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Item Test Item(2026-07-08)Item Microtubule Hyperstabilization as a Novel Mechanism of Insulin Resistance(The University of Arizona., 2026-05-08)Insulin stimulates the insertion of glucose transporter 4 (GLUT4) into the plasma membrane of skeletal muscle and adipose cells, allowing for glucose uptake to maintain homeostasis. Microtubules (MTs) are an essential part of this process, as they allow for GLUT4-storage vesicles (GSVs) to reach and insert into the plasma membrane. This insulin-stimulated glucose uptake (ISGU) is disrupted by insulin resistance, a hallmark of type II diabetes mellitus (T2DM), causing decreased ISGU and chronic elevation of blood glucose. Although previous research by our lab found that insulin increases MT acetylation and stabilization, the function of this modification remains unclear. In this follow-up study, we set out to determine whether MT acetylation and stabilization are required for ISGU. We targeted α-tubulin acetyl transferase 1 (ATAT1), the primary protein responsible for MT acetylation, as well as its upstream activator, transforming growth factor β activated kinase 1 (TAK1), and modulated their activity to determine the role of MT dynamics in the insulin pathway. We discovered that siRNA-mediated knockdown in 3T3L-1 adipocytes of neither TAK1 nor ATAT1 impairs ISGU. Follow-up studies using the reported MT-targeting small molecule GM-90631 revealed that μM dose treatments compromise MT integrity whereas nM doses do not interfere with MT integrity yet increase MT acetylation and decrease ISGU in 3T3-L1 adipocytes. We confirmed this result via treatment with the histone deacetylase inhibitor Trichostatin A, which caused MT hyperacetylation and hyperstabilization and decreased ISGU at 400 and 800 nM concentrations. We hypothesize that MT hyperstabilization restricts MT dynamics required for ISGU, leading to insulin resistance. Since inflammatory cytokines like TNF-a and TGF-β activate the TAK1/ATAT1 nexus, we propose that MT hyperstabilization is driven by inflammation, a key factor involved in the pathogenesis of T2DM, which leads to decreased ISGU by insulin target tissues, causing insulin resistance.Item Characterization of a Two-Photon Rubidium-87 Optical Clock(The University of Arizona., 2026)Atomic clocks are based on highly stable and well-characterized atomic transitions, mak-ing precise control and understanding of systematic frequency shifts essential for improved timekeeping performance. This thesis presents an experimental study of light-induced Stark shifts in rubidium and their impact on precision laser spectroscopy relevant to atomic frequency standards, as well as the effects of residual amplitude modulation on the laser lock point and the resulting sensitivity of both short- and long-term stability. A laser-based spectroscopy system was developed to probe rubidium transitions while enabling controlled variation of optical intensity. The optical beam was experimentally characterized through calculations of beam waist and measurements of power to accurately determine the intensity at the interaction region. Frequency shifts arising from the AC Stark effect were measured as a function of optical power, allowing extraction of the differential polarizability between atomic energy levels using a theoretical model relating energy shifts to electric-field intensity. Uncertainty analysis was performed through systematic propagation of experimental errors associated with beam geometry, optical power calibration, and frequency measurements. In addition, residual amplitude modulation generated by electro-optic phase modulation was investigated as a significant source of systematic error in frequency stabilization systems used in atomic clocks. The magnitude and behavior of RAM were experimentally characterized, and its impact on frequency stability was quantified by measuring the sensitivity of the laser lock point to controlled variations in RAM. Potential mitigation strategies were then explored through active pre-compensation of RAM using an amplitude electro-optic modulator in a closed-loop feedback system.Item Intertwining Pollution and Community Science to Model Soil and Dust Metal(Loid)S Exposures Post Climatic Events in Rural Populations(The University of Arizona., 2026)Metal(loid)s are widespread in the environment, whether naturally or anthropogenically, which can propose a profound threat to human health. Therefore, reliable, community-engaged and cost-effective techniques are needed to improve our understanding of environmental pollution and to serve rural areas. The prolonged resistance and accumulation of metal(loid)s across different environmental media e.g., soil, sediment, and dust require exposure science efforts and public health prevention/intervention strategies. To maintain the wellbeing of rural communities, there is a suite of methods that can be used to monitor, source track, and characterize potential metal(loid) concentrations in the environment and potential environmental health risks. This work focuses on co-created community science to reveal the intertwined interactions between climatic events on metal(loid)s longevity and distribution across environmental media and over different land settings. The first study validated the Portable X-Ray Fluorescence’s (pXRF) utility in community soil monitoring efforts to measure metal(loid)s linked to anthropogenic sources. Overall, from an exposure science and public health perspective, the pXRF sufficiently characterized arsenic (As), copper (Cu), lead (Pb), and zinc (Zn) concentrations in “impacted areas” when compared to the “gold standard” analytical technique, inductively coupled plasma mass spectrometry (ICP-MS). It is noteworthy to consider how natural sources, regional geology, and site conditions can impact background metal(loid) values, which in turn, can influence the enrichment and pollution levels. Therefore, to enhance the pXRF reliability, using a soil matrix approach during calibration is optimum for regions known to have higher naturally occurring elements. In summary, the pXRF can be a cost-effective alternative to screen As, barium (Ba), calcium (Ca), Cu, manganese (Mn), Pb, and Zn in soil and protect environmental public health. While it is well known that there is no safe level of Pb exposure, residential sites still suffer from Pb contamination. In disaster prone regions, Pb contamination is reflected by its origin and in general, anthropogenic sources are well documented. However, in rural areas, particularly after climatic events, there is little to know about Pb origins, primarily due to the lack of established environmental data. After a sequence of natural disasters in Gila County, Arizona, USA, community members raised concerns about metal(loid)s exposure and origin. To address these concerns, non-residential sediments (0–2 cm, 2–15 cm, and 15–30 cm), household soil (0–2 cm), and indoor and outdoor dust samples were analyzed for metal(loid)s concentration via ICP-MS. In this second study, Pb isotopic composition was also determined for a randomly selected 30% of samples across all media types. Pb isotopic analysis is a convenient and well-established method for tracking contamination sources in the environment. This study determined whether wildfire and flooding contributed to elevated Pb exposure and associated metal(loid) concentrations. Through Pb isotopic ratios and various statistical approaches, the geogenic and anthropogenic sources of Pb were characterized across multiple environmental media. To the best of our knowledge, this is the first study to report the Pb isotopic ratio composition for wildfires in Arizona, investigate Pb source apportionment across different environmental media, and examine the role of flooding in Pb remobilization. The third study continued work in the same study area, now employing a Monte Carlo-based probabilistic assessment to examine how wildfire and subsequent flooding influence exposure to As, cadmium (Cd), Cu, chromium (Cr), Pb, Mn, nickel (Ni), and Zn from non-residential sediment and residential soil and indoor/outdoor dust. This work weaved the various datasets to investigate: (1) The contribution of different environmental media to adult and child exposure and the associated cancer/noncancer risks; (2) Which exposure route(s) contributes the greatest potential risk to vulnerable populations, i.e., child; and (3) If flooding increased the risk of metal(loid)s exposure in residential settings. The children’s mean cumulative non-carcinogenic risk e.g., hazard index was driven by As, Cu, and Mn in outdoor dust followed by Pb and Zn in soil. Arsenic incidental ingestion and to a lesser degree Pb from residential outdoor dust was the prominent exposure pathway, leading to an unacceptable carcinogenic risk for children over 78 years of exposure i.e., 1.6 cancer cases for every 10,000 children. The fourth study evaluated metal(loid) concentrations in dust generated from different plant species during wildfires of varying burn severities. To achieve this, incomplete combustion conditions from the Telegraph and Mescal Wildfires in the Tonto National Forest, Arizona, USA were simulated in a controlled laboratory setting. Sixteen plant species from Sonoran Desert Scrub, Interior Chapparal, and Madrean Evergreen Woodland biotic communities were collected and thermally degraded at three different temperatures representing low (200°C), moderate (350°C), and high (550°C) burn severities. The results reveal the intertwined factors in a terrestrial ecosystem that influence metal(loid)s distribution across inhalable particles generated from wildfire slow pyrolysis. By combining plant biology (e.g., physiology and accumulation patterns) and geochemistry, this fourth study's findings are expected to inform metal(loid) exposure assessments in similar biotic communities across the western United States. The findings from this research will highlight community vulnerabilities and resiliencies, inform fire and forest management agencies, as well as efforts related to environmental public health protection.Item Transient ACE Inhibition Induces Sex-Specific Reprogramming of the Cardiac Macrophage Transcriptome(The University of Arizona., 2026)Hypertension-driven cardiac remodeling is increasingly understood to involve immune mediated processes in addition to hemodynamic stress. Among cell populations present in the heart, macrophages play a significant role in shaping inflammatory and fibrotic signaling within the myocardium. Angiotensin-converting enzyme inhibitors (ACEi) are widely used in the treatment of hypertension and have been shown in male spontaneously hypertensive rats (SHR) to provide long-term protection against target organ damage that persists after treatment cessation. While these effects are typically attributed to reduced angiotensin II actions at the fibroblasts, growing evidence suggests that ACE inhibition may also influence immune cell biology. Whether transient ACE inhibition alters macrophage transcriptional programs, as well as if these effects differ between males and females, remains unclear. To address this question, adult male and female SHR were treated with vehicle or ACEi (enalapril, 30 mg/kg/day) for two weeks followed by a two-week washout period. Left ventricular non-cardiomyocyte, CD31-negative cells were isolated and analyzed using single nucleus RNA sequencing. Eighteen distinct cell clusters were identified, five of which were classified as macrophages. Only three of the five cell clusters were included in analysis, as they were the most abundant. Differential gene expression analyses were performed within macrophage-containing clusters, and significant genes were evaluated for functional enrichment using STRING. The largest cluster was identified as resident cardiac macrophages (Ccr2-, Ly6c-), with the other two clusters identified as inflammatory, antigen-presenting (Ccr2+, Ly6c+), and tissue adapted-antigen-presenting (Ccr2+, Ly6c-). In controls, macrophages from male and female hearts displayed differences in gene expression that was broadly characterized by a higher immune activation signature in females in all three clusters - suggestive of sex-specific immune programming. Following transient ACE inhibition, macrophage clusters showed sex- and cluster specific patterns of transcriptional change. In males, the top biological process (gene ontology (GO) term) among significantly upregulated genes was regulation of phagocytosis, whereas in females, the top GO term was T cell activation. This suggests that the resident cardiac macrophages in males took on a greater resolving phenotype, while in females this same cluster became more primed for activation. In the inflammatory, antigen-presenting cluster (Ccr2+, Ly6c+) there were no significant biological processes that were enriched among significantly up or downregulated genes from males, but there was enrichment in females, with the top biological process downregulated being regulation of GTPase activity. In the tissue-adapted, antigenpresenting (Ccr2+, Ly6c-) cluster, the top GO term among significantly upregulated genes was positive regulation of cytokine production and among downregulated genes was regulation of cell-cell adhesion. In this cluster in female cells, there were no significant biological processes that were identified among significantly up or downregulated genes. Together, these findings suggest that transient ACE inhibition induces sustained transcriptional changes in cardiac macrophages and highlight sex as a key factor influencing macrophage-mediated responses during hypertension and its treatment.