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Wide-Field Optical Imaging Of Neurological Disorders And Sleep In Mice, Lindsey M. Brier

Arts & Sciences Graduate Student Theses and Dissertations

Neuroimaging has revolutionized the way in which we understand the hierarchical organization of the amazingly complex, interconnected human brain. Neuroimaging techniques, like functional magnetic resonance imaging (fMRI), have provided high quality structural and functional data, providing multiple in-depth analyses and biomarkers of disease processes. In animal models, mechanistic studies can uncover root pathologies that aren’t explorable in humans. In mice, brain functional connectivity (FC) can be measured via Optical Intrinsic Signal (OIS) imaging – a modality that measures vascular reactivity as a surrogate for neural activity via quantification of fluctuations in oxygenated-hemoglobin (similar to the blood oxygen level dependent (BOLD) …

Histamine Production By Airway Resident Haemophilus Species Induces Rhinitis, Michael Lint

Arts & Sciences Graduate Student Theses and Dissertations

Allergic rhinitis is one of the most common chronic illnesses in America, affecting more than 60 million people each year. Allergies develop when sensitization to an environmental allergen result in the production of antigen-specific IgE. Subsequent exposure to the allergen, detected by IgE, then binds to the surface of mast cells triggering the release of inflammatory mediators particularly histamine, which contribute to characteristic allergic symptoms of nasal itching, sneezing, and wheezing. Although fundamental mechanisms underlying allergy development have been previously characterized, recent research has implicated commensal bacteria residing in the respiratory tract in contributing to the development of allergic inflammation, …

The Influence Of The Gut Microbiota On Asthma In School-Aged Children And Adults, Naomi Grace Wilson

Arts & Sciences Graduate Student Theses and Dissertations

Asthma is a common respiratory disease with a highly heterogeneous pathophysiology. The human gut microbiota, comprising of all the microorganisms that inhabit the gastrointestinal tract, is linked to the development of asthma and can alter airway inflammation in animal models. The idea that the gut microbiota can have bidirectional cross-talk with the lung, such as gut dysbiosis affecting lung disease, is termed the gut-lung axis. While the gut microbiota of early life has been an area of particular interest for asthma pathogenesis research, the effect of its taxonomic and functional composition after asthma diagnosis is less clear. This dissertation employs …

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

Arts & Sciences Graduate Student 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 …

Understanding The Spectrum Of Dnmt3a Mutations In Neurodevelopmental Disease, Diana Christian Beard

Arts & Sciences Graduate Student Theses and Dissertations

Epigenetic mechanisms are critical for precisely controlling gene expression programs to allow for the development and function of the brain, and disruptions of these processes are highly associated with neurodevelopmental disease. DNA methylation is one mechanism used to regulate gene expression, and neurons employ a unique form of DNA methylation particularly at CA dinucleotides (mCA), that is not widely observed in other somatic cell types. The DNA methyltransferase DNMT3A is required to establish mCA, and mutations in DNMT3A are associated with autism spectrum disorder (ASD) and an overgrowth and intellectual disability disorder called Tatton-Brown Rahman Syndrome (TBRS). However, it remains …

Mechanisms And Consequences Of Microtubule-Based Symmetry Breaking In Plant Roots, Natasha Anriel Bilkey

Arts & Sciences Graduate Student Theses and Dissertations

Directional growth in plants is primarily determined by the axis of cell expansion, which is specified by the net orientation of cortical microtubules. Microtubules guide the deposition of cellulose and other cell wall materials. In rapidly elongating cells, transversely oriented microtubules create material anisotropy in the cell wall that prevents radial cell expansion, channeling cell expansion in the longitudinal direction. Mutations perturbing microtubule organization frequently lead to aberrant cell growth in land plants, with some mutations leading to helical growth patterns (called ‘twisted mutants’), often in roots. This phenotype manifests as right-handed or left-handed twisting of cell files along the …

Zebrafish Swim Capacity, Gait, And Posture During Innate Spinal Cord Repair, Nicholas Oliver Jensen

Arts & Sciences Graduate Student Theses and Dissertations

Adult zebrafish are capable of anatomical and functional recovery following severe spinal cord injury. Significant advances for understanding the cellular and molecular mechanisms of innate spinal cord repair are best supported by accurate assessment of swim function. This study introduces neuromuscular-associated measurements derived from gait and posture, compares new and classical functional measurements longitudinally, and provides a comprehensive correlative analysis of various functional and cellular regeneration outputs. It also explores trajectories of functional regeneration through tensor decomposition and demonstrates that swim function at 2 weeks post-injury can be used to predict 8-week regeneration outcomes. By establishing swim quality metrics which …

The Effect Of Oxytocin Receptor Genetic Variants On Oxytocin Response, Manasi Malik

Arts & Sciences Graduate Student Theses and Dissertations

Oxytocin is a nonapeptide hormone that modulates social behavior, mediates the lactation reflex, and induces and strengthens uterine contractions. Each year, oxytocin is administered to about half of laboring patients for induction and augmentation, and to almost all patients for prevention of post-partum hemorrhage – a total of four million patients per year in the United States alone. However, response to oxytocin varies widely between individuals, and complications including uterine hyperstimulation, uterine atony, required Cesarean section, and postpartum hemorrhage can arise from either excessive or inadequate oxytocin response. To avoid these adverse events, it is critically important to identify individuals …

Spike-Timing-Dependent Plasticity Alters Sensory Network Connectivity, Adalee Lube

Arts & Sciences Graduate Student Theses and Dissertations

A fundamental question in neuroscience is: how does a sensory system optimize detection of behaviorally relevant stimuli, when those stimuli and the sensory environment are constantly changing? Spike-timing-dependent plasticity (STDP), in which synapse strength changes based on the relative timing of pre- and post-synaptic spiking, has been implicated in changes in neuronal connectivity thought to underlie learning and memory. Synaptic strength changes caused by STDP have been shown in optic tectum, visual cortex, hippocampus, and other brain regions in vitro across many organisms like fish, frogs, and mice. Although it is possible that STDP mechanisms underlie changes in sensory neuron …

Wild Plant–Pathogen Interactions Across Gradients Of Urbanization And Latitude, Quinn N. Fox

Arts & Sciences Graduate Student Theses and Dissertations

In light of large-scale urbanization and rising global temperatures, it is essential to understand how environmental and climatic changes impact the ecology and evolution of species interactions. This thesis investigates interactions between wild plants and their pathogens across gradients in land use and latitude, and specifically tests the effects of multiple scales of climate variation on such interactions. In this work, I focused on a system of common herbaceous plants in the genus Plantago and their fungal powdery mildew pathogens. I studied their interactions across an urbanization gradient transecting the metropolitan area of St. Louis, Missouri and along a latitudinal …

Development Of Myelin In Wolfram Syndrome, Olga Reine Neyman

Arts & Sciences Graduate Student Theses and Dissertations

Wolfram syndrome is a rare, autosomal recessive disease traditionally characterized by juvenile onset insulin dependent diabetes, optic atrophy, deafness, and neurodegeneration often beginning in childhood and adolescence. The disease is caused by mutations in WFS1, which encodes for the protein wolframin and is associated with endoplasmic (ER) stress-mediated apoptosis. ER stress-related dysfunction may inhibit production of myelin during neurodevelopment in Wolfram syndrome, as active and developing oligodendrocytes are more vulnerable to ER stress than mature ones. It is known that white matter tracts are compromised in the disease, but many questions related to the vulnerability of myelin and its impact …

The Effects Of Aluminum Ion Exposure On Planarian Photophobic Response To Different Wavelengths Of Light, Anden J. Velez

Graduate Student Dissertations, Theses, Capstones, and Portfolios

Aluminum exposure has been linked to the development of neurological diseases (Kim et al., 2021). It has increased in quantity in the environment due to industrial activity in producing personal care products and fast food (Tietz et al., 2019). The freshwater invertebrate planarian flatworm Giardia dorotocephala (G. dorotocephala) serves as a model organism. Humans and planarians both express the ion channel transient receptor potential ankyrin 1 (TRPA1), which is responsible for thermotaxis, locomotive response to heat, and pain reception (Arenas et al., 2017). Aluminum exposure can exert ion channel-related toxicity via the TRPA1 protein. It has been found …

Evaluating The Impact Of Temperature And Artificial Light At Night On The Growth, Swimming Performance, And Corticosterone Levels Of Southern Leopard Frog (Lithobates Sphenocephalus) Tadpoles, Skylar Alexander

Honors Theses

Anthropogenic activities caused by urbanization have considerably altered our world’s ecosystems which has led to a global amphibian population decline. Encroaching and unyielding urbanization by humans has contributed to a rise in artificial light at night due to light pollution as well as increased temperature due to climate change. Both rising temperatures and artificial light at night (ALAN) have been shown to individually have negative effects on amphibian physiology such as increased stress and decreased behavior. However, due to the drastic nature of human imposition, amphibians typically encounter these anthropogenic stressors in combination. Therefore, it is important to understand how …

Multi-Scalar Contributions To Sex Differences In Brain Tumor Incidence And Outcome, Lauren Broestl

Arts & Sciences Graduate Student Theses and Dissertations

Nearly all complex human diseases exhibit some degree of sex difference in incidence, age of onset, disease severity, and/or response to treatment. Sex differences are observed in a wide range of nervous system disorders, including neurodevelopmental disorders, psychiatric diseases, neuroimmunological disorders, neurodegenerative diseases, and central nervous system (CNS) tumors. Males have increased incidence rates for most CNS tumor types. Sex differences in brain tumor incidence rates are observed in studies from around the world, across a wide range of cultures, in both pediatric and adult populations, and even extend to other species. Males also have decreased survival from brain tumors, …

Assessment Of Cross-Protective Responses To Emerging Variant Viruses, Rita Elaine Chen

Arts & Sciences Graduate Student Theses and Dissertations

Viruses pose a great threat to human health. Outbreaks and pandemics due to different viruses occur in all areas of the world. Two viruses, which emerged globally in the 1980s and in 2020, that are still causing ongoing pandemics in 2021 are dengue virus (DENV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respectively. These viruses circulate widely and currently infect hundreds of millions of people. Immunity from a previous infection may confer protection against subsequent infection of a related virus. Thus, understanding the degree of cross-protection can help define correlates of protection that are necessary to determine which people …

Leveraging Protein Dynamics To Drug Filovirus Protein-Nucleic Acid Interactions Using Simulations And Experiments, Matthew Alberto Cruz

Arts & Sciences Graduate Student Theses and Dissertations

Drug discovery targeting protein nucleic acid (PNI) and protein-protein interactions (PPI) remains a difficult task. How to identify druggable conformations and discover compounds binding to these conformations is an unsolved problem. Here, I describe how we apply computational and experimental approaches to probe the conformational landscape of a key immune antagonist protein from the Zaire ebolavirus. Viral Protein 35 (VP35) binds to the viral pathogen associated molecular pattern, double stranded RNA (dsRNA), and blocks activation of the interferon (IFN) response. Long time scale molecular dynamics simulations reveal that VP35 adopts an alternative conformation which opens a pocket absent in experimental …

Restoring The Mechanoresponsiveness Of Aged Bone To Mechanical Loading, Christopher John Chermside-Scabbo

Arts & Sciences Graduate Student Theses and Dissertations

Osteoporosis—a disease of low bone mass and a predisposition to fracture—remains a pressing public health burden. Osteoporotic fractures occur in 1 in 3 women and 1 in 5 men over the age of 50, at a cost of more than $22 billion annually in the US. To prevent osteoporotic fractures, we need additional strategies to increase bone formation and reverse the disease. A potent strategy to increase bone formation is mechanical loading. However, with aging, bone becomes less responsive to the same stimulus. Because we do not fully understand the age-related decrease in bone mechanoresponsiveness, we have been unable to …

Immunity To Emerging Rna Viruses, Emma Winkler

Arts & Sciences Graduate Student Theses and Dissertations

In the past decade, newly emerged and re-emerged pathogenic RNA viruses such as Ebola, H1N1, and Zika virus have become substantial threats to global health. Two notable examples include the explosive re-appearance of chikungunya virus in the 2000s in Asia and the Western Hemisphere and, more recently, the global COVID-19 pandemic. Therefore, an improved understanding of immunity to emerging RNA viruses is critical for defining host susceptibility and restriction factors to viral infection as well as appropriate vaccine and antiviral therapeutic design. Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that is maintained in an urban epidemic transmission cycle. While most …

An Evolving View Of Host-Microbiome Co-Development In Healthy And Undernourished Children, Robert Yuzen Chen

Arts & Sciences Graduate Student Theses and Dissertations

Affecting more than 795 million children under the age of 5, childhood undernutrition is one of the greatest impediments to the flourishing of humankind. Current dietary interventions fail to ameliorate many of the long-term sequelae of undernutrition, including immune system dysfunction, impaired vaccine responses, persistent central nervous system (CNS) dysfunction, and early mortality. These shortcomings suggest that our understanding of the biological state of undernutrition is incomplete, and that traditional food therapies fail to target key drivers of undernutrition-dependent pathologies. Recently, work from our lab has provided preclinical evidence demonstrating that impaired development of the distal gut microbiota plays a …

Iterative Machine Learning Of A Cis-Regulatory Grammar, Ryan Z. Friedman

Arts & Sciences Graduate Student Theses and Dissertations

Gene regulation allows for the quantitative control of gene expression. Gene regulation is a complex process encoded through cis-regulatory sequences, short DNA sequences containing clusters of transcription factor binding sites. Each binding site can occur millions of times in multicellular genomes, and seemingly similar collections of binding sites can have very different activities. A leading model to explain these degeneracies is that cis-regulatory sequences follow a “grammar” defined by the number, identity, strength, arrangement, and/or context of the underlying binding sites. Understanding cis-regulatory grammar requires high-throughput technology, quantitative measurements, and computational modeling. This thesis describes an iterative machine learning approach …

Cardiac Pericytes Mediate The Remodeling Response To Myocardial Infarction, Pearl Quijada, Shuin Park, Peng Zhao, Kamal Ss Kolluri, David Wong, Kevin D Shih, Kai Fang, Arash Pezhouman, Lingjun Wang, Ali Daraei, Matthew D Tran, Elle M Rathbun, Kimberly N Burgos Villar, Maria L Garcia-Hernandez, Thanh Td Pham, Charles J Lowenstein, M Luisa Iruela-Arispe, S Thomas Carmichael, Eric M Small, Reza Ardehali

Faculty, Staff and Students Publications

Despite the prevalence of pericytes in the microvasculature of the heart, their role during ischemia-induced remodeling remains unclear. We used multiple lineage-tracing mouse models and found that pericytes migrated to the injury site and expressed profibrotic genes, coinciding with increased vessel leakage after myocardial infarction (MI). Single-cell RNA-Seq of cardiac pericytes at various time points after MI revealed the temporally regulated induction of genes related to vascular permeability, extracellular matrix production, basement membrane degradation, and TGF-β signaling. Deleting TGF-β receptor 1 in chondroitin sulfate proteoglycan 4-expressing (Cspg4-expressing) cells reduced fibrosis following MI, leading to a transient improvement in the cardiac …

Assessment Of Natural Roost Availability And Artificial Roost Preference By Indiana Bats In Scott County, Kentucky, Shannon Kerry Howe

Online Theses and Dissertations

In addition to using natural roosts, Indiana bats (Myotis sodalis) form maternity colonies in artificial roosts such as rocket boxes and bark-mimic structures. However, few Indiana bat study systems contain multiple artificial roost types alongside natural roosting options. I sought to analyze roost use on a landscape with multiple roost types and determine the effects of reproductive condition on roost type and canopy closure selection. I also characterized the forest overstory composition and determined the quantity and quality of Indiana bat roosting habitat across the landscape. My field site was Veterans Memorial Wildlife Management Area (VMWMA) in Scott County, Kentucky, …

An Investigation Into Transcription Fidelity And Its Effects On C. Elegans And S. Cerevisiae Health And Longevity, Olivia S. Dinep-Schneider

Theses and Dissertations

mRNA molecules form an intermediate in the transfer of sequences from DNA to ribosomes in order to guide protein production. Errors can be introduced into mRNA, producing aberrant proteins which place a strain on cellular regulatory machinery, causing increased risks of apoptosis, cancer, and decreased fitness. These errors may be introduced due to decreased transcriptional proofreading capabilities, exposure to chemicals, or mistakes in RNA editing machinery. It is important to investigate these causes of transcription errors to better understand the long-neglected area of mRNA fidelity which has such significant impacts on our cellular functions. In this paper, it was determined …

Host-Acquired Virus Genes Support An Ancient Antiviral Role Of The Pirna Pathway In Dipterans, Rebecca Christian

Theses and Dissertations

Endogenous viral elements (EVEs) have been recently investigated as a source of transgenerational immune memory. These “viral fossils” are abundant in Aedes mosquitoes and partner with the host’s primary antiviral defense system, the RNA interference (RNAi) pathways. This partnership appears unique to mosquitoes, which encode an expansion of the Piwi endoribonucleases. To interrogate EVE-Piwi partnerships and their role in antiviral defense, I performed a comparative small RNA analysis of two naturally occurring EVE-virus pairs – one in the mosquito Aedes albopictus, and one in the midge Chaoborus americanus. Both express an EVE related to the nucleoprotein of their …

Locomotion And Life History In A Leaping Primate: Mechanics And Energetics Of Movement Throughout The Propithecus Lifespan, Nicholas Heslep

Masters Theses, 2020-current

Arboreal primates are typically altricial, exhibit long juvenile periods, and use dynamic locomotor behaviors that can be challenging and risky. Sifaka (Propithecus verreauxi) have particularly slow life histories for their size, with long juvenile periods, protracted reproductive careers, and long life spans. Slow somatic growth poses potential mechanical challenges for juvenile sifaka who use thigh-powered vertical clinging and leaping to follow group members during travel. I examined mechanical and energetic costs of movement in developing sifaka. I instrumented 8 wild sifaka (3 yearlings, 3 subadults, 2 adults) in 4 social groups with inertial sensors measuring tri-axial acceleration for …

The Response Of Microcystis And The Microbiome To Exogenous Hydrogen Peroxide, Bryan A. Puma

Masters Theses, 2020-current

Microcystis spp. produce prolific annual blooms in freshwater systems worldwide. The success of these blooms depends heavily on the Microcystis spp. overcoming environmental factors such as oxidative stress caused by reactive oxygen species (ROS) like hydrogen peroxide. Most Microcystis genomes do not contain many genes for responding to oxidative stress, including those that encode the enzyme catalase. Other cyanobacteria such as Prochlorococcus that also lack hydrogen peroxide degrading enzymes have been shown to benefit from partnerships with heterotrophic bacteria. Microcystis spp. may also receive similar benefits from heterotrophic bacteria in the phycosphere. To test this hypothesis, we examined the …

Characterizing The Effects Of Light On The Early Onset Photoreceptor Function Loss In Mucolipidosis Type Iv, Rebecca Cistulli

Masters Theses, 2020-current

Retinal degenerative diseases (RDD’s) are a diverse group of retinal disorders that cause visual impairment. While RDD prevalence is high, little is known about the molecular mechanisms underlying the pathogenesis within some of these disorders. Here we are trying to elucidate the molecular mechanisms that drive early onset photoreceptor function loss in the RDD, Mucolipidosis type IV (MLIV). MLIV is a lysosomal storage disorder that results from loss of function mutations in the MCOLN1 gene and leads to a disruption of autophagy. The MCOLN1 gene encodes a lysosomal cation channel called Trpml1. Based on previous data from our lab, we …

Understanding Context Dependent Responses To Climate Change In Arizona Tiger Salamanders (Ambystoma Mavortium Nebulosum), Kentrell Richardson

Masters Theses, 2020-current

Future emissions scenarios project climate change to increase average global temperatures by at least two ℃ in the next 50 years resulting in changes in local climate and causing increased variability within microclimates. Ectotherms are especially sensitive to climate change due to their dependence on environmental temperatures to regulate physiological functions. Changes in temperature are likely to impact thermally cued processes within amphibians and result in changes in variable magnitudes and directions within local populations.

Salamanders were placed in cups and partially submerged in a water bath and heated at a rate of ~0.27℃/ minute. Once salamanders were unable to …

Energy Homeostasis In An Extreme Vertebrate: Relationships Between Life-History Status And The Molecular Stress Response In Red-Sided Garter Snakes, Rysa Thomas

Masters Theses, 2020-current

Vertebrates experience diverse and unique life-history events, many of which are annual and energetically taxing. Energy is a limited resource and thus its careful budgeting is critical for successful transitions between life-history states and across the lifetime of a species. Glucocorticoids (GCs) regulate vertebrate energetics via partitioning of energy use and storage in metabolic tissues (liver, fat, muscle) and exert their effects through activation of two main receptor types, the glucocorticoid receptor (GR), responsible for mobilization of energy from storage tissues, and the mineralocorticoid receptor (MR), responsible for ion balance and osmotic homeostasis. Species adapted to extreme environments carefully balance …

Microglia Refine Early Multisensory Circuits In The Lateral Cortex Of The Inferior Colliculus In A Complement-Dependent Manner, Shaida Hamidi

Masters Theses, 2020-current

Microglia cells (MGCs), the resident macrophage of the brain, play a pivotal role in synaptic pruning of newly established circuits during early critical periods. Classical complement cascade signaling enables MGCs to identify unnecessary or underutilized contacts and specifically target them for removal and subsequent degradation. Such recognition and engulfment behaviors require receptor-ligand interactions, whereby “eat me” tags (complement component 3, C3) bind their cognate receptor (complement receptor 3, CR3) expressed on MGCs. Compromised complement signaling in certain systems results in under-pruning or unrefined map configurations, and is thought perhaps to underlie certain autism-related behavioral phenotypes (e.g. sensory hypersensitivities, decreased social …