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Targeting Endogenous Homeostatic Mechanisms for the Treatment of Cocaine Use Disorder: Contribution of NR4A1 and Target Gene Expression
No full textCocaine use disorder continues to be a worldwide public health problem and currently there are no approved medications for its treatment. Decades of research have identified a number of targets that have largely been ineffective in reducing relapse. Drug- and cue-associated memories are important components of relapse that remain relatively unexplored. Given that chromatin modifications confer long-lasting changes in gene expression necessary for stable cellular phenotypes, histone modifications acquired during abstinence may cause individual genes to “remember” prior drug exposure. Additional research on the homeostatic mechanisms active during prolonged abstinence is required to develop novel pharmacotherapies that reduce context-dependent drug memories. In this dissertation, we address this gap in knowledge using our established cocaine self-administration model which induces long-lasting changes in gene expression and chromatin. First, we profiled gene expression at early and late abstinence across several different brain reward regions, including the nucleus accumbens (NAc), ventral tegmental area (VTA), and prefrontal cortex (PFC). We found that the transcription factor, nuclear receptor subfamily 4 group A member 1 (Nr4a1), is activated during early abstinence but declines at late abstinence. Nr4a1 target genes were differentially expressed at both early and late abstinence. Therefore, we asked if Nr4a1 mediates transient and sustained changes in gene transcription via the enrichment of permissive and repressive histone modifications associated with Nr4a1 binding at target genes. Using clustered regularly interspaced short palindromic repeats (CRISPR) activation and inactivation (CRISPRa/i), we demonstrated that activation of Nr4a1 suppresses cocaine mediated behavior via epigenetic regulation of target genes. Next, we established the utility of Cytosporone B, a pharmacological activator of Nr4a1, in regulating Nr4a1 activation and reducing context-dependent cocaine memories. Finally, to identify the source of Nr4a1 expression, we isolated specific neuronal cell types in the NAc and analyzed gene expression and histone modification enrichment. Then, using cell-type specific CRISPRa we show that Nr4a1 activation in adenosine A2a receptor neurons suppresses context dependent cocaine memories. Together, research from this dissertation describes the role of cell-type specific Nr4a1 in persistent gene activation during abstinence and cocaine reward
A Computational Approach to the Study of Trauma
No full textTrauma with hypovolemic shock is an extreme pathological state that challenges the body to maintain blood pressure and oxygenation in the face of hemorrhagic blood loss. In conjunction with surgical actions and transfusion therapy, survival requires the patient’s blood to maintain hemostasis to stop bleeding. The physics of the problem are multiscale: (1) the systemic circulation sets the global blood pressure in response to blood loss and resuscitation therapy, (2) local tissue perfusion is altered by localized vasoregulatory mechanisms and bleeding, and (3) altered blood and vessel biology resulting from the trauma as well as local hemodynamics control the assembly of clotting components at the site of injury. Building upon ongoing modeling efforts to simulate arterial or venous thrombosis in a diseased vasculature, we have developed models of trauma (both multiscale and machine-learning based) to understand patient risk and predict response. Key results were: (1) the upstream vascular network rapidly depressurizes to reduce blood loss, (2) wall shear rates at the hemorrhaging wound exit are sufficiently high (~10,000 s–1) to drive von Willebrand Factor unfolding, (3) full coagulopathy results in \u3e 2 L blood loss in 2 hours for severing all vessels of 0.13 to 0.005 mm diameter within the bifurcating network, whereas full hemostasis limits blood loss to \u3c 100 mL within 2 min, and (4) hemodilution from transcapillary refill increases blood loss and could be implicated in trauma induced coagulopathy. Machine learning based methods were also implemented to understand trauma patient outcomes. A 400-estimator gradient boosting classifier was trained to predict survival probability and the model is able to predict a survival probability for any trauma patient and accurately distinguish between a deceased and survived patient in 92.4% of all cases. Partial dependence curves (Psurvival vs. feature value) obtained from the trained model revealed the global importance of Glasgow coma score, age, and systolic blood pressure while pulse rate, respiratory rate, temperature, oxygen saturation, and gender had more subtle single variable influences. Shapley values, which measure the relative contribution of each of the 8 features to individual patient risk, were computed for several patients and quantified patient-specific warning signs
Empirical Analyses of Regulation and Negotiated Prices
No full textIn the first chapter of this dissertation, I study coverage requirements, a common regulation in the mobile telecommunications industry that intends to accelerate the roll-out of new mobile telecommunications technologies to disadvantaged areas. I argue that the regulation may engender entry deterrence effects that limit its efficacy and lead to technology introduction patterns that are not cost-efficient. To quantify the impact of coverage requirements on market structure and the speed and cost of technology roll-out, I develop and estimate a dynamic game of entry and technology upgrade under regulation. I estimate the model using panel data on mobile technology availability at the municipality level in Brazil. In counterfactual simulations, I find that coverage requirements accelerate the introduction of 3G technology by just over one year, on average, and reduce firms’ profits by 24% relative to a scenario with no regulation. I find the entry deterrence effects to be small. Moreover, an alternative subsidization policy leads to a similar acceleration in the roll-out of 3G and substantially higher aggregate profits, likely increasing aggregate welfare relative to coverage requirements. In the second chapter, I investigate how the portfolio of products carried by retailers influences wholesale and retail prices. To this end, I develop and estimate a model of retailer pricing and retailer-manufacturer negotiations over wholesale prices. The estimation approach extends existing econometric tools for multi-product bargaining models to a setting with optimal downstream pricing. I use the estimated model to simulate the effects of counterfactual scenarios in which private label products or the products of a national manufacturer are excluded from retailers’ product portfolios. I find that wholesale prices do increase, but those effects are small. Eliminating private label products leads to an average increase in wholesale prices of only 0.10%; retail prices increase by only 0.04%. Eliminating a national manufacturer’s products leads to increases in wholesale prices between 0.003% and 0.677%; retail prices decrease by 0.027%-4.210% due to downstream pricing incentives
A Contingent Theory of Governance for the Global Project Organization: The Effect of Uncertainty and Diversity on Order and Conflict
No full textThis dissertation explores how complex organizations operate in complex environments. Specifically, this dissertation aims to build a more complete view of how the project organization—a group of firms that comes together to execute a common goal—navigates relationships with the partners that comprise it and navigates the stakeholder relationships in the external environment in which it is embedded. In examining these complex organizations, I develop theory that explains how composition and governance differ for organizations comprised of multiple partners, and how and why key mechanisms—such as conflict—affect their ability to be successful. To investigate these questions, I draw on a dataset comprised of approximately 3000 project organizations comprised of over 100,000 partners that operate in 135 countries from the years 1999–2019. This dataset includes over 400,000 pages of project reports, which are analyzed through natural language processing, as well as the corpus of media reports reported within 50km of the projects. As such, this dissertation builds a contingent theory of the governance of project organizations through an empirical view of the project organization on a size and scale not previously seen in management research. The first chapter of this dissertation examines three diversity types—variety of functional roles, separation in institutional values, and financial disparity—to show how each type impacts conflict between members of the project organization and the project organization and external stakeholders. Furthermore, this work shows that under joint conditions of diversity, conflict can be reduced. The second chapter explores the plural governance of the project organization and examines the alignment of governance choice, uncertainty, and performance. Building on transaction cost theory, this chapter shows that the project organization experiences better performance under conditions of environmental uncertainty when it exhibits greater hierarchy, but only when the firm at the top of the hierarchy is knowledgeable of the external environment. Under conditions of behavioral uncertainty, the project organization experiences better performance when it has less hierarchy, but only in certain types of projects. The final chapter shows under what conditions development projects incite conflict between political, social and economic stakeholder groups. Institutional distance and non-competitive selection of project organization members exacerbate external conflict under conditions of elite bias, that is, when the project organization is not inclusive in its network of stakeholder relationships. Taken together, these three chapters offer a contingent theory of governance of the project organization by answering when and under what conditions the concentration of resources and relationships drives (or mitigates) conflict and affects the performance of the project organization
Characterizing the Outer Solar System with the Dark Energy Survey
No full textThis thesis presents a search for trans-Neptunian objects (TNOs) using data from the Dark Energy Survey. This population of minor bodies orbiting past Neptune is a relic of the formation history of the Solar System, with the current observed orbital distribution of these planetesimals bearing signatures of large-scale changes in the positions of the giant planets. The Dark Energy Survey (DES) covered 5000 deg2 of the southern sky in the grizY optical/NIR filter sets between 2013-2019, and the absence of repeated observations in a span of few hours, as typically employed by TNO surveys, makes the search process challenging. To accomplish this, I present new techniques to identify moving objects in catalogs coming from single-epoch images, techniques for linking orbits in a temporally sparse catalog, and a “sub-threshold significance” test, where the object is demanded to be detectable in a stack of the exposures in which the orbit indicates an object should be present, but was not individually detected. The search of the first four years of DES, corresponding to 60,000 exposures and 22 million transients, yielded 316 validates TNOs, with 50% completeness estimated at mr ≈ 23.3 for objects at distances 30 ≲ d ≲ 2000 au. The search over the full six years (80,000 exposures, 108 million transients) benefits from not only the two additional years of data, but from an optimized detection pipeline capable of finding fainter sources in the same images. This complete search yielded 769, with 50% completeness at mr ≈ 23.8 . I also present software for simulation of DES discoveries given a hypothetical TNO population, enabling statistical comparisons of hypothesis to the observed DES data. I also present a test of azimuthal isotropy for the population of extreme\u27\u27 TNOs (a \u3e 150 au , q \u3e 30 au) for evidence of gravitational perturbations from an unseen super-Earth in a distant orbit. By rotating the orbits of the detected eTNOs, I construct a synthetic population that reproduces the observed eTNOs in the orbital parameters a , e , i and absolute magnitude H , and that is uniform in {Ω,ω,M}. I show that the DES eTNOs are consistent with azimuthal isotropy, and thus do not require the existence of a distant Planet 9\u27\u27
Financing Adulthood: The Risks and Hopes of Parent Borrowing through the Parent Loans for Undergraduate Students (PLUS) Program
No full textFunding children’s college expenses can be a family project, often requiring substantial savings from parents and educational debt from children, but parents also borrow to support their children’s postsecondary ambitions. Despite growing use of debt to finance children’s college expenses, studies have overlooked parent borrowing’s role in intergenerational financial support. This study investigates parent borrowing through the federally-funded Parent Loans for Undergraduate Student (PLUS) program to illustrate the risks and hope current higher education policies demand of families across the income distribution who are working to provide a middle-class life for their children. To do so, this research uses three datasets from the National Center for Education Statistics, including the National Postsecondary Student Aid Study (NPSAS), a nationally-representative, cross-sectional survey of American undergraduates in 2015–16, the Beginning Postsecondary Student Longitudinal Study (BPS), a nationally-representative, longitudinal study of American undergraduates followed between 2003 and 2009; and finally, the Educational Longitudinal Study of 2002 (ELS:2002), a nationally-representative, longitudinal study of 10th-graders surveyed between 2002 and 2012. First, this study investigates the risks parents take when they borrow through PLUS by identifying parents’ debt burdens across the income distribution. Second, I consider whether parent borrowing delivers on parents’ hopes by examining whether PLUS eases children’s path into adulthood by increasing Bachelor’s degree attainment and financial wellbeing for families across the income distribution. My project finds that parents’, regardless of their means, are burdened by PLUS loans, albeit in different ways. In addition, PLUS loan debt is highest among high- and upper-middle income parents, demonstrating that college costs are beyond the means of even advantaged families. In addition, rather than supporting young adult children as they transition to adulthood, PLUS is not guaranteed to deliver on parents’ hopes. Instead, PLUS provides limited benefits in terms of degree attainment, and higher levels of PLUS loans are associated with greater financial stress for young adult children. I discuss the theoretical and policy implications for intergenerational family support, debt, and college affordability
Family Structure and Women’s Experiences of Intimate Partner Violence
No full textIntimate partner violence (IPV) is a pervasive problem. The WHO estimates that 30% of women worldwide who have been in a relationship report having experienced physical or sexual violence by an intimate partner. IPV can result in negative sexual, perinatal, physical, mental health, and economic consequences. Most studies on IPV explore risk by looking solely at the relationship between the assailant and the victim—specifically, the occurrence of IPV in married, cohabiting, and dating couples—but do not assess how family structure (polygynous marriage, unions with children, and extended family members in the home) may influence these experiences. Family structures vary across societies, and not all family forms are equally available to all people. Polygyny, for example, when one man has two or more wives, is officially practiced in over eight hundred societies worldwide. However, there is a paucity of research looking at how marital types (i.e., polygyny) relates to IPV. This multi-paper, multi-cite, and mixed-methods dissertation focuses on this gap in the literature. In Paper 1, I conduct a systematic review of prevalence studies that report IPV rates by various relationship and family structures. Findings from this review of 20 studies suggest 1) an association exists between Relationship Status and IPV, 2) there is not evidence of an association between Marriage Type and IPV, and 3) there is inconsistent support for a relationship between Family Structure and IPV. Paper 2 is a secondary data analysis of Ghana’s 2008 Demographic Health Survey exploring married women’s experiences with IPV. Polygyny was not found to be a significant predictor of IPV. Paper 3 is a qualitative study with Black Muslim women that seeks to understand their lived experiences with IPV and polygyny. Through phenomenological thematic analysis of 12 interview transcripts, I capture the essence of their experiences. Participants did not believe polygyny to be inherently more abusive than monogamy. Misconceptions surround polygyny, and this body of work aims to increase cultural competency in conversations about relationship and family types, and IPV
Narratives of Black Male Teachers in K-12 Public Schools: Contextualizing Teacher Retention and Teaching Trajectories with Morehouse College Alumni
No full textThe continued shortage of Black Male Teachers (BMTs) in the United States presents an opportunity to reexamine the factors that impact teacher retention among Black males in US public schools. One predominantly Black, all-male higher education institution—commonly referred to as an HBCU, which stands for Historically Black Colleges and Universities—Morehouse College, is poised to play a key role in developing a pipeline of quality BMTs for high-need public schools with the recent launch of the Morehouse Center for Excellence in Education. This mixed-methods study analyzed and explicated the complex experiences of Morehouse alumni who became K-12 public school teachers and will inform the direction of this new education program, helping to support the conditions to help it become the prototype for preparing young men of color for the layered social and economic politics they encounter as minorities in the education profession. I as the researcher used the theoretical frameworks of self-determination theory, sociocultural theory, and human capital theory to explore the narratives of Black male Morehouse College alumni who have taught in the US public school system for at least one full year. This relational inquiry engaged stories from major decision points in the men’s life journeys, including their decision to: (a) attend Morehouse College, (b) become a teacher, (c) pursue professional development or teacher certification, and (d) continue as a teacher. Through the analysis of interviews and survey data, I explored how teacher retention among Morehouse alumni is influenced by the intersections of self-motivation, professional development, and prior experience as a young male of color, including formative educational experiences
The Relational Role of Place in the Production of Racial Stratification
No full textIn this dissertation, I examine how we quantify the dynamic, cumulative effects of relational social exposures with longitudinal survey data. In Chapter 1, I demonstrate a new mediation framework for describing what are often conceptualized problematically as “neighborhood effects.” Findings from this study clarify the reciprocal, life-course process through which neighborhood is implicated in the early production of social inequality. In Chapter 2, I extend this mediation framework to respond to theoretical critiques of how variables for race are used in common regression frameworks in attempts to study structural racism. I demonstrate an alternative counterfactual approach to explain how multiple racialized systems dynamically shape health over time, examining racial inequities in cardio-metabolic risk. I decompose the observed disparity into three types of effects: a controlled direct effect (“unobserved racism”), proportions attributable to interaction (“racial discrimination”), and pure indirect effects (“emergent discrimination”). I discuss the limitations of counterfactual approaches while highlighting how they can be combined with critical theories to quantify how interlocking systems produce racial health inequities. In Chapter 3, I use this framework to examine the Black-white wealth gap in the United States. Descriptive and qualitative analyses have identified many mechanisms underlying wealth correlations across successive generations, but few studies have quantified the relative contributions of these interconnected and racialized systems of reproduction to the total gap we observe today. I define a wealth gap in 2015–17 between the grandchildren of those racialized as Black and the grandchildren of those racialized as white in 1968–70. I use a fully interacted counterfactual mediation framework to decompose this disparity into the historical, racialized contributions of 1) effects of home values in 1968–70 on home values in successive generations and 2) effects via educational attainment in successive generations. Findings from this study contribute to our understanding of the dynamic, racialized process of multigenerational place-based wealth accumulation and support the importance of historically contingent social policy centered on reparative justice
I Do? The Commitment of Nontenure Track Faculty to Their Departments
No full textNontenure track (NTT) faculty make up 73% of faculty at universities and colleges across the United States and nearly 67% of the faculty workforce at Masters colleges and universities (Larris, 2018). There are myriad reasons for this growth, including financial pressures placed on universities and incentives to be more marketable and competitive in the higher education marketplace. But within this faculty workforce, some NTT faculty may feel like second-class citizens in their department because of low wages and tenuous job security. In contrast, others may enjoy teaching the occasional class and consider the flexibility of NTT employment a benefit. With NTT faculty comprising an increasingly large share of the faculty workforce, it is important to understand the sense of commitment they have to their department, as it may impact the quality of undergraduate education. This study examined the level of commitment of NTT faculty to their departments, using a mixed-method approach that utilized a quantitative analysis, comprising responses from Three-Component Model of Commitment (TCMC) survey to assess the level of affective, continuance, and normative commitment of NTT faculty, and qualitative analysis of the responses from interviews of NTT faculty regarding department policies and practices that do or do not contribute to their commitment. This analysis also explored how the type of department – academic and professional – affected the organizational commitment of NTT faculty. The study’s conclusions provided new insight into the commitment of NTT faculty at Masters colleges and universities and offer an increased understanding of how department practices and policies contributed to NTT faculty commitment, which is essential for managing a productive and skilled faculty workforce