Life Sciences Commons^™

The Processing Of Amyloid Precursor Protein In The Central Nervous System Of Humans And Rhesus Macaques, Justyna Anna Dobrowolska

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Alzheimer's disease: AD) is the most common dementia, currently afflicting 30 million people worldwide, with prevalence steadily increasing. Over 99% of AD cases are classified as sporadic, in which the major risk factors are age: greater than 65 years) and the ApoE-ε4 allele: in a gene dose dependent manner). The minority of AD cases: less than 1%) are caused by autosomal dominant inheritance of a genetic mutation in one of three genes: Amyloid Precursor Protein: APP), Presenilin-1: PSEN1), or Presenilin-2: PSEN2). Mutation carriers will generally notice cognitive decline starting at a relatively young age, anytime between their 30s-50s, and eventually …

The Function Of Carmil1 In Migrating Cells, Marc Edwards

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This dissertation describes the physiological role of the Capping Protein- CARMIL interaction in migrating cells. I establish the CARMIL-CP complex as a key regulator of lamellipodial actin assembly and of lamellipodial dynamics. Membrane ruffling at the leading edge of motile cells and macropinocytosis were also found to be dependent on the CARMIL1-CP interaction. This is consistent with macropinocytosis and ruffling being dependent on a functional and dynamic lamellipodium.: Kerr and Teasdale, 2009).

In chapter two I demonstrate that the CBR of CARMIL1 is competent to inhibit CP in cells. I show that overexpression of the CBR in cells leads to …

Understanding Crx-Associated Retinopathies Using Animal Models, Nicholas Minh Abell Tran

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Cone-rod homeobox: CRX) protein is a "paired-like" homeodomain transcription factor that is essential for regulating rod and cone photoreceptor transcription. Mutations in human CRX are associated with the dominant retinopathies Retinitis Pigmentosa: RP), Cone-Rod Dystrophy: CoRD) and Leber Congenital Amaurosis: LCA), with variable severity. The goal of my dissertation project was to develop and characterize animal models to understand genetic mechanisms of phenotypic diversity in CRX-associated disease. Heterozygous Crx Knock-Out: KO) mice: "+/-") have normal vision as adults and fail to model the dominant human disease.

We generated two Crx Knock-IN: K-IN) mouse models: CrxE168d2: "E168d2") and CrxR90W: "R90W"), which …

The Diversity Of Quantitative Trait Loci In Yeast Sporulation Efficiency, Kimberly Lorenz

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A complex trait is one that exhibits continuous phenotypic variation due to genetic variation in many quantitative trait genes: QTGs). The ultimate goal of genetics is to relate genotype to phenotype; in the case of complex traits this requires a better understanding of what types of genes harbor causal natural variation, and what form the variation takes. Here I describe two experiments using the model complex trait of sporulation efficiency in the yeast Saccharomyces cerevisiae, one to specifically investigate how small effects contribute to a quantitative trait and the other to determine whether certain types of genes are more likely …

On The Origin Of Phenotypic Variation: Novel Technologies To Dissect Molecular Determinants Of Phenotype, Francesco Vallania

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This thesis describes the conception, design, and development of novel computational tools, theoretical models, and experimental techniques applied to the dissection of molecular factors underlying phenotypic variation. The first part of my work is focused on finding rare genetic variants in pooled DNA samples, leading to the development of a novel set of algorithms, SNPseeker and SPLINTER, applied to next-generation sequencing data. The second part of my work describes the creation of a reporter system for DNA methylation for the purpose of dissecting the genetic contribution of tissue-specific patterns of DNA methylation across the genome. Finally the last part of …

The Genetic Architecture And Evolution Of Brain Cortical Folding In A Pedigreed Primate Population, Elizabeth Grace Atkinson

Arts & Sciences Electronic Theses and Dissertations

Elevated neurological faculty, related to the dramatic increase in brain volume, is a hallmark of the primates. Cognitive capacity, the processing power and speed of the brain, is directly related to the number of neurons in the cerebral cortex and the connectivity network underlying information processing in the brain. Increased cortical folding (gyrification) allows for more neurons to be contained within the volume of the braincase and the arrangement of folds and ridges across the cerebral cortex is an indication of the underlying neural network connecting regions. The goal of this dissertation is to develop a better understanding of the …

Cooperative Tumor Suppression By Arf And P53, Jason Thomas Forys

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Cancer is a complex genetic disease characterized by the inactivation of tumor suppressor genes and enhanced activity of oncogenes leading to deregulated cellular proliferation. Two tumor suppressor genes, p53 and Arf, play important roles in protecting cells against numerous biological stresses. In response to oncogenic signals, increased ARF expression leads to the activation of p53, which in turn leads to the cessation of cell division or induction of an apoptotic response. Interestingly, p53 coordinates repression of Arf transcription, setting up a negative feedback loop with currently unknown physiological significance. Cells that lack p53 express elevated levels of ARF, but it …

The System I And System Iii Holocytochrome C Synthases In Cytochrome C Biogenesis, Brian San Francisco

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Cytochromes c are proteins that are involved in important redox reactions in organisms from every kingdom of life. C-type cytochromes, uniquely, possess a covalently bound heme. Since cytochromes c are assembled at their site(s) of function: outside of the cytoplasmic membrane in bacteria, in the chloroplast lumen, or in the mitochrondrial intermembrane space), their assembly poses unique challenges to heme trafficking and post translational modification. Three major systems exist in nature for cytochrome c assembly, termed systems I, II, and III. Using recombinant Escherichia coli, aspects of systems I and III were analyzed, with an emphasis on the synthase protein(s) …

Mutations Of Pdd1 Chromo- And Chromoshadow Domains Reveal Critical Functions For Each During Development Of Tetrahymena Thermophila, Rachel Schwope

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Pdd1 is a developmentally expressed HP1-like protein of Tetrahymena thermophila that is required during conjugation, when a copy of the cell's transcriptionally silent germline micronucleus differentiates into an active somatic macronucleus. Differentiation of these somatic chromosomes involves genome-wide fragmentation and amplification. These DNA rearrangements are facilitated by an RNAi mechanism, in which small RNAs target silencing histone modifications, H3K9 and H3K27 methylation, to Internal Eliminated Sequences: IESs), which are bound by Pdd1 and later excised from the genome. Pdd1 features two chromodomains, one of which shares homology with that of HP1, and a C-terminal chromoshadow domain. In this study, we …

The Mechanism Of The Gastric Epithelial Stem Cell Response To Metaplastic Injury, Shradha Sachin Khurana

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Almost nothing is known about the identity of the epithelial stem cell of the gastric corpus, either during normal turnover or in response to injury. Our lab has shown that injection of the selective estrogen receptor modulator tamoxifen leads to near complete atrophy of parietal cells by 3 days and induces expansion of an undifferentiated cell population within the normal stem cell niche in the isthmus of the gastric unit. Here we show that CD44 labels the membranes of such undifferentiated isthmal cells, both in the normal gastric epithelium and when those cells expand fourfold upon injury with tamoxifen. Loss …

The Effects Of Invasive Plants On Biodiversity Across Spatial Scales, Kristin Irene Powell

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Although introduced plant species are often considered to be one of the most notable anthropogenic threats to biodiversity, their influence on biodiversity remains controversial. Some studies have shown large declines in biodiversity in plant-invaded areas, whereas others have noted that plant invasions are rarely implicated as the cause of species extinctions. This dissertation aims to synthesize this seemingly conflicting literature on the effects of invasive plants on biodiversity. The overarching hypothesis in this research is that the effect of invasive plant species on biodiversity is scale-dependent, and the discrepancy among studies can be explained by a difference in the scales …

Quantification Of Conformational Heterogeneity And Its Role In Protein Aggregation And Unfolding, Nicholas J. Lyle

Arts & Sciences Electronic Theses and Dissertations

Proteins can exhibit significant conformational heterogeneity either under denaturing conditions or in aqueous solutions. The latter is true for a class of proteins whose sequences predispose them to form heterogeneous ensembles of conformations. Characterization of conformational heterogeneity in a protein ensemble requires the quantification of the amplitudes of spontaneous fluctuations in conjunction with information regarding coarse grain measures that report on the average sizes, shapes, and densities. This often demands multiplexed experimental approaches whose readouts are interpreted or annotated using ensembles drawn from atomistic or coarse grain computational simulations. Efforts to characterize conformational heterogeneity contribute directly to our understanding of …

The Natural Variants Of The Streptococcus Nad+-Glycohydrolase Spn Modulate Divergent Host Cell Signaling Pathways And Death, Sukantha Chandrasekaran

Arts & Sciences Electronic Theses and Dissertations

Streptococcus pyogenes has an arsenal of virulence factors that promote its ability to cause a broad range of diseases and fight host defenses. One of these factors is the S. pyogenes NAD+-glycohydrolase (SPN), which is secreted from the bacterial cell and translocated into the host cell cytosol where it contributes to cell death. Every strain examined to date has SPN and recent studies suggest that SPN is continuing to evolve diverging into two variants that correlate with tissue tropism, one of which lacks the signature NADase activity. SPN's roles in both cytotoxicity and niche selection are unknown. To gain insight …

Development Of Polarizable Force Field Models For Transition Metal Ions, Jin Yu Xiang

Arts & Sciences Electronic Theses and Dissertations

This dissertation focuses on the development of polarizable molecular mechanics (MM) force field models for the third-row transition metal (TM) ions. These TM ions perform important structural and chemical functions in a wide range of organic and biological environments because of the unique properties of the 3d orbitals. Being able study these systems in silico can provide a tremendous amount of information that is difficult to obtain through experiments. However, the standard treatment of ions in traditional MM models has shown to be insufficient for describing the d-shell electronic effects. In this work, empirical models for TM electronic effects are …

Dysfunctional Gene Regulation Of The Meiotic Program In An Interspecific Yeast Hybrid, Devjanee Swain Lenz

Arts & Sciences Electronic Theses and Dissertations

Speciation, the evolutionary process by which species arise, is a fundamental biological concept. One of the major goals of evolutionary genetics is to understand the genetic basis of reproductive isolation (RI), a collection of barriers that prevents two species from forming viable or fertile hybrids. Given the lack of viable or fertile hybrid progeny, identifying genes that impact RI as well as their functions has been difficult. Thus we lack a view of the total genetic contribution to RI. Recently the budding yeast Saccharomyces has served as an evolutionary model, as abundant sequence, expression, and phenotypic data exist for the …

Type 1 Diabetes And The Male Reproductive Axis, Erica Schoeller

Arts & Sciences Electronic Theses and Dissertations

Glucose regulation is important in both spermatogenesis as well as mature sperm function. The impact of diabetes on sperm function is becoming increasingly clear, though much work is still needed to elucidate the mechanism by which diabetes impairs spermatogenesis. Diabetes causes disruptions in the hypothalamic pituitary gonadal (HPG) axis, the regulatory system that controls reproduction. The HPG axis functions by secreting GnRH pulses from the hypothalamus, which bind to receptors on the pituitary and cause secretion of follicle stimulating hormone and luteinizing hormone, which then bind to receptors in the testes and facilitate spermatogenesis. Type 1 diabetes can severely impact …

Post-Translational Regulation Of Fas-Mediated Pparα Activation, Anne Patricia Louise Jensen-Urstad

Arts & Sciences Electronic Theses and Dissertations

The liver is a central organ to whole-body metabolism and mediates many of the adaptive responses to changes in nutrient availability, such that the appropriate energy sources are used and blood glucose levels maintained, whether directly after a meal or after a twelve-hour fast. The adaptive responses to fasting in liver are largely mediated by the nuclear receptor peroxisome proliferator-activated receptor α, or PPARα.

PPARα can be activated by a de novo synthesized lipid ligand—16:0/18:1- glycerophosphocholine (16:0/18:1-GPC)—the synthesis of which is dependent on fatty acid synthase (FAS), but little is known about the regulation of this pathway. My thesis focused …

The Uropathogenic Escherichia Coli Effector Ybcl Modulates The Innate Immune Response In The Urinary Tract, Megan Elizabeth Lau

Arts & Sciences Electronic Theses and Dissertations

Uropathogenic Escherichia coli (UPEC) are the primary etiology of urinary tract infections (UTIs), one of the most common bacterial infections afflicting the human population. While UPEC cause disease throughout the urinary tract, bladder infection, or cystitis, is most prevalent. A key aspect of UPEC pathogenesis in the bladder is the modulation of the host inflammatory response. At acute time points, UPEC delay the arrival of immune cells, such as neutrophils, to the bladder. The lack of neutrophils in the bladder lumen enables UPEC to replicate freely in the urine and invade the bladder epithelium, a requirement for bacterial persistence, in …

Structural Mechanism Of Orthopoxvirus Sabotage Of Mhci Antigen Presentation, William Howard Mccoy Iv

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Immunomodulatory proteins that subvert major histocompatibility complex class I: MHCI) antigen presentation can help viruses to evade cytotoxic T-lymphocyte: CTL) detection and clearance. Cowpox virus, like other orthopoxvirus family members, is a large DNA virus, whose genomic termini encode numerous immunomodulatory genes, including two ER-resident MHCI saboteurs: CPXV012 and CPXV203). CPXV012 inhibits peptide loading of MHCI within the peptide-loading complex: PLC), while CPXV203 inhibits surface expression of both murine and human MHCI through the use of a C-terminal ER-retention sequence: KTEL). An association: direct or indirect) between CPXV203 and MHCI was first demonstrated in pull-down experiments. This doctoral work explores …

Urine Trouble: A Molecular And Anatomical Examination Of Bladder Pain, Lara Wiley Crock

Arts & Sciences Electronic Theses and Dissertations

Interstitial cystitis or painful bladder syndrome (IC/PBS) is a chronic pain syndrome affecting 3-6% of women in the US. Some evidence suggests urothelial injury may cause some cases of IC/PBS. To examine how urothelial injury modulates bladder pain, three injury models were used: Infection with uropathogenic Escherichia coli (UPEC, inflammatory), Protamine sulfate (PS, non-inflammatory chemical), and lipopolysaccharide (LPS, non-infectious and inflammatory) treatment. Surprisingly, injury with PS decreased, while UPEC alone increased the pain response to bladder distention. These data suggest that changes in the urothelium may modulate some forms of IC/PBS. However, in most cases, patients with IC/PBS have no …

Identification Of Genetic Determinants Of Metastasis And Clonal Relationships Between Primary And Metastatic Tumors, Gaurav Singhal

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No abstract provided.

Control Of Neuroendocrine Cell Physiology By A Single Transcription Factor, Drosophila Basic Helix Loop Helix Regulator Dimmed, Tarik Hadzic

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Neuroendocrine cells feature a large capacity for the processing, accumulation and regulated release of bioactive peptides and peptide hormones. The ultrastructural correlate of this regulated secretory pathway is a specialized organelle, called a dense core vesicle: DCV). DCVs are typically larger than conventional, small synaptic vesicles. Past work has identified intrinsic DCV proteins: non-cargo proteins, like the processing enzyme, carboxypeptidase) or ancillary ones that play a role in DCV trafficking and exocytosis: like CAPS, the Ca2+-dependent activator protein for secretion). Currently, there is a lack of understanding of the developmental and physiological mechanisms that permit neurosecretory cells to coordinate and …

Characterization Of The Placenta-Specific 8.1 Gene Function During Zebrafish Embryogenesis, Haiting Ma

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The PLAC8 gene encodes for a small, cysteine-rich protein conserved in vertebrates that is a member of a large family of PLAC8-motif containing proteins with diverse functions in animals, plants, and algae. Recently, high levels of PLAC8 expression have been detected in aggressive colorectal cancer and invasive breast cancer, and potentially contributing to the cancer pathogenesis. However, the molecular and cellular functions of PLAC8 in vertebrate development, homeostasis, and disease remain unclear. To determine the function of PLAC8 under disease and normal conditions, in this thesis work, I identified plac8.1 as a PLAC8 homolog in zebrafish, a vertebrate model system …

Metagenomic Analyses Of The Human Gut Virome, Alejandro Reyes

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The human gut harbors tens of trillions of microbes belonging to all three domains of life, Bacteria, Archaea, and Eukarya; most are members of Bacteria. These organisms collaborate and compete for functional niches and physical space: habitats), together forming a continuously functioning metabolic organ that influences many aspects of host biology. The factors that drive the assembly, determine the stability, and shape the adaptive responses of the gut microbiota to a variety of perturbations are the subject of intense study as greater appreciation is gained of the importance of this microbial community for human health. My thesis focused on the …

Characterization Of Human Gut Microbiota Dynamics Using Model Communities In Gnotobiotic Mice, Nathaniel Patrick Mcnulty

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The human gut is colonized by a diverse array of microbes, collectively referred to as the microbiota. The microbiota's complexity poses significant challenges in characterizing the rules dictating its assembly, inferring the functional roles of its component species, and understanding how communities sense and respond to changes in their habitat. We developed defined, representative model communities comprised of sequenced human gut bacteria that could be characterized in a highly controlled manner in gnotobiotic mice, plus a suite of scalable molecular tools for assaying community properties. These tools were first used to evaluate how the microbiota is impacted by probiotic bacterial …

The Physiological And Morphological Responses Of The Bladder Urothelium To Differential Injury, Kristina Marie Stemler

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The bladder is the site of various diseases such as urinary tract infections: UTI), bladder pain syndrome/interstitial cystitis: BPS/IC), and bladder cancer. UTIs and BPS/IC primarily afflict women and treatment costs over $5 billion and almost $200 million respectively in 2006. Quality of life in BPS/IC patients is low; comparable to individuals with end stage renal disease. Recent research has identified a role for the epithelial lining of the bladder, which is usually targeted by these afflictions, in potentially contributing to enhancing pain. The bladder epithelium also showcases a rapid ability to regenerate after injury.

Knowledge of the contribution of …

Intermediate Level Mechanisms Supporting Face Perception, Eric J. Feczko

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I propose that the intermediate neural mechanisms involved in face processing may be better understood by studying concentric form-from-structure integration. This dissertation involves behavioral adaptation and masking experiments that provide evidence regarding whether face perception and concentric form-from-structure perception engage a common processing mechanism.

Despite faces being complex visual stimuli, humans are able to perceive and identify faces rapidly. Studies of face perception strongly suggest that this ability involves processing the arrangement of the face features. Although high-level aspects of face perception have been studied extensively, less is known about the intermediate mechanisms involved in face processing. Converging evidence has …

The Influence Of Diet On The Mammalian Gut Microbiome, Brian David Muegge

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The mammalian gut is residence to a large microbial community whose collective set of millions of genes: microbiome) encodes a vast array of functions, including many that process dietary components. Few tools are available to change the microbiome's properties to promote host health because the factors governing community assembly and operation are poorly understood. My thesis focused on the impact of one factor, host diet.

I used a variety of experimental and computational methods to perform a comparative metagenomic study of the fecal communities of 39 diverse mammals to assess microbiome variation. These animals included herbivores, omnivores and carnivores representing …

Concentration Coding In The Accessory Olfactory System, Hannah Ada Arnson

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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 …

Hematopoietic Stem Cells And Progenitors In Murine Autoimmune Arthritis, Kwadwo Asare Oduro Jr.

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Although the physiological role of stem cells in generating and maintaining a functional biological system is widely appreciated, very little is known about the behavior of these cells in pathological conditions. If and how these primitive cells are affected by a disease process or may contribute to the disease process has not been adequately explored. We have studied the Hematopoietic System, with particular emphasis on Hematopoietic Stem Cells: HSCs) and Progenitors, in a spontaneous murine autoimmune arthritis model. We found that these mice have a systemic increase in myeloid cells, which correlated with an increased frequency of granulocyte-monocyte progenitors relative …