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Molecular Responses to Oxidative Stress: From Extracellular Mitochondria to NRF2 Signaling and Translational Control
No full textOxidative stress disrupts cardiovascular homeostasis by impairing mitochondrial integrity, depleting antioxidant defense, and reprogramming protein synthesis. The work presented here interrogates these responses across organelle, cellular, and organismal scales through integrative biochemical, omics, and in vivo approaches. An acute H2O2 exposure prompted AC16 cardiomyocytes to expel a distinct pool of fragmented extracellular mitochondria (EM). These organelles exhibited depolarized membrane potential, reduced bioenergetics, and altered cristae morphology. Untargeted lipidomics revealed ceramide enrichment and pharmacological inhibition of ceramide biosynthesis markedly suppressed mitochondrial extrusion. Functionally, EM served as damage-associated molecular patterns (DAMPs), driving inflammatory responses in macrophages and thereby linking mitochondria quality control to sterile inflammatory signaling. Cross-species analyses of human (GTEx), Rhesus monkey, Fischer rat, and C57BL/6J mouse myocardium uncovered an age-dependent decline in NRF2 expression and activity at RNA transcript or protein levels. Aged NRF2 knockout mice developed premature eccentric hypertrophy, diastolic dysfunction, and shortened lifespan. Our findings indicate an early onset of maladaptive cardiac remodeling with the loss of NRF2. Ribosome-bound mRNA sequencing of oxidatively stressed HeLa cells identified 21 selectively loaded transcripts, including ATF3 and MAFF. Increased ribosome-associated ATF3 mRNA coincided with higher ATF3 protein levels, whereas MAFF translation was delayed despite the polysome enrichment. Silencing the ribosomal quality control protein RACK1 eliminated this delay, indicating translational checkpoint on the ribosomes that modulates stress-associated protein synthesis. Together these findings delineate a coordinated triad of oxidative stress adaptations: (1) ceramide-dependent mitochondrial extrusion that drives inflammatory signaling, 2) an age-associated decline in NRF2 antioxidant response linked to cardiac remodeling, and 3) ribosome surveillance mechanisms that regulate protein synthesis. This work advances mechanistic insights into how redox imbalance culminates in cardiac pathology and identifies therapeutic entry points for mitigating oxidative damage
Physical Emulation Of Nonlinear Spin System Hamiltonians Via Closed Loop Feedforward Control Of A Collective Atomic Spin
No full textIn recent decades the field of quantum computation has seen remarkable development. While much progress has been made toward the realization of a fully digital, scalable, and fault tolerant quantum computer, there are still many essential challenges to overcome. In the interim, direct emulation of quantum systems of interest can fill an important gap not only for exploring fundamental questions about many-body physics and the quantum to classical transition, but also for potentially providing alternative methods to verify results from quantum simulations. In this work we will demonstrate a method utilizing closed loop control of the collective magnetic moment of an ensemble of cold neutral atoms via non-destructive measurements to emulate various spin system Hamiltonians. By modifying the feedback control law appropriately we are able to generate nonlinear dynamical behavior in the ensemble, allowing us to explore the physics of collective spin systems at mesoscopic scales. Moreover, controlling the number of atoms in the collective spin can potentially allow us to investigate these dynamics in the transition from fully quantum to the classical limit. In particular, we emulate two models: the Lipkin-Meshkov-Glick (LMG) Hamiltonian, and a closely related model, the Kicked Top. In the former case, we show that our system undergoes a symmetry-breaking phase transition in the expected parameter regime. In the latter, we explore two interesting aspects: the formation of chaos, and a dynamically driven time crystal phase. We will then discuss the advantages and limits of this approach
Robust Learning, Inference and Uncertainty Quantification via Contrast
No full textIn this dissertation we develop tools for using contrast to improve trustworthiness in machine learning. We do this in two specific ways. We provide a new framework for producing counterfactuals which uses contrast to verify that they will have the intended effect without acting adversarially. We also propose a new fine-grained measure of aleatoric uncertainty and present a contrast based method for estimating this measure. First we address \textit{Counterfactuals}, which are modified inputs that lead to a different outcome and are an important tool for understanding the logic used by machine learning classifiers and how to change an undesirable classification. Even if a counterfactual changes a classifier's decision, however, it may not affect the true underlying class probabilities, i.e. the counterfactual may act like an adversarial attack and ``fool'' the classifier. We propose a new framework for creating modified inputs that change the true underlying probabilities in a beneficial way which we call \textit{Trustworthy Actionable Perturbations} (TAP). This includes a novel verification procedure using contrast to ensure that TAP change the true class probabilities instead of acting adversarially. Our framework also includes new cost, reward, and goal definitions that are better suited to effectuating change in the real world. We present PAC-learnability results for our verification procedure and theoretically analyze our new method for measuring reward. We also develop a methodology for creating TAP and compare our results to those achieved by previous counterfactual methods. Second, we propose a new and intuitive metric for aleatoric uncertainty quantification (UQ), the prevalence of class collisions defined as the same input being observed in different classes. We use the rate of class collisions to define the collision matrix, a novel and uniquely fine-grained measure of uncertainty. For a classification problem involving classes, the collision matrix measures the inherent difficulty in distinguishing between each pair of classes. We discuss several applications of the collision matrix, establish its fundamental mathematical properties, and show its relationship with existing UQ methods, including the Bayes error rate (BER). We also address the new problem of estimating the collision matrix using one-hot labeled data by proposing a series of innovative techniques to estimate . First, we learn a pair-wise contrastive model which accepts two inputs and determines if they belong to the same class. We then show that this contrastive model (which is PAC learnable) can be used to estimate the row Gramian matrix of , defined as . Finally, we show that under reasonable assumptions, can be used to uniquely recover , a new result on non-negative matrices which could be of independent interest. With a method to estimate established, we demonstrate how this estimate of , in conjunction with the contrastive model, can be used to estimate the posterior class portability distribution of any input. Experimental results are also presented to validate our methods of estimating the collision matrix and class posterior distributions on several datasets
Cogs in the Machine? Evaluating Individual Contributions to our own Oppression
No full textThe concept of structural oppression broadly refers to the idea that oppression is not merely an outcome of aggregating individually oppressive actions by discrete agents spread about society—rather, oppression is rooted in the very basic operations of our societies. Social norms, laws, political policy, the economy, and even the independently non-objectionable choices of individuals can bring it about. Simply put, oppression can be part of the fabric of our daily lives, so shaped by the social structures in which we live. The fundamental insight of structural views of oppression is that we must shift our attention to the social forces that structure our lives in order to understand how oppression works, and- importantly- how it may be overcome. We must take care, however, not to refocus our attention to the structural in such a way that neglects the significance of individual agency. Focusing too much on individual agency leads us to place blame on individuals for collectively detrimental outcomes, but focusing too much on social structure leads us to treat individual action as pre-determined, and so we undermine the importance of individual agency. This dissertation sets out to appreciate the impact of both. As with any large-scale social phenomenon, oppression comes about due to the structural shaping of the social environments in which individuals exercise their agencies. In the chapters that follow, I offer a method by which we can understand oppression as occurring in the interplay between social structure and individual behavior. Approaching the study of oppression as occurring within and among networks of individuals allows us to appreciate both its structural and agential elements, which provides us with a foundation for normative evaluations of our contributions to it. This dissertation utilizes the language and insights of social network theory to establish such a foundation. I argue for a view of oppression as a self-reinforcing pattern of unfairly restricted social relations that systematically disadvantages one social group in relation to another. In doing so, I will answer some of these questions and, in the traditional spirit of philosophy, raise more
Developing Novel Sensing Tools for Hormones and Neurotransmitters in Complex Biological Systems
No full textDisruptions in hormone and neurotransmitter signaling and metabolism cause many common disorders, including diabetes, a disorder caused by disruption of glucagon and insulin secretion in pancreatic islet cells, and hyperparathyroidism, a disorder caused by an over-secretion of parathyroid hormone that disturbs calcium homeostasis throughout the body. Improving treatments for these disorders requires new methods for accurate detection and quantification of the hormones and neurotransmitters released, as many of these compounds are not detected by existing optical or electrochemical techniques. Furthermore, crucial physiological functions rely on dynamic concentration changes of multiple hormones, neurotransmitters, or ions occurring at the same time; as such, understanding a given pathway often necessitates the measurement of multiple analytes simultaneously. This dissertation presents improvements to existing electrochemical and electrophysiological techniques, aiming to optimize them for use in neuroendocrine systems. In Chapter 2, a lipid membrane-based ion-selective electrode facilitates Ca2+ quantification in small volume samples. Polymer scaffolds incorporated into these black lipid membranes significantly improve their stability, enabling them to withstand greater electrical potentials and mechanical challenges for longer periods of time. To better characterize interactions between the polymer scaffold and the lipid membrane, Chapter 4 explores the polymer scaffold in another lipid environment, the lipid nanodisc, for the first time. Particle size measurements, thermal characterization, and temporal analysis provide further information on the molecular basis for the increased stability facilitated by the polymer scaffold. In Chapter 3, dual-barrel pipettes fabricated with carbon-fiber microelectrodes enable precision positioning for real-time detection and quantification of exocytosis in single-cell amperometry experiments. Together, these developments expand the tools available to study neuroendocrine signaling in real time and provide a foundation for the design of robust, multifunctional sensors.Release after 08/26/202
An Innovative Approach to Medical-Legal Partnership: Unauthorized Practice of Law Reform as a Civil Justice Pathway in Patient Care
No full textThis Article discusses the design of an innovative approach to the traditional medical-legal partnership. This potentially transformative service model proposes the use of unauthorized practice of law (UPL) reform to embed civil legal problem solving within a patient care setting. Unlike in the traditional medical-legal partnership — a service model which embeds lawyers within patient care settings to address patients’ justice needs — we explore the promise of patient advocacy through community-based justice workers (CBJWs): members of the community who are not lawyers but who have specialized legal training and authorization to provide civil legal help to those who need it most. This work is the result of a partnership between Innovation for Justice, a social justice legal innovation lab housed at both the University of Arizona James E. Rogers College of Law and the University of Utah David Eccles School of Business, and University of Utah Health. The present framework for UPL-reform-based medical-legal partnerships was developed through robust community-engaged research and design work across the 2022–23 academic year. This article discusses the research findings and proposes a framework for replication in other jurisdictions.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
Developments in Plant Genetics
No full textThis article, published in the VegIPM Newsletter (Vol. 16, No. 20), traces advances in plant genetics from the Green Revolution to Bt crops, while warning against past missteps like Lysenkoism.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
Habitat and Stocking Strategies for Native Fish Recovery in the Verde River Basin, Arizona
No full textNative fishes of the Colorado River Basin in the southwest United States rank among the most imperiled faunal groups worldwide. Their decline is linked to widespread habitat alteration and the subsequent proliferation of nonnative fishes that compete with and prey upon native taxa. Despite decades of conservation efforts, many of the native fishes remain at risk of extinction and there is continued interest in effective recovery strategies across the basin. This dissertation presents detailed investigations of native southwestern fishes, with a particular focus on Razorback Sucker Xyrauchen texanus in the Verde River, Arizona, a key tributary within the Gila River Basin. In this dissertation, I 1) review Razorback Sucker abundance, distribution, and conservation efforts within the Gila River Basin from 2004-2021, 2) evaluate and compare the survival and movement patterns of large (> 250 mm TL) and small (< 250 mm TL) Razorback Sucker stocked into mainstem and reservoir environments of the Verde River, 3) detail novel helicopter stocking methods for translocating endangered fishes to remote locations, and 4) assess how native fish abundance and habitat selection changes in response to nonnative piscivores in Fossil Creek, Arizona. More than 11 million Razorback Sucker were stocked into the Gila River Basin between 1980 and 2004; however, a population has failed to establish. From 2004-2021, 17,313 Razorback Sucker were stocked into the Verde River; but < 0.10% have been recapture and success has been limited. In 2022, I initiated a three-year stocking effort in which approximately 2,500 Razorback Sucker of two size classes were released annually in two locations, the mainstem Verde River and Horseshoe Reservoir. The goal was to evaluate whether reservoir stockings could enhance Razorback Sucker survival. In 2022 and 2023, the survival of small and large Razorback Sucker was negligible regardless of stocking location; however, in 2024 the 9-month post-stocking survival of Razorback Sucker increased to 5.7%. Overall, the survival of large fish was significantly greater than that of small fish and survival in the reservoir was higher than in the river. Mortality was attributed to water quality, specifically high-water temperature and stratification in the reservoir, as well as predation by nonnative fishes and piscivorous birds. Nonetheless, the survival of some Razorback Sucker in Horseshoe Reservoir offers hope for the species’ persistence in the Verde River Basin. Stocking Razorback Sucker into the mainstem river environment presented logistical challenges because it is inaccessible to traditional hatchery vehicles. I therefore commissioned a helicopter to transport Razorback Sucker to a remote location on the Verde River and compared the survival of fish stocked by helicopter to those stocked by conventional hatchery truck. The four-week post-stocking survival of fish stocked by helicopter and those stocked by hatchery truck into Horseshoe Reservoir was similar. Many of the observed mortalities were distant from release sites, suggesting fish mortality was not attributable to the stocking practices. Stocking fishes with a helicopter can be useful for fisheries conservation as it did not impact fish survival and allowed for broader distribution of stocked fish into previously inaccessible environments. Finally, I conducted snorkel surveys in Fossil Creek, Arizona, a Verde River tributary with an entirely native fishes upstream and a native and nonnative fishes downstream of a fish barrier to evaluate differences in species abundance and habitat selection in native fish communities with and without nonnative fish. The abundance of all Roundtail Chub Gila robusta, small (< 127 mm TL) Sonora Sucker Catastomus insignis, and all Speckled Dace Rhinichthys oscullus was significantly lower when sympatric with nonnative fishes; however, Desert Sucker Catostomus clarkii abundances were similar between reaches. When black bass were present, native fishes avoided pools and increased their selection for riffles, a likely predator avoidance behavior. These results highlight the distributional and behavioral consequences of native fishes occupying the same stream as nonnative fishes and highlights the importance of maintaining specific habitat-types when nonnative fishes are present in a river. Collectively, this research highlights the persistent challenges of conserving native fishes in the Verde River and offers practical insights to guide and improve future conservation efforts throughout the basin
Evaluation of Spatial Light Modulator for High Contrast Imaging
No full textHigh Contrast Imaging (HCI) systems are optimized to image faint objects located near bright point sources. This is essential to exoplanet imaging and the search for biological activity by spectroscopic characterization of exoplanet atmospheres. HCI systems for future large space telescopes capable of imaging about a dozen habitable exoplanets will require correction of >10,000 wavefront modes, but conventional Deformable Mirrors (DMs) only provide about 3,000 actuators. DMs that have ? 128×128 actuators are required by these upcoming projects, as identified in the 2019 NASA Exoplanet Exploration Program Technology Gap List1. A Spatial Light Modulator (SLM) can offer more actuators (about 2 x 106 actuators) than a conventional DM. SLMs can also offer a compact solution to this large-format DM challenge. Thanks to recent advances, SLMs can now offer both the actuator count and control speed (.7 kHz) required for exoplanet imaging for both ground and space telescopes. It is envisioned that existing SLMs could one day serve as a second-order correction after a first coarse correction using a conventional DM. While SLMs offer a promising solution to the large-format DM’s actuator count challenge, they have not yet been used in high contrast imaging correction in broadband light, and their stability, polarization, and chromaticity must be better understood and accounted for. In this thesis work, an SLM device was characterized and validated in the lab for use in HCI, measuring its contrast stability, polarization cross-talk, and chromaticity in the lab
Geologic Map of Arizona - 2000
No full textThis publication is a conversion of the Arizona Geological Survey's Map-35, "Geologic Map of Arizona - 2000" into an ESRI File Geodatabase. This vectorized version was created in 2013 as a digital trace of the original Map 35 (2000) and DGM-17 (2002) statewide map images for use in an Online Geologic Map of Arizona. The website hosting that online map version was later shut down in 2022. The purpose of this 2025 (re)publication is to restore public access to the 2013 map data while also lightly altering it to make it more compatible with the 2020 USGS Geologic Map Schema by distributing it as an ESRI File Geodatabase. Because this product is a conversion of a conversion, any deviations from the original Map-35 product should not be taken as geologically meaningful.Documents in the AZGS Documents Repository collection are made available by the Arizona Geological Survey (AZGS) and the University Libraries at the University of Arizona. For more information about items in this collection, please contact [email protected]