Life Sciences Commons^™

Wheelchair Propulsion For Everyday Manual Wheelchair Users: Repetition Training And Machine Learning-Based Monitoring, Pin-Wei Chen

Arts & Sciences Electronic Theses and Dissertations

Upper limb pain and injuries are prevalent among manual wheelchair users and can restrict their participation and daily activities. Due to the high repetition and force in wheelchair propulsion, chronic wheelchair propulsion has been linked to the risk of upper limb pain and injury. Prevention of upper limb pain and injury is a high priority in wheelchair-related research. Decades of research in wheelchair propulsion biomechanics have led to clinical practice guidelines (CPG). Unfortunately, a decade after the publication of the CPG, CPG-recommended propulsion is still uncommon. Hence, for the first aim, a randomized controlled trial pilot study with two groups …

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

Arts & Sciences Electronic 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 …

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

Arts & Sciences Electronic 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 Electronic 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 Electronic 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 …

Sideromycin Pathway Elucidation: Insights Into Salmycin Biosynthesis, Transport Paradigms, And Drug Release, Gerry Sann Macaraeg Rivera

Arts & Sciences Electronic Theses and Dissertations

Antibiotic resistance is an increasing threat in today’s society. In order to overcome resistant bacteria, it is necessary to discover new drugs with novel mechanisms of action. This work focuses on the sideromycin pathway, encompassing the biosynthetic production, mechanism of entry and hydrolysis-mediated drug release. Sideromycins are an interesting approach to combat the rise of antibiotic resistance since they provide a different avenue that overcomes problems that arise when entering the cell. The dissertation is separated into distinct sections dealing with the various areas of interest in the sideromycin pathway, particularly for the sideromycin, salmycin, produced by Streptomyces violaceus. The …

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

Arts & Sciences Electronic 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, …

Physiologic And Pathologic Profiling Of Clonal Variations, Wing Hing Wong

Arts & Sciences Electronic 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 …

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

Arts & Sciences Electronic 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+ …

Genomic Contributors To Individual Differences In Reward-Related Neural Activity, Lindsay Jane Michalski

Arts & Sciences Electronic Theses and Dissertations

Aberrant reward-related behavior, including impulsive and risk-taking behaviors, is a common feature of externalizing psychopathology (e.g., attention deficit hyperactivity disorder, antisocial personality disorder, and substance-use disorders). Through imaging studies, these behaviors have been linked to dysregulated reactivity within a diffuse reward-related corticostriatal neural network, including the striatum, frontal regions (namely orbital, ventromedial, and dorsolateral cortices), the insula, and the hippocampus. Because variability in risk-taking behavior and related psychopathology is moderately-to-largely heritable (i.e., with estimates ranging from 40 – 80%), a genetically-informed approach is well-positioned to provide valuable insight into the etiology of reward-related neural and behavioral phenotypes that characterize externalizing …

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

Arts & Sciences Electronic 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 …

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

Arts & Sciences Electronic 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 …

Development And Application Of Mass Spectrometry-Based Protein Footprinting In Structural Proteomics, Ming Cheng

Arts & Sciences Electronic Theses and Dissertations

Integral mass spectrometry (MS) has emerged as an important tool for protein structural characterization. It readouts are a broad range of structural information, including stoichiometry, interactions, conformations and conformation change, and dynamics. Protein footprinting is a pivotal component in the intergral MS toolkit.My dissertation centers around the development and application of protein footprinting to characterize protein structure. It is divided into seven chapters.Chapter 1 serves as the introduction for integral mass spectrometry in structural proteomic.In Chapter 2, we extended the fast-photochemical oxidation of proteins (FPOP) platform by adding the trifluoromethyl radical (•CF3) as a new reagent. We discovered that •CF3 …

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

Arts & Sciences Electronic 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 …

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

Arts & Sciences Electronic 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 …

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 Electronic 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 …

Functional Dissociations Revealed By Representational Similarity Analysis Of Color-Word Stroop, Michael Freund

Arts & Sciences Electronic Theses and Dissertations

The color-word Stroop task is often used in cognitive neuroscience as a common platform for both theoretical and experimental approaches to cognitive control. Yet traditionally, there has been tension between these two approaches. Theoretical models of Stroop have focused on representation: for example, how distributed and overlapping representations of the two stimulus dimensions (color, word) are prioritized, and how conflict between these dimen- sions is represented and used to regulate control. In contrast, neuroimaging experiments have primarily focused on ‘univariately’ (uniformly) mapping the effects of conflict to par- ticular brain regions. This focus on univariate changes in brain activity limits …

Mechanism Of Activation Of Uvrd Helicase By A Processivity Factor Mutl, Yerdos Ordabayev

Arts & Sciences Electronic Theses and Dissertations

E. coli UvrD is a superfamily 1A helicase/translocase involved in DNA repair, recombination, and replication. I investigated the role of E. coli MutL, a regulatory protein involved in methyl-directed mismatch DNA repair, in the regulation of UvrD-catalyzed DNA unwinding. Using single molecule fluorescence resonance energy transfer (FRET) and single round stopped-flow DNA unwinding experiments I demonstrated that MutL can activate latent UvrD monomer helicase activity and also stimulate UvrD dimer helicase activity. Furthermore, using analytical ultracentrifugation experiments I determined that a single MutL dimer is sufficient to activate UvrD monomer helicase. DNA unwinding experiments with a series of DNA substrates …

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

Arts & Sciences Electronic 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 …

Siderophore-Dependent Transport Paradigms For Iron Across The Bacterial Cell Envelope In The Human Pathogen Staphylococcus Aureus, Nathaniel Endicott

Arts & Sciences Electronic Theses and Dissertations

This work is focused on iron trafficking through ABC transporters in Staphylococcus aureus and combatting the growing antimicrobial resistance crisis by exploiting virulence factors as therapeutic targets. Specifically, the goal was to understand the role of a siderophore-binding lipoprotein FhuD2 in S. aureus iron trafficking. While S. aureus endogenously produces three metallophores for metal sequestration from the host, FhuD2 is thought to scavenge metals from hydroxamate-based xenosiderophores encountered in the host environment. FhuD2 is a critical virulence factor and vaccine candidate (Novartis) for MRSA. Since xenosiderophore scavenging systems are often dispensable, it was hypothesized that FhuD2 must be playing another …

Genomic Signatures Of Conflict And Cooperation In Plants And Social Amoebae, Katherine Sylvia Geist

Arts & Sciences Electronic Theses and Dissertations

Arms races involve bouts of reciprocal co-adaptation to a social environment. We have a strong sense for how arms races drive the evolution of genes in purely antagonistic contexts, such as host-pathogen or predator-prey. In these systems, conflict that produces arms races between two parties results in positive selection – the fixation of adaptive alleles between species – for both parties. However, we do not have an equal sense for how arms races during cooperative enterprises shape genic evolution. If we assume that arms races affect genic evolution similarly regardless of context – antagonistic or cooperative – then we would …

Regulation Of The Yeast Cell Cycle Checkpoint Kinase Tel1 At Double-Strand Dna Breaks And At Telomeres, Sarem Hailemariam

Arts & Sciences Electronic Theses and Dissertations

The work discussed in this dissertation focuses on two distinct areas that are critical for genome maintenance. Both areas are focused on the regulation of the Saccharomyces cerevisiae checkpoint kinase Tel1 by the MRX complex. Tel1 kinase initiates cell cycle checkpoint in response to double-strand DNA breaks. Tel1 also plays a major role in telomere maintenance. Tel1’s function both in checkpoint signaling and telomere regulation is dependent on the Mre11-Rad50-Xrs2 complex. In Chapter II, I describe a robust biochemical approach aimed at reconstituting the initial stages of double-strand DNA break response using purified proteins in order to address how the …

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

Arts & Sciences Electronic 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 …

Quantitatively Studying Tissue Damage In Multiple Sclerosis Using Gradient Recalled Echo Mri Sequences, Biao Xiang

Arts & Sciences Electronic Theses and Dissertations

Multiple Sclerosis (MS) is an unpredictable, often disabling disease of the central nervous system (CNS) that disrupts the flow of information within the brain, and between the brain the body. MS is the most common progressive neurologic disease of young adults, affecting approximately 2.3 million people worldwide. It is estimated that more than 700,000 individuals are affected by MS in United States. While MS has been studied for decades, the cause of it is still not definite and a fully effective treatment for MS is not yet available.

Magnetic resonance imaging (MRI) has been used extensively in MS diagnosis and …

Visual And Chemosensory Pathways Associated With Male Courtship Decisions In Drosophila Melanogaster, Ross Mckinney

Arts & Sciences Electronic Theses and Dissertations

Successful mating in diverse animal species often depends on ritualistic sequences of spatially and temporally coordinated behavioral elements. Yet, the sensory cues and neural circuits that mediate optimal mating display patterns are largely unknown. The courtship ritual in Drosophila melanogaster consists of a well-studied sequence of behavioral elements — including orienting, chasing, tapping, singing, and licking — that are known to depend on several sensory modalities, including both vision and chemosensation. However, the specific sensory inputs utilized by males to direct the spatial and temporal transitions between different elements of the courtship ritual are not well understood. In this thesis, …

Understanding The Transcriptional Mechanisms Underlying Dendritic Cell Development, Prachi Bagadia

Arts & Sciences Electronic Theses and Dissertations

Dendritic cells (DCs) comprise an important immune lineage that plays a critical role in initiating and sustaining the proper immune response. They can be divided into two distinct branches, classical/conventional DCs (cDCs) or plasmacytoid DCs (pDCs). cDCs can further be classified as cDC1 or cDC2. Each DC subset exerts unique functions in vivo and are necessary for a complete immune response. The precise transcriptional programs underlying DC specification and commitment remain unclear. cDC1, cDC2, and pDC all arise from the common DC progenitor (CDP) in the bone marrow. How the CDP gives rise to all three DC subsets in an …

The Role Of Mitofusins In The Osteoclast Lineage, Anna Ballard

Arts & Sciences Electronic Theses and Dissertations

Mitochondria exist in a highly dynamic network in many cell types, and mutations in mitochondrial transmembrane GTPase mitofusin2 (MFN2), a key factor that mediates mitochondrial tethering, cause defects in the nervous system. Intriguingly, the skeleton has been overlooked in patients with such mutations. Because expression of MFN2 and its homolog, mitofusin1 (MFN1) increase with maturation of osteoclasts (OCs), which are rich in mitochondria, we sought to determine the role of mitofusins in the OC lineage. Double knockout of Mfn1 and Mfn2 in OC precursors by Lysozyme-M cre reveals that mitofusin activity is required for OC function and maintenance of bone …

Siderophore-Dependent Transport Paradigms For Iron Across The Bacterial Cell Envelope In The Human Pathogen Staphylococcus Aureus, Nathaniel Endicott

Arts & Sciences Electronic Theses and Dissertations

This work is focused on iron trafficking through ABC transporters in Staphylococcus aureus and combatting the growing antimicrobial resistance crisis by exploiting virulence factors as therapeutic targets. Specifically, the goal was to understand the role of a siderophore-binding lipoprotein FhuD2 in S. aureus iron trafficking. While S. aureus endogenously produces three metallophores for metal sequestration from the host, FhuD2 is thought to scavenge metals from hydroxamate-based xenosiderophores encountered in the host environment. FhuD2 is a critical virulence factor and vaccine candidate (Novartis) for MRSA. Since xenosiderophore scavenging systems are often dispensable, it was hypothesized that FhuD2 must be playing another …

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

Arts & Sciences Electronic 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 …

Force Requirements And Force Generation During Endocytosis In Yeast, Jonah Kyle Scher-Zagier

Arts & Sciences Electronic Theses and Dissertations

Endocytosis is a process by which cells bring external materials into the intracellular environment and perform other essential biological functions. The main drivers of endocytosis include clathrin and actin, which help shape the membrane and form the endocytic invagination. In mammalian cells and other cells lacking a wall, the primary barriers to endocytosis are the bending rigidity of the cell membrane and surface tension. However, in cells with a rigid cell wall, such as those of yeast, this process is opposed by a substantial pressure within the cell, known as the turgor pressure, which is generated by a difference in …