Life Sciences Commons^™

Glycan Precursor Transport In Cryptococcus Neoformans, Lucy X. Li

Arts & Sciences Electronic Theses and Dissertations

Glycans play diverse biological roles, ranging from structural and regulatory functions to mediating cellular interactions. For pathogens, they are also often required for virulence and survival in the host. Our interest in glycoconjugates stems from their role in the fungal pathogen Cryptococcus neoformans. This yeast colonizes the lungs and disseminates to the brain of immunocompromised individuals, where it causes a meningoencephalitis that is frequently lethal, killing almost 200,000 people each year. The major virulence factor of this yeast is a polysaccharide capsule that enables it to manipulate the host immune response and resist host antimicrobial defenses.

Synthesis of the capsular …

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 …

Typical And Atypical Development Of The Brain’S Functional Network Architecture, Ashley Nicole Nielsen

Arts & Sciences Electronic Theses and Dissertations

The human brain is a complex organ that gives rise to many behaviors. Specialized neural regions cooperate as functional networks that form an intricate functional architecture. Development provides a unique window into how brain functioning and human thinking are affected if the necessary neural features and connections are not fully formed. Similarly, developmental disorders can shed light on atypical trajectories of neural systems that may lead to or be a consequence of symptomatic behavior. A description of the typical and atypical development of functional networks is essential to identify the features of brain organization critical for mature human thinking and …

Modeling Mechanisms Behind Force Generation By Actin Polymerization, Seyed Fowad Motahari

Arts & Sciences Electronic Theses and Dissertations

Actin polymerization is the primary mechanism for overcoming the large turgor pressure that opposes endocytosis in yeast. While generation of pushing forces by actin polymerization is fairly well understood, it is not clear how actin polymerization produces pulling forces. In order to understand this process, it is necessary to simulate polymerization of filaments having various types of interactions with the membrane. Since existing methodologies in the literature do not treat such problems correctly, we develop a thermodynamically consistent methodology for treating polymerization of filaments having arbitrary interaction potentials with the membrane. Then I perform stochastic simulations for a system of …

Dissemination Of The Apicomplexan Parasite, Toxoplasma Gondii, Lisa L. Drewry

Arts & Sciences Electronic Theses and Dissertations

The parasitic protist Toxoplasma gondii is a common pathogen of rodents and felines that also infects humans. The most severe clinical manifestations of toxoplasmosis in humans derive from the systemic dissemination of T. gondii, during which the parasite penetrates biological barriers and accesses protected host compartments such as the central nervous system. T. gondii dissemination is enabled by the intrinsic gliding motility of extracellular parasites, which allows for travel to new host cells and tissues, and also powers the invasion of diverse host cells including migratory leukocytes. Dissemination is further advanced when migrating infected leukocytes shuttle intracellular parasites to new …

The Role Of The Ascc Complex In The Alkylation Damage Response, Jennifer Soll

Arts & Sciences Electronic Theses and Dissertations

DNA alkylation damage is caused by various agents that are present in the environment as well as cellular metabolism and can be induced by certain chemotherapeutic agents. Thus, the repair of damaged DNA is critical for genomic maintenance. The ALKBH family of proteins plays a central role in the repair of specific alkylated lesions, including 1-methyladenine (1meA) and 3-methylcytosine (3meC). A major outstanding question in the field of alkylation repair is the role of associated protein partners in the function of the human AlkB homologues. Here, I demonstrate that the ALKBH3 associated complex ASCC (comprised of ASCC1, ASCC2, and ASCC3) …

The Role Of Ifrd1 In The Recruitment And Function Of Reserve Stem Cells In Regeneration And Cancer, Mark Anthony Lewis

Arts & Sciences Electronic Theses and Dissertations

Mature cells can reprogram into a proliferative, progenitor-like state to repair tissue following injury and inflammation. Differentiated cells in diverse tissues can become proliferative via a dedicated, evolutionarily conserved program we termed paligenosis. We detailed how paligenosis occurs, in both gastric chief and pancreatic acinar cells, in a step-wise manner that involves: 1) autodegradation of mature cell components; 2) re-expression of progenitor genes; 3) re-entry into the cell cycle. This process is governed by mTORC1, a fundamental cellular energy sensor and regulator of protein translation. Blocking mTORC1 permitted autophagy and metaplastic gene induction but blocked cell cycle re-entry at S-phase. …

Activation Of Toll-Like Receptor 3 Translates To Long-Term Post-Viral Lung Disease, Xinyu Wang

Arts & Sciences Electronic Theses and Dissertations

Chronic obstructive lung disease (COPD) causes substantial human and economic costs both in the US and worldwide. To identify the molecular mechanisms to allow for targeted therapies for COPD, we developed a high-fidelity mouse model of chronic lung inflammation using the natural rodent pathogen Sendai virus (SeV). While nucleic acid-sensing pattern recognition receptors are important for innate immune responses to viral pathogens, there have been few studies investigating their role in the context of chronic disease. Here we show that Toll-like receptor 3 (Tlr3) signaling is required for the development of chronic lung disease in a postviral mouse model. Activation …

A Neural Network For Uncertainty Anticipation And Information Seeking, Jensen Kael White

Arts & Sciences Electronic Theses and Dissertations

In a world flooded with ‘click bait’, ‘alternative facts’, and ‘fake news’ one’s ability to seek out, discern, and value information is of utmost importance. Although contemporary phenomena, these cultural ills take advantage of an evolutionarily-preserved drive for humans and nonhuman animals to monitor for and pursue opportunities to gain information. Indeed, in a natural environment where rewards are scarce and can be risky, animals often seek sensory cues as a source of information about future outcomes. Interestingly, humans and nonhuman animals will seek sensory information that provides advance information that predicts an outcome even when this information does not …

Development Of Novel Tumor-Targeted Compounds For Boron Neutron Capture Therapy, Micah John Luderer

Arts & Sciences Electronic Theses and Dissertations

Glioblastoma multiforme (GBM) represents the most common primary brain tumor among adults. Despite surgical resection and aggressive chemoradiotherapy regimens, the current 2- and 5-year survival rates are only 27% and 9.8%, respectively. The low survival stems from the poor response to conventional therapy and underscores the critical need to develop new therapeutic approaches for GBM treatment. The high recurrence rate observed in GBM is in part attributed to the hypoxic (poorly oxygenated) tumor microenvironment. Hypoxic tumor conditions have been shown to increase metastasis, promote angiogenesis, and confer resistance to chemotherapy and radiation.

Hypoxic tissues are inherently radiation resistant due to …

Mapping And Functional Analysis Of Cis-Regulatory Elements In Mouse Photoreceptors, Andrew Hughes

Arts & Sciences Electronic Theses and Dissertations

Photoreceptors are light-sensitive neurons that mediate vision, and they are the most commonly affected cell type in genetic forms of blindness. In mice, there are two basic types of photoreceptors, rods and cones, which mediate vision in dim and bright environments, respectively. The transcription factors (TFs) that control rod and cone development have been studied in detail, but the cis-regulatory elements (CREs) through which these TFs act are less well understood. To comprehensively identify photoreceptor CREs in mice and to understand their relationship with gene expression, we performed open chromatin (ATAC-seq) and transcriptome (RNA-seq) profiling of FACS-purified rods and cones. …

Integrative Analysis To Investigate Complex Interaction In Alzheimer’S Disease, Zeran Li

Arts & Sciences Electronic Theses and Dissertations

Alzheimer’s disease (AD) is a neurodegenerative disorder featuring progressive cognitive and functional deficits. Pathologically, AD is characterized by tau and amyloid β protein deposition in the brain. As the sixth leading cause of death in the U.S., the disease course usually last from 7 to 10 years on average before the consequential death. In 2019 there are estimated 5.8 million Americans living with AD affecting 16 million family members. At certain stage of the disease course, patients with inability of maintaining their daily functioning highly depend on caregivers, primarily family caregivers, that incur estimated 18.4 billion unpaid hours of cares, …

The Evolutionary And Functional Roles Of Synonymous Codon Usage In Eukaryotes, Zhen Peng

Arts & Sciences Electronic Theses and Dissertations

Most amino acids are encoded by multiple synonymous codons. Although alternative usage of synonymous codons does not affect the amino acid sequences of proteins, researchers have been reporting evidence for functional synonymous codon usage at the species- and gene-specific levels for over four decades. It has been shown that variations in synonymous codon usage can affect phenotypes through diverse mechanisms such as shaping translation efficiency and mRNA stability. On the other hand, the common view that cellular and organismal phenotypes are primarily determined by proteins whose functions are primarily determined by amino acid sequences, often drives the assumption that synonymous …

The Role Of Smc3 In Mouse Embryonic And Adult Hematopoiesis, Tianjiao Wang

Arts & Sciences Electronic Theses and Dissertations

Acute myeloid leukemia (AML) is a heterogeneous disease, characterized by recurrent genetic mutations. Mutations in the cohesin complex are one of the 8 functional categories of mutations in AML. SMC3 encodes a subunit of the cohesin complex, which has important roles in chromosome segregation, genome instability, and gene expression. In the first chapter of the dissertation, we discuss the genetics of AML, normal functions of the cohesin complex, and the interplay between cohesin mutations and myeloid malignancies.

SMC3 is recurrently mutated in AML and other myeloid malignancies. In the second chapter of the dissertation, we compare the consequences of Smc3 …

Mechanics Of Phenotypic Aging Trajectories In C. Elegans And Humans, William Zhang

Arts & Sciences Electronic Theses and Dissertations

Overall, my dissertation integrates longitudinal measurements of physiology to investigate the aging process. In the first half, I examine the surprising and largely unexplained degree of variation in lifespan within even homogeneous populations. I sought to understand how physiological aging differs between long- and short-lived individuals within a population of genetically identical C. elegans reared in a homogeneous environment. Using a novel culture apparatus, I longitudinally monitored aspects of aging physiology across a large population of isolated individuals. Aggregating several measures into an overall estimate of senescence, I find that long- and short-lived individuals start adulthood on an equal physiological …

The Degenerating Star Clock: Circadian Clock Regulation Of Astrogliosis And Implications For Alzheimer’S Disease, Brian Vincent Lananna

Arts & Sciences Electronic Theses and Dissertations

Sleep disruption and circadian dysfunction are common symptoms of aging and neurodegenerative diseases, including Alzheimer’s disease (AD). The molecular rhythms in transcription/translation that govern these behavioral processes are mediated by clock genes and can be abrogated by deletion of the master circadian transcription factor Bmal1 (Arntl). We have shown that disruption of clock gene function in the mouse brain causes astrogliosis, synaptic damage, oxidative stress, and exacerbated neurodegeneration. However, the molecular mechanisms linking the circadian clock to these phenotypes and their implications for AD pathology remain largely unknown. Astrocyte activation occurs in response to diverse insults, and plays a critical …