Digital Commons Network^™

Developing Genetic Tools For Engineered Probiotics, Matthew Brooks Amrofell

McKelvey School of Engineering Theses & Dissertations

The gut microbiome is increasingly understood to play a key role in human health. Commensal gut microbes influence immunity, pathogen colonization, digestion, and brain chemistry, to name a few impacts on host physiology. As such, efforts to diagnose and treat diseases through manipulation of the microbiome are becoming more commonplace. To date, these efforts revolve around introducing defined native consortia or a single engineered strain. Engineered strains, compared to consortia, offer the advantages of known mechanisms of action, more predictable pharmacokinetics and pharmacodynamics, and easier manufacturing, among others. Safe and effective engineered strains should sense and respond to the gut …

Mapping, Modifying, And Stimulating Skeletal Nerves To Explore Their Regulatory Role In Bone Metabolism, Alec Thomas Beeve

McKelvey School of Engineering Theses & Dissertations

The skeleton is innervated by sensory and sympathetic nerves, which are known facilitators of pain and vasoregulation. Recent studies suggest that nerves in bone play an additional direct role in regulating bone metabolism through local release of neuropeptides near bone cells; however, this remains controversial. The overall hypothesis of this thesis is that skeletal nerves are therapeutic targets for increasing bone mass and enhancing bone health. To address the feasibility of nerve-targeted skeletal therapeutics, the work in this thesis explores mapping, modification, and stimulation of nerves in bone and the subsequent effects on bone formation and metabolism.Bone is innervated by …

Development And Maturation Of Human Pluripotent Stem Cell Derived Pancreatic Islets, Punn Augsornworawat

McKelvey School of Engineering Theses & Dissertations

Cell replacement therapy for severe diabetes is a promising strategy to restore long term normoglycemia. With limited availability of cadaveric islets from compatible donors, cellular engineering via human pluripotent stem cells differentiation to insulin-secreting stem cell derived islets (SC-islets) provides a useful alternative as they can be generated in unlimited supply. Nonetheless, SC-islets generated with current protocols are not as well performing when compared to native human islets due to poor β cell yields and low mature β cell genes expression. Herein, I use single-cell technologies and bioinformatics to uncover mechanisms associated with pancreatic development to recapitulate β cell differentiations. …

Deep Learning For Tomographic Image Reconstruction Guided By Generative Models And Image Science, Sayantan Bhadra

McKelvey School of Engineering Theses & Dissertations

Tomographic image reconstruction is generally an ill-posed inverse problem. Such inverse problems are typically regularized using prior knowledge of the sought-after object property. Recently, deep neural networks have been actively investigated for regularizing image reconstruction problems by learning a prior for the object properties from training images. Deep generative models such as generative adversarial networks (GANs) have demonstrated the ability to learn object distributions comprehensively and synthesize high-quality images. This dissertation explores novel generative model-constrained reconstruction methods that employ state-of-the-art GANs in the context of ill-posed tomographic imaging problems. The symbiotic relationship between image science and deep learning to enable …

Advancements In Magnetic Resonance Image Guided Radiotherapy, Austen Curcuru

McKelvey School of Engineering Theses & Dissertations

Magnetic resonance image guided radiation therapy (MRgRT) devices are a recently developed technology that integrate the excellent soft tissue contrast and real-time imaging capabilities of MRI with a medical linear accelerator (Linac). This provides an unprecedented ability to guide and adapt radiation therapy treatments based on real-time cine imaging. However, the merging of these technologies has come with unique challenges. MRI lacks the geometric fidelity of computed tomography (CT). Spatial inaccuracies in MRI can result from magnetic field (B0) or center frequency variations, gradient-induced eddy currents, and magnetic field gradient imperfections (e.g., nonlinearities, poor calibration, concomitant fields, and unsatisfactory electronic …

To Ascertain Scientific Reliability In Pet Imaging For Alzheimer Disease, Charles Chen

McKelvey School of Engineering Theses & Dissertations

Alzheimer disease is one of the deadliest and most expensive diseases in the United States. Knowing whether a family member has Alzheimer disease may help households better plan for health-related expenses. However, fewer than half of primary care physicians report being comfortable diagnosing cognitive impairment due to Alzheimer disease. One solution is to supplement cognitive assessments with biomarkers to track abnormal levels of amyloid-β and tau, the pathological hallmarks of Alzheimer disease. Among these, positron emission tomography (PET) has emerged as an established standard that other biomarkers are compared to. However, as PET imaging moves from being used in research …

The Role Of Trpv4 In The Intervertebral Disc Response To Mechanical Loading, Garrett Easson

McKelvey School of Engineering Theses & Dissertations

Low back pain (LBP) is one of the most common and debilitating musculoskeletal disorders in the world, with a lifetime prevalence above 80%. The cause of LBP is multifactorial, with intervertebral disc (IVD) degeneration being one of the most prominent contributors to its development. IVD degeneration occurs due to aging, aberrant mechanical loading, and injury. The IVD responds to these stimuli and experiences inflammation, catabolism, neovascularization, and innervation. While the degenerative cascade is well characterized, how the IVD transduces mechanical loading and injury stimuli into a degenerative response is still poorly understood. Mechanosensitive ion channels are one mechanism that musculoskeletal …

Numerical Simulation, Turbulence Modeling And Active Flow Control Of High Lift Aerodynamic Flows, Karsten Hendrickson

McKelvey School of Engineering Theses & Dissertations

The accurate predictions of 3D high lift flows have proven to be a significant challenge for Computational Fluid Dynamics (CFD) using the Reynolds-Averaged Navier-Stokes (RANS) equations with a turbulence model. While RANS methods typically require less computational resources than Scale Resolving Simulation (SRS) methods, they generally struggle to accurately predict flow separation and the complex interactions that occur between the fuselage, different elements of the wing, the engine nacelle, and the accompanying support hardware. As a result, significant effort has been put in improving the accurate prediction of these flows with the goal of developing better computational methodologies and turbulence …

Ai-Driven Neuro-Oncology Imaging Analysis Of Intracranial Tumors, Satrajit Chakrabarty

McKelvey School of Engineering Theses & Dissertations

According to 2016 cancer statistics, brain tumors are the leading cause of cancer-related morbidity and mortality around the world. More than 100 types of brain tumors, distinguishable by unique histopathological features, have been identified that differ significantly in prognosis and treatment strategies. Currently, histopathology is the diagnostic standard for characterizing brain tumors, which carries risks and potential complications. So, MRI is frequently used as an alternative to or in conjunction with histopathology due to its non-invasive nature and high soft-tissue contrast. With the emergence of artificial intelligence (AI) based approaches, different machine learning (ML) and deep learning (DL) models have …

Nanoparticle Nucleation, Trapping, & Effluent Charging In Low-Temperature Plasmas, Eric Husmann

McKelvey School of Engineering Theses & Dissertations

Nanoparticles in nonthermal plasmas (i.e., dusty plasmas) have been the subject of both great concern and great promise. For microelectronics fabrication, particles from nonthermal plasmas behave as a problematic system impurity; however, due to the interesting properties of the nanoparticles which can be synthesized in nonthermal plasmas, there has been much interest to develop nonthermal plasma-synthesized nanoparticles for a wide range of applications. Given this interest in nonthermal dusty plasma systems, understanding how systematic parameters affect dusty plasma systems is of great importance. As such, this work will focus on three particular phenomena: how systematic parameters affect nanoparticle formation, how …

Mechanisms Of Kcnq1-Calmodulin Channel Complex Activation To Dual Open States, Po Wei Kang

McKelvey School of Engineering Theses & Dissertations

Voltage-gated potassium channels (KV) facilitate cellular excitability essential for cardiac contraction and neuronal spiking. In response to changes in the membrane potential, KV channels conduct transmembrane K+ flux to terminate action potentials. Myriad drugs target KV channels to achieve therapeutic goals such as anti-arrhythmic and anti-convulsant effects. Owing to their physiological significance, KV channels are exquisitely regulated by a cohort of auxiliary proteins and signaling molecules. The KCNQ1 or KV7.1 voltage-gated potassium channel stands out as an archetype in this regard. Modulators such as the KCNE subunit family, membrane lipid PIP2, and calmodulin (CaM) enable KCNQ1 to conduct phenotypically distinct …

Colorectal And Ovarian Cancer Imaging Using Optical Coherence Tomography And Photoacoustic Tomography, Hongbo Luo

McKelvey School of Engineering Theses & Dissertations

Human colorectal cancer and ovarian cancer remain the leading causes of cancer mortality. However, if diagnosed early, both cancer types have high patient survival rate. Endoscopic screening and surveillance are particularly helpful in providing physicians with in situ information for diagnosis. Compared to traditional ultrasound endoscopy, optical endoscopy can provide higher imaging resolution with more detailed tissue morphology. Also, differences in tissue optical properties (e.g., scattering, absorption) can also by revealed with optical imaging methods. In this thesis, two optical coherence tomography (OCT) catheters are introduced for ex vivo sample studies and in vivo patient studies to differentiate malignant tumor …

Tfa Inference: Using Mathematical Modeling Of Gene Expression Data To Infer The Activity Of Transcription Factors, Cynthia Ma

McKelvey School of Engineering Theses & Dissertations

Transcription factors (TFs) are a set of proteins that play a key role in the information processing system that enables a cell to respond to changes in internal and external state. By binding near a gene in a cell’s DNA, a TF can influence that gene’s expression level, triggering the appropriate increase or decrease in production levels of proteins that are needed to handle stressors like a change in nutrient availability or damage to the cell’s internal structures. Transcription factor activity (TFA) is a measure of how much effect a TF has on its target genes in a given sample …

Identification And Characterization Of Targets Of Metastasis In High-Grade Serous Ovarian Cancer, Emilee Nicole Kotnik

Arts & Sciences Electronic Theses and Dissertations

High-Grade Serous Ovarian Cancer (HGSC) is a highly metastatic cancer with the majority of patients presenting in advanced stages. Currently there are limited targeted treatment options for patients, especially for women with high metastatic tumor burdens. In order to improve patient outcomes, we have aimed to identify and characterize novel targets of metastasis utilizing sequencing from patient tumors and a functional genomic screen. First, we identified genetic alterations of metastasis and short survival by characterizing the genomic and transcriptomic alterations of primary and metastatic tumors in HGSC patients from 23 short-term survivors (overall survival (OS) <3.5 years) and 16 long-term survivors (OS >5 years). We compared somatic …

Opening Dual Enrollment: How Removing Barriers To Entry Influences The Participation Of Historically Excluded Students, Rachel Martin

Arts & Sciences Electronic Theses and Dissertations

A majority of high school students in the United States aspire to earn a postsecondary degree, yet far fewer of these students enroll in and complete college. Further, matriculation and degree attainment is not equitable across race and class, despite the high aspirations that students across identity markers hold. These inequities are artifacts of an educational system that has separated students by race, class, and perceived academic ability for over 100 years. In the U.S., white and wealthy students are traditionally tracked into “high-level” classes that prepare them for college, staffed with highly trained teachers and gold standard resources. On …

A Framework For Investigating Random Ensembles Of Structured Ecosystems And Quantifying Their Emergent Coarse-Grainability, Jacob Moran

Arts & Sciences Electronic Theses and Dissertations

The interface between statistical physics and theoretical ecology has a long history, employing powerful concepts such as ensemble approaches and typicality to study emergent properties of ecosystems. This of course raises the question of what ensembles are useful to describe the typical behaviors of evolution and ecology, but so far, the traditional context of high-diversity ecology has considered ensembles of random, unstructured ecosystems. Although much insight has been gained in this regime, one naturally wonders how representative are random ensembles of real, natural ecosystems that are arguably atypical and highly structured by evolution. Moreover, the question of coarse-graining ecosystems has …

The Effect Of Ionization Density In Applications Of Radiation Detection, Dosimetry, And Therapy, Daniel Mulrow

Arts & Sciences Electronic Theses and Dissertations

This dissertation covers a wide range of topics but is linked by the common theme of radiation interacting with materials and studying the result of those interactions. The introduction describes the fundamentals of how radiation interacts with material and how we are able to detect that radiation and the application of how we use those interactions in radiation oncology. The thesis starts with a chapter detailing the temperature dependence of the photophysics in two organic scintillators. This chapter is the foundation for a future study that will look the degree to which these scintillators can distinguish between gammas and neutrons …

Essays In Transportation Economics And Regional Science, Minsung Park

Arts & Sciences Electronic Theses and Dissertations

This dissertation comprises three chapters that attempt to examine the effects of new infrastructure of transportation systems.

This first chapter "The Impact of High Speed Rail on Traffic Congestion" examines the impact of high-speed rail systems on highway congestion, using the case of South Korea. I use different strategies to address the endogeneity problem of evaluating the impact of transport infrastructure on traffic congestion. The results indicate that building high-speed rail lowers demand for intercity driving by 7.5\% to 30.9\%. However, the detailed data suggests that the reduction in congestion comes primarily from night time, during which high-speed trains do …

An Investigation Of Second-Site Non-Complementation Among Motile Cilia Genes In Chlamydomonas Reinhardtii, Gervette M. Penny

Arts & Sciences Electronic Theses and Dissertations

ABSTRACT OF THE DISSERTATIONAn Investigation of Second-Site Non-Complementation among Motile Cilia Genes in Chlamydomonas reinhardtii by Gervette M. Penny Doctor of Philosophy in Biology and Biomedical Sciences Molecular Genetics and Genomics Washington University in St. Louis, 2023 Professor Susan K. Dutcher, Chair

Motile cilia are complex microtubule-based organelles used by eukaryotic cells for locomotion or directing fluid flow. In humans, motile cilia defects cause primary ciliary dyskinesia (PCD), characterized by neonatal respiratory distress, recurrent lung infections, bronchiectasis, and low nitric oxide. Situs inversus and/or male infertility are present in about 50% of cases. PCD inheritance is recessive; both copies (alleles) …

Sources And Consequences Of Cell-To-Cell Variability In Gene Expression, Avinash Ramu

Arts & Sciences Electronic Theses and Dissertations

Gene expression is a stochastic process. A population of genetically identical cells grown in an identical environment can express different amounts of any given gene. This cell-to-cell variability in gene expression often underlies important phenotypic differences between cells. If we understand the sources of cell-to-cell variability in gene expression this can help uncover the mechanisms of transcription. The core of this thesis is split into two chapters related to cell-to-cell variability in gene expression. I first examine the sources and impact of cell-to-cell variability on a specific phenotype, a signaling pathway response. In the next chapter I discuss the results …

Characterizing The Significance Of Polya Tracks In Gene Regulation And Disease, Geralle Norlene Powell-Rodgers

Arts & Sciences Electronic Theses and Dissertations

The regulation of gene expression is essential for all domains of life. Control of gene expression occurs during each of the three steps of mRNA translation into protein. The fidelity and rate of the third step of translation, elongation, has been established as a key regulator of gene expression through its effects on mRNA stability and, thus, protein abundance. Consequently, studies focusing on factors that affect mRNA stability, including mRNA sequence composition and structure, have become integral to understanding the role of translational control in gene regulation. In Chapter 1, I discuss mechanisms of translational control, focusing on the gene …

Evaluating The Function Of Dnmt3a Mutations Associated With Acute Myeloid Leukemia And Dnmt3a Overgrowth Syndrome, Yang Li

Arts & Sciences Electronic Theses and Dissertations

Heterozygous loss-of-function mutations in the DNMT3A gene are the most common cause of clonal hematopoiesis, and among the most common initiating events for Acute Myeloid Leukemia (AML). Meanwhile, mutant DNMT3A cause an overgrowth syndrome, DNMT3A Overgrowth Syndrome (DOS, also known as Tatten-Brown-Rahmen syndrome, TBRS). Amino acid R882H mutation is the most frequent variance of DNMT3A, while the rest of the mutations spread out on the entire gene of DNMT3A. Over 70% of DNMT3A mutants cause loss of function change. A reduction of DNMT3A activity causes a canonical, focal hypomethylation phenotype in hematopoietic cells, which is associated with immortalization of hematopoietic …

The Role Of Ns1 In Flavivirus Immunity And Pathogenesis, Alex W. Wessel

Arts & Sciences Electronic Theses and Dissertations

ABSTRACT OF THE DISSERTATIONThe Role of NS1 in Flavivirus Immunity and Pathogenesis by Alex W. Wessel Doctor of Philosophy in Biology and Biomedical Sciences Immunology Washington University in St. Louis, 2023 Professor Michael Diamond, Chair Flaviviruses are a genus of enveloped, arthropod-transmitted RNA viruses that include clinically relevant pathogens such as yellow fever, dengue, Zika, and West Nile viruses. These viruses cause a spectrum of potentially life-threatening diseases including hepatitis, vascular shock, congenital abnormalities, and encephalitis. Dengue virus, alone, infects up to 390 million individuals in any given year, and its endemic regions continue to expand along with the geographical …

Three Essays On Public Attitudes Toward Federal Agencies, Zoe Ang

Arts & Sciences Electronic Theses and Dissertations

This dissertation is composed of three papers on public attitudes toward US federal agencies. In the first, entitled ``Political Influences of Public Attitudes toward Federal Agencies,'' I argue that individuals rely on agency-adjacent political information to form their attitudes because bureaucratic politics are relatively low-salience and individuals hold little specific knowledge with which to evaluate agencies. Using nationally representative surveys administered from 2007 to 2018, I find that individuals rely on political information to evaluate agencies. Copartisanship with the president and one's ideology, and to a lesser extent partisanship, influence attitudes toward agencies; this effect persists over time but varies …

Experimental Investigation Of Non-Hermiticity In Quantum Systems, Maryam Abbasi

Arts & Sciences Electronic Theses and Dissertations

The investigation of quantum systems in experimental setups involves interaction with the environment, which introduces channels of dissipation. These systems can be described by a non-Hermitian Hamiltonian, capturing the effect of gain and loss. Realizing these systems in classical cases demonstrates interesting phenomena such as topological features in the optical and mechanical domain, energy transfer, and enhancement in sensing. The primary focus of this thesis is the realization of the non-Hermiticity in a quantum system. To accomplish this, we harness multiple energy levels of an anharmonic superconducting circuit with coupling to an engineered bath to investigate the static and dynamic …

Bioinformatic Tools To Alleviate The Annotation Bottleneck Within Precision Oncology, Erica Kay Barnell

Arts & Sciences Electronic Theses and Dissertations

In the era of advanced ability to perform complex genomic sequencing, precision oncology has been adopted as the ideal paradigm for optimization of outcomes for patients with cancer. However, despite technological advances in all aspects of the massively parallel sequencing pipeline, the application of precision oncology to every clinical workflow has been unattainable. Suboptimal adoption of custom medicine within oncology is attributable to the annotation bottleneck, which currently demands inordinate manual and computational requirements for completion. Alleviation of the annotation bottleneck requires co-development of bioinformatic strategies and analysis knowledgebanks to automate variant identification and variant annotation for clinical utility. The …

Inflammation And Reward-Related Neural And Behavioral Phenotypes, Erin Bondy

Arts & Sciences Electronic Theses and Dissertations

Anhedonia transcends psychiatric diagnostic boundaries (e.g., depression, schizophrenia, PTSD) and is a marker of severe dysfunction and treatment resistance. Convergent evidence from non-human animal models and initial human studies suggests that elevated inflammatory signaling may induce anhedonia. However, the mechanisms underlying this association and the specific forms of reward processing that may be affected remain largely unknown. Here, two studies were conducted examining whether variability in reward-related brain measures and behavior may plausibly contribute to inflammation-related differences in reward processing. In the first study, data from children of European American ancestry of the Adolescent Brain Cognitive Development (ABCD) study of …

Dissecting Tau Isoform Control And Modeling Tauopathies In Directly-Reprogrammed Neurons, Lucia Capano

Arts & Sciences Electronic Theses and Dissertations

Tauopathies are a family of neurodegenerative disorders whose pathology include intracellular tau aggregates, synaptic dysfunction, and neuronal death. Advanced age is the strongest risk factor for developing a tauopathy, independent of a predisposing mutation, therefore the ability to study tauopathies in adult human neurons is vital to understand the age-associated changes which underly disease onset. Tau, the protein product of the gene Microtubule Associated Protein Tau (MAPT), is expressed highly in neurons. There are six tau isoforms whose splicing control and expression is both developmentally and tightly regulated, with only one isoform expressed in fetal brain and all six expressed …

The Role Of The Neurodevelopmental Disorder Gene Myt1l In Mammalian Brain Development, Jiayang Chen

Arts & Sciences Electronic Theses and Dissertations

Recent human genetic studies have associated mutations in a gene called Myelin Transcription Factor 1 Like (MYT1L) with neurodevelopmental disorders (NDDs). Patients with MYT1L loss of function (LoF) mutations (MYT1L Syndrome patients) demonstrate shared symptoms such as microcephaly, attention deficit and hyperactivity disorder (ADHD), and obesity. Despite prior studies showing MYT1L overexpression facilitates neuronal differentiation in vitro, its functions in vivo, especially in the mammalian brain, and how its mutation leads to human disease pathology remains poorly understood. Here, I established the first mouse model of MYT1L Syndrome mimicking a patient specific LoF mutation. I found mice with Myt1l heterozygous …

Non-Adjacent Anti Cyclobutane Pyrimidine Dimers As Intrinsic Probes Of Non-B Form Secondary Structures Of Dna, Natalia Eugenia Gutierrez Bayona

Arts & Sciences Electronic Theses and Dissertations

G-quadruplexes are four-stranded structures of DNA composed of G-quartets that have been proposed to play an extremely important role in replication, transcription, and translation. It has, however, been extremely difficult to unequivocally demonstrate that G-quadruplexes form in living cells due to the lack of probes that would allow for their unambiguous detection and location without disrupting the DNA or the cellular environment. To circumvent these problems, it was proposed that DNA itself could be used as an intrinsic photoprobe for certain classes of G-quadruplex structures and other non-B DNA conformations in vivo. Recently, we discovered that UVB irradiation of human …