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Full-Text Articles in Biology

The Role Of The Neurodevelopmental Disorder Gene Myt1l In Mammalian Brain Development, Jiayang Chen May 2023

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

Arts & Sciences Graduate Student 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 …

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Wide-Field Optical Imaging Of Neurological Disorders And Sleep In Mice, Lindsey M. Brier May 2023

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) …

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Improving Neoantigen Prioritization Methods For Personalized Cancer Vaccines, Huiming Xia May 2023

Improving Neoantigen Prioritization Methods For Personalized Cancer Vaccines, Huiming Xia

Arts & Sciences Graduate Student Theses and Dissertations

Neoantigens are novel peptide sequences resulting from sources such as somatic mutations in tumors. Upon loading onto major histocompatibility complex (MHC) molecules, they can trigger recognition by T cells. Neoantigen targeting therapies including personalized vaccines have shown promise in the treatment of cancers, particularly when used in combination with checkpoint blockade therapy. Thus, accurate identification and prioritization of neoantigens is critical for conducting neoantigen-based clinical trials, predicting treatment response, and understanding mechanisms of resistance. With the advent of whole exome and RNA sequencing technologies, researchers and clinicians are now able to computationally predict neoantigens based on patient-specific mutation information. However, …

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Identification And Characterization Of Targets Of Metastasis In High-Grade Serous Ovarian Cancer, Emilee Nicole Kotnik May 2023

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

Arts & Sciences Graduate Student 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)5 years). We compared somatic mutations, …

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Sources And Consequences Of Cell-To-Cell Variability In Gene Expression, Avinash Ramu May 2023

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

Arts & Sciences Graduate Student 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 …

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Assessment Of Cross-Protective Responses To Emerging Variant Viruses, Rita Elaine Chen May 2023

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 …

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Understanding Thermotolerance In Photosynthetic Cells: From Green Algae To Land Plants, Erin Marie Mattoon May 2023

Understanding Thermotolerance In Photosynthetic Cells: From Green Algae To Land Plants, Erin Marie Mattoon

Arts & Sciences Graduate Student Theses and Dissertations

Global temperatures are increasing, causing damage to crop plants, algae, and reducing food and biofuel production. To meet increasing demand for food and energy, we must engineer thermotolerant crops and algae that will thrive in the increasingly warm environment. However, there are many things we do not understand about how photosynthetic cells cope with high temperatures. Primarily, we do not fully understand which genes are required for thermotolerance and how different intensities and durations of high temperature periods may change this list. In this thesis, I employed high-throughput, quantitative, and genomic approaches including transcriptomics, proteomics, and genome-wide pooled mutant screens …

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Maternal-Fetal Circadian Communication During Pregnancy, Keenan Bates May 2023

Maternal-Fetal Circadian Communication During Pregnancy, Keenan Bates

Arts & Sciences Graduate Student Theses and Dissertations

Circadian rhythms in gene expression and hormones are ubiquitous across species and across cell types. Circadian rhythms depend on a transcription-translation negative feedback loop that drives many daily rhythms in behavior and physiological processes. Circadian rhythms regulate many aspects of reproduction, such as fetal development and birth timing. Mammalian pregnancy presents a unique situation with circadian rhythms in the mom and, eventually, in the fetus. Prior studies showed that circadian rhythms develop in utero and that maternal signals, such as glucocorticoids, may act to entrain or drive daily rhythms in the fetus. However, there remains considerable debate about when and …

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Dissecting Tau Isoform Control And Modeling Tauopathies In Directly-Reprogrammed Neurons, Lucia Capano May 2023

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

Arts & Sciences Graduate Student 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 …

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Identifying The Molecular Fate Logic Underlying Direct Neuronal Conversion, Kitra Cates May 2023

Identifying The Molecular Fate Logic Underlying Direct Neuronal Conversion, Kitra Cates

Arts & Sciences Graduate Student Theses and Dissertations

The development of techniques to model adult-onset neurodegeneration are increasingly important as the global aging population rises. Neurodegenerative disease modeling using cellular reprogramming requires the generation of neurons that recapitulate molecular signatures of neuronal cell identity, maturity, and pathogenesis. Ectopic expression of microRNAs-9/9* and microRNA-124 (miR-9/9*-124) directly convert human adult dermal fibroblasts (hDF) into microRNA-induced neurons (miN). This direct conversion provides a platform to study adult-onset neurodegeneration, as it bypasses pluripotency and maintains molecular age-associated properties of patient-derived cells. In coordination with transcription factors, miR-9/9*-124 reprogramming can generate subtype-specific neurons, which can be used for the study of genetic processes …

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Multi-Scalar Contributions To Sex Differences In Brain Tumor Incidence And Outcome, Lauren Broestl May 2023

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, …

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Wild Plant–Pathogen Interactions Across Gradients Of Urbanization And Latitude, Quinn N. Fox May 2023

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 …

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Restoring The Mechanoresponsiveness Of Aged Bone To Mechanical Loading, Christopher John Chermside-Scabbo May 2023

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 …

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Leveraging Protein Dynamics To Drug Filovirus Protein-Nucleic Acid Interactions Using Simulations And Experiments, Matthew Alberto Cruz May 2023

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 …

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Zfp36 Family-Mediated Post-Transcriptional And Bhlhe40-Mediated Transcriptional Regulation Of T Cell Responses, Melissa Erin Cook May 2023

Zfp36 Family-Mediated Post-Transcriptional And Bhlhe40-Mediated Transcriptional Regulation Of T Cell Responses, Melissa Erin Cook

Arts & Sciences Graduate Student Theses and Dissertations

T cells are potent immune responders and cytokine producers. Appropriate regulation of T cell-derived cytokines is needed to allow enough production to coordinate immune responses but restrict excessive production to limit tissue damage. Herein, we explore post-transcriptional and transcriptional control of T cell cytokine production in multiple contexts. We find that during homeostasis, CD4+ and CD8+ T cells require the collective functions of the ZFP36 family of RNA-binding proteins (ZFP36, ZFP36L1, and ZFP36L2) to negatively cytokine production. Triple deletion of ZFP36 family members exclusively in T cells results in a spontaneous and lethal autoinflammatory syndrome not present when deleting any …

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Individual And Social Influences On Cigarette Smoking During Pregnancy, Alexandra Noel Houston-Ludlam May 2023

Individual And Social Influences On Cigarette Smoking During Pregnancy, Alexandra Noel Houston-Ludlam

Arts & Sciences Graduate Student Theses and Dissertations

Population-level trends on sociodemographic risk factors for cigarette smoking during pregnancy (SDP) and outcomes for offspring exposed to maternal SDP are well established. However, the more complex task of understanding individual risk-prediction, including differences by maternal race/ethnicity, and its clinical application, remains incomplete. Characterizing the relative influence of environmental and individual characteristics as risk or protective factors for continued SDP is a necessary next step for informing individual- and public health-level interventions to produce successful smoking cessation prior to pregnancy, substantially reducing smoking-related mortality in child-bearing people. In this dissertation, I wanted to explore how multiple levels of influence, from …

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The Microbes Within: Pathogen In-Host Adaptation And The Gut Microbiome During Persistent Colonization And Recurrent Infection, Joohee Choi May 2023

The Microbes Within: Pathogen In-Host Adaptation And The Gut Microbiome During Persistent Colonization And Recurrent Infection, Joohee Choi

Arts & Sciences Graduate Student Theses and Dissertations

Microbes not just surround us; they are inside of us. The gut microbiome has emerged in recent years as an important modulator of health and is thought to have co-evolved with us throughout evolutionary history. On the other hand, our immune systems are constantly surveilling and battling infection by external pathogens— some of which still manage to evade our immune response and colonize our bodies long-term. In this Thesis, I investigated microbes inhabiting our bodies in various contexts to understand their impact on human health.In Chapter 2, I discuss the effects of fecal microbiome transplant (FMT) study drug RBX2660 on …

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Circumventing Drug Resistance With Small Molecule Inhibitors Of Mycobacterium Tuberculosis, Gregory Alexander Harrison May 2023

Circumventing Drug Resistance With Small Molecule Inhibitors Of Mycobacterium Tuberculosis, Gregory Alexander Harrison

Arts & Sciences Graduate Student Theses and Dissertations

The disease tuberculosis caused by Mycobacterium tuberculosis (Mtb) remains a global health threat, and the antibiotic resistance crisis challenges our ability to treat Mtb infections. For example, out of the approximately 10 million cases of tuberculosis each year, an estimated 10.7% of new cases and 27.2% of previously treated cases are resistant to the frontline antibiotic isoniazid (INH). There is a clear need for new therapies that enhance our current regimen and target these genetically resistant strains.Identifying ways to enhance the antimicrobial activity of INH has the potential to significantly improve the efficacy of frontline treatment regimens. To this end, …

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Function And Regulation Of Virulence-Associated Siderophores In Uropathogenic Enterobacterales, James Robert Heffernan May 2023

Function And Regulation Of Virulence-Associated Siderophores In Uropathogenic Enterobacterales, James Robert Heffernan

Arts & Sciences Graduate Student Theses and Dissertations

Siderophores are small molecules created by fungi and bacterial cells to help obtain iron. This may extend to cells in iron-limiting environments within host organisms. Certain siderophores are associated with increased virulence in urinary tract infections (UTIs). Siderophore system activity is typically regulated by feedback inhibition via ferric uptake regulator (Fur) which, in the presence of cytosolic iron, binds to a ~19 base pair inverted DNA repeat (9-1-9) called a Fur box. Once bound to this motif, the iron-Fur complex suppresses siderophore expression when adequate bacterial iron status is achieved. Many organisms produce more than one siderophore, and in the …

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Zebrafish Swim Capacity, Gait, And Posture During Innate Spinal Cord Repair, Nicholas Oliver Jensen May 2023

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 …

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Ribosomes As Sensors: How Cells Utilize The Translational Process To Monitor Cellular Conditions, Kyusik Q. Kim May 2023

Ribosomes As Sensors: How Cells Utilize The Translational Process To Monitor Cellular Conditions, Kyusik Q. Kim

Arts & Sciences Graduate Student Theses and Dissertations

The discovery that collisions between ribosomes are the key signaling event that triggers quality control and stress response pathways in eukaryotes has changed our understanding of how cells sense and respond to the environment. Collided eukaryotic ribosomes adopt a unique structure, providing a mechanistic basis for how environmental signals can be sensed by the translational machinery and propagated into wider reprogramming of gene expression. Indeed, the use of ribosomes as a signaling hub is quite apt, as ribosomes make intimate contact with both mRNA and tRNAs. This enables them to monitor the integrity of genetic information coming from the nucleus …

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Identification And Characterization Of Targets Of Metastasis In High-Grade Serous Ovarian Cancer, Emilee Nicole Kotnik May 2023

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

Arts & Sciences Graduate Student 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 …

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Iterative Machine Learning Of A Cis-Regulatory Grammar, Ryan Z. Friedman May 2023

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 …

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Multi-Omics Understanding Of Heterogeneity, Progression, And Therapeutic Vulnerabilities In Kidney Disease And Cancer, Yize Li May 2023

Multi-Omics Understanding Of Heterogeneity, Progression, And Therapeutic Vulnerabilities In Kidney Disease And Cancer, Yize Li

Arts & Sciences Graduate Student Theses and Dissertations

Kidney disease and cancer are both highly heterogeneous diseases, meaning that they exhibit significant variability in their underlying causes, mechanisms, progression, and responses to therapy. Traditional approaches to studying these diseases have focused on individual molecular or cellular pathways, which can provide limited information on the complexity of the disease. By combining multi-omics technologies, we can gain a more comprehensive understanding of the molecular and cellular changes that occur in kidney disease and cancer and identify new therapeutic targets and personalized treatment options.As a kidney disease, clear cell renal cell carcinomas (ccRCCs) represent ~75% of RCC cases and account for …

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Fluorescent-Based Approaches For Quantifying Bacterial Transcription Initiation Kinetics, Drake Jensen May 2023

Fluorescent-Based Approaches For Quantifying Bacterial Transcription Initiation Kinetics, Drake Jensen

Arts & Sciences Graduate Student Theses and Dissertations

All cellular life depends on the precise regulation of its genome to adapt to environmental changes. This thesis focuses on exploring gene expression mechanisms at the level of transcription. Transcription is the process in which the enzyme RNA polymerase (RNAP) uses DNA as a template to generate nascent RNA. RNAP first binds to a regulatory sequence within the DNA called a promoter. The combined processes that occur at the promoter define transcription initiation, including promoter binding, promoter opening around the transcription start site, and initial synthesis of short RNA transcripts. Once RNAP escapes the promoter, it elongates the initial RNA …

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Circadian Protein Bmal1 Regulates Astrocyte Activation And Protein Degradation In Health And Disease, Celia Augusta Mckee May 2023

Circadian Protein Bmal1 Regulates Astrocyte Activation And Protein Degradation In Health And Disease, Celia Augusta Mckee

Arts & Sciences Graduate Student Theses and Dissertations

The circadian clock regulates gene transcription to control daily rhythms in cellular function, behavior, and disease. Circadian dysfunction is a symptom of aging and neurodegenerative diseases, and recent studies suggest reciprocal regulation between impaired clock function and neurodegeneration. In addition to the clock regulating neuronal activity, non-neuronal glia cells of the brain also possess functional circadian clocks which control their responses to daily oscillations in brain activity, cellular stress, and metabolism. Astrocytes directly support brain function through synaptic interactions, neuronal metabolic support, neuroinflammatory regulation, and control of neurovascular coupling at blood and cerebrospinal fluid (CSF) barriers. Emerging evidence suggests that …

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The Effect Of Oxytocin Receptor Genetic Variants On Oxytocin Response, Manasi Malik May 2023

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 …

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The Role Of Mavs And Interferon-Lambda In Regulating Astrovirus And Norovirus Infections, Heyde Makimaa May 2023

The Role Of Mavs And Interferon-Lambda In Regulating Astrovirus And Norovirus Infections, Heyde Makimaa

Arts & Sciences Graduate Student Theses and Dissertations

Although they globally cause viral gastroenteritis in children, astroviruses are understudied due to the lack of well-defined animal models. While muAstVs chronically infect immunodeficient mice, a culture system and understanding of their pathogenesis is lacking. Here, we describe a platform to cultivate muAstV using air–liquid interface (ALI) cultures derived from mouse enteroids, which support apical infection and release. Chronic muAstV infection occurs in the small intestine and correlates with higher IFN-λ expression. MuAstV stimulates IFN-λ production in ALI, recapitulating our in vivo findings. We demonstrate that goblet cells and enterocytes are targets for chronic muAstV infection in vivo, and that …

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Examining Therapeutic Targets For Central Nervous System Autoimmune Disease, Sindhu Manivasagam May 2023

Examining Therapeutic Targets For Central Nervous System Autoimmune Disease, Sindhu Manivasagam

Arts & Sciences Graduate Student Theses and Dissertations

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) that leads to demyelination, axonal damage, and neuronal loss. Patients are typically diagnosed early in adulthood and due to the chronic nature of the disease, will continue to develop symptoms over their lifetime. Currently available therapeutics for MS focus on symptomatic relief and reduce severity of relapses; however, they are unable to prevent disease progression or promote recovery. Therefore, there is a critical need to understand the biological mechanisms driving neuroinflammatory and neurodegenerative processes in MS and to translate these findings into novel therapeutic strategies.Here we …

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Development Of Myelin In Wolfram Syndrome, Olga Reine Neyman May 2023

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 …

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