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- Genre: Masters Thesis
- Resource Type: Text
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
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
This study focuses on mapping faults along the Creeping Section of the San Andreas Fault (CSAF) in California between San Juan Bautista (121.54°W 36.85°N) and Parkfield (120.41°W 35.87°N). I synthesize high-quality base data, including and lidar topography from B4, EarthScope, and USGS 3DEP, recent maps of decadal-scale along-fault shear strain, and aerial and satellite imagery. Using these data, I produced (covering 150 km at 1:10,000 scale) three geospatial map datasets with attributes: geomorphic indicators of faulting, surficial geology, and active fault traces.The CSAF's creeping movement, though likely not associated with large earthquakes, has the potential to cause damage to infrastructure. Accurate fault mapping facilitates fault displacement hazard assessment. This type of work is useful for California state regulations, particularly the Alquist-Priolo Act of 1972, providing insights for engineering site assessments and fault exclusion zones.
I discern, categorize, and rank geomorphic indicators to support fault line placement. This approach contributes to the identification of surface expression of creeping faults where the surface has undergone alteration in response to displacement along the fault. I created a surficial geologic map spanning from San Juan Bautista to the southern extent of EarthScope lidar coverage (120.59°W 36.03°N). I categorized each fault as either a primary or secondary fault trace and further broke them into confidence levels based on interpretations of indicators along with structural geologic reasoning and
topographic patterns. Accessible target areas containing initial low confidence mapping or interesting structures were visited in the field.
Zones along the creeping section exhibit structures such as a pressure ridge found 25 km north of Parkfield, sigmoidal faults and sagponds observed near Paicines Ranch (121.29°W 36.68°N), en-echelon faults, horsetail splays and Riedel shear structures near Lewis Creek (120.87°W 36.29°N). Controls on the structural style along the CSAF are the results of geologic units through which the faults cut and fault zone width and trend.
ContributorsPowell, Joseph Hoss (Author) / Arrowsmith, Ramon (Thesis advisor) / Scott, Chelsea (Thesis advisor) / DeVecchio, Duane (Committee member) / DeLong, Stephen (Committee member) / Arizona State University (Publisher)
Created2023