase coverage and potent Wnt/?-catenin pathway suppression. Scaffold modifications, including quinazoline, aza-quinazoline, and quinoxaline cores, were systematically optimized to improve Wnt modulation, GBM and AML cytotoxicity, and surrogate ADME properties such as microsomal stability, solubility, and predicted oral bioavailability. Structural analyses informed further SAR campaigns across multiple regions of the pharmacophore, including region-specific modifications to improve metabolic stability and selectivity. The ‘flipped’ series was further derived from the non-orally bioavailable DYR747 and yielded analogs with enhanced oral bioavailability while retaining moderate Wnt inhibition. Notably, this series also generated the first EGFR inhibitor within the program, demonstrating unprecedented cytotoxicity against GBM. In parallel, the aryl-piperazine series produced DYR895, a proof-of-concept compound with demonstrated in vivo efficacy in a CRC model. Continued optimization led to the discovery of diamino-pyridine analogs, which further improved Wnt inhibition and cancer cell cytotoxicity while limiting CNS exposure, ideal for peripheral diseases. This body of work delivers a comprehensive medicinal chemistry strategy for targeting kinase-driven cancer stemness pathways using both inhibitor and degrader modalities. The findings establish foundational tools and translational leads for therapeutic intervention in cancers with a high unmet clinical need.Release after 01/01/203
Ultrafast Spectroscopy Investigating Aggregation Dynamics: Methylene Blue Photocatalysis and Zinc(II)-Tripyrrindione Fluorescence
No full textUltrafast spectroscopies were employed to investigate aggregation and concentration-dependent effects in systems involving photocatalysis and the non-Kasha fluorescence of a relatively new metal–ligand complex. This thesis addresses how interactions between solute molecules and their environment alter optical properties, as our findings can inform strategies for catalyst loading concentrations and the selection of metal–ligand combinations for fluorescence-based sensing. Since the critical relaxation timescales in these systems occur on the femtosecond to hundreds of picoseconds scale, we use a variety of ultrafast methods to characterize these properties.The first two chapters contextualize the molecules, light sources, and experiments discussed in Chapters 3 through 5. Chapter 3 uses a combination of steady-state and transient absorption (TA) spectroscopy to verify the triplet-enabled photocatalytic mechanism of methylene blue in the oxidative hydroxylation of arylboronic acid. Kinetic modeling of its populations confirms the dimeric form undergoes rapid nonradiative decay, suggesting that increasing catalyst loading can lead to diminishing returns by promoting the formation of nonreactive aggregates. Building on this, Chapter 4 applies two-dimensional electronic spectroscopy (2DES) with a broadband probe to the same catalytic reaction, further resolving spectral features found in TA and revealing unexpected differences in the linewidths of the monomer and dimer ground-state bleaches (GSB). The final chapter explores the unusual fluorescence behavior of a pair of metal–ligand complexes, in which emission occurs from a state higher than the lowest-energy doublet, consistent with non-Kasha fluorescence. A subtle difference in ligand substituents results in dramatically different fluorescence decays: one complex exhibits strong concentration dependence in the coordinating solvent pyridine, while the other consistently shows biexponential decay. Altogether, this thesis demonstrates how ultrafast techniques can probe subtle, transient photophysical properties in systems undergoing aggregation—systems that hold promise for greener catalysis and biosensing applications, such as organic dyes and biologically compatible metals like zinc.Release after 08/29/202
The Mass and Clustering of Dynamical Halos
No full textThe halo model has been the standard framework to study the large-scale structure of the Universe over the last two decades. With the availability of increasingly high-resolution dark matter simulations and observational galaxy surveys, the current halo model is not flexible enough to incorporate higher precision constraints in a simple manner. We propose a rethinking of the conventional halo definitions to one that is both accurate to current numerical simulations and physically intuitive. This dissertation presents my work towards building an improved and interpretable halo definition. First, I show how we can use the dynamical structure of dark matter halos to motivate a physical mass definition. This new paradigm is known as dynamical halos, which are defined as the collection of orbiting particles. Then, I study the dynamical halo's clustering statistics, in which I demonstrate how they can be accurately (percent level) described with simple, and easy to interpret, models. I show that these models are highly accurate across all scales without introducing ad hoc corrections, even for traditional halo definitions. Finally, I detail the development of Oasis, a code and algorithm to generate dynamical halo catalogs for any numerical simulation
New Invasive U.S. Cotton Insects Training
No full textThis video recording accompanies the presentation New invasive U.S. cotton insects training (Ellsworth, Reyes, Keith, & Zilnik, 2025; http://hdl.handle.net/10150/678361). The training summarizes a tri-lateral series of educational sessions conducted in August–September 2025 to strengthen early detection and response capacity against two invasive insect pests threatening U.S. cotton production: the two-spot cotton leafhopper (Amrasca biguttula) and the cotton seed bug (Oxycarenus hyalinipennis). Hosted collaboratively by the Arizona Cotton Research and Protection Council, Mexican partners in Mexicali, and the University of Arizona’s Yuma Agricultural Center, these sessions engaged frontline inspectors, supervisors, and pest control advisors in recognizing diagnostic features, understanding pest biology, and assessing potential impacts. The program combined high-quality images, citizen science records (iNaturalist), and preserved specimens to enhance accurate field identification and to distinguish target species from common look-alikes. Distribution updates highlighted the rapid spread of A. biguttula from Florida into the U.S. Cotton Belt and the establishment of O. hyalinipennis in California. Training outcomes confirmed participants’ ability to identify both pests in adult and immature stages, supporting regional preparedness and coordinated response efforts. This initiative underscores the importance of proactive education and cross-border collaboration in managing invasive threats to cotton production systems. Recorded and edited by Noe Barrios and Robert Masson at the Yuma County Cooperative Extension.Documents in the Arizona Pest Management Center collection are made available by the Arizona Pest Management Center (APMC) and the University Libraries at the University of Arizona. For more information about items in this collection, please contact https://acis.cals.arizona.edu/about-us/arizona-pest-management-center
Investigation of Calmodulin Interactions in Dictyostelium discoideum Chemotaxis
No full textIn the model organism Dictyostelium discoideum, the purpose of calcium signaling inchemotaxis to cAMP is not well understood. The calcium-sensing protein calmodulin, highly conserved across eukaryotes, may play a role in chemotactic calcium signaling, as shown by other work with calmodulin antagonists. I investigated the role of calmodulin in chemotaxis signaling and found that the calmodulin antagonist W-7 may affect phosphorylation of the chemotactic proteins PKBA, PKBR1, and ERK1 and ERK2. Phosphorylation of these proteins begins with stimulation of the cAMP receptor 1 (cAR1), and preliminary experiments show cAR1 may co-immunoprecipitate with calmodulin, which indicates a possible interaction. To further investigate a possible cAR1-calmodulin interaction, I performed bioluminescence resonance energy transfer (BRET) experiments with the two proteins. I detected a BRET signal that, although not affected by cAMP stimulation, may indicate an interaction between cAR1 and calmodulin. For the further identification of calmodulin-binding proteins, I developed a protocol for the purification of calmodulin-binding proteins using Calmodulin-Sepharose beads in D. discoideum. Overall, my results suggest a possible interaction between the receptor cAR1 and the Ca2+ signaling protein calmodulin in D. discoideum. I have also worked towards developing a method of identifying other calmodulin-binding proteins using Calmodulin-Sepharose beads that will be useful in investigating the role of calmodulin and calcium signaling in chemotaxis.Release after 08/18/203
Comparative Analysis Across Advanced Diffusion MRI Techniques for Detection of Alzheimer’s Disease Pathology
No full textAlzheimer’s disease (AD), an irreversible neurodegenerative brain disease, is characterized by hallmark pathologies such as beta-amyloid plaques, neurofibril tangle, and cellular degeneration, making diagnosis challenging due to comorbidities and other dementias. Traditional MRI can detect late-stage degeneration and morphology changes but fails to sense subtle microstructural changes that happen in the early stages of the disease. This thesis aimed to identify clinically applicable diffusion MRI metrics capable of early detection of AD pathology. Results in this thesis, from a post-mortem microstructural MRI study in the hippocampus and entorhinal cortex using traditional diffusion encodings, highlighted MR metrics that are sensitive to the progression of neurofibril tangle infestation and beta-amyloid plaque presence. While promising diagnostic tools were identified during this study, the clinical implementation of these metrics remains challenging due to the time-intensive acquisitions, MRI hardware needs, and computational demands. In this thesis, these challenges were addressed, with an alternative diffusion acquisition, q-space trajectory imaging (QTI), capable of sensitizing the MRI signal to specific geometries and sizes resulting in reduced acquisition time needs. A validation of the QTI framework was conducted in a series of differing microstructural phantoms and showed key similarities to the traditional diffusion MRI framework metrics along with differing strengths. In an evaluation of both frameworks in AD post-mortem hippocampus, QTI showed improved early detection of AD when compared to the already promising traditional diffusion markers
Physics-Informed Artificial Intelligence for Multi-Scale Energy Systems
No full textThe increase of renewable energy, combined with the increased vulnerability of critical infrastructure to natural and human disasters, requires efficient simulation and optimization of energy system operations. In addition, coordination of multiple technologies requires seamless bridging of vastly different time scales. In this thesis, we outline our efforts to use physics-informed artificial intelligence in a principled manner to accelerate steady-state optimization and market clearing in power systems and dynamic transient simulation in natural gas systems. We also offer some thoughts about how to couple these technologies towards higher-fidelity simulation and more strategic day-ahead and real-time decision making. The two main problems considered are DC-Optimal Power Flow, to which we apply active set learning, and Unit Commitment of dual-fuel generators, which we model as a Markov Decision Process. Finally, we opine on the role that emerging generative AI tools may play in advancing this work, and provide a small, yet illustrative case-study on unit commitment to illustrate the potential to use the Decision Flow algorithm to generate probabilistic samples of generator statuses
Experimental Validation of Covert Communication On Software-Defined Radios
No full textThe fundamental information-theoretic limits of covert, or low probability of detection (LPD),communication have been extensively studied for over a decade, resulting in the square root law (SRL): only ??? covert bits can be reliably transmitted over time-bandwidth product ?, for a constant ? > 0. Attempting to transmit more information either results in detection or decoding issues. The SRL imposes significant constraints on hardware realization of provably-secure covert communication. Thus, experimental validation of covert communication is underexplored: to date, only two experimental studies of SRL-based covert communication are available, both focusing on a quantum optical channel. Here, initial results have been gathered demonstrating provably-secure covert radio-frequency (RF) communication using software-defined radios (SDRs). These validate theoretical predictions and open practical avenues for implementing covert communication systems, as well as raise future research questions. This thesis explores the theoretical and practical realization of covert communications on a discrete-time additive white Gaussian noise (AWGN) channel using SDRs. Careful signal design, power control, and synchronization are proposed to be critical in realizing the limits of covert communication. As such, a high performance radio network has been designed and constructed on the ORBIT Lab’s grid of SDRs for controllable, repeatable testing. An accompanying software package building on radio FPGA firmware and the USRP hardware driver (UHD) resources is used to overcome the unique challenges of covert communication. This thesis derives a lower bound for the probability of error of a maximally advantaged adversary in a covert communications scheme over AWGN channels. The lower bound is experimentally
verified using the designed radio system to gather real-world performance data. This outcome validates and extends previous work on covert communications in the discrete-time domain
Exploring the Relationship of Indigenous Identity, Perceived Stress, and Healthcare Utilization Among Indigenous Identifying Students Attending The University Of Arizona
No full textThe University of Arizona currently has more Indigenous identifying students attending the college in history. Despite this, Indigenous students are the least likely of all measured racial and ethnic groups to use on campus healthcare. This mixed methods dissertation aims to understand potential reasons for the declining rates of use by seeing if Indigenous identity impacts healthcare decision making, as well as explore other potential barriers to care. First is a scoping review that evaluates the known relationship between Indigenous identity and measurements of stress with United States based Indigenous populations. The second utilizes the Indigenous qualitative research method of Talking Circles with undergraduate and graduate Indigenous identifying students for barriers to accessing healthcare and how Indigenous identity impacted by the university system. The final aim is quantitative; utilizing surveys with Campus Health’s healthcare utilization questions, the Multigroup Ethnic Identity Measure (MEIM) and Perceived Stress Scale 10 (PSS-10) to determine if there is a significant relationship between Indigenous identity and utilization of Campus Health. This dissertation identifies many barriers to on campus healthcare for Indigenous students at the University of Arizona related to health literacy, perceived and actualized costs, and mistrust of the university. While Chapter 2 explores how Indigenous identity affects all aspects of students' lives, Chapter 3's results do not capture these nuances due to potential survey instrument limitations. The dissertation concludes by suggesting next steps to address barriers and calls for further research to improve current measurements of Indigenous identity. Release after 07/01/202