Regulation of Brain Infiltrating Immune Cells by MIR-155 Expression in T Cells and Dendritic Cells

Thompson, Jacob William The University of Utah ProQuest Dissertations & Th 2023 해외박사(DDOD)

During neuroinflammation, immune cells infiltrating into the CNS express and release a wide range of factors to either drive inflammation or keep it under control. This balance is regulated in part by a pro-inflammatory microRNA-155. miR-155 is expressed highly in the serum and CNS lesions of patients with multiple sclerosis. Mice lacking miR-155 have reduced disease severity during the progression of experimental autoimmune encephalomyelitis (EAE), due in part to a reduction in CNS-infiltrating Th17 T cells. I was able to utilize single-cell RNA sequencing to clearly demonstrate a reduction in CNS-infiltrating T cells, dendritic cells, and macrophages in mice lacking miR-155 expression in all cell types. I further determined, using conditional knockout mice, that although miR-155 is expressed highly throughout the immune system, not all cell types require miR-155 expression to drive EAE disease severity. Deletion of miR-155 in T cells lead to a drastic reduction in EAE disease, similar to the whole-body deletion, whereas deletion in dendritic cells lead to a less disease progression but to a lesser extent. Macrophages, while expressing high levels of miR-155, did not need miR-155 expression for full EAE disease severity. I further look into the possible interactions that DCs might have with resident glial cells during neuroinflammation to better understand how these cells could be contributing to disease. I also look into novel roles that miR-155 binding may have on non-canonical binding sites within the CDS, alternative splicing of the IL7R, and the roles of miR-155-containing extracellular vesicles during EAE.

Experimental Analysis of Heat Transfer in the Atmospheric Boundary Layer over a Thermally Heterogeneous Land-Surface

Morrison, Travis James The University of Utah ProQuest Dissertations & Th 2021 해외박사(DDOD)

An accurate representation of the transport of heat at the earth’s surface is important for the modeling and understanding of the atmospheric boundary layer. For decades, heat transport has been studied experimentally through the surface energy balance (SEB), which has been difficult to close and remains an outstanding problem in the boundary layer community. The SEB has traditionally been studied as a one-dimensional column, neglecting the important impacts of spatial heterogeneity. Herein we address the assumptions of spatial homogeneity through development of new measurement techniques with thermal imagery, as well as, collecting data from a high-density array of sensors to compute the governing equations in all three dimensions. To accomplish this experimental data from both the Mountain Terrain Atmospheric Modeling and Observations Program (MATERHORN) and the Idealized Planar Array experiment for quantifying Spatial Heterogeneity (IPAQS) are used to advance our understanding of the SEB from a multi-dimensional approach. Both data sets are acquired at the seemly flat and thermally heterogeneous desert playa at the U.S. Army Dugway Proving Grounds Surface Layer Turbulence and Environmental Science Test (SLTEST) facility, in Utah’s West Desert. The presented analysis and methodologies are particularly focused measuring terms which arise from the decomposition of the substantial derivative in the temperature tendency equation. Through study of the transport terms of heat (i.e., advection, dispersive fluxes, and turbulence) over scales of O ∼10 m–100 m we show the importance of horizontal variability on the turbulent sensible heat flux, horizontal advection, and dispersive fluxes and their impact on the SEB. Lastly, these results are used to help begin to parameterise these often unresolved transport terms using direction from recent large eddy simulation results. Initial findings show a promising link between surface temperature heterogeneity strength and the transport terms.

Implications of Language in the Therapeutic Process and Relationship with Gender Nonconforming Individuals

Metzler, S. Candice The University of Utah ProQuest Dissertations & Th 2020 해외박사(DDOD)

The underlying goal of all five of the chapters in this manuscript is to better understand how language facilitates or impedes care for gender nonconforming (GN) people, individuals who experience and/or express aspects of gender that do not conform to social expectations, through (1), access (2), knowledge, (3), quality of care, and (4) education. GN individuals are more likely to need access to mental health treatment, yet many avoid seeking care out of fear of further mistreatment. This study seeks to understand how language may play a role in the care process and access to care. Chapter 1 is an introduction to the idea of language as a regulatory process. This chapter is an introduction to the population and reviews relevant literature. Chapter 2 explores institutional language as a key element for access to care by examining intake forms collected from mental health clinics throughout the state of Utah. Chapter 3 examines the role of social work education in preparing students for practice with GN individuals. This exploration is conducted by examining descriptions of gender and GN experience from the perspective of social work students. Chapter 4 explores how social work students ascribe meaning to GN experiences may reflect patterns of communication and influence the therapeutic relationship and working alliance. Chapter 5 is a summary of the research findings. This chapter addresses the implications of the research findings and provides specific practice, education, and policy recommendations.

Too Few to Count: An Exploration of Perceptions of Heart Health among African Americans Living in Geographic Areas of Low Cultural and Community Density

Flattes, Valerie Jean The University of Utah ProQuest Dissertations & Th 2020 해외박사(DDOD)

Cardiac risk factors disproportionately affect African Americans in the United States (US). African Americans are more likely to die from heart disease. The same is true for African Americans in the state of Utah where they comprise less than 2% of the population. Most research studies about heart disease have been conducted in areas where the African American population is larger. There are no areas or communities of high African American population density or cultural concentration in Utah like one would find in other areas of the United States (e.g., the southeastern United States or urban settings). There is minimal research regarding the perception of heart health in this minority community in Utah.The purpose of this study was to explore the meaning of heart health among a sample of African American participants living in Utah. This qualitative descriptive study focused on their thoughts about how they understand the concept of heart health, where they got information about heart health, and what influenced their understanding including experiences in health care and their interactions with healthcare providers. The approach involved ethnographic data collection methods and grounded theory coding and analysis techniques. Twenty people between the ages of 40–79 were interviewed. Interviews were transcribed, coded, and analyzed. Participant observation involved participation in social and health activities with African Americans from the area. Field notes were kept to document experiences and for journaling.Participants described very little formal information about heart health but did relate their understanding to their personal and family experiences with illness. They discussed not having access to providers who look like them and dealing with daily challenges that tended to increase stress. Central themes identified in their accounts were Heart is Healthy if the Body is Healthy, Interaction With the Healthcare System, Minority-Related Stress, and Living With Racism.Several recommendations based on findings may be useful in improving disparities related to heart health. These include improving health literacy and education about heart health through tailored and targeted messaging and. increasing the number of African American students in the health professions in Utah and retaining them when they are ready to practice. Further research should explore comparing African Americans living in different contexts to reveal within-group differences.

Long-term, Adverse Cardiovascular, Genitourinary, and Gastrointestinal Outcomes Among Endometrial Cancer Survivors in a Population-based Cohort Study

Soisson, Sean Patrick The University of Utah ProQuest Dissertations & Th 2017 해외박사(DDOD)

Endometrial cancer is the second most common cancer among female cancer survivors in the United States. A variety of long-term, adverse health effects have been observed among endometrial cancer survivors but the relationship between endometrial cancer diagnosis and treatment and these outcomes among survivors, years after diagnosis remains poorly understood. Because of the high survival rate and the increasing rate at which new cases are being diagnosed, examining the risk for long-term, adverse health effects among endometrial cancer survivors is essential.Cohorts of 2,648 endometrial cancer survivors diagnosed in Utah between 1997 and 2012 and 10,503 age-matched, cancer-free women from the general population were identified. Electronic medical record data including all International Classification of Diseases , 9th revision (ICD-9) diagnosis codes from Utah's two largest healthcare providers as well as statewide ambulatory surgery and inpatient records were used to capture all available cardiovascular, genitourinary, and gastrointestinal outcomes. Cox regression models were used to estimate risk for outcomes between survivors and individuals in the general population at 1-5 and >5-10 years after diagnosis. Cox regression models were also used to examine potential risk factors for various conditions among endometrial cancer survivors.Endometrial cancer survivors were at elevated risk for cardiovascular, genitourinary, and gastrointestinal disorders overall and for dozens of more specific outcomes within these broader categories compared to the general population. Between 1-5 years after diagnosis,endometrial cancer survivors treated with surgery in conjunction with chemotherapy and/or radiation were at elevated risk for heart, circulatory system, urinary system, genital organ, upper gastrointestinal, lower gastrointestinal, abdominal hernia, and liver disorders compared to those treated with surgery alone. Elevated risk for abdominal hernias and lower gastrointestinal disorders persisted between >5-10 years after diagnosis.These results present sufficient evidence that endometrial cancer survivors experience a greater burden of adverse cardiovascular, genitourinary, and gastrointestinal outcomes many years after diagnosis compared to the general population and that these outcomes may be related to cancer treatment. Many of these conditions contribute to increased morbidity and mortality and adversely affect quality of life. For these reasons, greater attention should be focused both on long-term surveillance and prevention of these conditions among endometrial cancer survivors.

Seismic Discrimination of Earthquakes and Explosions Using Comparisons of Local Magnitude (ML) and Coda Magnitude (MC)

Holt, Monique Maria The University of Utah ProQuest Dissertations & Th 2021 해외박사(DDOD)

The Comprehensive Nuclear-Test-Ban Treaty (CTBT) bans nuclear weapons testing worldwide. Seismology is often used for treaty verification due to its ability to characterize surficial and underground explosions. An important aspect of this characterization is seismic discrimination or using seismology to distinguish anthropogenic explosions from natural earthquakes. The difference between local magnitude (ML) and coda duration magnitude (MC) is a seismic depth discriminant that is designed to work on seismic events recorded at local distances (< 250 km). Depth discrimination relies on the fact that seismic events occurring below a certain depth could not possibly be anthropogenic (i.e., could not be nuclear explosions). However, shallow events may require further investigation. A pilot study found that ML–MC was more negative for shallow, mining-induced events than for deeper, tectonic earthquakes in Utah. Since ML is a function of amplitude and MC is a function of duration, this means the waveforms of shallow events are longer than those of deep events. My dissertation explores ML–MC as a discriminant to see if it can be used to help verify the CTBT. First, I investigated how ML–MC varied with depth for earthquakes in Yellowstone National Park (USA), Oklahoma and Kansas (USA), and Italy. I found that ML–MC increased with depth the same way in each region, and the increase was statistically significant. Then, I found the optimum form and conditions to apply ML–MC using a catalog of earthquakes, mining induced events, and explosions from Utah. Data collected within 100 km of a seismic event best separate deep earthquakes from shallow explosions. This study includes the pursuit of a decision boundary using a traditional grid search and logistic regression. Additionally, I searched ML–MC equation coefficients to determine if its discrimination abilities could be enhanced. The performance of ML–MC can be improved, though the current formulations are near optimal. Lastly, I apply ML–MC to the seismic data of nuclear explosions recorded at local-to-regional distances. Though it works best on small events recorded locally, ML–MC successfully discriminates larger earthquakes and nuclear explosions at slightly greater distances (> 250 km).

Interrogating Catalytic Processes with Data Science, Computational Chemistry, and Synthesis

Grosslight, Samantha Marie The University of Utah ProQuest Dissertations & Th 2021 해외박사(DDOD)

This dissertation utilizes data-driven workflows to gain a deeper understanding of the features influencing selective catalytic processes. Selectivity within catalytic processes can be affected by numerous components, such as the reacting partners, ligand, and additives. Additionally, the degree to which different reaction components affect selectivity may not be the same. This can make gaining mechanistic insight into catalytic processes challenging. Furthermore, this complexity can pose challenges in predicting the outcome when a reaction component is changed. This dissertation investigates different types of catalytic processes using various tools within data science and computational chemistry to gain insight into mechanistic details. A particular focus is placed upon utilizing data-driven workflows that use tools such as multivariate linear regression (MLR), transition state analysis (TS), and experimentation.An overview of all general considerations and tools applied within this dissertation is discussed in Chapter 1. Variations of this data-driven workflow are used for three diverse projects within this dissertation. Chapter 2 evaluates the site-selective acylation of steroidal natural products with BINOL derived chiral phosphoric acids (CPA). Catalyst features that were uncovered to be critical for site-selectivity were the proximal steric bulk in addition to the non-covalent interactions between the substrate and catalyst. Chapter 3 integrates an atroposelective Pd catalyzed Negishi cross-coupling with pyridine heterocycles. MLR and TS analysis are being used to decipher the reaction components that are critical for dictating atroposelectivity. Finally, Chapter 4 extends these tools to the site-selective Pd-catalyzed cross-coupling of polychlorinated heterocycles, focusing on understating the role that phosphine ligands can have on selectivity.By utilizing a data-driven workflow, diverse catalytic processes can be studied to understand the implications that various reaction components can have upon selectivity. This can guide the changes, such as using new ligands, that should be made to affect the desired outcome.

Model Simulation and Experimental Study of the Electrolytic Metal Recovery, Purification, and Separation Processes—Cu, Ni, Zn Electrowinning and Li Isotope Separation

Zhang, Zongliang The University of Utah ProQuest Dissertations & Th 2020 해외박사(DDOD)

Electrowinning process is widely used in the production of many metals such as Cu, Ni, and Zn, and it is by nature complex and consumes a huge amount of energy. Therefore, improving the understanding on the electrowinning process and optimizing the operation have attracted great attention. Among all the researching methods, modeling and simulation are effective and economic ways to study the electrowinning process. Fortunately, the electrowinning processes of different metals share common fundamental concepts. In this dissertation, a versatile, comprehensive model was built with the same structure and general process features for Cu, Ni, and Zn. For Cu electrowinning, the current efficiency prediction was incorporated with two different methods, i.e., the empirical equation method and the side reaction kinetics method. For Ni electrowinning, the effect of electrode diaphragms on the process was included with a new method developed in this research. The influence of electrode diaphragms on operation was studied with this model. For Zn electrowinning, the model incorporated the current efficiency prediction with the calculation of both the Zn deposition reaction kinetics and the hydrogen evolution kinetics. All the models were validated with the comparison of model results and experimental data. Li isotope separation was also investigated with both experimental and numerical simulation methods. Li isotopes are important strategic resources, which are in great demand in the nuclear power industry. As predicted by the model simulation, experimental research confirmed the excellent Li isotope separation effect with the electrochemical separation method proposed in this dissertation.

Development of Dissociative Bioorthogonal Reactions Based on the Isonitrile Tetrazine Reaction

Tu, Julian The University of Utah ProQuest Dissertations & Th 2021 해외박사(DDOD)

Dissociative bioorthogonal chemistry, which relies on a chemoselective reaction between two functional groups that are nontoxic, inert to endogenous biomolecules, and stable under physiological conditions, allows for advancements in the fields of chemical biology and therapeutics research. Such dissociative reactions have been employed in controlling biomacromolecule activity, in drug delivery, in materials chemistry, and in diagnostic assays. This dissertation research describes the development of new dissociative bioorthogonal chemistries based on the reaction between isonitriles and 1,2,4,5-tetrazines. It also explores an alternative drug delivery method based on bioorthogonal chemistry.The 3-isocyanpropyl and tetrazylmethyl protecting groups able to be removed bioorthogonally were developed in this dissertation. The removal of these moieties is based on the inverse electron demand Diels-Alder reaction between isonitriles and tetrazines. Following cycloaddition, a variety of functional groups caged by 3-isocyanopropyl groups were released by β-elimination, and such a reaction was shown to be compatible in live zebrafish. In the case of tetrazylmethyl caged molecules, a 1,4-elimination of either phenols or amines was observed after cycloaddition. When tetrazylmethyl and 3-isocyanopropyl caged compounds were reacted with one another, the controlled dual release of both payloads was achieved and demonstrated in live zebrafish.An atypical structure-activity relationship between the isocyano group and substituents around the tetrazine was also discovered. It was shown that bulky tetrazine substituents accelerate the cycloaddition due primarily to dispersion forces. Leveraging this effect, asymmetric tetrazines combining bulky and electron-withdrawing substituents were synthesized and shown to react with isonitriles rapidly.The drug delivery platform explored in this dissertation is based on an enrichment triggered release. It was hypothesized that targeting extracellular internalizing receptors that undergo endocytosis would significantly increase the bimolecular rate due to increased local concentration. Fluorogenic bioorthogonal probes targeting prostate specific membrane antigen and folate receptor were synthesized to test this hypothesis. In preliminary cell studies, it was demonstrated that the desired appearance of fluorescence signal was achieved in intracellular vesicles, indicating that indeed a reaction occurred upon internalization.Dissociative bioorthogonal chemistry schemes stand to progress applications in the life sciences. The chemistries and delivery platform described in this dissertation are meaningful advancements in the field and will lend themselves to future chemical biology applications.

T Cell Receptor-independent Factors that Control Secondary Effector CD4+ T Cell Function

Meek, Stephanie Michelle The University of Utah ProQuest Dissertations & Th 2018 해외박사(DDOD)

The activation of CD4+ T cells is controlled via three distinct signals: TCR recognition of the peptide:MHCII complex, coactivation via ligands and receptors expressed on antigen-presenting cells and the T cell, and Signal 3 cytokine signaling. It is this third signal that leads to initial differentiation into the multiple T helper subsets such as Th1, Th2, Th17, and Treg. While the role of Signal 3 cytokines is well-defined in programming differentiation after activation of naive T cells, their effects on memory CD4+ T cell responses have not been extensively studied. Here we show that interruption of cytokine signaling during secondary CD4+ T cell responses alters their effector function. These effects are independent of TCR affinity for antigen, demonstrating a critical role for appropriate cytokine signaling in the successful production of robust secondary CD4+ T cell responses.During secondary challenge with Listeria monocytogenes, CD4+ T cell responses are differentially regulated by Type I IFN (IFN-I) and IL-12. Effector function is depressed in the presence of IFN-I signaling, while IL-12 promotes the differentiation of highly functional secondary effector cells. Additionally, the mechanisms of regulation by both cytokines may intersect, as IFN-I inhibits the production of IL-12 as well as IFN款, a critical cytokine for Th1 responses and bacterial clearance. Expansion kinetics are also controlled via these cytokines, with IL-12 promoting robust initial expansion and IFN-I inhibiting expansion but required for limiting contraction during memory formation.Importantly, memory CD4+ T cells alone are able to mediate significant protection from heterologous secondary challenge with Listeria. This protection is entirely dependent upon TNF, as neutralization of this cytokine results in complete loss of CD4+ memory T cell-mediated protection. Surprisingly, IFN款 is not required for protection mediated by secondary effector CD4+ T cells in this setting, though it is required for protection from primary challenge with Listeria. Rather, TNF-dependent differentiation of secondary effector Th1 cells drives increased classical macrophage activation, leading to more rapid bacterial clearance. Together, we demonstrate an important role for cytokine signaling in determining the strength of the secondary response of CD4+ T cells, which can directly influence the protective capacity of these memory cells depending on the type of infection.