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MULTISCALE MODELING OF FEEDBACK REGULATION DURING CELLULAR POLARITY ESTABLISHMENT
Get PDFCell polarity is essential for various cellular processes, including differentiation, migration, and morphogenesis. Understanding the mechanistic basis of polarity is important for uncovering how cells perform these complex tasks. I used multiscale mechanistic models, including differential equations and particle-based simulations, to study polarity dynamics. Yeast is a well-established model for investigating polarity. In Chapter 2, I show that two coupled positive feedback loops are sufficient to drive early-phase polarity dynamics during yeast mating. In Chapter 3, I demonstrate that addition of a delayed negative feedback loop allows the polarity site to be rapidly dismantled following loss of pheromone signal. Chapter 4 examines how negative feedback via vesicle trafficking disrupts polarity, raising questions about how yeast maintain stable polarity despite the strong disturbing effect. In Chapter 5, I apply the principles of coupled feedback loops to random X chromosome inactivation (XCI) essential for dosage compensation in females. I demonstrate that a positive feedback loop involving the long non-coding RNA Xist and the silencing factor SPEN, coupled with a negative feedback loop with repression of an Xist activator, captures the N-1 rule of random XCI. Together, this work highlights how multiscale mechanistic models offer insights into the regulation of polarity and broader biological processes.Doctor of Philosoph
A Critique of the Attention Economy: Flourishing, Autonomy, and Corruption
Get PDFThe attention economy is a widespread market characterized by two types of transactions: people exchange their attention for access to new media services; these companies then sell our attention, and the information they have gathered by means of it, to advertisers. My dissertation argues that the attention economy is an impediment to human flourishing—that it is deeply at odds with intimate relationships, attentional virtues, autonomy, and valuing attention properly. First, I argue that dating apps, an attention economy service, undermine ways of thinking central to forming and maintaining committed romantic relationships. Their choice structure fosters a people-shopping mindset of exit and optimization. This economic way of thinking is morally degrading in the context of intimate relationships. Moreover, dating apps have diminished the availability of other modalities of dating and have created a collective action problem.Second, I explicate how sustained attention is inhibited by the attention economy and I argue that this capacity is essential to virtue and human flourishing. In particular, the attention economy inhibits the cultivation of the specific virtues of aloneness and stillness. These virtues have inherent value and are essential for achieving other valuable goods, such as self-knowledge and social commitments. Social media also engenders positional competition for inherently scarce, attention-based goods like popularity. Third, I argue that the attention economy infringes upon one’s autonomy by significantly interfering with control over sustaining and directing one’s attention. The attention economy is pervasive, practically necessary, and hidden. It objectionably interferes with people’s second-order preference satisfaction and their internal preference formation. And, one’s attention-based social obligations are at odds with the obligation to protect one’s autonomy from the attention economy.Fourth, I argue that the attention economy expresses and promotes corrupted attitudes about attention, namely, that attention is instrumentally valuable, commensurable with market goods, and valuable solely for its quantity. I develop a threshold view of when this corruption occurs for attention and defend my view from Brennan & Jaworski’s critique of the argument that markets express corrupted attitudes.Doctor of Philosoph
Evolution of Physiology and Virulence in Bordetella
Get PDFPertussis (whooping cough) is an acute, re-emerging disease and global health threat. Bordetella pertussis, the causative agent, survives only in the human respiratory tract and briefly during transmission between hosts. B. pertussis evolved from B. bronchiseptica, a closely related subspecies that causes long-term, chronic infections in a broad range of mammals. During infection, Bordetella spp must adjust their physiologies to survive in different microenvironments and defend against host responses by producing virulence factors (such as adenylate cyclase toxin; ACT). Two two-component regulatory systems (TCSs) are important during Bordetella spp infection: BvgAS and PlrSR. BvgAS regulates expression of all known protein virulence factor-encoding genes, but less is known about the PlrSR regulon. Bordetella spp are obligate aerobes that rely on cytochrome oxidases for respiration. First, we investigated the role of cytochrome oxidases during infection. The three cytochrome oxidases conserved in B. pertussis (CydAB1, CtaCDFGE1, and CyoABCD1) are sufficient for B. bronchiseptica colonization and persistence in mice. No single cytochrome oxidase is necessary for B. bronchiseptica persistence in mice, and CyoABCD1 alone is sufficient. Second, we conducted a comparative analysis of B. bronchiseptica and B. pertussis ACT production, secretion, and acylation, and investigated the role of ACT acylation during infection. Our data indicate that B. bronchiseptica produces and secretes more ACT than B. pertussis that is not fully acylated. Furthermore, our data indicate non-acylated ACT is at least partially functional during the initial stage of infection. Finally, we characterized structural elements of the plrSR gene cluster and identified two internal promoter regions that are not regulated by BvgAS or PlrS. Of the genes surrounding plrSR that we tested, rsmB, which is not expressed under in vitro growth conditions, and trkAH were not required for B. bronchiseptica persistence in mice. However, a possible functional dependence between BB0263 and plrS was discovered and requires further exploration. By understanding the evolution of virulence in Bordetella spp, we gain broader insight into the evolution of respiratory pathogens to the mammalian respiratory tract. Furthermore, improved vaccination and therapeutic strategies are required to combat the global burden of pertussis, and thus the investigation of new targets is critical.Doctor of Philosoph
Red Stars, Green Planets: Evaluating Planetary Habitability in Light of M-Dwarf Superflares
No full textM-dwarf stars frequently emit high-energy flares; superflares, with energies of at least erg, are not uncommon. Repeated superflares can render planets uninhabitable, but at the same time, M-dwarfs do not emit the ultraviolet radiation that Earth-like life would need to catalyze prebiotic chemistry necessary for RNA synthesis except during powerful flares. Life around M-dwarfs may require that the host star's flare activity be ``just right,'' with high-energy flares frequent enough to support prebiotic chemistry but not frequent enough to irreversibly damage planetary atmospheres. M-dwarf flares may even facilitate the detection of habitable planetary atmospheres: if the largest flares are followed by large coronal mass ejections (CMEs), an Earth-like atmosphere struck by such a CME would respond with a correspondingly intense auroral display. The most extreme exoaurorae could be visible from ground-based facilities with high-resolution spectroscopy targeting the brightest visible oxygen auroral emission line at 5577~\AA. If strong emission is detected at the oxygen auroral line in the aftermath of a powerful M-dwarf flare, such emission could be evidence that a planet with an oxygen-rich atmosphere orbits the M-dwarf and is reacting to the impact of a CME. Here, I present the observational and theoretical studies that collectively form my dissertation, analyzing the impact of high-energy M-dwarf flares on planetary habitability, ozone depletion, prebiotic chemistry, and possible exoauroral emission.Doctor of Philosoph
CAN A SMART RING IMPROVE SLEEP? INVESTIGATING THE EFFECT OF A 4-WEEK OURA RING TRIAL ON SLEEP DURATION AND QUALITY
Get PDFThis study evaluated the effects of a smart ring on sleep and cardiovascular health in middle-aged adults. Twenty-six individuals (57.7% female; age [Mean±SD]: 49.2±5.2 years) were given an Oura Ring and full access to its associated smartphone application for 4 weeks. Changes in objective sleep outcomes (duration, latency, efficiency), subjective sleep quality, arterial stiffness, and heart rate variability (HRV) were evaluated over the duration of the study. There were no significant changes in sleep duration (p=0.427), latency (p=0.739), efficiency (p=0.990), or quality (p=0.923) across the 4 weeks. Additionally, there were no significant changes in arterial stiffness (p=0.691) or HRV (p=0.438). These results suggest that in middle-aged adults, the standalone use of an Oura Ring for 4 weeks is not enough to elicit changes in sleep and subsequent changes in cardiovascular health. Future research should evaluate Oura Rings in conjunction with other intervention strategies to improve sleep and overall health.Master of Art
USE OF A PRIORI AND A POSTERIORI METHODOLOGIES TO INFORM THE DEVELOPMENT OF FEASIBLE EATING STRATEGIES THAT PROMOTE GLYCEMIC MANAGEMENT IN YOUNG PEOPLE WITH TYPE 1 DIABETES
Get PDFThere are no evidence-based eating strategies for youth with type 1 diabetes, despite established understanding that nutrition is fundamental to glycemic management and complication prevention, and self-management is worse during adolescence compared to all other life stages. Critically, existing eating strategies do not provide guidance related to timing, frequency, or macronutrient composition of eating occasions to optimize short-term or longer-term glycemic measures. The objective of this dissertation was to inform the development of eating strategies that consider these factors, with the ultimate goal of prospectively evaluating their effectiveness for improving of glycemic management among youth with type 1 diabetes. In Aim 1, we developed a daily eating behavior pattern focused on number and timing of eating occasions and distribution of macronutrients throughout the day, and conducted a pilot trial to explore feasibility and diabetes management benefits among 52 adolescents with type 1 diabetes. We observed excellent retention (85%), attendance (15.8[SD=0.6]/16 sessions), food log adherence (4.0[SD=2.6]/≥3 logs per week), ≥90% participation in evaluation procedures, and no adverse effects. Endline adherence to most (≥3) goals was ≥90% according to unannounced dietary recalls. Hemoglobin A1c decreased on average by 0.3(SD=0.9)% (p=0.03). Youth and parents (>85%) endorsed acceptability. Findings supported progression to a trial to evaluate effectiveness. Aim 2 was a secondary analysis using 175 days of overlapping eating, insulin, physical activity, continuous glucose monitoring, and clinical data from 49 participants in the Aim 1 trial. We trained a generalized additive model that incorporated predictors over a 6-hour window divided into 1-hour intervals (-2 to -1 hours, -1 to 0 hours, 0 to +1 hours, +1 to +2 hours, +2 to +3 hours, +3 to +4 hours), to predict near-term time in range (0 to +4 hours). We demonstrated a proof-of-concept for the intended application of the model: a personalized, adaptive eating decision support tool that enables users to select from meals/snack options and adjust timing to optimize near-term glycemic management amidst food or timing constraints. Our studies lay groundwork for the development of behaviorally interpretable, specific and feasible eating strategies that youth with type 1 diabetes can use to support day-to-day management.Doctor of Philosoph
Equity-Focused School Improvement
Get PDFTo provide all students with an equitable school experience, several decades of reform have prompted schools across the nation to develop school improvement plans. This practice has become so deeply institutionalized that almost all states require schools to engage in the school improvement planning process (Every Student Succeeds Act, 2015; Fernandez, 2011; Wronowski et al., 2022). Yet, limited empirical evidence exists to suggest this common practice produces its intended results. Educational opportunities and student achievement outcomes continue to be disparate.This exploratory, instrumental case study investigates how schools within Wake County Public School System (WCPSS) navigate the state-mandated school improvement process to identify and address educational inequities. Grounded in Critical Policy Analysis (CPA) and informed by an integrated conceptual framework—the Equity-Focused Improvement Framework—containing elements of Culturally Responsive School Leadership (CRSL) and Improvement Science (IS), the study conducted a qualitative content analysis of 198 WCPSS school improvement plans (SIP) for the 2022-2024 two year SIP cycle. Informed by the findings of the content analysis, a second cycle of data collection was conducted using semi-structured interviews with principals leading schools whose SIPs indicated evidence of equity-focused improvement strategies. Designed to provide a broad picture of the SIP landscape in WCPSS, this study found that equity-focused improvement was minimally present in 2022-2024 SIPs. However, this study also found a small sample of schools whose SIPs were rich outliers in the overall data, providing insight into how equity-focused improvement can be integrated in school improvement within the context of the current policy landscape. This study contributes to both scholarship and practice a practical tool, the Equity-Focused Improvement Framework, for conceptualizing the intersection of equity leadership and continuous improvement. This study also points to a need for ensuring that policy guidance and supports are enacted in ways that empower schools to move beyond compliance towards transformational change.Doctor of Educatio
Human, Nature and Politics in Xie Lingyun and Wang Wei's Poetry
Get PDFThe thesis examines Chinese traditional nature poetry from the perspective of ecocriticism. Using Xie Lingyun and Wang Wei as a case study, the thesis aims to explore the dilemma between environmental politics and utopic visions of reclusion. The thesis reveals nuanced differences between poetry in ecosystem, and its metaphors for political ambition and reclusion. In political sphere, Xie Lingyun expresses his political ambition about utilizing environmental politics to change nature. Conversely, Wang Wei advocates for a “nonaction” (wu wei) method of government by distancing himself to direct political conduct. As for enlightenment and reclusion, the two poets reach the abstract enlightenment and concrete utopia based on Daoist self-cultivation. Xie Lingyun’s utopia is to form a community that can unify heaven and humanity through mountain reclusion. Wang Wei’s utopia, by contrast, is to create an isolated society such as Peach Blossom Spring through a distant countryside reclusion. Facing the dilemma between politics and reclusion, both poets lingers between Confucianism and Daoism in their different life periods. Xie Lingyun uses Confucianism in environmental politics and uses Daoism as a regimen to live longer. On the other hand, Wang Wei’s version of Daoism is while he implements his political duties and reclusive cultivation, he simultaneously finds a third space between Confucianism and Daoism. The thesis will follow the road maps of introduction, three chapters, and conclusion. The introduction mainly presents the intellectual background and historical facts. Chapter one will discuss how Confucian action contributes to Xie Lingyun’s environmental politics, while Daoist nonaction contributes to Wang Wei’s attitude. Chapter two will focus on how the two poets attain enlightenment in an instantaneous moment where existence and nonexistence combine and contrast. The Chapter will compare Xie Lingyun’s utopia as unification of human and heaven with Wang Wei’s Daoist ideal state. Chapter three will show how the poets dilemma between political ambition to reclusion by associating their biographical experience and Chinese philosophical standpoints. The conclusion will further develop research directions.Master of Art
LATE PLEISTOCENE SLIP RATES ALONG THE SALINE VALLEY FAULT ZONE, EASTERN CALIFORNIA
Get PDFGeologic relationships indicate 9-10 km of dextral-oblique shear along the Panamint Valley-Hunter Mountain-Saline Valley fault system began after ~3.7 Ma, suggesting slip rates of 2-3 mm/yr. Present geodetic measurements, however, show faster slip rates of 4-6 mm/yr, implying an acceleration over the past few million years. Slip rates along the Saline Valley fault zone (SVFZ) near the Inyo Mountains remain poorly defined. This study reconstructs ~28 m vertical displacement of alluvial fan surfaces at McElvoy Canyon, dating to approximately 12-14 ka based on soil and pavement development, supported by 10Be exposure ages (Lee et al., 2009). Although the fault surface isn’t exposed here, nearby dips of ~35 ± 10° suggest extension rates of 3.0 ± 1.3 mm/yr parallel to the HMF. These findings support a relatively recent acceleration in the fault system’s movement.Master of Scienc
Geographic, organizational, and individual variation in non-medical exemptions to kindergarten vaccination requirements in the US.
Get PDFKindergarten vaccine requirements prevent the spread of communicable diseases, including measles, but require high participation to achieve herd immunity. Recently, rates of non-medical exemptions to kindergarten vaccine requirements have increased, along with outbreaks of vaccine-preventable disease. Understanding common characteristics among geographic areas, organizations, and individuals with high non-medical exemption rates is crucial in developing interventions to increase vaccine uptake and protect children from vaccine-preventable disease. This systematic review aims to quantitatively summarize the direction and magnitude of the associations between geographic, organizational, and individual variation in non-medical exemptions