Dissertations

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Computational drug discovery for advanced prostate cancers
(2024-05) Zhang, Weijie
Prostate cancer (PC) is one of the most diagnosed malignancies and a leading cause of cancer deaths in US men. Though primary and localized PC can be well-managed by current interventions, a fraction of PC will progress to castration-resistant prostate cancer (CRPC), a lethal subtype that displays universal resistance to standard-of-care (SOC) therapies. Given the current lack of efficacious treatments, survival among CRPC patients remains poor. Therefore, there is an urgent need to develop new treatment strategies to combat advanced PC. Traditional drug development pipelines, however, remain costly and time-consuming. Recently, there has been a rapid increase in available cancer genomic, phenotypic, and high-throughput drug screening data; this has enabled the invention of computational approaches to quickly repurpose existing compounds and consequently shorten the cycle of designing new therapeutics. Nonetheless, there is still a lack of integration of efficient computational methods for discovering new treatment opportunities for CRPC. Thus, it remains imperative to establish efficient in-silico drug repurposing pipelines for CRPC that leverage computational models. Such methods will enable the rapid discovery of treatment options to improve CRPC prognoses and patient outcomes and have the potential to be applied to other diseases to advance our knowledge towards better patient care. To this end, this dissertation leverages computational approaches to cast light on drug resistance mechanisms and facilitate rapid drug repositioning for advanced PC. Chapter 1 systematically reviews recent advances in computer-aided drug discovery strategies for PCs. Chapter 2 develops a computational pipeline to screen for new drugs against resistance to androgen-deprivation therapies (ADTs) in CRPC and nominates COL-3 which shows higher efficacy in ADT-resistant models in vitro. Chapter 3 designs an analytical pipeline to select effective treatments against neuroendocrine prostate cancer (NEPC)—a detrimental CRPC subtype with extremely limited treatment options—and proposed nicotinamide phosphoribosyltransferase (NAMPT) inhibitors as drug candidates. A novel biomarker discovery approach is also developed to select robust key genes strongly associated with response to NAMPT inhibitors. Chapter 4 and Chapter 5 tackle intratumoral heterogeneity which is often linked to therapy resistance in many cancers. Chapter 4 discusses recent approaches for predicting drug response at an individual-cell level to depict variations in therapeutic vulnerability within tumors. Finally, Chapter 5 develops a new computational algorithm to infer cellular drug response and showcases drug discovery applications for diverse heterogeneous tumors, including taxane resistant CRPC. Collectively, this dissertation develops and implements computational frameworks to quickly identify efficacious drug candidates for advanced PC patients. Proposed drugs are also validated experimentally using appropriate models in vitro and warrant further investigations. Once clinically validated, these drugs can be used to tailor PC patient care and help curb the current high mortality rate in these advanced diseases. Meanwhile, this work also presents methodological contributions toward single-cell drug sensitivity predictions and applications of drug discovery for heterogeneous tumors. In addition, the proposed computational methods may be adapted to enable efficient drug screens in many other diseases.
Metabolism and CNS Distribution of Selected Histone Deacetylase Inhibitors
(2024-03) Zhang, Wenqiu
Brain tumors are the leading cause of cancer-related death in children and efficacious treatment remains a critical unmet need. The blood-brain barrier (BBB) is a major hurdle for effective delivery of treatments for tumors in the central nervous system (CNS). While the paracellular transport of large, hydrophilic molecules is largely limited by tight junctions, efflux transporter systems are a key element of the BBB that can limit the penetration of lipophilic drugs. Histone deacetylase inhibitors (HDACIs) have been widely explored for their application in oncology, including the field of neuro-oncology. Despite their high in vitro potency and CNS-penetration-favorable physicochemical properties, the in vivo efficacy of HDACIs has been poor for CNS tumor treatment. This lack of in vitro-in vivo correlation may be in part attributed to poor CNS distribution. In this thesis project, we investigated the CNS distribution of three potent HDACIs, panobinostat, vorinostat, and quisinostat, following systemic administration. We characterized the systemic pharmacokinetics and CNS distributional kinetics of these compounds in wild-type and transgenic mice lacking p-glycoprotein (P-gp) and/or breast cancer resistance protein (Bcrp), two major efflux transporters expressed at the BBB. The in vitro stability studies show that all three hydroxamic acid-based HDACIs are enzymatically metabolized in mouse plasma, highlighting the need for careful sample handling to have accurate measurements of in vivo drug concentrations. In vivo experiments in the different mouse genotypes show that the CNS distribution of panobinostat and quisinostat is moderately limited by P-gp, but not Bcrp. Although the CNS penetration of vorinostat was not restricted by P-gp and Bcrp, its small unbound CNS tissue-to-plasma partition coefficients suggest that other efflux transporters could be involved. In addition, our results show that a tolerable dosing regimen of panobinostat would not result in adequate CNS exposure of unbound panobinostat in patients. In summary, our data show that the lack of adequate exposure of the active moieties can be a major reason for the lack of efficacy of these HDACIs in the CNS when systemically delivered. This result indicates that alternative approaches to improve delivery (e.g., convection-enhanced delivery or focused ultrasound) should be considered.
An Optimal Control Perspective on Externally Induced Tipping of Rigidly Shifting Systems
(2024-02) Zhang, Grace
The standard setting for rate-induced tipping involves fixing a particular parameterized family of smooth forcing functions and identifying a critical value of the rate parameter. In contrast, we consider a broad collection of all possible forcing functions, continuous but not necessarily smooth, and seek a general property possessed by those which effect tipping behavior. We focus on rigidly shifting asymptotically autonomous scalar systems x ̇ = f(x + λ(t)) and identify a nonsmooth choice of forcing function λ(t) which is an optimal tipping strategy in the sense that it utilizes the least possible maximum speed. Under a co-moving change of coordinates, the problem of finding this optimal λ(t) becomes dual to the problem of finding an additive control function that achieves basin escape with minimum fuel. We show the optimizer is a bang-bang control. The outcome is a lower bound on the speed |λ ̇(t)| that must be attained at least once in order to induce tipping. Its value depends on the total arclength ∞s∞|λ ̇(t)| dt of forcing, and may be interpreted as a safe threshold rate associated to each given arclength, such that if the speed of forcing remains everywhere slower than this, tipping cannot occur. The bound is tight in the sense that there exists a forcing function which induces tipping, possesses the required arclength, and never exceeds the threshold speed. Further, the threshold speed is a strictly decreasing function of arclength, thus capturing the abstract trade off between how fast and how far of a minimal disturbance characterizes tipping. While our results assume a scalar setting, the prospect of generalizing to n-dimensions is discussed and formulated as a conjecture. The control-theoretic construction used in deriving the above inspires a new theory of resilience, which is a slight modification of the intensity kof attraction framework of McGehee and Meyer. This is a family of resilience values parameterized by a number representing the allowable L1 norm of perturbations; in the limit as the integral-constraining parameter grows unbounded, these values approach the intensity of attraction. This integral-constrained intensity of attraction has the advantage of increased descriptiveness under scenarios where limited total resources are available for perturbing the system. We suggest it to be the natural choice for quantifying the resilience of a rigidly shifting system to externally-forced tipping.
Improving Bacterial Therapeutics and Diagnostics through Synthetic Biology
(2022-05) Zhang, Qiuge
Bacteria can be engineered as vehicles for context-dependent protein production, enabling the diagnosis and treatment of numerous diseases. However, translation to clinical applications still requires concurrent efforts to enhance tunability, specificity, efficacy, and safety. Our work contributes to three such areas. First, we performed model-guided engineering of DNA sequences with predictable site-specific recombination (SSR) rates, demonstrating that recombinase attachment sites with predictable SSR rates could be used to achieve kinetic control in gene circuit design. This high-throughput, data-driven method enhanced our understanding of recombinase function and expanded the synthetic biology toolbox, and it can enable rational tuning of the response dynamics of bacterial diagnostics and the pharmacokinetic profile of bacterial therapeutics. Second, we engineered Escherichia coli to sense extracellular proteins. A cell-surface sensor is crucial to enable broad diagnostic and therapeutic applications of bacteria; however, Gram-negative bacteria such as E. coli can only detect small molecules that cross the cell envelope. We proposed a novel strategy that leverages protein-specific attenuation of maltodextrin uptake via engineered LamB porins to modulate intracellular maltose signaling, thereby linking the extracellular protein concentration to the cell response. We then demonstrated its modularity to detect different target proteins and its tunability to alter the dose-response curves. Endowing E. coli with this ability to sense extracellular proteins would enable detection of clinically relevant proteins both in vitro and in vivo. Finally, E. coli strain Nissle 1917 (EcN) is a versatile probiotic that is safe for human consumption; however, its use in diagnostic and therapeutic oral delivery applications is hindered by the low pH and high concentration of bile salts in the gastrointestinal tract that reduce EcN viability. We performed adaptive laboratory evolution on EcN to select for mutated populations with greater tolerance to pH and bile and we identified specific mutations that contribute to their enhanced viability in the presence of these chemical stressors. The developed strains may not only enhance the bioavailability of orally administered EcN but also modulate their interactions with intestinal cells, suggesting potential applications to improve gut health. In summary, through biomolecular engineering, genetic circuit design, mechanistic and data-driven modeling, and strain development, our research has contributed to improved understanding and engineering of bacterial properties that should accelerate their translation to diagnostic and therapeutic applications.
Impacts of Recreational Cannabis Legalization: Substance Use Development, Pre-Existing Vulnerability, and Psychosocial Outcomes
(2022-05) Zellers, Stephanie
Alcohol, tobacco, and cannabis are three of the most commonly consumed substances in the United States. The development of substance use is influenced by genes, the familial environment, and unique environmental exposures. One such exposure is legal policy surrounding the purchase and consumption of these substances, and cannabis policies in particular are changing dramatically across the United States, raising concerns about the potential for public health consequences associated with substance use. In the present work, we focus on the development of substance use in a normative community sample, as well as perturbations to substance use development and substance related outcomes as a consequence of recreational legalization using causally informative genetic longitudinal designs. Study 1 explores normative developmental trends of cannabis use in recreationally illegal environments and its relationship to development of alcohol and tobacco consumption from adolescence through mid-adulthood. Study 1 also investigates the genetic and environmental influences underlying all three substances and influences unique to each substance over time. Study 2 evaluates the causal impact of recreational legalization on cannabis frequency with a co-twin control model, as well as the changes to the magnitude genetic and environmental influences on cannabis use in a longitudinal gene-environment interaction model. Study 3 expands on this to evaluate the impact of recreational legalization on a broad range of psychiatric and psychosocial outcomes associated with cannabis use, and further examines whether vulnerable individuals are at exacerbated risk for negative outcomes due to legalization. Together, these studies use rigorous designs to expand on the existing literature and provide evidence consistent with a causal impact of cannabis legalization on cannabis use. Furthermore, our results suggest that cannabis legalization may perturb normative adult decreases in substance intake, but this is not coupled with negative psychosocial outcomes in adulthood.
Predicting Fit of Filtering Facepiece Respirators Through New Face Anthropometry and 3D Face Shape Acquisition
(2024-05) Yu, Minji
This research investigated the relationship between face shape and respirator fit, with a focus on enhancing the fit and design of filtering facepiece respirators (FFRs). The study addressed the need for improved respirator fit, particularly in occupational settings where respiratory protection is paramount for safeguarding workers' health. Combining anthropometric analysis, three-dimensional (3D) scanning technology, quantitative fit testing, and predictive modeling, this research assessed the impact of face shape on respirator fit. It examined the limitations of traditional two-dimensional anthropometric measures in predicting FFR fit and proposed a novel framework based on 3D-derived face shapes and dimensions. Key findings highlighted the importance of predicting respirator fit based on diverse facial shapes and sizes. By integrating face anthropometric and geometric data into respirator design processes, manufacturers can develop more ergonomic and effective respiratory protective equipment. Such predictive capabilities can aid individuals in selecting respirators that are more likely to provide a secure fit, thereby enhancing the overall effectiveness of protection and reducing the risk of exposure to airborne hazards. The implications of this research extend beyond occupational safety and health, encompassing broader public health considerations, particularly in the context of infectious disease outbreaks like the COVID-19 pandemic. By advancing the understanding of respirator fit, this research contributes to the development of evidence-based practices for respiratory protection, ultimately enhancing the well-being and safety of workers worldwide.
Two Essays on User Behavior Across Digital Platforms
(2024-05) Xie, Qi
Unlike traditional business models, platforms enable direct interactions between agents. In the digital economy era, platforms have become more extensive and drive an explosion in content creation, distribution, and interaction. Platform managers aim to enhance user experience, boost engagement, and optimize revenue. However, the interactions between individuals and the platform, as well as among users themselves, raise significant issues such as fairness and consumer welfare, which policymakers need to address. For both platform developers and policymakers, it’s important to understand how users are interacting with each other and with the platform's interfaces and policies. This dissertation examines user behaviors across various digital platforms to derive insights that can guide platform designs. This overarching theme is organized into two interrelated parts: The first stream focuses on the examination of content consumption on digital media platforms. In Essay I, I study user engagement dynamics with two specific interfaces: the “content discovery page," where users browse and select content, and the “consumption page," which allows for consecutive consumption without the need for exploration. Using individual level data from a digital video platform in China, I develop an empirical model framework capturing the dynamic decision-making processes in content discovering and viewing and allowing for individual heterogeneity. The findings show that content variety has differential impacts on user behavior across two interfaces. In addition, I identify distinct user types with varying behavioral patterns and characteristics, offering insights that could inform algorithm designs for better targeting on digital platforms. In Essay II, I explored how policy design impacts participants' behavior on digital platforms, focusing on the evaluation mechanism in the context of crowdsourcing platforms. In this essay, I study a policy design approach, “strategic opacity”, i.e., the intentional obfuscation of evaluation criteria. I employed filed experiments on a real-world crowdsourcing platform. Our findings indicate that strategic opacity can reduce gaming to the system without reducing participation, thereby enhancing platform integrity. Overall, my research contributes to a deeper understanding of user behaviors on digital platforms, providing valuable insights for enhancing platform strategy and user experience. As digital platforms continue to evolve, this work will have substantial relevance and impact in guiding their development.
Government Contract Transparency and Payoffs from Political Connections
(2024-05) Yao, Yixin Ethan
I examine how the disclosure of government contract information required by the Federal Funding Accountability and Transparency Act (FFATA) since 2007 affects firm political campaign contributions. The public disclosure of details of government contracts after FFATA can be used by firms to identify politicians who can influence government contract allocations in favor of their campaign donors. Consistent with this expectation, I find that, in the post-FFATA period, firms significantly increase contributions to politicians who are more influential in government contract allocations. Correspondingly, I find that politicians engage in increased contract allocations in favor of campaign donors after FFATA. These results are more pronounced for politicians in competitive races, for non-competitive government contracts, and for firms that were less strategic campaign donors before FFATA. Overall, the results highlight an unintended consequence of government contract disclosures – that government contract transparency helps firms build more effective political connections and increases rewards for their political contributions.
Liberty, Guns, And Pocket Constitutions: Constructing A White Nation Through Legal Discourse In The Pacific Northwest
(2022-04) Wright, Robin
This dissertation investigates the mainstreaming of far-right politics by examining the production of a right-wing discourse focused on the radical defense of the U.S. Constitution in the Pacific Northwest. Despite its progressive image, The Pacific Northwest is a compelling site for analysis, as Euro-American settlers have long sought to render the region as a place reserved for white residents. Through a series of case studies exploring campaigns ranging from gun ownership to First Amendment rights, I argue that activists mobilize a conservative constitutional discourse to re-establish white territorial control at the local and regional level. Examining the circulation of this conservative constitutional discourse, I demonstrate the extent to which activists use constitutionally coded-appeals to position white able-bodied men as the legitimate representatives of “the people.” I show that in doing so, activists engage a constitutional discourse that reproduces the legal, political, and cultural conditions of possibility for white supremacist systems while disavowing an explicit logic of racial superiority. My research demonstrates how right-wing movements use a constitutional discourse to channel regional concerns about changing demographics and shifting representation into white nationalist demands. I thus contend that this constitutional discourse enables a paradoxical turn to extra-legal and sometimes violent actions, as right-wing activists disrupt and delegitimize state action while asserting their own popular authority as the sovereign. My dissertation makes an important contribution to geography, critical race studies, and legal studies by showing how a socio-spatial analysis of law must be mobilized in order to understand the shifting ideologies of race shaping contemporary right-wing movements.
Police Misconduct, Monetary Sanctions, and Insurance Models in the Modern Police Accountability Era
(2024-05) Wulff, Stephen
Despite many police accountability efforts underway in the contemporary United States, financial immunization of officers continues to enable police impunity. Legal scholars have examined these issues from the vantage points of law and how governments pay for misconduct (Schwartz 2014, 2016); they have also mapped the police liability insurance terrain (Rappaport 2016, 2017). Yet little is known about how police accountability activists and municipal actors—e.g., public officials, police leaders, risk managers—approach and perceive the overlapping issues of insurance, risk management, police accountability, and police misconduct settlements. Furthermore, despite pioneering research in this area by legal scholars, few in-depth municipal case studies currently exist, especially from a sociological and sociolegal perspective. My qualitative case study of municipalities in Minnesota operating with and without market-based insurance elucidates how activists and key municipal representatives approach and perceive these issues and examines a potential insurance alternative. My dissertation grapples with a fundamental paradox: policing as an institution is charged with social control of the general public; however, police violence reflects a breakdown in the social control of what sociologist Howard Becker (1963) refers to as “rule enforcers.” To understand contemporary efforts to stem police violence, my project examines the role that insurance and risk management strategies play—or could potentially play—in regulating police departments and individual officers. I extend the sociology of punishment literature by reinterpreting Feeley and Simon’s (1992) classic “new penology” paradigm through a social movement lens. They argue that a late-twentieth-century penal shift occurred away from rehabilitation toward managing aggregates of dangerous criminal categories (e.g., violent offenders) using risk management approaches. I extend their thesis by examining how police accountability groups are implicitly inverting the new penology onto police in an effort to manage aggregates of dangerous police categories (e.g., violent officers) using risk management approaches. My study also extends the sociology of punishment literature on “monetary sanctions.” Existing research focuses on all the costs imposed by the criminal legal system on denizens accused and/or convicted of a crime (Harris 2016). Instead of focusing on how cities (like Ferguson, Missouri) budget for revenue generated from monetary sanctions and the micro-level predatory effects these sanctions have on traditional offenders, my project illuminates: 1) how police misconduct payouts contribute to tax revenue shortfalls, which can trap cities in long-term debt cycles; and 2) how financially immunizing officers and departments has meso-level predatory effects on cities by diverting tax revenue from the public sector to cover payouts. Since the 2014 killing by police of unarmed African American Michael Brown in Ferguson, policing has faced a public legitimacy crisis. To address core issues raised by Black Lives Matter and other racial justice movements in response to such killings—namely, racial injustice and police impunity—public debate has centered on adopting existing accountability mechanisms and reforms (e.g., body cameras, police de-militarization) (Weitzer 2015). Following the 2020 murder by police of George Floyd in Minneapolis, some activists and community members have also called for defunding and/or abolishing police (Coleman 2020). Meanwhile, policing scholars have identified new accountability mechanisms (e.g., critical incident reporting) to address the weaknesses of past policing reforms (Walker and Archbold 2019). However, insurance as an accountability mechanism has received scant attention in both scholarly and national debates. My study seeks to add to the existing sociological and related interdisciplinary literatures, while shedding light on the salience of this accountability mechanism, by: 1) Elucidating key stakeholders’ approaches to and perceptions of existing and potential insurance models and risk management strategies for regulating police behavior. 2) Uncovering and/or further elucidating municipal, non-profit, and/or private sector insurance and risk management practices that either perpetuate or reduce police impunity and police violence. 3) Informing scholarly and policy discussions on reforming police via insurance. 4) Examining the implications of a potential insurance alternative.
Dogged Optimism: Striving and Waiting in Rural Chinese Students’ Negotiations of Social Mobility
(2024-06) Wang, Weijian
This critical ethnography examines the arduous pursuit of upward social mobility among young students in a rural mountain township in Southeastern China. It explores how rural Chinese students from Watershed School (pseudonym) navigate and negotiate upward social mobility within stratified educational and social systems. Despite the obstacles posed by stratified social class and the rural-urban divide, achieving social and geographical mobility has become a compelling imperative for rural youth in contemporary China. Drawing on interdisciplinary perspectives from Global South youth studies and the sociology of education, this dissertation focuses on the role of education in shaping rural students’ life trajectories. It also investigates these students’ strategies to navigate the intricate interplay between schooling, stratification, and the urgent demand for social mobility. The stories underpinning this dissertation were derived from two years of fieldwork at Watershed School, beginning in 2019 when my participants were in ninth grade. This study reveals that Watershed School, produced as a stratified and waiting educational space, has profoundly shaped the life opportunities of its students with varying academic performances. Through the implementation of tracking practices, such as academic grouping and the incorporation of labor education, the school served as an influential institute that propelled some students to strive for educational success while leaving others waiting. Consequently, striving and waiting emerged as two distinct strategies adopted by the students in navigating the tensions between the desire for mobility and the stratified social reality. Both the striving and waiting rural students have developed a culture that I call “dogged optimism” to cope with the imperative for social mobility within a stratified system. The culture of dogged optimism serves as a form of social navigation, enabling them to navigate the challenges and opportunities inherent in being aspirational subjects in contemporary Chinese society. This dissertation argues that a critical rethinking of dominant narratives of social mobility rooted in education is necessary to go beyond the limitations of this positive yet tenuous optimism among marginalized youth. I argue that a pedagogy of the nearby, which prioritizes facilitating the capabilities for critical reflexivity and action rather than an illusionary distant future, opens up possibilities for rural Chinese students to reconstruct social relations and foster critical hopes. Engaging in critical dialogue within the field of Global South youth studies and considering the distinctive Chinese local contexts, this dissertation provides a localized cultural analysis of rural Chinese students’ subjective experiences of social mobility. It offers implications for interrogating the deeply ingrained connections between education and social mobility.
Cultivating Educators of Color: The Role of School in Shaping Students of Color's Perceptions About Teaching
(2024) Becquer, Frances
Seeking to enhance efforts toward diversity in the teaching profession, this study used a heuristic methodology to explore how the lived experiences of high school students of Color participating in an education pathways high school course shaped their perceptions of the teaching career. Critical race theory (CRT), critical whiteness studies, and culturally relevant pedagogy (CRP) and their interrelatedness provide an understanding of the role of race in K–12 education. There is an overlap that exists between CRP, CRT, and whiteness studies. CRT provides the lens to understand racism, and critical white studies unpack White privilege. Thus, CRT and critical whiteness studies contextualize CRP, enabling the means to examine how race has been used, institutionalized, and maintained in schools (Sleeter, 2017) and making them tools for isolating race and racism effects on education. The findings of this study reveal challenges and motivations shaping the aspirations of students of Color who are considering teaching careers. While students reported feeling excluded due to implicit biases and societal stigmas, they also found belonging through supportive teachers and diverse peers. Students expressed being driven by social justice to become teachers and were discouraged by the lack of support they experienced as students and the societal devaluation of the profession. Consequently, this study highlights the need for a diverse and supportive education system. Implementing culturally proficient practices, dismantling negative perceptions, and providing information about teaching careers can help students of Color change their perceptions of teaching as a career.
Anomalous Amyloid-Beta Exposure And Bbb Insulin Resistance Induce Cerebrovascular Dysfunction In Alzheimer’S Disease
(2024-04) Wang, Zengtao
Cerebrovascular dysfunction is increasingly recognized as an early event and a significant contributor to Alzheimer’s disease (AD). Mounting evidence has linked AD to type 2 diabetes mellitus (T2DM), both of which manifest insulin resistance in the blood-blood brain barrier (BBB) endothelium that lines the cerebrovascular lumen. While insulin signaling regulates amyloid-beta (Aβ) trafficking and accumulation at the BBB, enhanced accumulation of Aβ within the BBB endothelium may cause insulin resistance. However, the synergistic effect of Aβ exposure and disrupted insulin signaling on BBB dysfunctions during AD and T2DM remains unclear. This thesis aims to establish causal connections between insulin resistance, BBB dysfunction, and AD pathogenesis. A graphic abstract is provided in Figure 1.6. The first part of the thesis focuses on Aβ exposure at the BBB. We have employed dynamic SPECT/CT imaging and pharmacokinetic (PK) modeling to analyze trafficking of different Aβ isoforms. Our findings revealed that Aβ42 exhibited a greater propensity to accumulate in the BBB endothelium (Chapter 2). We further performed cellular uptake and molecular imaging studies to demonstrate that Aβ40 and Aβ42 employed distinct molecular pathways for cell entry and intracellular trafficking in the BBB endothelial cells (Chapter 3). The second part of the thesis characterizes the insulin signaling pathway at the BBB. We have mapped the dynamics of insulin-responsive pathways in BBB endothelial cells using time-series transcriptomic analysis. The results suggested that inflammation-related pathways are downregulated by insulin treatment (Chapter 4). Further, insulin was found to dose-dependently regulate the expression of vascular cell adhesion molecule 1 (VCAM1), which is an inflammatory marker. A systems biology model was established, and VCAM1 expression was quantitatively simulated under disease conditions by incorporating proteomics and transcriptomics data into the model (Chapter 5). The third part of the thesis explores the contributing role of other pathological conditions that manifest insulin resistance in causing BBB dysfunction. Our findings revealed that loss of endothelial-pericyte interaction was associated with disrupted insulin signaling in both cell types. Further, the balance between matrix metalloproteinases and their endogenous inhibitors was dysregulated to compromise BBB integrity (Chapter 6). To explore the role of dyslipidemia, we have evaluated the therapeutic benefits of APOA-I mimetic peptide 4F and found that 4F mitigated Aβ42 exposure at the BBB endothelium in AD mice, potentially via modulation of the endocytosis and exocytosis processes (Chapter 7). Taken together, these findings provide novel insights into how Aβ42 exposure and insulin resistance may synergistically contribute to BBB dysfunction and how other pathological conditions with insulin resistance exacerbate these processes. Such discoveries facilitate the understanding of cerebrovascular pathology in AD and the identification of novel therapeutic targets.
Disciplinary Literacy, Reading, and Middle School ELA Teachers: A Multi-Case Exploratory Study
(2024) Taylor, Anna
Middle school serves as an important transitional stage in U.S. educational systems, as the foundational learning of the elementary grades gives way to the specialized, disciplinary studies privileged in secondary and post-secondary schools. The purpose of this qualitative study was to explore how middle school English Language Arts (ELA) teachers shaped the operational curriculum in their classrooms, in light of disciplinary literacy. Disciplinary literacy has emerged as an important field of research in secondary literacy in the past fifteen years; this study built upon several bodies of literature, including disciplinary literacy, ELA, and studies of educator decision-making. After examining this literature, I created a complex conceptual framework that anchored my study of educator decision-making in middle school ELA classrooms. Research questions examined teacher factors such as training and beliefs, contextual factors such as school and state expectations, and the ways that the operational curriculum in their classrooms reflected these factors.A qualitative, multi-case design was implemented to examine the instructional decision-making of two focal ELA teachers in a single school: Erin, a first-year teacher of eighth grade, and Natasha, a 16th year teacher of seventh grade. Conducting the study in one school enabled careful examination of shared contextual factors, such as school expectations and the absence of official curriculum, as well as unique individual factors, such as teachers’ beliefs, training, and past teaching experiences. Data collected included multiple rounds of interview data, notes from 8-10 classroom observations, artifacts of classroom instruction, and researcher memos and jottings. Data were analyzed through rounds of qualitative coding and analysis, drawing on provisional codes from the study’s conceptual framework. The study showed that educators shape their classrooms’ operational curriculum based on myriad factors. Teacher factors, such as access to materials and personal interest, and contextual factors, such as state standards and school-level expectations for instruction, directly shaped the operational curriculum in each classroom. Literary study, generally viewed as the heart of ELA in traditional and disciplinary literacy paradigms, was evident but not central to instruction in participants’ classrooms. This study indicates the need for additional teacher- and classroom-focused ELA disciplinary literacy research.
Exploring Space: Examining Spatial Cognitive Processes Recruited by Students and Teachers in Naturalistic Social Interaction Throughout a Summer Elementary School Engineering Unit
(2024-05) Valerie, Jesslyn
Spatial reasoning skills are a great predictor of students’ Science, Technology, Engineering, and Mathematics (STEM) achievement and attainment. However, researchers have mainly viewed spatial reasoning skills as an internal cognitive process that is measured through the administration of psychometric testing and laboratory experiments. Further, while spatial reasoning is focal in shaping one’s thinking and learning in an engineering context, there is a lack of understanding of how and when spatial thinking is useful in K-12 engineering classrooms. This dissertation extends the current understanding of spatial thinking by examining how various cognitive resources and material resources are utilized, discussed, and enacted by elementary school students and their instructors to support one’s engagement in spatial reasoning. The current study collected data from a three-week summer learning program, with one week dedicated to engineering units. During the space and aviation week of the summer program, students worked collaboratively in groups of two to four students to create two Alka-Seltzer rocket ships. The researcher chose a collaborative learning environment for the study to observe how spatial reasoning processes occur in the context of social interaction. The study utilizes an interaction analysis method to analyze moment-by-moment social interaction and object representations that took place in student-to-student and students-to-teacher interactions. This study provides a qualitative account that examines spatial reasoning in naturalistic social interaction to extend the understanding of how spatial reasoning is useful in K-12 engineering education. In addition, this dissertation provides an understanding of how various material resources are effective in cultivating various spatial reasoning processes. The results of the study showcase ten different spatial cognitive processes that are observable through social interactions. Students and teachers utilized a plethora of spatial cognitive processes throughout the engineering unit and at varying stages of the engineering design process. The study demonstrates that, as the activity progressed, students’ engagement in spatial cognitive processes shifted. Complex challenges that arose during the engineering activity pushed students to come up with creative solutions by calling upon a wide array of spatial cognitive processes. While the timeframe of the activity was short, the study was able to demonstrate nuanced development in students’ spatial reasoning through social interaction. Finally, while engaging in spatial cognitive processes, students also drew upon various material resources to assist them. The study found that different materials possess unique spatial properties and elicit different types of spatial cognitive processes.
Balancing Novelty, Safety, and Availability: The Trifecta of Outcomes in Pharmaceutical Supply Chains
(2024-05) Tyagi, Hanu
Global pharmaceutical supply chains have garnered unprecedented attention, particularly in the wake of the COVID-19 pandemic. Despite their importance, pharmaceutical supply chains are plagued by numerous challenges such as stagnating innovation, increasing drug shortages, and drugs with compromised quality reaching patients. While efforts to resolve these issues hold potential, their implementation often inadvertently leads to unintended consequences. Such tradeoffs, i.e., solutions to one problem unintentionally creating another problem, present a challenge for pharmaceutical supply chains. Despite the central role of tradeoffs in Operations Management research, their understanding within the pharmaceutical supply chain context remains limited. This dissertation serves as an exploration of the tradeoffs within pharmaceutical supply chains. Titled “Balancing Novelty, Safety, and Availability: The Trifecta of Outcomes in Pharmaceutical Supply Chains,” it delves into fundamental questions, such as What is the nature and the extent of these tradeoffs? and, How can supply chain stakeholders mitigate their impact? By concentrating on three pivotal outcomes – novelty, safety, and availability – I examine how efforts meant to improve one of the three outcomes could unintendedly impact other outcomes. Chapter 1 serves as a motivation for the topic and provides a brief overview of the ensuing dissertation essays. In Chapter 2, I show how enhanced transparency in clinical trials, intended to enhance patient safety, may hinder drug novelty. In Chapter 3, I examine the adverse effects of the expedited approval process, aimed at improving the availability of novel drugs, on drug safety. In Chapter 4, I delve into the impact of quality failures on drug availability, discerning when failures help or hurt availability. Chapter 5 concludes with insights the dissertation entails for Operations Management scholars, managers, and policymakers. These dissertation essays aim to evaluate the inherent tradeoffs within the pharmaceutical industry and propose interventions for mutually enhancing operational outcomes. While the overarching goal is to improve outcomes within the pharmaceutical supply chain, the insights from this work also inform a wider array of Operations Management questions beyond the confines of the pharmaceutical industry.
Essays on Sales Gamification
(2024-05) SU, YUANCHEN
Traditional sales compensation schemes typically rely on straightforward metrics such as commissions and bonuses tied directly to sales outcomes. While effective in driving certain sales outcomes and salespeople’s behaviors, these compensation schemes often overlook the nuanced motivational drivers and psychological dynamics that can significantly influence sales performance. In the evolving landscape of sales management, gamification (e.g., contests, leaderboards, and random rewards) has emerged as a powerful tool to enhance the motivation and performance of salespeople. Gamification introduces elements traditionally found in games, such as competitive and random aspects, into non-gaming environments like the workspace, education, self-improvement, and lifestyle. According to surveys, about 70% companies listed in the Global 2000 use gamification and over 89% of employees said gamification made them more productive. The sales gamification is usually short-term and is on top of the traditional compensation schemes (e.g., commissions and bonuses) as supplementary pay. This dissertation explores the application of sales gamification, focusing on two categories of distinct gamification programs: (1) contests with leaderboards, and (2) random rewards. By integrating principles from behavioral economics, these essays offer a novel perspective on the design and effectiveness of sales gamification tools that transcend traditional compensation structures. This approach seeks to leverage the natural human inclinations for game elements as drivers for enhanced performance. The two essays in this dissertation are united by their focus on sales gamification but diverge in their specific mechanisms and implications. The first essay delves into the use of contests as motivational tools. While the standard expected utility models with rational agents predict that disclosing the interim standings in a contest is not beneficial to the principal (Weigelt et al. 1989), but contests are used pervasively. In addition, empirical works show inconsistent patterns of how standings influence agent’s subsequent performance. This essay contributes towards understanding these puzzles by introducing social motivation into agent behavior. I provide evidence of the social comparison effects on efforts induced by interim disclosure. The second essay investigates the impact of gamification that includes random or lottery-like elements on sales performance. This approach grows out of the longstanding literature on the superiority of variable ratio reinforcement (Ferster and Skinner 1957) but was under-studied when it is used as supplementary compensation. This essay fills this gap and contributes towards understanding how the windfalls influence the subsequent effort by introducing individuals’ mis-specified beliefs about independent stochastic events, similar to hot-hand vs. gambler’s fallacy. Both essays are also linked to behavioral economics, which provides a framework for incorporating psychological factors into economic decisions. This theoretical orientation is critical, as it challenges the conventional rational agent model prevalent in standard economic theory, introducing a more nuanced view of human behavior that includes heuristics and biases. In both essays, I develop theoretical models incorporating behavioral economics elements to hypothesize the potential impacts of gamification. The predictions are tested with real-world data from sales gamification programs, bridging theory with real-world applications. More broadly, my work contributes to a more nuanced view of gamification. In contrast to the managers’ overwhelmingly positive view of sales gamification, my essays document unmistakably negative consequences of certain elements of these programs and point to the need of careful design of these programs.
Essays on Design, Operation, and Pricing of On-Demand Service Systems
(2024-04) Shen, Xiaobing
In this dissertation, we describe research on the design, operation, and pricing of on-demand service systems. We use the term "on-demand service systems" to refer to systems distinguished by two important features: (1) an "on-demand" feature, with requests arising randomly over time without prior booking or notice and (2) a "resource reusability" feature, with the fulfillment of demand involving the usage of resources for a limited (and random) amount of time. We model the systems as closed queueing systems and provide non-asymptotic performance guarantees.
Development And Application Of Targeted Dna Sequencing Tools To Profile Microbiome-Wide Antimicrobial Resistance And Pathogens Of Public Health Importance
(2024-02) Slizovskiy, Ilya
Antimicrobial resistance (AMR) poses critical health challenges as drivers of frequent and severe global outbreaks. In the U.S. alone, AMR accounts for one infection every eleven seconds, and one death every fifteen minutes. Bacterial antimicrobial resistance genes (ARGs) are the underpinning determinants of AMR, and traditionally prevention and surveillance efforts have focused on cultivating and studying resistant pathogens harboring DNA-encoded ARGs, isolated from human, animal, food, and environmental sources. However, across most compartments of the biosphere, bacteria reside as community members of complex microbial ecosystems with diverse ecological interactions and defined niche profiles. The perspective of the community-level composition and processes that lead to AMR rise and dissemination is rarely accounted for. Though culture-independent methods like PCR have been used for decades, recent advances in the field of metagenomics offers the possibility of directly sequencing the entire genetic milieu across the total microbiota within a sample (i.e. the ‘metagenome’). This technique offers an ecosystem-wide glimpse into bacterial community members, their genes, and their functional potential. However, metagenomic sequencing is rarely adopted in public health surveillance and tracking of pathogens, as well as risk assessment of AMR. The resulting sequencing data offers a low resolution and fragmented view of AMR hazard potential within microbial communities which is not conducive to motivating quality evidence-based decision-making for clinicians, public health practitioners, food producers, and policy makers. This dissertation consists of four integrated studies that attempt to: (1) Formalize the major impediments precluding informative metagenomic sequencing and data analysis in the study of AMR and its hazard potential; (2) Demonstrate an improved metagenomic approach to elucidate epidemiological trends in a major public health context of AMR; (3) Innovate and implement a novel metagenomic sequencing platform and associated bioinformatic tools to address impediments to metagenomic sequencing and enhance risk characterization of AMR; and (4) Extend technical metagenomic innovations for deployment in public health surveillance and monitoring activities. All metagenomic methods involved the use of unique human, animal, environmental, and food safety-related samples, and all studies were conducted using systems in vivo, in vitro, and / or in silico.
Development of Drug Candidates Targeting Mitochondrial Bioenergetics for Cancer Treatment
(2024-05) Schumacher, Tanner
Cancer tumors have been shown to be metabolically heterogeneous in their means for acquiring bioenergetics, biosynthetic components for generating biomass, and controlling redox equilibrium. Differences in oxygen and nutrient availability, along with rapid proliferation, drives spatial metabolic phenotypes within a tumor. Having an adaptable metabolism allows for sustained growth in differing microenvironments. Metabolic adaptability of malignant tissues has posed a challenge for current therapies, as treatment of one metabolic pathway has been overcome by a compensatory upregulation of another pathway. Hence, targeting the ability of tumors to adapt their metabolism shows promise as a novel effective therapeutic strategy. In this regard, we have taken up two projects to inhibit metabolic heterogeneity in cancers. One project involves the design and synthesis of a novel small molecule inhibitor of mitochondrial pyruvate carrier (MPC), called D7. We have shown that D7 is specifically potent in highly energetic oxidative cancer cells, inhibits mitochondrial pyruvate import at nanomolar concentrations, and causes a monocarboxylate transporter 1 (MCT1) dependent intracellular accumulation of lactate. In addition, D7 has been shown to be well tolerated when administered in vivo, providing up to ~71% tumor mass reduction in a 67NR syngraft model and ~41% tumor mass reduction in a highly aggressive isogenic 4T1 syngraft model. The second project involves the repurposing of FDA approved metabolically targeting agents as anticancer agents. An extensive literature search in identifying FDA approved drugs or drug candidates with either glycolysis or oxidative phosphorylation (OxPhos) inhibition properties resulted in the selections of ~30 drugs for further evaluation. After preliminary evaluation in our lab, we further narrowed down our original list of ~30 drugs to 4 drug candidates: BAY-876 (glycolysis inhibitor), niclosamide (OxPhos inhibitor), and pyrvinium pamoate (OxPhos inhibitor) and IMD-0354 (OxPhos inhibitor). As single agents these candidate compounds were shown to induce compensatory metabolic pathways that were found to be suppressed when administered as combination therapies, highlighting the capacity for these candidates to be repurposed as anticancer agents targeting cancers metabolic adaptability. In addition, these candidate compounds were shown to be well tolerated in vivo in our lab, with single agent administration showing 61-68% tumor reduction in a 67NR syngraft model.