Biology Commons^™

Joint Estimation Of Perceptual, Cognitive, And Neural Processes, Katherine Heisey

Arts & Sciences Graduate Student Theses and Dissertations

Humans are remarkable in their ability to perform highly complicated behaviors with ease and little conscious thought. Successful speech comprehension, for example, requires the collaboration of multiple sensory, perceptual, and cognitive processes to focus attention on the speaker, disregard competing cues, correctly process incoming audio stimuli, and attach meaning and context to what is heard. Investigating these phenomena can help unravel crucial aspects of human behavior as well as how the brain works in health and disease. However, traditional methods typically involve isolating individual variables and evaluating their decontextualized contribution to an outcome variable of interest. While rigorous and more …

Effects Of Agonistic Anti-Cd137 Antibody On Chikungunya Virus Infection And B Cell Responses, Jun Hong

Arts & Sciences Graduate Student Theses and Dissertations

CD137, a member of the tumor necrosis factor receptor superfamily of cell surface proteins, acts as a costimulatory receptor on T cells, natural killer cells, B cell subsets, and some dendritic cells. Agonistic anti-CD137 monoclonal antibody (MAb) therapy has been combined with other chemotherapeutic agents in human cancer trials. Based on its ability to promote tumor clearance, we hypothesized that anti-CD137 MAb might activate immune responses and resolve chronic viral infections. We evaluated anti-CD137 MAb therapy in a mouse infection model of chikungunya virus (CHIKV), an alphavirus that causes chronic polyarthritis in humans and is associated with reservoirs of CHIKV …

Identification And Characterization Of A Novel Non-Homologous End Joining Factor Mri, Putzer Joseph Hung

Arts & Sciences Graduate Student Theses and Dissertations

Non-homologous end joining (NHEJ) is the predominant DNA double-strand break (DSB) repair pathway in G1-phase cells. In particular, developing lymphocytes utilize NHEJ to repair physiologic DSBs generated during the processes of antigen receptor gene assembly and class-switch recombination (CSR). Thus, proper regulation of NHEJ is important not only for immune repertoire diversification, but also for the prevention of chromosomal translocations or deletions that can arise from misrepaired DSBs. The XRCC4-like factor (XLF) has been strongly implicated in promoting NHEJ, presumably by tethering broken DNA ends together in a sleeve-like complex, but its necessity appears to be cell context-dependent. While XLF …

Conformational Basis And Small Molecule Antagonists Of E. Coli Adhesion To The Urinary Tract, Vasilios Kalas

Arts & Sciences Graduate Student Theses and Dissertations

Urinary tract infections (UTIs) are one of the most prevalent infections, afflicting 15 million women per year in the United States with annual healthcare costs exceeding $2-3 billion. Uropathogenic Escherichia coli (UPEC) are the main etiological agent of UTIs and employ numerous virulence factors for host colonization. The most common adhesive mechanism by which UPEC mediate host-pathogen interactions is the chaperone-usher pathway (CUP), which is responsible for the assembly of proteinaceous surface appendages termed pili. Generally, CUP pili function in adherence or invasion of host tissues and in biofilm formation on medical devices and body habitats. CUP pili are highly …

The Role Of Apolipoprotein E In Alzheimer Disease: From Therapy To Mechanism, Tien-Phat Vuong Huynh

Arts & Sciences Graduate Student Theses and Dissertations

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with irreversible damage to the brain, which manifests in cognitive dysfunction, memory loss, and eventual death. The pathological hallmarks of AD are amyloid plaques, which are cerebral aggregates consisting of fibrils of the amyloid β-protein (Aβ), and filamentous lesions of the microtubule-associated protein tau known as neurofibrillary tangles. In the early 1990s, the apolipoprotein E (apoE) was found to co-localize with amyloid plaques. The ε4 allele of the APOE gene was sequentially identified as the strongest genetic risk factor for AD, increasing the risk by 4 – 12-fold, whereas the ε2 allele …

Plant Biomechanics: No Pain, No Gain For Birch Tree Stems, A. M. Schlegel, E. S. Haswell

Biology Faculty Research

Allometric relationships between organism size and shape are often described in developmental or evolutionary terms. A new study characterizes a collapsing birch tree mutant and provides a genetic entry point into the biomechanical control of tree allometry.

A Noncanonical Function Of The Telomerase Rna Component In Human Embryonic Stem Cells, Kirsten Ann Brenner

Arts & Sciences Graduate Student Theses and Dissertations

Telomeres are stretches of TTAGGG nucleotide repeats located at the ends of linear chromosomes that shorten with progressive cell division and prevent genomic instability at the cost of limiting a cell’s capacity to proliferate. This limitation can be overcome by telomerase, a ribonucleoprotein complex that elongates telomeres via reverse-transcription of the template telomerase RNA component (TERC). Recent studies have reported potential functions of TERC outside of its role in telomere maintenance. These noncanonical functions of TERC are however poorly defined, and the molecular mechanisms and biological relevance behind such functions remain elusive. Here, we generated conditional TERC knock-out human embryonic …

Activation And Regulation Of The Alkbh3-Ascc Alkylation Repair Pathway, Josh Brickner

Arts & Sciences Graduate Student Theses and Dissertations

DNA repair is essential to prevent the cytotoxic or mutagenic effects of various types of DNA lesions. These lesions are sensed by distinct pathways to recruit repair factors specific to type of damage. In particular, the ALKBH family of proteins recognizes and repairs specific alkylated lesions, including 1-methyladenine (m1A) and 3-methylcytosine (m3C). A major outstanding question in the field is how the AlkB homologue ALKBH3 and its associated protein partners are recruited to sites of alkylation damage and how this repair activity is regulated. Understanding the upstream signaling events that mediate recognition and repair of DNA alkylation damage is particularly …

Transcriptional Regulation Of Adipose Tissue Development By Pexrap And Med19, John Dean

Arts & Sciences Graduate Student Theses and Dissertations

Targeting adipose tissue function to decrease adiposity and improve insulin sensitivity could treat obesity and diabetes. How the nuclear receptor PPARγ regulates the development of two functionally distinct types of adipose tissue, brown and white fat (BAT and WAT), as well as the browning of white fat, remains unclear. Our previous studies suggest that PexRAP, a peroxisomal lipid synthetic enzyme, regulates PPARγ signaling and white adipogenesis.Here, we show that PexRAP is an inhibitor of brown adipocyte gene expression. PexRAP inactivation promoted adipocyte browning, increased energy expenditure, and decreased adiposity. Identification of PexRAP-interacting proteins suggests that PexRAP function extends beyond its …

T Cell Immunity In Pancreatic Cancer Is Undermined By Dendritic Cell Dysfunction, Samarth Hegde

Arts & Sciences Graduate Student Theses and Dissertations

Pancreatic cancer carries a dismal prognosis, and desperately needs viable therapeutic interventions beyond chemo-radiation. T cell-dependent immunotherapies have shown great promise in several tumor types, but have not been effective for the vast majority of pancreatic cancer patients. This is, in part, due to our limited understanding of how antigenicity of pancreatic lesions is recognized, and how adaptive immunity is overcome in this disease. We sought to study tumor-immune interactions and identify mechanisms for this immune-failure using several spontaneous and unperturbed mouse models of pancreatic adenocarcinoma. We found that early pancreatic lesions fail to elicit tumor-limiting CD4+ TH1 and CD8+ …

Elucidating Enhancer Function In Epidermal Development And Filaggrin Loss-Of-Function Variants In African American Atopic Dermatitis, Mary Elizabeth Mathyer

Arts & Sciences Graduate Student Theses and Dissertations

The epidermis is the outermost tissue of the skin and provides the body’s first line of defense against external assaults. The epidermis is primarily composed of keratinocytes that terminally differentiate and rise apically toward the surface to form the semipermeable barrier of the skin. A hallmark of keratinocyte terminal differentiation is the expression of genes from the Epidermal Differentiation Complex (EDC) locus. Many of the EDC protein products contribute to the structural integrity of the skin barrier, evidenced by several gene knockouts such as loricrin, and even genetic variation within gene coding sequences, that modulate the integrity of the skin …

The Transcription Factor Bhlhe40 Regulates Tissue-Resident Macrophages And Type 2 Immunity, Nicholas N. Jarjour

Arts & Sciences Graduate Student Theses and Dissertations

Transcriptional control of gene expression is essential for life, tailoring protein production to development and environment to maintain organismal homeostasis. A limited set of proteins termed transcription factors are critical to this process. As our understanding of these central regulators has improved, new aspects of cell and organismal biology have been revealed. Herein, we demonstrate the importance of the transcription factor Bhlhe40 to tissue-resident macrophages, T helper type 2 cells, and type 2 immune responses, revealing novel transcriptional control of macrophages and unexpected cytokine regulation of helminth infection. We find that Bhlhe40 is cell-intrinsically required for normal proliferation of large …

Phylogenetic And Genomic Characterization Of The Host-Pathogen Arms Race Between Bacterial Pathogens And Gossypium Hirsutum, Anne Zimmerman Phillips

Arts & Sciences Graduate Student Theses and Dissertations

Hosts and pathogens are eternally intertwined in an evolutionary arms race. When a pathogen causes a disease outbreak, scientists must identify resistance strategies that can durably tilt the arms race in favor of the host. This requires a deep understanding of both the genetic and environmental contexts in which the outbreak occurs. In this thesis I investigate the bacterial pathogens Xanthomonas citri pv. malvacearum (Xcm) and Pseudomonas syringae that caused disease outbreaks on Gossypium hirsutum from 2011-2017. I use pathogen genomics and host transcriptomics to develop hypotheses for how these pathogens emerged and how they cause disease. Phylogenetics and virulence …

Physiologic And Pathologic Profiling Of Clonal Variations, Wing Hing Wong

Arts & Sciences Graduate Student Theses and Dissertations

This thesis sought to provide a better understanding of clonality in various malignant and non-malignant settings using a variety of genomic analytical tools. Clonality is pre-defined as the presence of a mixed population of cells in which each sub-population has distinct somatic mutation profile. It is a common feature in cancers where subpopulations of cells arise as a result of independent, yet continual acquisition of somatic mutations. The clonal architecture of cancers can be used as a diagnostic and prognostic biomarker as well as to monitor disease progression or resolution. Besides cancer, clonal variability and expansion is also implicated in …

Generation And Utilization Of Diverse Memory B Cells After Flavivirus Challenges, Rachel Wong

Arts & Sciences Graduate Student Theses and Dissertations

Over the course of an effective immune response to an infection, two distinct B cell populations are generated to provide protection against reinfection, long-lived plasma cells (LLPCs) and memory B cells (MBCs). LLPCs and MBCs originate from germinal center (GC) B cells that have undergone B cell receptor (BCR) affinity maturation through iterative rounds of somatic hypermutation, proliferation, and selection. Thus, LLPCs and MBCs can bind to their antigen with higher affinity than their naïve B cell precursors. LLPCs constitutively secrete antibodies and can provide sterilizing immunity that pre-exists subsequent infections. MBCs, on the other hand, are quiescent and provide …

Investigating Biological Mechanisms Of Radiation Resistance In Advanced Stage Cervical Cancer, Fiona Ruiz

Arts & Sciences Graduate Student Theses and Dissertations

The current standard of care treatment for locally advanced cervical cancer is curative intent pelvic radiation with concurrently administered platinum chemotherapy (CRT). This treatment strategy is effective for many patients, but 33-50% of patients treated with CRT develop disease recurrence. Metastatic and recurrent cervical cancer is an incurable condition, and many of the currently available treatments are associated with significant morbidity and mortality. Identifying these patients upfront is a challenge that clinicians face when developing treatment strategies. Previous studies used to catalog the genomic and transcriptomic landscape of cervical cancer lacked high quality corresponding clinical follow up data for patients, …

An Evolving Epigenome That Determines Tissue And Cell Specificity, Renee Louise Sears

Arts & Sciences Graduate Student Theses and Dissertations

Understanding the mechanisms driving phenotypic variation is a major goal of biology that unifies classical genetics with the emerging fields of genomics and epigenomics. Human and mouse share over 90% of genes and global tissue-specific patterns of expression are maintained between the species. Thus, it is hypothesized that gene expression is influenced through distinctive regulation among species in order to account for the unmistakable phenotypic divergence. DNA methylation, histone modifications, open chromatin patterns, transcription factor binding, and other epigenetic factors are all associated with shaping, maintaining, and repressing regulatory regions which in turn coordinate gene expression. It is vital to …

The Biomedical Application Of Chimeric Antigen Receptor T Cell Therapy, Jessica Devenport

Arts & Sciences Graduate Student Theses and Dissertations

No abstract provided.

Finding And Analyzing De Novo Mutations In The Exomes Of Parent-Offspring Trios Of Spontaneous Chiari Malformation Type 1 Patients, Brian Leon Ricardo

Arts & Sciences Graduate Student Theses and Dissertations

Chiari Malformation Type 1 (CM1) is a neurodevelopmental disorder that occurs when one of the cerebellar tonsils herniates past the foramen magnum causing headaches, motor or sensory deficits, sleep apnea, and difficulty swallowing. This disorder is estimated to affect 1% of the population but due to the need of neuroimaging for diagnosis and the presence of asymptomatic patients there is still uncertainty about the exact proportion of the population affected. CM1 often presents itself with other neurodevelopmental disorders such as syringomyelia, scoliosis, and known genetic syndromes such as Klippel-Feil and Marfan syndromes. Twin, family, and familial clustering studies have established …

Onramp: A Galaxy-Based Platform For Collaborative Annotation Of Eukaryotic Genomes, Yating Liu, Luke Sargent, Wilson Leung, Sarah C.R. Elgin, Jeremy Goecks

Biology Faculty Research

G-OnRamp provides a user-friendly, web-based platform for collaborative, end-to-end annotation of eukaryotic genomes using UCSC Assembly Hubs and JBrowse/Apollo genome browsers with evidence tracks derived from sequence alignments, ab initio gene predictors, RNA-Seq data and repeat finders. G-OnRamp can be used to visualize large genomics datasets and to perform collaborative genome annotation projects in both research and educational settings.

The Impact Of Genetic Background And Cell Lineage On The Level And Pattern Of Gene Expression In Position Effect Variegation, Sarah C.R. Elgin, Sh Wang

Biology Faculty Research

"Background: Chromatin-based transcriptional silencing is often described as a stochastic process, largely because of the mosaic expression observed in position effect variegation (PEV), where a euchromatic reporter gene is silenced in some cells as a consequence of juxtaposition with heterochromatin. High levels of variation in PEV phenotypes are commonly observed in reporter stocks. To ascertain whether background mutations are the major contributors to this variation, we asked how much of the variation is determined by genetic variants segregating in the population, examining both the level and pattern of expression using the fruit fly, Drosophila melanogaster, as the model.

Results: Using …

From Single Cells To Human Disease: High-Resolution Phenotyping Of Male Infertility Models Using Single-Cell Rna Sequencing, Min Jung

Arts & Sciences Graduate Student Theses and Dissertations

Male infertility is a complex disease that can result in significant emotional distress and treatment costs. Globally, male infertility affects 7% of males, and while its incidence is rising, its etiology remains elusive. In order to improve patient care, it is critical to identify the nature of spermatogenic failure in as many men as possible. The extensive cellular heterogeneity of testis has limited the application of bulk expression measurements to capture crucial information to dissect molecular mechanisms of defects in the infertile patients. Thus, the application of single-cell RNA-sequencing on male germ cells provides an amazing new set of scientific …

The Impact Of Mrna Structure On Trna Selection And Ribosome Rescue, Erica Nicole Thomas

Arts & Sciences Graduate Student Theses and Dissertations

The faithful and rapid translation of proteins from genetic information is an essential feature of the ribosome. The general process of tRNA selection is governed by the ability of the ribosome to select for the aminoacylated tRNA (aa-tRNA) that matches the codon in its A-site. The efficiency and accuracy of this selection depends on the ability of nucleotides to form proper hydrogen bonds. While much is known about how chemical alterations of tRNA and rRNA can impact the fidelity of translation, less is known about how similar changes to mRNA affect decoding. In this work, we describe several studies aimed …

Mesothelium-Derived Factors Shape Tissue Resident Macrophage, Chin-Wen Lai

Arts & Sciences Graduate Student Theses and Dissertations

The studies outlined in this thesis provide several new insights into Msln-related pathways necessary for peritoneal immune responses and mucosal repair. We found that Msln and its binding partner mucin 16 from mesothelium influenced peritoneal and pleural macrophage differentiation. We found that Msln was required for proper tissue repair after colonic biopsy injury and was required for maximal polyp growth in APCMin/+ mice. Overall, this work describes mesothelial and epithelial-derived factors that are important for tissue resident macrophage differentiation and wound repair after colonic mucosal injury. Understanding the complex interactions between stromal cells and immune cells will lead to better …

Fast-Forward Protein Folding And Design: Development, Analysis, And Applications Of The Fast Sampling Algorithm, Maxwell Isaac Zimmerman

Arts & Sciences Graduate Student Theses and Dissertations

Molecular dynamics simulations are a powerful tool to explore conformational landscapes, though limitations in computational hardware commonly thwart observation of biologically relevant events. Since highly specialized or massively parallelized distributed supercomputers are not available to most scientists, there is a strong need for methods that can access long timescale phenomena using commodity hardware. In this thesis, I present the goal-oriented sampling method, Fluctuation Amplification of Specific Traits (FAST), that takes advantage of Markov state models (MSMs) to adaptively explore conformational space using equilibrium-based simulations. This method follows gradients in conformational space to quickly explore relevant conformational transitions with orders of …

Expression And Function Of Snornas In Acute Myeloid Leukemia, Wayne Alsworth Warner

Arts & Sciences Graduate Student Theses and Dissertations

Small nucleolar RNAs (snoRNAs) are non-coding RNAs that contribute to ribosome biogenesis and RNA splicing by modifying ribosomal RNA and spliceosome RNAs, respectively. These modifications are critical for a variety of cellular processes, including ribosomal biogenesis and splicing of RNAs. Recent studies have suggested an expanded role for snoRNAs beyond ribosomal biogenesis and splicing, including, regulation of chromatin structure, metabolism, and neoplastic transformation. The contribution of snoRNAs to the regulation of normal and malignant hematopoiesis is largely unknown. The lack of a method to accurately and comprehensively assess snoRNA expression has limited research in this area. In particular, array-based methods …

Understanding Excitation Energy Quenching In Isia, Hui-Yuan Steven Chen

McKelvey School of Engineering Graduate Student Theses & Dissertations

Cyanobacteria are photoautotrophic organisms that contribute a significant amount of global primary productivity. They are found in freshwater, marine and even some extremely severe environments. Among those environments, iron deficiency is one of the most common stress conditions in cyanobacterial habitats. To survive, cyanobacteria have evolved and developed several strategies to alleviate the damage caused by iron deficiency.

Iron stress-inducible protein (IsiA) is a chlorophyll-binding membrane protein found in cyanobacteria grown in iron-deficient conditions. During the past decades, considerable effort has been put on understanding how IsiA functions to help cyanobacteria survive iron deficiency. It has been reported that IsiA …

Individual Differences In Human Brain Functional Network Organization, Benjamin A. Seitzman

Arts & Sciences Graduate Student Theses and Dissertations

The human brain is organized at many spatial scales, including the level of areas and systems. Resting-state functional magnetic resonance imaging is a non-invasive technique that allows for the study of areal- and systems-level brain organization in vivo. Over two decades of research has sought to identify and characterize the functional communities that comprise the brain’s network architecture. Consequently, a convergent description of group-average functional network organization in healthy adults has emerged. Recent advances have allowed for the study of such organization in single individuals. Investigation of functional network organization in highly sampled individuals has revealed brain regions that deviate …

Determining The Genetic Contributions Of The Williams Syndrome Critical Region To Behavior Using Mouse Models And Human Genetics, Nathan David Kopp

Arts & Sciences Graduate Student Theses and Dissertations

Williams syndrome is a neurodevelopmental model caused by the deletion of 26-28 genes on chr7q11.23. The loss of these genes affects multiple organ systems resulting in severe cardiovascular disease, craniofacial dysmorphology, intellectual impairment, a specific Williams syndrome cognitive profile made up of deficits in visual-spatial processing with preserved language skills, and a characteristic hypersocial personality. The reciprocal duplication occurs at a lower frequency and manifests with diametric phenotypes to the deletion. This suggests that this locus harbors dosage sensitive genes that play a role in neurodevelopment. Large efforts have been taken to identify which genes are responsible for causing the …

Aging Of The Reproductive System And Of Germline Stem Cells In Caenorhabditis, Zuzana Kocsisova

Arts & Sciences Graduate Student Theses and Dissertations

C. elegans hermaphrodites display dramatic age-related decline of reproduction early in life while somatic functions are still robust. To understand why the germline fails so early, we analyzed the assembly line of oocyte production that generates fertilized eggs in mated hermaphrodites with sufficient sperm. Aging germlines displayed both sporadic and population-wide changes. A small fraction of aging animals displayed endomitotic oocytes in the germline and other defects. By contrast, all animals displayed age-related decreases in germline size and function. As early as day 3 of adulthood, animals displayed fewer stem cells and a slower cell cycle, which combine to substantially …