Life Sciences Commons^™

The Evolution Of Transposable Elements As Cis-Regulatory Elements In Mammals, Alan Y. Du

Arts & Sciences Electronic Theses and Dissertations

Transposable elements (TEs) are mobile genetic elements that make up a large proportion of mammalian genomes. Although TEs are highly prevalent genomic sequences, they have been understudied as they were once labeled as “junk DNA.” Despite their initial status as simple genomic parasites, recent studies have implicated TEs as cis-regulatory elements, supplying promoters, enhancers, and boundary elements. Functional testing of regulatory activity, however, remains a significant bottleneck. Nonetheless, due to their repetitive nature, TEs provide a unique model to examine the evolution of cis-regulatory elements, which has traditionally been difficult to study due to lack of homology at the sequence …

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 …

Association Of Structural Variation (Sv) With Cardiometabolic Traits In Finns, Lei Chen

Arts & Sciences Electronic Theses and Dissertations

Cardiovascular diseases (CVDs) are known to be associated with a variety of quantitative risk factors such as cholesterol, metabolites, and insulin. Understanding the genetic basis of these quantitative traits can shed light on the etiology, prevention, diagnosis, and treatment of disease. However most prior trait-mapping studies have focused on single nucleotide variants (SNVs) and Indels, with the contribution of structural variation (SV) remaining unknown. In this thesis, we present the results of a study examining genetic association between SVs and cardiometabolic traits in the Finnish population. In the first chapter, we used sensitive methods to identify and genotype 129,166 high-confidence …

Examining Early Interactions Between Innate Airway Resident Immune Cells And Mtb-Specific Factors During Pulmonary Infection With Mycobacterium Tuberculosis, Micah D. Dunlap

Arts & Sciences Electronic Theses and Dissertations

Mycobacterium tuberculosis (Mtb) is the leading cause of death by an infectious agent in the world today, infecting roughly one quarter of humans. Despite this, the mechanisms of early pathogenesis and host protective innate immune responses remain poorly understood and uncharacterized.

Lung resident Alveolar Macrophages (AMs) are the first host contact with Mtb bacilli after inhalation and are thus key mediators of the early pulmonary immune response. AMs are generally believed to reside entirely in the airway, but it was recently demonstrated that they have the capacity to egress and enter into granulomas during pulmonary infection with hypervirulent Mtb. Furthermore, …

Understand And Predict Microbiome And Resistome Dynamics In Response To Perturbations Across Diverse Populations And Environments, Manish Boolchandani

Arts & Sciences Electronic Theses and Dissertations

Complex microbial communities are at the interface of human, animal and environment interconnected ecosystem, where they can move within and between these entities. These microbial communities are mostly beneficial, maintaining the host health and homeostatic state. However, these communities can also serve as reservoirs of antibiotic resistance (AR) genes that may disseminate to pathogen bacteria, compromising the treatment options. Like other microbial communities, human gut microbiome is highly dynamic and can get acutely perturbed with the changes in the habitat, diet, lifestyle and disease. A perturbed gut community structure has profound impact on the host health and physiology. Use of …

Modularity Of Feedback For State-Dependent Guidance Of Navigation In Mouse Visual Cortex, Andrew M. Meier

Arts & Sciences Electronic Theses and Dissertations

Navigating through unpredictable environments requires an efficiently organized sensory system capable of adapting to behavioral demands. In the mammalian visual system, two adaptations which have arisen to meet these demands are parallel processing and top-down feedback of internally generated expectations and contextual information for adjusting responses to match the needs of the current behavioral task. Mouse visual cortex exhibits the latter of these organizing principles, like other mammals, in the form of a molecular layer (Layer 1) which receives feedback to contextually adapt sensory responses from the outside world. The first of these organizing principles, parallel processing streams, generally takes …

The Roles Of Plasmepsins Ix And X In Malaria Parasite Biology, Armiyaw Sebastian Nasamu

Arts & Sciences Electronic Theses and Dissertations

Proteases of the malaria parasite Plasmodium falciparum have been targeted for drug discovery for decades. The P. falciparum genome encodes ten aspartic proteases called plasmepsins, which are involved in diverse cellular processes. In this work we address the roles of two of these plasmepsins, plasmepsins IX and X (PM IX and X), the two least studied aspartic proteases in blood stage malaria parasites till date. We explore the essentiality of these proteases in parasite development, attempt to identify their substrates and the ability to drug them. We show that PM IX is essential for erythrocyte invasion, acting on rhoptry secretory …

Molecular Mechanisms Responsible For Functional Cortical Plasticity During Development And After Focal Ischemic Brain Injury, Andrew Wiggen Kraft

Arts & Sciences Electronic Theses and Dissertations

The cerebral cortex is organized into functional representations, or maps, defined by increased activity during specific tasks. In addition, the brain exhibits robust spontaneous activity with spatiotemporal organization that defines the brain’s functional architecture (termed functional connectivity). Task-evoked representations and functional connectivity demonstrate experience-dependent plasticity, and this plasticity may be important in neurological development and disease. An important case of this is in focal ischemic injury, which results in destruction of the involved representations and disruption of functional connectivity relationships. Behavioral recovery correlates with representation remapping and functional connectivity normalization, suggesting functional organization is critical for recovery and a potentially …

The Role Of Fibrillin-1 In Eye Development And Disease, Wendell Brooks Jones

Arts & Sciences Electronic Theses and Dissertations

The ciliary zonule of the human eye consists of a circumferential array of fibers that connect the ocular lens to the nonpigmented ciliary epithelium (NPCE) located at the inner wall of the eye. Zonular fibers consist of bundles of beaded filaments called microfibrils. Microfibrils are major structural elements of the extracellular matrix and are present in pure form in the ciliary zonule. Microfibrils are composed principally of fibrillin-1 (FBN-1); a large extracellular matrix glycoprotein. In humans, mutations in FBN1 underlie Marfan syndrome; a pleiotropic connective tissue disorder that profoundly affects the eye. Ocular manifestations include ectopia lentis (dislocated lenses), cataracts, …

The Molecular And Cellular Basis For Cold Sensation, Daniel Brenner

Arts & Sciences Electronic Theses and Dissertations

The ability to sense changes in temperature is crucial to surviving harsh environments. Over the last decade several ion channels that have been proposed to be cold sensitive have been identified, most notably TRPM8 and TRPA1. Although these molecules have been extensively studied in vitro, their exact roles in cold sensation in vivo are still debated. This uncertainty is in large part due to problems with the standard methods of testing cold sensitivity in vivo, which often rely on subjective measures of cold responsiveness. Experiments using these subjective measures have been repeated by different groups and have yielded conflicting results, …

Concentration Coding In The Accessory Olfactory System, Hannah Ada Arnson

All Theses and Dissertations (ETDs)

Understanding how sensory systems encode stimuli is a fundamental question of neuroscience. The role of every sensory system is to encode information about the identity and quantity of stimuli in the environment. Primary sensory neurons in the periphery are faced with the task of representing all relevant information for further processing by downstream circuits, ultimately leading to detection, classification and potential response. However, environmental variability potentially alters stimulus properties in non-relevant ways. Here, we address these problems using the mouse accessory olfactory system: AOS) as a model. The AOS is an independent olfactory system possessed by most terrestrial vertebrates, although …