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Cyclodextrin-Based Supramolecular Drug-Delivery Nanomaterials And Shear-Thinning Hydrogels Using Ring-Opening Metathesis Polymerization, Ruihan Li

Arts & Sciences Graduate Student Theses and Dissertations

Cyclodextrins (CD) are a family of oligosaccharides that can non-covalently and precisely bind small hydrophobic drug molecules, such as antibiotics and anticancer drugs, through well-defined host-guest interactions inside the inner cavity of the macrocycle. Ring-opening metathesis polymerization (ROMP) is a versatile, functional group tolerant method of polymerization that is underexplored in biomedical applications relative to the more common controlled chain-growth polymerizations. In this dissertation, I describe my efforts to combine the supramolecular chemistry of CDs with that of ROMP using specialized functional monomers to synthesize several CD-based polymeric drug delivery nanomaterials. For example, in Chapter 2, a new type of …

On The Challenges And Rewards Of Analyzing Molecular Dynamics At The Terabyte And Millisecond Scale, Justin Roy Porter

Arts & Sciences Graduate Student Theses and Dissertations

Molecular Dynamics (MD) and Markov state models (MSMs) are powerful tools for estimating and concisely representing the conformational ensemble accessible to biological macromolecules, particularly proteins. Conformational ensembles are of special importance biological function, both in health and disease, because biology derives from molecules’ entire conformational distribution rather than any single structure. Consequently, MD is poised to become a powerful tool for personalized medicine and for the study of molecular sequence-function relationships generally. However, because of their hyperdimensionality and size, just generating MD datasets and Markov state models (MSMs) that represent biologically relevant molecules is a substantive technical challenge. Then, even …

Causal Function And Bias Correlation Of The Orbitofrontal Cortex In Economic Choices, Shi Weikang

Arts & Sciences Graduate Student Theses and Dissertations

Economic choices entail two mental processes, value calculation and value comparison (Niehans, 1990). Studies in the last twenty years have shown that neurons in the orbitofrontal cortex (OFC) could support both processes. Namely, in the studies in which monkeys chose between two juice options with various amounts, three functional cell groups had been found in the OFC: offer value cells encode the value of individual juices, chosen juice cells encode the choice in a binary way and chosen value cells encode the value of the chosen juice (Padoa-Schioppa and Assad, 2006). These results suggest a decision circuit within OFC with …

Influence Of Focal Activity On Macroscale Brain Dynamics In Health And Disease, Zachary Pollack Rosenthal

Arts & Sciences Graduate Student Theses and Dissertations

Macroscopic recordings of brain activity (e.g. fMRI, EEG) are a sensitive biomarker of the neural networks supporting neurocognitive function. However, it remains largely unclear what mechanisms mediate changes in macroscale networks after focal brain injuries like stroke, seizure, and TBI. Recently, optical neuroimaging in animal models has emerged as a powerful tool to begin addressing these questions. Using widefield imaging of cortical calcium dynamics in mice, this dissertation investigates the mechanisms by which focal disruptions in activity alter brain-wide functional dynamics. In two chapters, I demonstrate 1) that focal sensory stimulation elicits state-dependent, global slow waves propagating from primary somatosensory …

Regulation Of Metabolic Stress By The Snhg3 Locus, Arthur Curtis Sletten

Arts & Sciences Graduate Student Theses and Dissertations

Dyslipidemia and lipotoxicity are pathologic signatures of the metabolic syndrome and type 2 diabetes. Excess lipid causes cell dysfunction and induces cell death through pleiotropic mechanisms that link to oxidative stress. However, pathways that regulate the response to metabolic stress are not fully understood. To identify novel genes involved in metabolic stress, our group performed an unbiased forward genetic screen for lipotoxicity resistance. My studies focused on characterizing one of the mutant cell lines isolated from this screen, in which promoter trap mutagenesis disrupted one allele of the small nucleolar RNA hosting gene 3 (Snhg3). I demonstrate that diminished expression …

Role Of Interferon Receptors In Sting-Associated Autoinflammatory Disease In Mice, William Alexander Stinson

Arts & Sciences Graduate Student Theses and Dissertations

Over the past decade, the cGAS-STING pathway has emerged as a principal component of innate DNA sensing. Its activation of type I interferon (IFN) elicits host immune activation and in the absence of cGAS or STING, mice are rendered critically susceptible to infection by viruses and bacteria. Breakdowns in the molecules that regulate this pathway can promote unrestrained cGAS-STING activation and the development of various forms of autoimmune disease. For instance, gain-of-function mutations in STING cause autoinflammatory lung disease in mice and STING-associated vasculopathy with onset in infancy (SAVI) in humans. However, our understanding of the mechanisms that underlie STING-dependent …

Genetic Risk Factors For Neurodevelopmental Disorders: Insights From Hipsc-Cerebral Organoids, Michelle L. Wegscheid

Arts & Sciences Graduate Student Theses and Dissertations

Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder (NDD) characterized by remarkable phenotypic variability, where affected children manifest a spectrum of central nervous system (CNS) abnormalities, including brain tumors, impairments in attention, behavior, learning disabilities, and an increased incidence of autism spectrum disorder (ASD). A significant barrier to the implementation of precision medicine strategies for children with NF1 is a lack of prognostic risk factors to guide clinical management. However, emerging population-based genotype-phenotype association studies have suggested that the germline NF1 gene mutation may represent one clinically actionable risk factor for NF1-associated neurodevelopmental abnormalities. As a critical step in …

Weedy Rice As A Model System For The Study Of Microevolutionary Interactions In Agricultural Contexts, Marshall Jon Wedger

Arts & Sciences Graduate Student Theses and Dissertations

Just under one-half of the global population relies on cultivated rice (Oryza sativa) astheir primary source of calories, making the optimization of rice agriculture immensely important. One of the primary constraints to rice agriculture is the de-domesticated (feral) form of rice known as ‘weedy rice’ that aggressively competes for space, soil nutrients, and light. Heavy infestation can reduce crop yields by as much as 80%. As a closely-related weedy descendant of cultivated rice, chemical control is difficult in rice fields, and physical weeding is labor intensive, time consuming, and largely ineffective due to early life-stage mimicry of the crop. Weedy …

The Role Of Neuronal Atp-Sensitive Potassium Channels In Learning And Memory, Shaul Vladimir Yahil

Arts & Sciences Graduate Student Theses and Dissertations

ATP-sensitive potassium (KATP) channels link cellular metabolism and membrane excitability in many tissues, including brain and pancreas. Gain-of-function (GOF) mutations to KATP channels cause neonatal diabetes, with some patients exhibiting developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. Diabetic symptoms have been attributed to loss of membrane excitability and insulin secretion in pancreatic β-cells, though the origin of neurological deficits and the effects of neuronal KATP-GOF mutations more generally remain elusive. In this dissertation, I will present evidence that mice expressing KATP-GOF mutations pan-neuronally (nKATP-GOF) demonstrated sensorimotor and cognitive deficits, whereas hippocampus-specific hKATP-GOF mice exhibited predominantly learning and memory deficits. …

Examining Individual Differences In Forgetting From Long-Term Memory, Christopher Lee Zerr

Arts & Sciences Graduate Student Theses and Dissertations

Forgetting reflects the decreased likelihood of memory retrieval over time. With a few exceptions, although the mean likelihood of retrieval (or retention) across experimental conditions may differ markedly, rates of forgetting across those conditions do not differ. Similarly, although groups (e.g., young and old adults) may differ in the amount retained at a given point in time, the rates of forgetting tend not to differ across groups. In contrast, recent work suggests that individual differences in rates of forgetting may emerge when more sensitive statistical analyses are used on person-level performance. Some person-level variables purported to influence forgetting rate include …

Cancer Epigenome Reprogramming, Jennifer Ann Karlow

Arts & Sciences Graduate Student Theses and Dissertations

The identification of recurrent genetic mutations in cancer and their functionalcharacterization has provided a strong foundation for our understanding of tumorigenesis. The more recent observation of recurrent and specific epigenetic changes also present in cancer has widened this view, now establishing cancer as a disease of both genetic and epigenetic misregulation. Enhancers, genomic regions primarily responsible for tissue-specific gene expression, have been shown to be frequent targets of both genetic and epigenetic abnormalities. The observation that DNA methylation within regulatory regions has traditionally correlated with reduced gene expression, coupled with the known role of enhancers in regulating tissuespecific gene expression, …

Developments In Proteomics, Trans-Splicing Technology And Endogenous Transcript Manipulation, Justin Alexander Melendez

Arts & Sciences Graduate Student Theses and Dissertations

Technological innovation drives scientific discovery, unlocks new avenues of research, and allows us to ask questions in ways that were previously unavailable. With each technological advance, our ability to perturb and explore biological systems has grown in ways previously unimagined. The theme of my thesis is the development of new technologies in biology. To this end, I have worked on three technologies that contribute to the areas of protein sequencing, RNA barcoding for trans-splicing and single-cell applications, and a new method for transcriptional knockdown. In my first project, digital analysis of proteins by end sequencing (DAPES), we set out to …

Limits On Parameter Estimation Of Quantum Channels, Vishal Katariya

LSU Doctoral Dissertations

The aim of this thesis is to develop a theoretical framework to study parameter estimation of quantum channels. We begin by describing the classical task of parameter estimation that we build upon. In its most basic form, parameter estimation is the task of obtaining an estimate of an unknown parameter from some experimental data. This experimental data can be seen as a number of samples of a parameterized probability distribution. In general, the goal of such a task is to obtain an estimate of the unknown parameter while minimizing its error.

We study the task of estimating unknown parameters which …

Deep Learning For Automatic Microscopy Image Analysis, Shenghua He

McKelvey School of Engineering Graduate Student Theses & Dissertations

Microscopy imaging techniques allow for the creation of detailed images of cells (or nuclei) and have been widely employed for cell studies in biological research and disease diagnosis in clinic practices.Microscopy image analysis (MIA), with tasks of cell detection, cell classification, and cell counting, etc., can assist with the quantitative analysis of cells and provide useful information for a cellular-level understanding of biological activities and pathology. Manual MIA is tedious, time-consuming, prone to subject errors, and are not feasible for the high-throughput cell analysis process. Thus, automatic MIA methods can facilitate all kinds of biological studies and clinical tasks. Conventional …

Predicting Patient Outcomes With Machine Learning For Diverse Health Data, Dingwen Li

McKelvey School of Engineering Graduate Student Theses & Dissertations

As digitized clinical and health data become ubiquitous, machine learning techniques have shown promise in predicting various clinical outcomes. In this thesis research, we exploit three types of data including (1) data collected through wearables outside hospitals, (2) electronic health records (EHR) data of inpatient in general hospital wards, (3) intraoperative data collected during surgery. This thesis work investigates machine learning approaches for the diverse clinical and health data with distinctive characteristics and challenges in the context of real-world clinical applications. Specifically, this thesis makes the following contributions to the state of the art of clinical machine learning.

Extracting informative …

Improving Resource Efficiency In Cloud Computing, Jiayi Song

McKelvey School of Engineering Graduate Student Theses & Dissertations

Customers inside the cloud computing market are heterogeneous in several aspects, e.g., willingness to pay and performance requirement. By taking advantage of trade-offs created by these heterogeneities, the service provider can realize a more efficient system. This thesis is concerned with methods to improve the utilization of cloud infrastructure resources, and with the role of pricing in realizing those improvements and leveraging heterogeneity. Towards improving utilization, we explore methods to optimize network usage through traffic engineering. Particularly, we introduce a novel optimization framework to decrease the bandwidth required by inter-data center networks through traffic scheduling and shaping, and then propose …

Defining The Epigenetic And Transcriptional Regulatory Mechanisms By Which Hrsv Ns1 Alters Host Transcriptional Response, Nina Rose Beri

Arts & Sciences Graduate Student Theses and Dissertations

No abstract provided.

Probing New Physics Beyond The Standard Model Via New Neutrino Interactions, Garv Chauhan

Arts & Sciences Graduate Student Theses and Dissertations

The Standard Model (SM) of Particle Physics provides a self-consistent quantum field theoretic framework to explain three of the four known fundamental forces (electromagnetic, weak, strong) along with classifying all known elementary particles. Since its conception in the 1960s, the SM has been one of the most tested theories of physics and has withstood all experimental batterings. In spite of these successes, there are compelling indications, both experimental and theoretical, that require us to expand our understanding of the nature beyond the SM (BSM). Arguably the most glaring indication of BSM physics is the observation of neutrino oscillations, which implies …

Dissecting The Molecular Mechanism Of Familial Cardiomyopathies, Sarah Ruth Clippinger Schulte

Arts & Sciences Graduate Student Theses and Dissertations

Familial cardiomyopathies, including hypertrophic (HCM), restrictive (RCM) and dilated cardiomyopathy (DCM), are the leading cause of sudden cardiac death in young people. These diseases, which are characterized by altered cardiac contractility and remodeling of the heart, can lead to heart failure. These diseases are primarily caused by point mutations in sarcomeric proteins that generate or regulate heart contraction, such as troponin T. In the heart, the troponin complex together with tropomyosin lie along the actin filament and regulate myosin’s ability to bind actin and produce force. Here I show how mutations in troponin T affect contractility at the molecular level …

Influence Of Aging And Cerebrovascular Disease On Neuroimaging Measures Of Alzheimer Disease, Lauren Nicole Koenig

Arts & Sciences Graduate Student Theses and Dissertations

The overall goal of this dissertation is to gain a better understanding of how Alzheimer disease relates to normal aging and cerebrovascular disease to impact neuroimaging measures in a clinically meaningful way. Both aging and cerebrovascular disease are known to influence measures of Alzheimer disease, making it difficult to separate what changes are attributable specifically to Alzheimer disease. We hypothesize that a better understanding of these relationships will allow future studies to appropriately take these factors into account. In Chapters 2 and 3 we attempt to separate out the influences of normal aging and Alzheimer disease on measures of atrophy. …

Structural Variants Are A Major Source Of Gene Expression Differences In Humans And Often Affect Multiple Nearby Genes, Alexandra Jane Scott

Arts & Sciences Graduate Student Theses and Dissertations

Structural variants (SVs), including copy number variants (CNVs), balanced rearrangements, and mobile element insertions (MEIs), are an important source of diversity in the human genome but their functional effects are not well understood. SVs are technically difficult to detect and genotype1, and mapping is dependent on deep whole genome sequencing (WGS) which was, until recently, unaffordable for large cohorts. For these reasons SVs are not included in most genome-wide studies of functional variants, despite the fact that SVs are known causal agents in multiple clinical disorders2-16. However, recent advancements in high-throughput sequencing technologies that allow for widespread use of WGS, …

Deep Multi-Omics Investigations Elucidate Novel Oncogenesis Paradigms, Therapeutic Targets, And Mechanisms Of Treatment Resistance In Cancer, Daniel Cui Zhou

Arts & Sciences Graduate Student Theses and Dissertations

No abstract provided.

A Systematic Study Of Neutron Production In Two Versions Of The Mevion Proton-Therapy System, Nima Tatari

Arts & Sciences Graduate Student Theses and Dissertations

This thesis presents a study of neutron production in two types of proton-therapy systems: passive scattering Mevion S250, and active scanning Mevion S250i. The scattering system has been operating at Washington University in St. Louis since 2013. The scanning system was installed in the same building in 2020. The scanning system has the advantage of producing fewer neutrons due to a focused scanned beam and the absence of beam scatterers, collimators, and a static brass aperture. A systematic particle transport Monte Carlo analysis using the Geant4 toolkit has been performed to track the neutrons produced in various components of each …

Regional Reprogramming And The Small Intestine: Analysis And Modeling Of Adaptive Regeneration Of The Epithelium, Sarah Elizabeth Waye

Arts & Sciences Graduate Student Theses and Dissertations

The small intestine in homeostasis is capable of regular regeneration, but in cases of massive injury like Short Bowel Syndrome, the innate human response often fails to fully compensate for the loss of nutrient absorptive surface area that accompanies bowel resection. Murine models display an active compensatory reaction deemed “adaptation” in which the surface area of the bowel is increased to accommodate nutrient absorptive needs. This observation has highlighted several gaps in knowledge regarding bowel adaptation. Firstly, what occurs on a molecular level in murine models during adaptation? Secondly, how can the findings in mice be applied to humans in …

Identification Of Multi-Tissue Protein Quantitative Trait Loci And Causal Inference Of Protein Effects In Neurological And Other Complex Human Diseases Via Mendelian Randomization, Chengran Yang

Arts & Sciences Graduate Student Theses and Dissertations

Alzheimer disease (AD) is the most common neurodegenerative disease, affecting 6.2 million people mostly aged 65 years or older in the United States as of early 2021. AD has been widely studied and characterized worldwide, but there is still no effective treatment or cure. Even the latest FDA-approved treatment, Aducanumab, cannot stop decline or improve cognition. To develop a truly effective treatments, researchers keep discovering genetic and molecular mechanisms underlying the disease. Protein biomarkers are keys to bridge the mechanisms to disease. Here, I first used a high-throughput proteomic dataset from three tissues (CSF, plasma, and brain) with array-based genotype …

An Investigation Of Sensory Percepts Elicited By Macro-Sieve Electrode Stimulation Of The Rat Sciatic Nerve, Nikhil Shiva Chandra

McKelvey School of Engineering Graduate Student Theses & Dissertations

Intuitive control of conventional prostheses is hampered by their inability to replicate the rich tactile and proprioceptive feedback afforded by natural sensory pathways. Electrical stimulation of residual nerve tissue is a promising means of reintroducing sensory feedback to the central nervous system. The macro-sieve electrode (MSE) is a candidate interface to amputees’ truncated peripheral nerves whose unique geometry enables selective control of the complete nerve cross-section. Unlike previously studied interfaces, the MSE’s implantation entails transection and subsequent regeneration of the target nerve. Therefore, a key determinant of the MSE’s suitability for this task is whether it can elicit sensations at …

Numerical Investigations Of Logic Gates And Transistors In Quantum And Classical Information Processing, Anthony Corbin

McKelvey School of Engineering Graduate Student Theses & Dissertations

The development of numerical analysis techniques for electromagnetics and quantum mechanics problems has dramatically increased the rate of new discoveries. Propelled by the exponential growth of computers over the past decades, numerical software has brought the ability to reliably experiment with new ideas and predict new phenomena, even before the physical realizations of these ideas in the labs. This work will demonstrate the application of this capability by applying numerical analysis techniques to design and analyze new devices. First, a system of optical logic gates using a nonlinear metallodielectric grating is completely designed and simulated using numerical analysis. Second, the …

Development And Application Of A Novel Acoustic Microfluidic Technology For Single Cell Per Well Trapping And High-Resolution Analysis Of Cilia Motion In Chlamydomonas Reinhardtii, Mingyang Cui

McKelvey School of Engineering Graduate Student Theses & Dissertations

Acoustic manipulation of cells and microorganisms is a label-free and contact-free technique with promise for biological and biomedical applications. When exposed to an ultrasonic standing wave field, particles suspended in microfluidic channels will be moved to pressure minima (nodes) or maxima (antinodes) due to the acoustic impedance mismatch between particles and the suspension medium. Cilia motion is fundamental to understanding biological and biomedical problems related to dysfunctional human cilia, including primary ciliary dyskinesia, blindness, and male infertility. However, in vivo and ex vivo mammalian ciliated cell research is laborious and time-consuming due to difficulty in growing, maintaining, and imaging these …

On The Study Of Age-Related Physiological Decline In C. Elegans, Drew Benjamin Sinha

McKelvey School of Engineering Graduate Student Theses & Dissertations

Aging decline is a universal and unescapable phenomenon; as organisms reach maturity and continue living, physiological function inevitably declines, resulting in mortality. While the study of mortality has been long studied, technical and practical challenges have limited the equally important study of how/when individuals deteriorate and what types of factors affect that deterioration. This gap in knowledge is not only evident in a relative lack of empirical data on physiological decline, but considerable debate around the analysis and conceptual interpretations of the little data that is available.

In this dissertation, I use quantitative reasoning and analysis of longitudinal data to …

Interfacial Engineering And Photoelectrochemistry Of Patterned Metal/Semiconductor Heterostructures, Che Tan

McKelvey School of Engineering Graduate Student Theses & Dissertations

Photoelectrochemical (PEC) cells enable the conversion of solar energy into storable fuels, which is critical in overcoming the intermittent nature of this largest renewable source. However, the majority of semiconductors used as photoelectrodes in these cells have low conversion efficiencies and/or stabilities. Silicon (Si) is an attractive semiconductor material for photoelectrodes, but the development of efficient Si-based photoanodes is challenging due to their instability in alkaline solutions. Thus, one focus of this dissertation is the design and fabrication of highly stable nickel (Ni)-patterned Si photoanodes through interfacial engineering of the barrier heights. Recently, hot carriers in plasmonic metal nanostructures have …