Dissertations

Persistent link for this collection

Search within Dissertations

Browse

Recent Submissions

Now showing 1 - 20 of 10450
  • Item
    The Paradoxical Twenty-Fifth: Performance, Race, and Conditional Belonging on the American Imperial Frontier, 1882-1918
    (2024) Dollison, Natalie
    The Twenty-Fifth Infantry Regimental Band was part of only four segregated Black Army regiments assembled from the Union’s Black volunteer units in the aftermath of the Civil War. Through nearly eight decades of public entertainment, the Band’s performances were both carefully circumscribed as well as spontaneous, choreographed but with room for improvisation. The Band not only acted as military public relations. It was instrumental in the production of a historical consciousness that bound the expanding settler citizenry of new U.S. territories to the idea of nationhood and to the places to which these settlers felt newly entitled. Through extensive archival and ethnographic research, I examine performance as both discourse and ritual mediated by the standards of the Department of War, making the Band’s performances a valuable tool of the ideological state apparatus. The Band’s performances were in support of the ideology of the United States but were also a site of struggle over its terms. That struggle took place in the medium of performance. This dissertation analyzes these performances and how the Band adapted to the changing boundaries of American geography and cultural memory through a variety of frameworks focusing on the visual, aural, and kinesthetic qualities of each type of performance. The musicians’ performative dynamic with a given audience was necessarily reconfigured each time the regiment was assigned to a new location. With each move, the Band contended with novel intersections of the U.S. settler and imperial project and the myriad social relations—interethnic, interracial, and international—that undergirded them.
  • Item
    Optimization of Signal-Detection Methods in Novel Databases: a Focus on Direct-Acting Antivirals
    (2023) Dauner, Daniel
    An adverse drug event (ADE) is an injury resulting from medical intervention related to a drug, and they include medication errors, adverse drug reactions, allergic reactions, and overdoses. In 2019, the Food and Drug Administration (FDA) identified the following outcomes as potential signals of serious risks associated with direct-acting antivirals (DAAs): angioedema, dysglycemia, and hepatic decompensation and hepatic failure. The risk of angioedema or dysglycemia while on DAA therapy was identified through post-market surveillance, and prior studies did not include these two outcomes and had mixed results for the risk of hepatic decompensation. The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) is a database containing ADE reports that were submitted to the FDA. The reports need to be investigated, and when working with large databases, signal detection algorithms (SDA) are used to decide which reports are significant. Signal detection algorithms are statistical methods used to measure disproportionality, which quantifies unexpectedness. The purposes of SDAs are 1) flag potential signals that might be missed, 2) prioritize resources for signal detection and clinical review on most likely candidates, 3) detect more complex patterns in the data which are harder to detect via manual review, and 4) prioritization of potential signals. This dissertation will use the newly identified potential DAA signals to investigate and increase the efficiency of SDAs. It will assess the effects of subgroup analysis on SDAs and develop predictive models using FAERS data; and evaluate the association of DAA exposure and identified potential signals in a real-world population of commercially insured patients form the Merative MarketScan Research Databases. Subgroup analysis can address confounding and further classify signals to be investigated. Logistic regression-based signal detection algorithms are superior to disproportionality analysis due to their ability to account for potential confounders and masking factors. It is important to assess and compare the performance of other machine learning algorithms to logistic regression. Lastly, there is interest in pharmacovigilance and pharmacoepidemiology in using real-world data as a complementary data stream to spontaneous report databases. The current study used medical and pharmacy claims from the Merative MarketScan Commercial Databases to evaluate and validate the possible risks of angioedema, dysglycemia, and hepatic decompensation associated with DAAs identified through post-market surveillance.
  • Item
    A materials science approach to treating respiratory distress syndromes and advanced COVID-19 infections
    (2023-01) Ciutara, Clara
    Lung Surfactant (LS) is a mixture of lipids and proteins lining the air/water interface in the alveoli. LS facilitates breathing, mainly by reducing the air/water interfacial tension, and thus the energy required to breathe. The lack of functional LS is associated with two pathological conditions: Neonatal Respiratory Distress Syndrome (NRDS) and Acute Respiratory Distress Syndrome (ARDS). NRDS occurs in premature infants who have not developed LS secretion system, while ARDS happens when the lung is injured and the inflammatory response leads to LS inactivation. To date, the state-of-art replacement surfactants are extracted from animals, of which the exact composition is not known and could vary from animal to animal. This raises concerns regarding contamination and quality-control. Additionally, the animal-derived LS has not been effective in treating ARDS as the body's innate immune system inactivates LS, both endogenous and exogenous. This lack of quality-controlled, effective LS thus calls for a systematic understanding of clinical lung surfactant formulation, as well as an investigative study into LS inactivation mechanism during ARDS progression and its treatment. The contribution of my PhD work can be divided into three major themes. First, I have developed an understanding of how formulation affects clinical lung surfactant viscoelasticity and subsequent intratracheal delivery to treat neonatal respiratory distress syndrome. Second, I demonstrated that Langmuir trough, a tool classically used to study lipid monolayer, can be used for measurements of dilatational modulus (resistance to area change) of the lung surfactant system and inflammation products. Third, I investigated dynamics of lung surfactant in the presence of inflammation products, and discovered a mechanism by which a potentially fatal lung collapse can take place. Ultimately, the unified understanding of these phenomena will serve as a powerful weapon against the respiratory distress syndromes. This overarching understanding of the LS system can further be extended to other membrane and interfacial phenomena.
  • Item
    Design, Synthesis, and Evaluation of Pyrazinoic Acid-Derived Antituberculars for Drug-Resistant Mycobacterium tuberculosis
    (2022-01) Cole, Malcolm
    Tuberculosis (TB), an infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb), is a major cause of suffering worldwide. The impact of this disease has been exacerbated by the ongoing coronavirus pandemic, reversing much recent progress that had increased diagnosis and treatment rates in the preceding decade. In addition to ongoing issues related to public health shortcomings and lack of access to treatment, the emergence and spread of resistant strains is an increasing cause for concern. While the antitubercular pipeline has produced a few new antibiotics in the 21st century, more novel treatments are urgently needed to keep abreast of resistant strains. This dissertation describes efforts to create new therapeutic options for resistant TB, centered around pyrazinoic acid (POA), the active form of pyrazinamide (PZA), an important first-line TB drug.Recently, a growing number of reports have highlighted the promise of β-lactam conjugates in selectively targeting resistant organisms. β-lactams are a widely-employed class of antibiotics that target cell wall biosynthesis. Bacteria can evade this activity through expression of β-lactamases, powerful enzymes that destroy the electrophilic β-lactam warhead. However, researchers have learned to take advantage of this resistance mechanism, designing β-lactam conjugates that release a molecular payload following β-lactamase cleavage. This strategy, referred to here as β-lactamase-mediated fragmentation, is explored in great detail in Chapter 1, including descriptions of its discovery and applications in a variety of fields, including diagnostics, cellular imaging, and antibiotic design. Chapter 2 describes our own work in this space, designing β-lactam conjugates bearing POA as a Mtb-selective warhead. This strategy circumvents the most common resistance mechanism against PZA, imparting activity in an Mtb macrophage infection model (where conventional β-lactams are typically ineffective). We also provide preliminary mechanistic evidence that our conjugates act as codrugs, achieving antibacterial activity through action of the β-lactam scaffold as well as the POA warhead. In Chapter 3, we remove the β-lactam scaffold and focus on POA itself, reporting a series of new analogues featuring substitutions on the pyrazine ring. We identify several analogues with improved activity over POA, and use biochemical techniques to demonstrate they are inhibitors of PanD, a putative target of POA. We use the structure of our most active lead and recent structural insights into PanD to design additional inhibitors with comparable antimycobacterial activity, providing proof-of-concept for future structure-based design of new PanD inhibitors.
  • Item
    Enlarge Practical DNA Storage Capacity: The Challenge and The Methodology
    (2023-12) Wei, Yixun
    As global data generation is increasingly expanding, traditional data storage especiallyarchival storage is facing severe challenges. The typical storage medium like tape, HDD, and SSD do not provide sufficient storage density as well as sufficient durability. People are seeking DNA as a promising storage medium for archiving digital data. Despite pioneering efforts demonstrating the feasibility of DNA-based data storage, the realization of a large-scale DNA storage system remains in its infancy. The theoretical potential for ultrahigh storage density in DNA is hindered by practical limitations, including various system overheads. This thesis delves into the practical implementation of DNA storage capacity, acknowledging the ongoing rapid development of DNA storage-related biotechnologies. The study systematically reviews system overheads and corresponding capacities based on current technologies. Key factors influencing DNA storage capacity, such as DNA strand length, encoding density, parallel factor, and the number of usable primers, are explored. Constrained by current DNA synthesis, sequencing, and PCR technology, factors like strand length, encoding density, and parallel factor are all constrained. However, the most critical challenge lies in primer-payload collisions, which significantly reduces the number of usable. As a result, DNA tube storage capacity falls short of expectations (e.g., Terabytes per DNA tube), remaining below three hundred gigabytes. To address the primer-payload issue and enhance the number of usable primers and storage capacity, this study proposes and evaluates solutions from three perspectives. The first approach involves post-processing DNA payloads to rectify collisions. Given the primer-payload collision is a pair of almost identical subsequences (longer than 12 bases) between primer and payload, we decide to change payload from two aspects: content (DNA mapping) and length (DNA cutting). DNA cutting generates DNA strands with variable lengths to break up a collided subsequence into two parts and remove the original collisions. Four optional payload lengths are selected based on the assumption that the current maximum payload length is 200. The combination of the four lengths can cut most collisions as long as the distance between collisions is long enough. A heuristic algorithm is proposed to determine which collision to cut if there are multiple collisions densely grouped. The DNA mapping maps an original DNA sequence to a new sequence so that the original collision is removed. Three meticulously designed mappings are introduced that can always obey the homopolymers and GC content bioconstraints. A combination of DNA cutting and mapping is further discussed to make use of both methods’ advantages and offset their disadvantages. The evaluation shows the combination of the two methods can help increase 25% storage capacity. After exploring the post-processing, we further investigate the potential of a collision resistant encoding scheme. An analysis of existing encoding schemes and their corresponding storage capacity indicates that it pays to trade a few encoding densities for better collision resistance. Therefore, we first summarize the potential collision-resistant patterns. We then develop an encoding scheme (i.e., CAC) to encode DNA sequences with the collision-resistant patterns. CAC encodes the current DNA sequence based on the observation of previous DNA sequences so that it introduces 1) no homopolymers, 2) fewer complementary sequences, and 3) more balanced GC content in the current DNA sequence. Evaluation shows CAC can almost double the number of usable primers and leads to a 50% increase in storage capacity. More evaluation results show CAC is also comparable to other existing encoding schemes in terms of encoding speed and error recoverability. Besides, a collision-aware data allocation scheme is proposed to allocate data to different tubes if they collide with different sets of primers. With this allocation as a pre-process, primers disabled in a tube due to collision are still usable in other tubes. Thus, the overall storage capacity increases. To better fit the goal: fewer common collided primers among tubes, or in other words minimum overall collided primers, a special clustering criteria is proposed together with a hierarchical clustering procedure. The evaluation shows a 20% increase in the overall storage capacity. Besides, we also check the influence of different chunk sizes. Chunk size as the clustering granularity will affect not only clustering quality but also clustering speed and sequencing per file retrieval. A smaller chunk size will have better clustering quality but slower clustering speed and need more sequencing to retrieve a file as the file is split into many small chunks. The evaluation shows 4KB chunk is a reasonable size to balance all the factors. Finally, several potential future works are discussed. First, via summarizing and comparing the potential improvements of different DNA storage-related technologies, we find a potential breakthrough in relaxed primer design rules and generate more primers. Second, several potential enhancements are noted to better utilize the solutions proposed in this thesis including speed-up of CAC, better cooperation between pre Last, a potential DNA sequence level data compression and data deduplication for DNA storage is pointed out. By minimizing redundancy in both DNA sequences and digital data, we can reduce the number of synthesized DNA strands. This approach accelerates the sluggish DNA synthesis process and results in cost savings for the overall synthesis.
  • Item
    The Influence of 3D Interfaces on Mechanical Behavior of Nanolaminated Bimetallic Composites
    (2024-01) Cheng, Justin
    Cu/Nb nanolaminates containing 3D interfaces (3D Cu/Nb) are used in this study to demonstrate the effects of controlled interface structure on mechanical behavior and unit deformation activity in nanostructured alloys. 3D interfaces are internal boundaries that exist on length scales relevant to unit deformation mechanisms and contain nanoscale chemical and crystallographic heterogeneities in all spatial dimensions. 3D interfaces are a new method to manipulate alloy microstructure whose effects on plastic deformation have not been previously explored in depth. Elucidation of the link between 3D interface structure and mechanical behavior will provide key insights into nanoscale metallic deformation allowing for materials that exhibit near-theoretical strengths while also being highly deformable. The exploration of these themes requires understanding of a wide range of topics in physical metallurgy, which is reflected in the structure of this thesis. Chapter 1 begins with a high-level overview of the motivation and methodology of this work. Chapters 2 introduces fundamental concepts of metallic deformation at the macroscale and the atomic scale. Chapter 3 explores the participation and influence of interfaces in atomic scale deformation and ties the nanoscale to the mesoscale by discussing previous findings about atomically sharp 2D interfaces on nanocrystalline alloy mechanical behavior. Chapter 4 introduces the experimental methods required to characterize 3D interfaces structurally and mechanically. Chapter 5 presents structural characterization results, while Chapter 6 presents mechanical characterization results. Chapter 6 contains findings from mechanical testing, while also providing discussion connecting 3D interface structure detailed in Chapter 5 to observed 3D Cu/Nb mechanical behavior. The information from these techniques are crucial to forming structure-behavior relationships detailing the effect of 3D interfaces on unit deformation, but they cannot probe the atomic scale alone, so synthesis of computational results with experimental results is also discussed in Chapter 6. Chapter 7 concludes with a summary of key findings of this and proposes future work addressing new scientific issues raised by this work.
  • Item
    The Chance of a Life: A New Materialist Comparative Study on Biopoiesis
    (2020-01) Butler, Justin
    The Chance of a Life: A New Materialist Comparative Study on Biopoiesis analyzes works of fiction, film, and poetry in order to develop a notion of biopoiesis. The dissertation grounds its analytic methodology in the writings of the French biochemist Jacques Monod, the French post-structuralist philosopher Louis Althusser, and the dissertation of Karl Marx. In so doing, the methodology consciously joins humanistic and scientific modes of thinking in order to articulate a concept of biopoetics that, in dialogue with biopolitics, diverges from the latter’s efforts to administer or control life. The role of the aleatory is explored as a material substrate for thinking the emergence of life that, in a new materialist spirit, challenges notions of teleology and dialectics. Insights from this discussion are then deployed in analyses of the novel Truismes, by the French author Marie Darrieussecq; the film La caza, by the Spanish director Carlos Saura; and selected poetry by the Spanish poets José Angel Valente and Fernando Merlo. Chapter 1 contemplates the figure of flesh Truismes in order to develop a bioepoetic understanding of the role of flight in a deterritorializing dynamic. Chapter 2 examines how, in La caza, the matter of biological disease bears on the questions of biopolitics and democracy. Chapter 3 analyzes poetic iterations of corporeality by Valente and Merlo in order to reveal an ethics of supplementarity in new materialism. The conclusion of the dissertation situates the chapters’ findings within received understandings of historical or vulgar materialism so that the dissertation’s own intervention can be contextualized.
  • Item
    Born Unveiled: The Process, Protest, and Product of Racialization Among International Black African Collegians in US Graduate Education
    (2024-01) Watson, Ashley
    This dissertation focuses on the racialization of graduate international Black African collegians (IBAC) and the effects it has on their racial identity development. The intercentricity of race maintains that race is a defining factor for how one is situated in US society. However, many international students do not come from communities stratified by race first. For example, Black US Americans (BUSA) are socialized to view race as a master narrative from an early age. Yet, IBAC, are socialized in ways that tend to prioritize clan, tribal, or ethnic heritage as differentiating characteristics. I argue that despite being raced as similar, BUSA and IBAC undergo different socialization processes and therefore, the identity formation around race for IBAC follows a different trajectory than that of BUSA. The study includes semi-structured interviews conducted with ten graduate IBAC recruited through purposeful selection. Transcripts were analyzed using interpretative phenomenological analysis, a qualitative approach which seeks to provide detailed examinations of a person’s lived experiences. Based on this analysis, four thematic clusters and 14 subthemes were identified revealing how participants made sense and meaning of their racialization. The first theme, Becoming Veiled, outlines the process of becoming Black in a US context. The second theme, Living Under the Veil, draws attention to how IBAC maneuver through highly racialized environments. The final two themes, Resisting/Refusing the Veil and Opting Out both relate to how participants enact their agency to preserve their core essence. This dissertation extends current understanding of international student identity development by bringing into conversation critical intercultural studies, sociology, Black studies, and comparative education. Results from this study (in conversation with others) makes a strong case for reconsidering a blanket application of Cross’ (1978) Nigrescence Model as a schema for all Black students.
  • Item
    Facilitating Organizational Change: Using CHAT to Connect Community Engagement and Diversity, Equity, and Inclusion at an Engaged Institution
    (2024-01) Telles, Arien
    There is limited understanding of the connections between community engagement and racial DEI at colleges and universities working to institutionalize engagement. Community engagement is not being institutionalized within an educational system that is a blank slate, nor does it operate within a vacuum. Community engagement operates within a racially inequitable system, yet there is a lack of empirical studies investigating how DEI is addressed as colleges and universities perform the work of transformation. This study provides insight into the ways racial DEI operates within community engagement, both overtly and covertly, in colleges and universities that are working towards organizational transformation into engaged institutions. In addition to responding to a gap in the literature, this study contributes to the field by identifying and analyzing the role of racial DEI within community engagement by considering what organizational contradictions exist when analyzing how community engagement and diversity, equity, and inclusion operate together. Using cultural-historical activity theory (CHAT) as a theoretical framework and analytical tool, the findings of this study provide several implications for research and practice as it relates to organizational change approaches that reveal insights into complex institutional challenges aimed at addressing pressing social issues.
  • Item
    Application of Improved Aerosol Deposition to Deposit Functional Films and Atomistic Investigation of Dynamic Response of Particle During Ballistic Impact
    (2023-01) Song, Guanyu
    Aerosol deposition (AD) is a novel approach to producing robust nanocrystalline thin films or thick ceramic coatings at room temperature. It is hence applicable to variable substrates from low-melting metal substrates to refractory ceramic substrates. Aerosolizing precursor powder into appropriate size distribution and concentration is crucial to making films with good adhesion. The fluidized bed is a common approach, which is driven by a pressure difference for aerosol generation. Nonetheless, this method often fails to make aerosol flow with proper size distribution without pre-treatment on precursor powder.Furthermore, owing to its solid-state deposition property, particle-substrate interaction plays an essential role in AD, especially in making thin films with nanoparticles. Numerous experimental and simulation studies have been investigated to physically and theoretically understand events of particle-substrate interaction in AD. However, thermal energy evolution and structural transformation in nanoparticles have so far not been fully elucidated. Therefore, the purpose of the studies proposed here is to develop different methods for generating aerosol flow, subject to the type of as-deposited coatings, and to perform simulation studies focusing on nanoparticle-substrate interaction at an atomistic scale. The first portion of my dissertation will focus on combining the spray pyrolysis technique with aerosol deposition (AD) for producing Yttria-stabilized zirconia (YSZ) based thermal barrier coatings (TBCs). The desired outcome of this study is to achieve an in-flight synthesis of applied particles in AD and deposit synthesized YSZ particles into layers. We additionally investigate the effect of operating conditions of spray pyrolysis on the size distribution of synthesized particles, the impact of substrate hardness on the coatings growth rate, and the influence of solute composition in precursor liquid on the thermal performance of as-deposited YSZ coatings. The second portion of my dissertation will develop a voice-coil-based powder dispensing system for aerosol generation, coupling it with conventional aerosol deposition (AD) and co-deposit thermoelectric coatings with variable elements ratio by this improved AD setup. Transport properties of as-deposited samples with different amounts of the doped element will be measured to know the dopant effect on the thermoelectric performance of as-deposited coatings. The third portion of my dissertation will focus on elucidating nanoparticle-substrate interaction in aerosol deposition at an atomistic scale via molecular dynamics (MD) simulations. Yttria-stabilized zirconia (YSZ) is selected as the material for both impacting nanoparticles and substrates. The simulations that will be performed can be categorized into cold impact and thermal impaction simulations. In cold impact simulations, we will study the influence of impact speeds on thermal energy evolution, structural transformation, and mechanical deformation in nanoparticles and substrates. In thermal impact simulations, we will investigate the role that ratio of translational kinetic energy and thermal energy in nanoparticles plays and demonstrate the influence of this ratio on nanoparticle behavior during the collision process. The final section of my dissertation focuses on investigating the effects of particle grain size on its plasticity, deformation mechanism, and dislocation propagation during the ballistic impact. By using molecular dynamics simulation, we can study the microstructure transformation and dislocation interactions in the particle over the compressive strains. The results indicate that impact velocity adversely affects the dislocation mobility in the particle, and there is increased dislocation density in the particle with a larger initial grain size.
  • Item
    Three Essays in Development Economics
    (2023-12) Vu, Khoa
    Vietnam has risen to become one of the fastest-growing economies in the world, yet the path to sustainable long-run economic growth remains elusive. This goal is further complicated by concerns about inequity and the recent global pandemic. In this dissertation, I tackle three important issues related to the quest for sustainable economic growth in Vietnam. I first examine whether expanding access to higher education has any impact on productivity at the worker level and firm level. I found that exposed workers are more likely to work in the service sector and, thus, the productivity of service firms rises in the long run. Second, I examine whether extending the maternity leave requirement has any implications on women's decisions to work in the formal sector. My findings indicate that women are more likely to move from informal work into formal jobs when the government extends the required maternity leave length from four months to six months. Third, I propose a new method to understand the impacts of the global pandemic on food security in Vietnam at a granular level.
  • Item
    Toward the Development of an Intervention to Improve Hearing Aid Access for Older People With Dementia
    (2024-01) Urbanski, Dana
    Over-the-counter (OTC) hearing aids were recently introduced to improve the affordability and accessibility of hearing aids; however, these devices are designed for self-directed hearing aid fittings which may not be feasible for all older adults. Notably, older people with co-occurring dementia and hearing loss are likely to face significant barriers when using OTC hearing aids. This creates an urgent health inequity: if people with dementia cannot successfully use OTC hearing aids, they may be left without an affordable and accessible option for their hearing healthcare. This dissertation includes three studies that establish necessary scientific groundwork for developing a behavioral intervention program to facilitate successful OTC hearing aid use in community-dwelling people with dementia and their family caregivers. The first study is a proof-of-concept trial which shows that OTC hearing aids are effective for well-selected older adult hearing aid candidates with mild-to-moderate hearing loss and normal cognition. The second study is a large secondary data analysis which reveals significant unmet hearing aid need in people with dementia—and shows that this need is disproportionately concentrated among people with dementia living at home in the community versus other institutional or congregate care settings. These data suggest an intervention for OTC hearing aid use might be most successful when targeted to community-dwelling people with dementia. Finally, the third study is a qualitative exploration of dementia care stakeholder views on the feasibility and acceptability of OTC hearing aids for community-dwelling people with dementia and their family caregivers. Results reveal key advantages of OTC hearing aids for people with dementia—but also indicate a host of stakeholder-perceived barriers which need to be addressed to promote successful OTC hearing aid use in this population.
  • Item
    Poly(propylene oxide)-poly(ethylene oxide) block copolymer mediated rescue of diseased blood-brain barrier
    (2021-01) Seo, Hannah
    Brain microvascular endothelial cells (BMECs) comprise the blood-brain barrier (BBB), which serves as the vital interface between the vasculature and the central nervous system and controls transport into and out of the brain. During many pathological conditions, BBB dysfunction causes or exacerbates neurological injury. Amphiphilic block copolymers of poly(propylene oxide) (PPO) and poly(ethylene oxide) (PEO) have been extensively employed in biomedical applications. One specific type of PPO-PEO block copolymers called poloxamer 188 (P188) has demonstrated wide utility as a cell membrane stabilizer in various disease settings, including in animal models of neurological injuries where P188 treatment improved BBB function. While animal models have substantiated the use of P188 for protecting the BBB and biophysical studies have enlightened our understanding of how P188 interacts with lipid bilayers, how P188 specifically affects the function and phenotype of the BMECs has not be thoroughly investigated. Furthermore, researchers have mainly focused on P188, but exploration of other hydrophilic dominant PPO-PEO block copolymers is warranted. In this work, we utilized an in vitro model of the BBB to specifically interrogate the impact of P188 and related PPO-PEO block copolymers to damaged BBB. Human induced pluripotent stem cell-derived BMECs were used as an in vitro model of the BBB to study the state of the BBB in childhood cerebral adrenoleukodystrophy and ischemic stroke. We established that P188 and PPO-PEO diblock copolymers can protect or rescue the BBB during certain disease conditions, leading to mitigation of disease phenotype and improved barrier function. To investigate the localization of a PPO-PEO diblock copolymer in cells, we employed confocal fluorescence microscopy and established groundwork for fluorophore-free, live-cell imaging via confocal Raman microscopy. Elucidation of the cellular responses to PPO-PEO block copolymer treatment of damaged BMECs in vitro could bridge the gap between studies using non-living biophysical systems and in vivo studies to allow for translational research that may enable the development of therapeutic solutions for neurological diseases.
  • Item
    Advancing Causal Analytics Using Biomedical Data
    (2024-01) shen, Xinpeng
    Understanding the distinction between association and causality is crucial in the fields of health informatics and biomedicine, as causality allows for the modeling of manipulable relationships. Various statistical methods have been developed as alternatives to randomized clinical trials, which often are impractical due to ethical or cost considerations. The process of causal analysis typically involves two steps: causal structure discovery and causal effect estimation (also known as causal inference). The process of extracting causal structure from observational data, known as computational causal structure discovery (CSD), is an emerging field that has garnered considerable attention in recent years. Once the causal structure is known, or partially understood, the estimation of specific causal effects can be undertaken using causal inference (CI) methods. As vast biomedical data repositories continue to emerge, understanding how to effectively process causal structure discovery and causal effect estimation has become crucial for better utilization of observational biomedical data. This thesis aims to contribute by exploring existing causal discovery methods and developing new methodologies to address practical challenges in discovering causal relationships from biomedical datasets. The work is composed of four chapters that explore the use of existing methodologies to discover causal relationships among biomarkers related to Alzheimer's disease (AD), estimate causal effects related to Alzheimer's disease, and propose two methods to address data challenges inherent in electronic health records (EHRs) datasets. Ultimately, the research presented in this thesis offers practical examples of applying CSD and causal inference methods to address biomedical problems. It also proposes two novel methods to navigate prevalent data challenges, which are crucial for effectively utilizing EHR data and extracting meaningful causal relationships.
  • Item
    Multiscale and Multiphysics of Blood Flow and Arterial Mechanics Growth and Remodeling
    (2024-01) Schmidt Bazzi, Marisa
    The circulatory system, resembling a complex network of pipes (blood vessels) and a ceaseless pumping system (heart), orchestrates the delivery of oxygen and nutrients to every cell and tissue in the human body. Unlike conventional engineering pipes, vascular tissue exhibits the remarkable ability to adapt its physical and mechanical properties in response to its environment, a phenomenon known as growth and remodeling (G&R). This process aims to maintain a balanced stress level, termed homeostatic stress.In healthy arteries, maintaining mechanical equilibrium involves a clever negative feedback loop that restores the system to its preferred state after any disturbances. However, when this delicate balance is disrupted, it can lead to a phenomenon called pathological G&R, characterized by a positive feedback loop. Aortic and intracranial aneurysms are prominent examples of this disrupted G&R. Characterized by the enlargement of vessels, aneurysms pose significant health risks, contributing to numerous annual fatalities. Moreover, blood disorders such as sickle cell disease can disrupt mechanical equilibrium by altering blood flow dynamics and creating localized hypoxia, especially in small arteries, such as the one found in our brain. Therefore, recognizing the connection between blood disorders and tissue-related diseases underscores the importance of exploring the interplay between fluid dynamics and tissue mechanics. This thesis investigates the interplay between computational fluid dynamics, mathematical modeling, and finite element analysis in the context of cardiovascular diseases. It primarily focuses on ascending thoracic and intracranial aneurysms related to sickle cell disease. We aim to enhance our understanding of the intricate mechanisms underlying vascular diseases. This heightened insight will be central in developing more holistic diagnostic and therapeutic approaches to effectively lessen their significant impact on individuals' health.
  • Item
    Wasps, vampires, and carrion flies: addressing the safety of the parasitoid Conura annulifera (Hymenoptera: Chalcididae), a promising biological control agent for the Galapagos Islands.
    (2023-12) Ramirez, Ismael
    The avian vampire fly, Philornis downsi (Diptera: Muscidae), is an invasive species in the Galapagos Islands that has caused significant mortality among endemic bird species. This thesis delves into the safety of the neotropical wasp Conura annulifera (Hymenoptera: Chalcididae) as a biological control agent against the avian vampire fly in the Galapagos Islands and encompasses four chapters addressing such safety. Chapter one scrutinizes the ecological specificity of pupal parasitoid species found in the native range of the avian vampire fly and other fly species in mainland Ecuador using food web analysis. Additionally, in Chapter two, I comprehensively characterized the composition of the carrion fly community in the Galapagos Islands, encompassing the abundance and distribution of both endemic and introduced species. Furthermore, I investigated the potential for competitive interactions between introduced and endemic carrion fly species and their implications for biological control. In Chapter Three, I examine the burrowing behavior of endemic and introduced carrion fly species in the Galapagos Islands and evaluate the ability of C. annulifera to locate and attack subterranean puparium as the soil is an effective barrier that provides refuge for non-target species that burrow. Finally, in Chapter Four, I assess the physical host preference of C. annulifera and its potential to parasitize non-target carrion fly species using no-choice trials in containment facilities of the Charles Darwin Research Station in the Galapagos Islands. The findings of this thesis provide informative insights into the intricate ecological interactions between the avian vampire fly, C. annulifera, and carrion fly species in the Galapagos Islands and Mainland Ecuador. Additionally, it sheds light on the safety of C. annulifera to serve as a biological control agent for the avian vampire fly. This knowledge is crucial information to decision-making officials regarding the potential introduction of C. annulifera to the Galapagos Islands to mitigate the detrimental effects of P. downsi on endemic bird populations and possible extinctions.
  • Item
    Unconventional Annulations within Aryne Methodology and Natural Product Biosynthesis
    (2023-12) Ritts, Casey
    Annulation reactions of linear, unsaturated substrates construct cyclic products that can contain substantially greater amounts of molecular complexity. Designed processes that leverage high energy intermediates are advantageous for expanding methods development via myriad trapping reactions of the reactive species. Our research group’s long-standing interest in the biosyntheses of polycyclic natural products has also led to fundamental studies on the cyclization reactions of polyunsaturated compounds. Specifically, we have explored the versatility of the cycloisomerization of multi-alkynyl substrates into aryne intermediates via the hexadehydro- Diels–Alder (HDDA) reaction and their subsequent trapping. Using HDDA benzynes, access to other high energy intermediates can be incorporated into the reaction path to facilitate additional annulation events. The first chapter of this thesis will detail an example of this concept that forms hypervalent main group intermediates through trapping of HDDA arynes using sulfinyl and phosphinyl reagents. These fleeting intermediates – all-carbon-ligated s-sulfuranes and s- phosphoranes – undergo reductive eliminations that form helical heteroaromatic compounds through C(sp2)–C(sp2) coupling.The second chapter discusses the biosynthesis of (+)-ottelione A, a 4-methylene-2- cyclohexenone natural product that exhibits potent antiproliferative activity via tubulin polymerase inhibition. We believe this compound is formed through a one-of-a-kind biosynthetic process that involves a spontaneous [3,3] sigmatropic (i.e., Cope) rearrangement. The enzymatic oxidation of the nominal precursor to (+)-ottelione A, a novel (acyclic) diarylheptanoid, initiates the multistep formation of a highly strained cyclonona-1,5-diene that undergoes a rare ambient temperature Cope rearrangement. The de novo syntheses of the nominal precursor, along with other diarylheptanoid analogs, was accomplished. Overall, a synthesis involving 10 steps (6 steps longest linear sequence, 38% isolated yield) was developed to provide material for biological studies involving the Ottelia alismoides plant and its protein extracts. These works share a common theme of leveraging strained, unsaturated systems for inducing unorthodox annulation processes.
  • Item
    The PRRSV-2 Saga: Evolutionary and Epidemiological Dynamics of Porcine Reproductive and Respiratory Syndrome Virus 2 in the United States
    (2024-01) Pamornchainavakul, Nakarin
    Porcine reproductive and respiratory syndrome (PRRS) has inflicted substantial economic losses on the US swine industry over the past three decades, driven by the main etiological agent, PRRSV-2, which continuously evolves and spreads despite control efforts. Enhancing disease control measures necessitates an understanding of evolutionary dynamics of PRRSV. By leveraging virus genetic data and bioinformatics tools, this dissertation aims to unravel how PRRSV-2 has adapted, persisted, and disseminated within the U.S. Chapter 1 provides a background of the disease, the virus itself, and the existing knowledge gaps. Chapter 2 employs nationwide PRRSV-2 genetic and geographic data to uncover the patterns of disease spread and the dynamics of the virus population within the U.S. In Chapter 3, we conduct an in-depth investigation into between-farm transmission of an emerging PRRSV-2 sub-lineage within a specific, swine-dense region, using genetic and animal movement data. Chapter 4 utilizes data from the largest active PRRS monitoring program in the U.S. to forecast the potential emerging variants. Finally, in Chapter 5, we pinpoint the origin of a novel PRRSV-2 variant through an advanced analysis of whole-genome sequences.Chapter 2 revealed a cyclical pattern of sub-lineages contributing to the overall PRRSV-2 population and a shift across time in major hotspots for inter-regional spread. In Chapter 3, we narrow our focus to intra-regional spread by applying molecular epidemiological tools to construct farm-to-farm transmission networks for an emerging PRRSV-2 sub-lineage. These networks allowed us to examine factors contributing to between-farm spread and highlighted the significance of live animal movement, while recognizing that most transmission events remained unexplained. Both Chapters 2 and 3 characterize the periodic emergence of novel genetic variants of PRRSV-2, and anticipating such emergence events could aid in more strategic disease control. Chapter 4 demonstrated the utility of phylogenetic branching patterns and putative antigenic differences as early indicators of variant emergence. Finally, in Chapter 5, we expand the discussion of variant emergence from the ORF5 gene to the whole genome perspective. Analysis of whole-genome sequences unveiled a recombinant ancestor for an emerging variant of concern and emphasized the role of genomic recombination in PRRSV-2 evolution. Ultimately, our findings address novel insights into PRRSV-2 evolution and epidemiology at various geographic scales, providing beneficial guidance for targeted and early-response PRRS mitigation strategies in the U.S.
  • Item
    Geomorphological and Archaeoastronomical Analysis of a Neolithic Landscape, Cranborne Chase, Southern Britain
    (2024-01) Burley, Paul
    Cranborne Chase in southwest England is a well-known area of Neolithic archaeology where a nexus of population growth, cultural evolution and resource extraction during the 4th millennium led to development of one of the highest densities of earthen monuments, including numerous long barrows, the largest and longest cursus in Britain, and many other structures. Natural physiographic characteristics of the study area in tandem with anthropomorphic modification of local vegetation patterns on the downs since the Mesolithic provided a distinctive setting where the Early- to Middle-Neolithic cultural landscape developed. However, reasons for siting monuments at certain locations within the complex chalkland landscape, the purpose of specific and unique architectural forms and features of the earthen structures, and spatial relationships between the pattern of monuments and elements of the surrounding environment as a whole remain largely enigmatic. Are there special features of the natural landscape that the Neolithic population valued for earthen monument development, and why was such a high density of earthen monuments developed there? This thesis describes geological and paleo-environmental characteristics and cultural features of the study area c. 4th millennium, evaluates similarities and differences associated with Neolithic and Bronze Age earthen and chambered burial sites located across Britain, and presents methods and results of an astrometric analysis of topographic position, monument orientation, and viewscape from earthen monuments at Cranborne Chase. Results of this study demonstrate that spatial and temporal relationships between the earthen structures and elements of the surrounding landscape, seascape, and skyscape are key to recognizing and understanding the symbolism and signification expressed by the monumental architecture. The cultural landscape – including the pattern of both natural features and earthen monuments at Cranborne Chase, the South Hampshire Lowlands, and surrounding region – expresses spatial and temporal unification by alignment between Earth and sky, and the living and the dead. In that way, the cultural landscape is related to a Neolithic cosmology emphasizing features of the landscape and skyscape.
  • Item
    Lowering Backgrounds and Thresholds in the Search for Light Dark Matter with SuperCDMS
    (2024-01) Nelson, Jack
    Cosmological observations have produced a wealth of evidence which demonstrates that the majority of thematter content in our Universe is “dark”. The identity of this dark matter remains elusive, as none of the members of the standard model of particle physics accurately describe its properties. This has prompted the scientific community to launch a broad search, spanning decades in time, mass and sensitivity, with the goal of detecting and identifying this source of new physics. The next generation of the Super Cryogenic Dark Matter Search (SuperCDMS) is currently under construction deep underground at SNOLAB. The experiment aims to expand the search for dark matter to lower masses (≲ 10 GeV/c2) and greater sensitivities using silicon and germanium detectors by minimizing experimental backgrounds and operating detectors with superb energy resolution. SuperCDMS will accomplish its low projected background in part by deploying a robust shield to protect its detectors from environmental radiation. This dissertation presents the results of simulations which demonstrate the success of the shield design at stopping radiogenic neutrons. The shield will be able to reduce these environmental sources to the point where coherent scattering from solar neutrinos are expected to dominate the nuclear recoil backgrounds. In order to search for such light dark matter masses, SuperCDMS uses sensitive transition edge sensors to measure small energy depositions in the detectors. The ultimate energy resolution of these devices, expected to be < 1 eV, has not yet been realized. This dissertation describes the analysis of a dark matter search performed at the University of Massachusetts Amherst with a prototype detector which uses SuperCDMS style sensors to achieve a baseline energy resolution of 2.3 eV. The results of this search demonstrate sensitivity to dark matter candidates with masses as low as ∼ 25 MeV.