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Genetic And Transcriptomic Aspects Of Major Depressive Disorder: In Vivo Functional Assays Of Risk-Associated Variation, Candidate Disease Cell Types, And Their Pharmacologic And Sex Interactions, Bernard Mulvey

Arts & Sciences Electronic Theses and Dissertations

Major depressive disorder (MDD) is a debilitating illness that affects hundreds of millions globally, with substantial personal, medical, economic, and societal consequences. While depression occurs more commonly in females, the biology of the brain and sex underlying this skewed prevalence remains unclarified. This body of work explores two aspects of how biological sex may influence the brain at the level of gene expression: through intrinsic sex differences and through sex-mediated effects of depression risk genetics.

The monoamine hypothesis of depression suggests that modulatory neurotransmitters including serotonin and norepinephrine constitute a key axis in development of MDD. Large-scale studies of MDD …

Understanding Control Of Metabolite Dynamics And Heterogeneity, Christopher John Hartline

McKelvey School of Engineering Theses & Dissertations

Microbes live in complex and continually changing environments. Rapid shifts in nutrient availability are a common challenge for microbes, and cause changes in intracellular metabolite levels. Microbial response to dynamic environments requires coordination of multiple levels of cellular machinery including gene expression and metabolite concentrations. This coordination is achieved through metabolic control systems, which sense metabolite concentrations and direct cellular activity in response. Several reoccurring control architectures are found throughout diverse metabolic systems, which suggests underlying evolutionary advantages for using these control systems to coordinate metabolism. One common, yet understudied, control architecture is the positive feedback metabolite uptake loop, which …

Ligand- And Strain-Specific Control Of Microbial Communities, Austin Grant Rottinghaus

McKelvey School of Engineering Theses & Dissertations

Microbes naturally coexist in complex, multi-strain communities that are valuable assets for their host. Commensal and probiotic microbes prevent pathogen colonization, reduce the frequency and severity of various ailments, provide essential nutrients, and offer various additional benefits. Understanding the dynamics of and tailoring microbial communities to provide additional beneficial functions is a primary focus of researchers in medicine and agriculture. To date, consortia have primarily been manipulated by supplementing the communities with microbes that were engineered in vitro or by introducing stimuli that alter the metabolism or composition of the community. This method has proven successful, with numerous microbes engineered …

Modeling, Analysis, And Simulation To Reveal The Mechanisms Of Ciliary Beating, Louis Woodhams

McKelvey School of Engineering Theses & Dissertations

Cilia are microscopic cellular appendages that help us breathe by clearing our airways, maintain the health of our central nervous system by circulating cerebrospinal fluid, and allow us to reproduce by transporting eggs and propelling sperm cells. Cilia even determine the asymmetry of our internal organs during embryonic development. However, the mechanisms underlying ciliary beating are not fully understood. Questions remain as to how arrays of the motor protein dynein generate the propulsive waveforms observed in cilia and how structural elements within the cilium and its connection to the cell deform during beating. In the current work, mathematical modeling, analysis, …

Development Of The Assessment Of Clinical Prediction Model Transportability (Apt) Checklist, Sean Chonghwan Yu

McKelvey School of Engineering Theses & Dissertations

Clinical Prediction Models (CPM) have long been used for Clinical Decision Support (CDS) initially based on simple clinical scoring systems, and increasingly based on complex machine learning models relying on large-scale Electronic Health Record (EHR) data. External implementation – or the application of CPMs on sites where it was not originally developed – is valuable as it reduces the need for redundant de novo CPM development, enables CPM usage by low resource organizations, facilitates external validation studies, and encourages collaborative development of CPMs. Further, adoption of externally developed CPMs has been facilitated by ongoing interoperability efforts in standards, policy, and …

Development Of Noninvasive Biomarkers For Cervical Spondylotic Myelopathy, Dinal Jayasekera

McKelvey School of Engineering Theses & Dissertations

Cervical spondylotic myelopathy (CSM) represents the most common cause of chronic spinal cord injury (SCI) in adults. Many patients with symptomatic CSM will experience a decline in neurological function and consequently undergo surgical decompression. Unfortunately, surgeons are unable to adequately counsel patients about the benefits of surgery because the natural history of disease and outcome after decompression vary widely among patients. This can hinder the decision-making capacity of patients and physicians. Therefore, we require additional tools to help guide therapy and counsel patients with CSM. Noninvasive biomarkers present valuable potential as predictors of a patient’s recovery in the long term. …

Role Of Ligand Architecture On Collective Cell Invasion, Amrit Bagchi

McKelvey School of Engineering Theses & Dissertations

Epithelial cell collectives utilize extra-cellular matrix (ECM) fibers to undergo collective migration critical in regeneration, repair and cancer metastasis. However, very little is known about the various factors which determine the ability of cellular collectives to utilize ECM fibers to undergo these critical processes in-vivo. First part of the dissertation focusses on understanding how cell collectives exploit specific properties, like stiffness and fiber length to undergo collective streaming. It is also unclear how cellular forces, cell-cell adhesion, and velocities are coordinated within streams. To independently tune stiffness and collagen fiber length, we developed new hydrogels and discovered invasion-like streaming of …

Mechanisms Of Primate Working Memory, Charles Damian Holmes

McKelvey School of Engineering Theses & Dissertations

One of the defining features of the behavior of many animal species is the ability to retain and utilize information from the environment even after it is gone. The encoding and utilization of information on short time scales is referred to as working memory. It is not yet fully understood how the brain accomplishes working memory.

This dissertation presents three studies that help to characterize the working memory system of primates. All three studies involve primates performing saccades during a spatial memory task. The first study demonstrates that while the local field potential power is contralaterally tuned (i.e., power is …

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 …

The Effects Of Host-Like Environmental Signals And Gene Expression On Capsule Growth In Cryptococcus Neoformans, Yu Min Jung

McKelvey School of Engineering Theses & Dissertations

Cryptococcus neoformans is a fungal pathogen that causes cryptococcosis, a disease that kills almost 200,000 people worldwide each year. A unique feature of this deadly yeast is its polysaccharide capsule, which is known to be associated with its virulence. Here, we systematically explore the effects of all possible combinations of 4 capsule-inducing signals on gene expression, cell size, and capsule size. These signals are medium (YPD, DMEM or RPMI), temperature (30°C or 37°C), CO₂ (room air or 5%), cAMP (0 mM or 20 mM), and pH buffer (HEPES/no HEPES). We explore the effects of exogenous cAMP at a range …

Anti-Amyloid Chimeric Antigen Receptor Macrophages For Alzheimer's Disease Immunotherapy, Qiuyun Pan

McKelvey School of Engineering Theses & Dissertations

Alzheimer’s disease is the most common cause of dementia. None of the available drugs can cure the disease. Chimeric Antigen Receptor (CAR) macrophages, because of their phagocytic activity, have potential as a cellular treatment for amyloid aggregation. In this study, we generated an anti-amyloid CAR hematopoietic progenitor cell line. By inducing the progenitor cell line to differentiate into macrophages, we show that the anti-amyloid CAR-Macrophage has enhanced specific phagocytic activity towards amyloid in in vitro experiments. In addition, in ex vivo experiments, anti-amyloid CAR significantly reduces the plaque load on brain slice from APP/PS1 mice when compared to a non-targeted …

Understanding The Role Of Involucrin In Skin Inflammation, Alina Schmidt

Arts & Sciences Electronic Theses and Dissertations

Terminally differentiated keratinocytes are essential for skin barrier function and are surrounded by an involucrin (IVL)-rich cornified envelope. Increased IVL expression in the epidermis is associated with recent positive selection in European populations, yet the functional significance of this finding is unclear. An upstream enhancer of IVL, the 923 enhancer, regulates IVL expression, and the impact of IVL enhancer variants on involucrin expression in modifying the penetrance of filaggrin (FLG) loss-of-function variants associated with atopic dermatitis (AD) has not been explored. I hypothesize involucrin to modulate the environmentally sensitive Vitamin D receptor (Vdr) activity in the epidermis and involucrin enhancer …

Multi-Omics Investigation Of Tumor Heterogeneity, Oncogenic Signaling, And Treatment Response In Human Cancers, Yige Wu

Arts & Sciences Electronic Theses and Dissertations

Cancer is a highly complex disease with aberrations at the genetic, epigenetic, transcriptomic, and protein levels that drove its phenotypic diversity. Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, comprising roughly 80% of cases. To define the epigenetic and transcriptomic regulation of ccRCC at the single nucleus (sn) level, we performed snRNA-seq and snATAC-seq in 34 and 28 samples respectively, including primary tumors and normal adjacent tissues, and matched them with bulk proteogenomics data. We identified tumor-specific markers and tumor subpopulations using snRNA-seq, which demonstrated diverse pathway activity within and across patients. PBRM1 and …

The Myriad Of Things: Paleoethnobotany Of The Chenopodium Album Aggregate In Northern China, Mana Hayashi Tang

Arts & Sciences Electronic Theses and Dissertations

Carbonized macrobotanical remains of the Chenopodium album aggregate (Amaranthaceae) are highly ubiquitous at archaeological sites. These chenopods are early successional plants and ruderals, which grow well in disturbed ecosystems, including those that they co-habit and co-create with humans. Often distinguished from known agricultural crops (e.g., rice, millet) as a weed, chenopods have received less attention in early food culture studies, despite their ethnohistory as a grain crop, vegetable, and famine food. Their seed remains in northern China exhibit regionally variable morphological attributes, different from those seen in chenopod cultivars of the Americas. Their morphological variability may be a result of …

Characterizing The Role Of Interferons In Host-Microbe Interactions In Disseminated Murine Norovirus Infection And Steady-State Hematopoiesis, Forrest Walker

Arts & Sciences Electronic Theses and Dissertations

Interferons are critical cytokines responsible for regulating host-microbe interactions in the context of infectious disease as well as homeostatic interactions with the host’s native microbiota. Although significant knowledge regarding the role of interferons in these interactions has been gained in the past sixty years, the diversity of microbes with which the host interacts and the plethora of interferons (with over twenty distinct cytokines organized into three types, based on their receptor utilization) which the host uses in these responses leads to a significant number of interactions which remain to be characterized. Here, we further dissect the role of interferons in …

Antigen Presentation In Central Nervous System Antitumor Immunity, Jay Aaron Bowman-Kirigin

Arts & Sciences Electronic Theses and Dissertations

Glioblastoma multiforme (GBM) patients face limited treatment options and poor outcomes. The median survival is less than two years, and there are no FDA approved immune therapies. Although GBM itself is an immune-suppressive, heterogeneous tumor, the lack of FDA approved immune therapies might be in part because the cancer immunity cycle is less well understood for GBM than for other tumor types. My studies focused on developing mouse models of malignant glioma that more faithfully recapitulate human GBM from an immunologic perspective, and on defining the role of the conventional dendritic cell 1 subset (cDC1) and lymphatic drainage in central …

Techniques For Spatial Analysis Of C. Elegans Anatomy And Reporter Expression, Nicolette Marie Laird

Arts & Sciences Electronic Theses and Dissertations

Quantitative analysis of microscopy images is integral to investigating biological phenomena. Despite a variety of tools to aid in analyzing C. elegans images, quantitative microscopy studies are still difficult due to the flexible and deformable nature of the nematode. These differences in posture and shape must first be corrected before analysis. Manual approaches to solve these problems are time intensive and infeasible for large datasets. Additionally, current automated tools rely on high-magnification imaging using labeled nuclei as fixed markers for comparison. Labelling can be achieved either with transgenic animals or fluorescent dyes; however, both of these can be impractical for …

Unraveling Population Heterogeneity Using Single-Cell Analysis, Wenjun Kong

Arts & Sciences Electronic Theses and Dissertations

The human body contains approximately 100 trillion cells, encompassing distinct cell types that serve diverse functions. Understanding cell population heterogeneity is vital for uncovering different biological functions and mechanisms. In addition, cells at transition during continual processes, such as development, reprogramming, and disease, are essential for painting the entire blueprint and highlighting critical stages of the progression trajectory. For instance, cell fate engineering holds much promise for generating clinically valuable cell types from mature somatic cells. Nonetheless, current reprogramming protocols are inefficient, and charting the changes in cell identity during such processes can help design strategies to mitigate the off-target …

Molecular Characterization Of Integrase-Rna Interactions And Their Role In The Replication Of Hiv-1 And Other Retroviruses, Christian Shema Mugisha

Arts & Sciences Electronic Theses and Dissertations

HIV-1 integrase (IN) enzyme has an emerging non-catalytic role in particle maturation, whichinvolves its binding to the viral genome in virions. Allosteric integrase inhibitors (ALLINIs) and class II integrase substitutions inhibit the binding of IN to the viral genome and cause formation of eccentric non-infectious HIV-1 particles. These viruses are characterized by the mislocalization of the viral ribonucleoprotein complexes between the translucent conical CA lattice and the viral lipid envelope. We have previously demonstrated that IN binding to the viral genome is mediated by basic residues within the C-terminal domain of IN. In the first chapter, we show how basic …

Assembly And Repair Of Photosystem Ii, Virginia M. Johnson

Arts & Sciences Electronic Theses and Dissertations

Photosystem II is a light-driven water-plastoquinone oxidoreductase present in cyanobacteria, plants, and algae. It is the photosynthetic membrane protein complex responsible for oxidizing water into molecular oxygen, which is necessary for life as we know it. As a multi-subunit membrane-protein-pigment complex, Photosystem II undergoes a complex cycle of assembly, damage, and repair called the Photosystem II lifecycle. This cycle must consistently occur to maintain a high level of photosynthetic activity at the cellular level. Cyanobacteria, oxygenic photosynthetic bacteria, are frequently used as model organisms to study oxygenic photosynthetic processes due to their ease of growth and genetic manipulation. Cyanobacterial PSII …

Mechanisms Of Voltage-Gated Sodium Channel (Nav1.5) Regulation By Intracellular Fgfs, Paweorn Angsutararux

McKelvey School of Engineering Theses & Dissertations

Voltage-gated sodium channels (NaV) conduct the inward current responsible for the initiation and propagation of the electrical signals in myocytes and neurons, known as action potentials (AP). Precise regulation of cardiac NaV1.5 opening and closing is essential for maintaining a normal heart beat. A disruption of NaV1.5 function, especially of its inactivation after opening, results in inherited cardiac arrhythmias such as Long QT Type 3 (LQT3) syndrome. This pathology is caused by an increase in the late INa that enters myocytes later in the AP and prolongs its duration. Late INa is also enhanced in acquired diseases such as heart …

The Role Of Soxe Transcription Factors In Melanoma Initiation, Eva Tulchinsky Kramer

Arts & Sciences Electronic Theses and Dissertations

Cutaneous melanoma, a cancer of transformed melanocytes, has the highest mortality rate among skin cancers and remains difficult to treat once metastasized. Melanoma is characterized by high genetic heterogeneity, implicating epigenetic dysfunction as an additional regulator of oncogenesis. Indeed, an increasing number of epigenetic modifiers and modifications have been identified in melanoma linked to faster melanoma onset, and then targeted with therapeutics with success. Thus, identifying and mechanistically characterizing these epigenetic and transcriptional alterations in melanoma will further our understanding of their contributions to oncogenesis and enable more diverse therapeutic options.

To evaluate global epigenetic and transcriptional differences between melanocytes …

T Cell Regulation Of Regenerative Environment In Acellular Nerve Allograft Repaired Peripheral Nerves, Deng Pan

Arts & Sciences Electronic Theses and Dissertations

Peripheral nerve injury (PNI) is common and has debilitating long term sequelae. Development of new therapies to improve regeneration following PNI is therefore critical. Acellular nerve allografts (ANAs) are increasingly utilized in the clinic for the repair of PNI and an improved mechanistic understanding of nerve regeneration through ANA is important for developing better therapies. Inflammation is an important aspect of regeneration, and the role of macrophage has been increasingly documented. Other aspect of inflammation has not been well-defined. In particular, there is limited understanding on the role of T cells in the regeneration of peripheral nerve. However, evidence in …

Defining The Role Of Rare Genetic Variants That Drive Risk And Pathogenesis Of Alzheimer’S Disease, Matthew James Rosene

Arts & Sciences Electronic Theses and Dissertations

Alzheimer’s disease (AD) is the leading cause of dementia and is pathologically defined by the aggregation of extracellular amyloid plaques and intracellular neurofibrillary tangles. Rare heritable mutations within the genes for amyloid precursor protein (APP) and presenilin 1 (PSEN1), and presenilin 2 (PSEN2) cause early onset AD and account for approximately 1% of AD cases. While the majority of AD cases are late-onset (LOAD), which is defined by a markedly more complex genetic architecture that is comprised of many genetic risk factors that influence AD through multiple cellular pathways. The advent of deep sequencing analyses have allowed for the identification …

Overcoming Genetic Heterogeneity In Glioblastoma By Targeting Transcriptional Dependencies, Tatenda Mahlokozera

Arts & Sciences Electronic Theses and Dissertations

Glioblastoma (GBM) is the most common intrinsic central nervous system malignancy in adults, accounting for approximately 45% of such cancers. Despite advances in chemo- and radiotherapeutic approaches for various malignancies over the past decade, GBM remains an incurable disease with a dismal prognosis. Even after treatment with the current standard of care, which consists of maximal safe surgical resection, radiotherapy, and both concomitant and adjuvant chemotherapy with temozolomide, median survival is only approximately 17 months. Both treatment failure and difficulties in developing novel targeted therapies for GBM have partly been attributed to the molecular and cellular inter- and intra-tumoral heterogeneity …

Candida Species And Bacterial Strains In The Vaginal Microbiome, Brett Tortelli

Arts & Sciences Electronic Theses and Dissertations

The vaginal environment is a dynamic ecosystem, hosting various microbial species from diverse taxa including bacteria, fungi and viruses. The composition of bacteria within the vaginal microbiome has gained a lot of recent attention and has been associated with reproductive health and disease. The vaginal microbiome of healthy reproductive-aged women is frequently dominated by Lactobacillus species and has low species diversity when compared to other anatomic sites. The composition of the bacterial community is often described in terms of five common community types. Four of the five community types are dominated by a single Lactobacillus species (L. crispatus, L. iners, …

Tertiary Lymphoid Tissue In The Urinary Bladder Of Aging Mice And Women, Marianne Morris Ligon

Arts & Sciences Electronic Theses and Dissertations

Urinary tract infections (UTIs) are the most common infection of women, affecting roughly half of all women during their lifetime. UTIs frequently recur within 6 months to 1 year of the initial infection to cause recurrent UTIs (rUTIs). Repeated treatment of rUTIs with antibiotics may lead to antibiotic resistance, disruption of the microbiota, and adverse effects of the drugs. To avoid excess antibiotic use, there is an urgent need to understand the mechanisms of host defense against infection to identify new targets for UTI treatment and prophylaxis in women with rUTIs. Postmenopausal and older women have the highest risk of …

Understanding The Influence Of Individual-Level Sources Of Pathology Variation On Neuroimaging Measures Of Alzheimer Disease, Austin Andrew Mccullough

Arts & Sciences Electronic Theses and Dissertations

The overall goal of this dissertation is to gain a better understanding of how current Alzheimer disease pathologic progression models interact with sources of individual-level variation in pathology to influence overall disease progression in a clinically meaningful way. Many sources of variation, both internal (e.g., genetic mutations, heterogeneity of tau pathology) and external (e.g., diet and exercise, sleep quality), are known to influence disease progression and symptom onset in AD. With the advent of therapies that have shown successful reduction of amyloid load in trials and the rapid progression of anti-tau therapies, we hypothesize that a better understanding of how …

Control Of Intestinal Turnover And Cell Death Through Canonical Autophagy Pathways Within Mouse And Human Epithelia, John Steven Ekman

Arts & Sciences Electronic Theses and Dissertations

Regulation of epithelial turnover is essential for the maintenance of the structure and function of the intestine. The balance of intestinal epithelial turnover is known to be modulated by cell-extrinsic cytokines such as Tumor Necrosis Factor (TNF). Likewise, cell-intrinsic modulation of survival and death is afforded by a highly-conserved, multi-step pathway termed autophagy. In this body of work, I have characterized a specific and potent role for autophagy in protecting mouse intestinal epithelial cells (enterocytes) from TNF-triggered cell death. Specifically, I have found that the autophagy initiation factor Atg14 is central to mediating this protective role. Utilizing conditional loss of …

Sex Differences In Cancer Metabolism Contribute To Sex-Specific Treatment Responses, Jasmin Inge Sponagel

Arts & Sciences Electronic Theses and Dissertations

Many human diseases show sex differences in incidence, age of onset, and outcome, including autoimmune diseases, neurological diseases, psychiatric disorders, cardiovascular diseases, metabolic diseases, neurodevelopmental disorders, and cancer. For most cancers, incidence and mortality rates are higher in males. Lung and brain cancers are no exception. Overall, lung cancer is more common in males. Furthermore, mortality rates of non-small cell lung cancer (NSCLC), the most common subtype of lung cancer, are significantly higher in males. The underlying reasons for sex differences in NSCLC mortality rates are largely unknown. Most brain cancers are also more common in males. The male prevalence …