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- Genre: Academic theses
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I studied the evolution and cell biology of Paramecium tetraurelia—a model ciliate with over 40,000 distinct protein-coding genes resulting from as many as three ancient whole-genome duplication events. I was interested in the functional diversification of these gene duplicates at the level of protein localization, but the commonly used tools to study this were tedious. I instead applied a protein-correlation profiling approach to this system by way of generating a dozen sub-cellular fractions with different protein constituents due to the density of their resident organelle and then assayed these fractions using quantitative mass spectrometry. Each protein’s unique abundance profile provided evidence for its subcellular localization, and I used both supervised and unsupervised classification algorithms to cluster proteins together based on the similarity of these profiles to several hundred “marker proteins” which I manually curated. After expanding the protein inventory for numerous organelles by as many as a thousand proteins, I determined many features not previously understood or appreciated such as mosaic biochemical pathways, evidence for differential sorting mechanisms, and the abnormal evolutionary patterns of the mitochondrial proteome of ciliates. I developed a simple bioinformatic tool to probe spatial proteomics datasets more easily for proteins of interest. I demonstrate its applicability using a handful of well-characterized proteins in the budding yeast Saccharomyces cerevisiae as well as interesting proteins in less well-studied model systems like P. tetraurelia and the apicomplexan Toxoplasma gondii to both recapitulate known interactions and discover new ones. Finally, I look for large-scale evidence of gene duplicates relocalizing to new cellular compartments in P. tetraurelia and S. cerevisiae using this new dataset and a previously generated one, respectively. I find thousands of pairs of duplicates which are differentially identified and display evidence for subcellular divergence, and this seems to be largely decoupled from large changes in protein sequence but are instead associated with indels in their N-terminal peptide. These findings support the use of high-throughput proteomic techniques to determine evidence of functional divergence of gene duplicates. Taken together, this works provides a deep characterization of one of the largest unicellular proteomes in nature.
ContributorsLicknack, Timothy James (Author) / Lynch, Michael (Thesis advisor) / Wideman, Jeremy (Committee member) / Chen, Julian (Committee member) / Taylor, Jay (Committee member) / Arizona State University (Publisher)
Created2022
Description
Embryonic and juvenile development consist of a series of complex and rapid changes driven by a suite of crucially timed developmental cues within the cell. The developmental process begins at the moment of zygote activation, “jump-started” by maternal factors such as mRNA and proteins until transcription can be zygotically-driven. Regulation of transcription initiation plays a crucial role in this process, as minute changes in the timing, density, and characteristics of gene expression can have drastic effects on the zygote’s development. Specific promoter elements can be linked to different patterns of transcription, driving both ubiquitous and sharply regulated gene expression, thus forming the basis for the time-sensitive developmental processes. In order to better understand the genes expressed during different stages of development and the impact of promoter elements on transcription patterns and transcript concentrations within the cell, I created a Gene Expression and Promoter Atlas in two species within the cryptic species complex, Daphnia pulex. I surveyed five embryonic and two juvenile developmental stages in both a North American and mitochondrially European Daphnia pulex utilizing developmental landmarks to visually stages embryos. A total of 17,993 genes were identified in the European species and 15,295 were identified in the North American species, with 11,551 orthologs identified between the two. I utilized the transcription start site (TSS) profiling method STRIPE-seq to identify promoter motifs and RNA-seq to survey mRNA concentration at each stage, generating a wealth of genetic data. The methodology for library construction and the dataset generated therein provide an informative basis for further comparative developmental studies and the elucidation of full gene functionality in an emerging model organism.
ContributorsWalls, Sarah (Author) / Lynch, Michael (Thesis advisor) / Raborn, R. Taylor (Committee member) / Mangoni, Marco (Committee member) / Harris, Robin (Committee member) / Arizona State University (Publisher)
Created2022
Description
Bexarotene is a Food and Drug administration (FDA)-approved therapeutic used in the treatment of cutaneous T-cell lymphoma (CTCL). However, bexarotene therapy causes significant side effects like hyperlipidemia and hypothyroidism due to crossover activity with retinoic acid receptor (RAR), thyroid hormone receptor (TR), and liver X receptor (LXR) signaling, respectively. More recently bexarotene has shown promise to reverse neurodegeneration, improve cognition and decrease levels of amyloid- β in transgenic mice expressing familial Alzheimer’s disease (AD) mutations. Bexarotene is a high affinity ligand for the retinoid X receptor (RXR) that heterodimerizes with the liver- X- receptors (LXR) and with peroxisome proliferator-activated receptor-gamma (PPARϒ) to control cholesterol efflux, inflammation, and transcriptionally upregulates the production of apolipoprotein (ApoE) in the brain. Enhanced ApoE expression may promote clearance of soluble Aβ peptides from the brain and reduce Aβ plaques, thus resolving both amyloid pathology and cognitive deficits. The present study assessed the potential of bexarotene and a group of 62 novel rexinoids to bind and activate RXR using a series of biological assays and screening methods, including: 1) a mammalian two-hybrid system (M2H) and an 2) Retinoid X Receptor response element (RXRE)-mediated reporter assays in cultured human cells. Moreover, Liver X Receptor response element (LXRE)-mediated luciferase assays were performed to analyze the ability of the novel analogs to activate LXRE - directed transcription, and to induce ApoE messenger ribonucleic acid (mRNA) in U87 glial cells. Furthermore, the most potent analogs were analyzed via quantitative polymerase chain reaction (qPCR) to determine efficacy in modulating expression of two critical tumor suppressor genes, activating transcription factor 3 (ATF3) and early growth response 3 (EGR3). Results from these multiple assays indicate that the panel of RXR ligands contains compounds with a range of activities, with some analogs capable of binding to RXR with higher affinity than others, and in some cases upregulating ApoE expression to a greater extent than bexarotene. The data suggests that minor modifications to the bexarotene core chemical structure may yield novel analogs possessing an equal or greater capacity to activate RXR and may be useful as therapeutic agents against CTCL and Alzheimer’s disease.
ContributorsReshi, Sabeeha Mushtaq (Author) / Jurutka, Peter (Thesis advisor) / Wagner, Carl (Committee member) / Marshall, Pamela (Committee member) / Arizona State University (Publisher)
Created2023
Description
Mutation is the source of heritable variation of genotype and phenotype, on which selection may act. Mutation rates describe a fundamental parameter of living things, which influence the rate at which evolution may occur, from viral pathogens to human crops and even to aging cells and the emergence of cancer. An understanding of the variables which impact mutation rates and their estimation is necessary to place mutation rate estimates in their proper contexts. To better understand mutation rate estimates, this research investigates the impact of temperature upon transcription rate error estimates; the impact of growing cells in liquid culture vs. on agar plates; the impact of many in vitro variables upon the estimation of deoxyribonucleic acid (DNA) mutation rates from a single sample; and the mutational hazard induced by expressing clustered regularly interspaced short palindromic repeat (CRISPR) proteins in yeast. This research finds that many of the variables tested did not significantly alter the estimation of mutation rates, strengthening the claims of previous mutation rate estimates across the tree of life by diverse experimental approaches. However, it is clear that sonication is a mutagen of DNA, part of an effort which has reduced the sequencing error rate of circle-seq by over 1,000-fold. This research also demonstrates that growth in liquid culture modestly skews the mutation spectrum of MMR- Escherichia coli, though it does not significantly impact the overall mutation rate. Finally, this research demonstrates a modest mutational hazard of expressing Cas9 and similar CRISPR proteins in yeast cells at an un-targeted genomic locus, though it is possible the indel rate has been increased by an order of magnitude.
ContributorsBaehr, Stephan (Author) / Lynch, Michael (Thesis advisor) / Geiler-Samerotte, Kerry (Committee member) / Mangone, Marco (Committee member) / Wilson, Melissa (Committee member) / Arizona State University (Publisher)
Created2023
Description
Large-scale civil infrastructure systems are critical for the functioning and development of any society. However, these systems are often vulnerable to degradation and the effects of aging, necessitating consistent monitoring and maintenance. Current methods for infrastructure maintenance primarily rely on human intervention and need the implementation of advanced sensing and computing technologies in field operations and maintenance (O&M) tasks. This research aimed to address these gaps and provide novel contributions. Specifically, the objectives of this study were to leverage artificial intelligence models to enhance point cloud noise processing, to automate tree species detection using Mask R-CNN, and to integrate imagery data and LiDAR datasets for real-time terrain analysis. First, the study proposed leverages neural networks to eliminate unwanted noise from point cloud datasets, enhancing the accuracy and reliability of infrastructure data. Secondly, the research integrated Mask R-CNN into automated tree species detection. This component offers an efficient solution to identify and classify vegetation surrounding infrastructure, enabling infrastructure managers to devise proactive vegetation management strategies, thereby reducing risks associated with tree-related incidents. Lastly, the study fused image and LiDAR datasets to support real-time terrain analysis. This integrated approach provides a comprehensive understanding of terrain characteristics, allowing infrastructure managers to assess slope, elevation, and other relevant factors, facilitating proactive maintenance interventions and mitigating risks associated with erosion. These contributions collectively underscore the potential of artificial intelligence models in advancing the operations and maintenance practices of large civil infrastructure systems. By leveraging these models, infrastructure managers can optimize decision-making processes, streamline maintenance efforts, and enhance critical infrastructure networks' overall resilience and sustainability.
ContributorsPaladugu, Bala Sai Krishna (Author) / Grau, David (Thesis advisor) / Ernzen, James (Committee member) / Standage, Richard (Committee member) / Arizona State University (Publisher)
Created2023
Description
The consequences of failures from large-diameter water pipelines can be severe. Results can include significant property damage, damage to adjacent infrastructure such as roads and bridges resulting in transportation delays or shutdowns, adjacent structural damage to buildings resulting in loss of business, service disruption to a significant number of customers, loss of water, costly emergency repairs, and even loss of life. The American Water Works Association’s (AWWA) 2020 “State of the Water Industry” report states the top issue facing the water industry since 2016 is aging infrastructure, with the second being financing for improvements. The industry must find innovative ways to extend asset life and reduce maintenance expenditures. While are many different assets comprise the drinking water industry, pipelines are a major component and often neglected because they are typically buried. Reliability Centered Maintenance (RCM) is a process used to determine the most effective maintenance strategy for an asset, with the ultimate goal being to establish the required function of the asset with the required reliability at the lowest operations and maintenance costs. The RCM philosophy considers Preventive Maintenance, Predictive Maintenance, Condition Based Monitoring, Reactive Maintenance, and Proactive Maintenance techniques in an integrated manner to increase the probability an asset will perform its designed function throughout its design life with minimal maintenance. In addition to determining maintenance tasks, the timely performance of those tasks is crucial. If performed too late an asset may fail; if performed too early, resources that may be used better elsewhere are expended. Utility agencies can save time and money by using RCM analysis for their drinking water infrastructure. This dissertation reviews industries using RCM, discusses the benefits of an RCM analysis, and goes through a case study of an RCM at a large aqueduct in the United States. The dissertation further discusses the consequence of failure of large diameter water pipelines and proposes a regression model to help agencies determine the optimum time to perform maintenance tasks on large diameter prestressed concrete pipelines using RCM analysis.
ContributorsGeisbush, James R (Author) / Ariaratnam, Samuel T (Thesis advisor) / Grau, David (Committee member) / Chong, Oswald (Committee member) / Arizona State University (Publisher)
Created2024
Description
Phenotypic evolution is of great significance within biology, as it is the culmination of the influence of key evolutionary factors on the expression of genotypes. Deeper studies of the fundamental components, such as fitness effects of mutations and genetic variance within a population, allow one to predict the evolutionary trajectory of phenotypic evolution. In this regard, how much the change in mutational variance and the ongoing natural selection influence the rate of phenotypic evolution has yet to be fully understood. Therefore, this study measured mutational variances and the increasing rate of genetic variance during the experimental evolution of Escherichia coli populations, focusing on two growth-related traits, the populational maximum growth rate and carrying capacity. Mutational variances were measured by mutation-accumulation experiments, which allowed for the analysis of the effects of spontaneous mutations on growth-related traits in the absence of selection. This analysis revealed that some evolved populations developed a higher mutational variance for growth-related traits. Further investigation showed that most evolved populations have also developed a greater mutational effect, which could explain the increase in mutational variance. Finally, the genetic variances for most evolved populations are lower than expected in the absence of selection, and the involvement of either stabilizing or directional selection is evident. Future experiments with a larger sample size of experimentally evolved populations, as well as more intermediate timepoints during experimental evolution, may provide further insight regarding the complexities of the evolutionary outcomes of these traits.
ContributorsGonzales, Jadon (Author) / Lynch, Michael (Thesis advisor) / Geiler-Samerotte, Kerry (Committee member) / Ho, Wei-Chin (Committee member) / Arizona State University (Publisher)
Created2023
Description
The world faces significant environmental and social challenges due to high economic development, population growth, industrialization, rapid urbanization, and unsustainable consumption. Global communities are taking the necessary measures to confront these international challenges and applying sustainable development principles across all sectors. Construction is a critical driving instrument of economic activity, and to achieve sustainable development, it is vital to transform conventional construction into a more sustainable model. The research investigated sustainable construction perceptions in Kuwait, a rapidly growing country with a high volume of construction activities. Kuwait has ambitious plans to transition into a more sustainable economic development model, and the construction industry needs to align with these plans. This research aims to identify the characteristics of sustainable construction applications in the Kuwaiti construction market, such as awareness, current perceptions, drivers and barriers, and the construction regulations' impact. The research utilized a qualitative approach to answer research questions and deliver research objectives by conducting eleven Semi-structured interviews with experienced professionals in the Kuwaiti construction market to collect rich data that reflects insights and understandings of the Kuwaiti construction industry. The Thematic analysis of the data resulted in six themes and one sub-theme that presented reflections, insights, and perspectives on sustainable construction perceptions in the Kuwaiti construction market. The research findings reflected poor sustainable construction awareness and poor environmental and social application in the construction industry, the determinant role of construction regulations in promoting sustainable construction. and barriers and drivers to sustainable construction applications. The research concluded with answers to research questions, delivery of research objectives, and an explanation of sustainable construction perceptions in the Kuwaiti construction market.
Contributorsalsalem, mohammad salem (Author) / Duran, Melanie (Thesis advisor) / Chong, Oswald (Committee member) / Sullivan, Kenneth (Committee member) / Grau, David (Committee member) / Arizona State University (Publisher)
Created2023
Description
Microbial diversity manifests differently in different ecological niches of the body, with greater diversity generally expected in the gut, given that different locations have unique roles to play in the digestive system. Most microbial research is conducted using fecal samples, meaning the resulting microbes come from various places all throughout the intestines and not specific locations. The Integrative Human Microbiome Project (HMP2), provides a unique opportunity to study microbiomes of both the rectum and ileum through the use of biopsy samples taken from both locations. Using the data provided the microbiome compositions of the rectum and ileum were able to be studied and analyzed to showcase how those microbes associated with clinical variables. Inflammatory bowel diseases are complex diseases that are heterogeneous at clinical, immunological, molecular, genetic, and microbial levels. While it is known that those affected by these diseases have microbiomes that differ from those with healthy guts, not much is known about which changes in the microbiome represent causes rather than effects from changes in health.
ContributorsVecchio, Kurt (Author) / Zhao, Yunpeng (Thesis advisor) / Wang, Yue (Committee member) / Jurutka, Peter (Committee member) / Arizona State University (Publisher)
Created2023
Description
The accelerated pace of globalization necessitates that civil engineering graduates possess a broad spectrum of competencies to meet the evolving needs of a dynamic, interconnected professional environment. This necessity encompasses a blend of practical, personal, and intercultural skills in aspiring engineers, driven by employers' increasing demand for multifaceted skill sets. International research experiences are pivotal in bridging the gap between traditional academic training and the complexities of the real world, offering substantial benefits in terms of personal growth, intercultural understanding, and enhanced research innovation through exposure to diverse methodologies and global professional networks. Despite these advantages and the critical need for engineers adept at navigating the global landscape, participation in international programs remains markedly low among civil engineering graduates, underlining an urgent need for increased engagement and methodological research to elucidate the immediate and long-term benefits of such experiences. This dissertation critically assesses the effects of international research experience on developing key competencies of graduate students, including personal, academic, and professional development, intellectual growth, and intercultural competence. Recognizing the scarcity of rigorous, empirical studies capturing the comprehensive benefits of abroad research, this study adopts a mixed-methods approach, combining quantitative surveys with qualitative interviews to enhance the validity and reliability of findings through data triangulation. Additionally, data collection occurs at multiple time points before and after the experience, providing an in-depth exploration of how such experiences contribute not only to immediate skill enhancement but also to sustained competence development. The research addresses a critical gap in the existing literature, providing evidence-based insights into the multifaceted value and transformative potential of these experiences on graduate engineering competence advancement. The findings indicate improvements in academic proficiency, marked by adopting innovative research techniques and professional capabilities through expanded networks and enhanced communication skills. Moreover, immersion in international settings elevated students' self-reliance and global consciousness, alongside fostering comprehensive growth in intercultural understanding, thereby contributing to their holistic development across personal, intellectual, and professional domains. Through this comprehensive analysis, the study aims to offer actionable recommendations for designing and evaluating future research programs abroad to foster engineering graduates with the advanced competencies required to tackle contemporary challenges and flourish in the global environment.
ContributorsMehrabi Moezabadi, Daniel (Author) / Grau, David (Thesis advisor) / Ariaratnam, Samuel (Thesis advisor) / Edward Gibson, George (Committee member) / Arizona State University (Publisher)
Created2024