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- Genre: Academic theses
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Purpose: To examine: (1) whether Non-Hispanic Blacks (NHB) and Non-Hispanic Whites (NHW) with diagnosed arthritis differed in self-reported physical activity (PA) levels, (2) if NHB and NHW with arthritis differed on potential correlates of PA based on the Social Ecological Model (Mcleroy et al., 1988), and (3) if PA participation varied by race/ethnicity after controlling for age, gender, education, and BMI. Methods: This study was a secondary data analysis of data collected from 2006-2008 in Chicago, IL as part of the Midwest Roybal Center for Health Promotion. Bivariate analyses were used to assess potential differences between race in meeting either ACR or ACSM PA guidelines. Comparisons by race between potential socio-demographic correlates and meeting physical activity guidelines were assessed using Chi-squares. Potential differences by race in psychosocial, arthritis, and health-related and environmental correlates were assessed using T-tests. Finally, logistic regression analyses were used to examine if race was still associated with PA after controlling for socio-demographic characteristics. Results: A greater proportion of NHW (68.1% and 35.3%) than NHB (46.5% and 20.9%) met both the arthritis-specific and the American College of Sports Medicine (ACSM) recommendations for physical activity, respectively. NHB had significantly lower self-efficacy for exercise and reported greater impairments in physical function compared to NHW. Likewise, NHB reported more crime and less aesthetics within their neighborhood. NHW were 2.56 times more likely to meet arthritis-specific PA guidelines than NHB after controlling for age, gender, education, marital status, and BMI. In contrast, after controlling for sociodemographic characteristics, age and gender were the only significant predictors of meeting ACSM PA guidelines. Discussion: There were significant differences between NHB and NHW individuals with arthritis in meeting PA guidelines. After controlling for age, gender, education, and BMI non-Hispanic White individuals were still significantly more likely to meet PA guidelines. Interventions aimed at promoting higher levels of physical activity among individuals with arthritis need to consider neighborhood aesthetics and crime when designing programs. More arthritis-specific programs are needed in close proximity to neighborhoods in an effort to promote physical activity.
ContributorsChuran, Christopher (Author) / Der Ananian, Cheryl (Thesis advisor) / Adams, Marc (Committee member) / Campbell, Kathryn (Committee member) / Arizona State University (Publisher)
Created2013
Description
Surface plasmon resonance (SPR) has emerged as a popular technique for elucidating subtle signals from biological events in a label-free, high throughput environment. The efficacy of conventional SPR sensors, whose signals are mass-sensitive, diminishes rapidly with the size of the observed target molecules. The following work advances the current SPR sensor paradigm for the purpose of small molecule detection. The detection limits of two orthogonal components of SPR measurement are targeted: speed and sensitivity. In the context of this report, speed refers to the dynamic range of measured kinetic rate constants, while sensitivity refers to the target molecule mass limitation of conventional SPR measurement. A simple device for high-speed microfluidic delivery of liquid samples to a sensor surface is presented to address the temporal limitations of conventional SPR measurement. The time scale of buffer/sample switching is on the order of milliseconds, thereby minimizing the opportunity for sample plug dispersion. The high rates of mass transport to and from the central microfluidic sensing region allow for SPR-based kinetic analysis of binding events with dissociation rate constants (kd) up to 130 s-1. The required sample volume is only 1 μL, allowing for minimal sample consumption during high-speed kinetic binding measurement. Charge-based detection of small molecules is demonstrated by plasmonic-based electrochemical impedance microscopy (P-EIM). The dependence of surface plasmon resonance (SPR) on surface charge density is used to detect small molecules (60-120 Da) printed on a dextran-modified sensor surface. The SPR response to an applied ac potential is a function of the surface charge density. This optical signal is comprised of a dc and an ac component, and is measured with high spatial resolution. The amplitude and phase of local surface impedance is provided by the ac component. The phase signal of the small molecules is a function of their charge status, which is manipulated by the pH of a solution. This technique is used to detect and distinguish small molecules based on their charge status, thereby circumventing the mass limitation (~100 Da) of conventional SPR measurement.
ContributorsMacGriff, Christopher Assiff (Author) / Tao, Nongjian (Thesis advisor) / Wang, Shaopeng (Committee member) / LaBaer, Joshua (Committee member) / Chae, Junseok (Committee member) / Arizona State University (Publisher)
Created2013
Description
This dissertation investigates the condition of skeletal muscle insulin resistance using bioinformatics and computational biology approaches. Drawing from several studies and numerous data sources, I have attempted to uncover molecular mechanisms at multiple levels. From the detailed atomistic simulations of a single protein, to datamining approaches applied at the systems biology level, I provide new targets to explore for the research community. Furthermore I present a new online web resource that unifies various bioinformatics databases to enable discovery of relevant features in 3D protein structures.
ContributorsMielke, Clinton (Author) / Mandarino, Lawrence (Committee member) / LaBaer, Joshua (Committee member) / Magee, D. Mitchell (Committee member) / Dinu, Valentin (Committee member) / Willis, Wayne (Committee member) / Arizona State University (Publisher)
Created2013
Description
Heart failure is a major worldwide health concern and is the leading cause of hospitalization among elderly Americans. Approximately 50% of those diagnosed with heart failure have heart failure with preserved ejection fraction (HFPEF). HFPEF presents a therapeutic dilemma because pharmacological strategies that are effective for the treatment of heart failure and reduced ejection fraction have failed to show benefit in HFPEF. Long term moderate intensity exercise programs have been shown to improve diastolic function in patients HFPEF. High intensity interval training (HIIT) has been shown to improve diastolic function in patients with heart failure and reduced ejection fraction. However, the effects of high intensity interval training in patients with HFPEF are unknown. Fourteen patients with HFPEF were randomized to either: (1) a novel program of high-intensity aerobic interval training (n = 8), or (2) a commonly prescribed program of moderate-intensity (MOD) aerobic exercise training (n = 6). Before and after four weeks of exercise training, patients underwent a treadmill graded exercise test for the determination of peak oxygen uptake (VO2peak), a brachial artery reactivity test for assessment of endothelium-dependent flow-mediated dilation (BAFMD), aortic pulse wave velocity assessment as an index of vascular stiffness and two-dimensional echocardiography for assessment of left ventricular diastolic and systolic function. I hypothesized that (1) high-intensity aerobic interval training would result in superior improvements in FMD, aortic pulse wave velocity, VO2peak, diastolic function and, (2) changes in these parameters would be correlated with changes in VO2peak. The principal findings of the study were that a one month long high intensity interval training program resulted in significant improvements in diastolic function as measured by two-dimensional echocardiography [pre diastolic dysfunction (DD) grade - 2.13 + 0.4 vs. post DD grade - 1.25 + 0.7, p = 0.03]. The left atrial volume index was reduced in the HIIT group compared to MOD ( - 4.4 + 6.2 ml/m2 vs. 5.8 + 10.7 ml/m2, p = 0.02). Early mitral flow (E) improved in the HIIT group (pre - 0.93 + 0.2 m/s vs. post - 0.78 + 0.3 m/s, p = 0.03). A significant inverse correlation was observed between change in BAFMD and change in diastolic dysfunction grade (r = - 0.585, p = 0.028) when all the data were pooled. HIIT appears to be a time-efficient and safe strategy for improving diastolic function in patients with heart failure and preserved ejection fraction. These data may have implications for cardiovascular risk reduction in this population.
ContributorsAngadi, Siddhartha (Author) / Gaesser, Glenn A (Thesis advisor) / Mookadam, Farouk (Committee member) / Swan, Pamela (Committee member) / Vega-Lopez, Sonia (Committee member) / Lee, Chong (Committee member) / Arizona State University (Publisher)
Created2012
Description
Recombinant protein expression is essential to biotechnology and molecular medicine, but facile methods for obtaining significant quantities of folded and functional protein in mammalian cell culture have been lacking. Here I describe a novel 37-nucleotide in vitro selected sequence that promotes unusually high transgene expression in a vaccinia driven cytoplasmic expression system. Vectors carrying this sequence in a monocistronic reporter plasmid produce >1,000-fold more protein than equivalent vectors with conventional vaccinia promoters. Initial mechanistic studies indicate that high protein expression results from dual activity that impacts both transcription and translation. I suggest that this motif represents a powerful new tool in vaccinia-based protein expression and vaccine development technology.
ContributorsFlores, Julia Anne (Author) / Chaput, John C (Thesis advisor) / Jacobs, Bertram (Committee member) / LaBaer, Joshua (Committee member) / Arizona State University (Publisher)
Created2012
Description
Objective: Increasing fruit/vegetable (FV) consumption and decreasing waste during the school lunch is a public health priority. Understanding how serving style of FV impacts FV consumption and waste may be an effective means to changing nutrition behaviors in schools. This study examined whether students were more likely to select, consume, and waste FV when FVs were cut vs. whole. Methods: Baseline data from the ASU School Lunch Study was used to explore associations between cut vs. whole FV serving style and objectively measured FV selection, consumption, and waste and grade level interactions among a random selection of students (n=6804; 47.8% female; 78.8% BIPOC) attending Arizona elementary, middle, and high schools (N=37). Negative binomial regression models evaluated serving style on FV weight (grams) selected, consumed, and wasted, adjusted for sociodemographics and school.
Results: Students were more likely to select cut FVs (IRR=1.11; 95% CI: 1.04, 1.18) and waste cut FVs (IRR=1.20; 95% CI: 1.04, 1.39); however, no differences were observed in the overall consumption of cut vs. whole FVs. Grade-level interactions impacted students’ selection of FVs. Middle school students had a significantly higher effect modification for the selection of cut FVs (IRR=1.18; p=0.006) compared to high school and elementary students. Further, high school students had a significantly lower effect modification for the selection of cut FVs (IRR=0.83; p=0.010) compared to middle and elementary students. No other grade-level interactions were observed.
Discussion: Serving style of FV may impact how much FV is selected and wasted, but further research is needed to determine causality between these variables.
ContributorsJames, Amber Chandarana (Author) / Bruening, Meredith (Thesis advisor) / Adams, Marc (Thesis advisor) / Koskan, Alexis (Committee member) / Arizona State University (Publisher)
Created2021
Description
The TP53 tumor suppressor gene is the most frequently mutated gene in human cancers. In the highly aggressive triple negative breast cancer (TNBC), TP53 is mutated in 80% of cases. TNBC lacks viable drug targets, resulting in a low prognosis (12.2% 5 year survivability rate). As such, the discovery of druggable targets in TNBC would be beneficial. Mutated p53 protein typically occurs as a missense mutation and often endows cancer cells with gain of function (GOF) properties by dysregulating metabolic pathways. One of these frequently dysregulated pathways is the Hippo/Yes-associated protein-1 (YAP1)/WW Domain Containing Transcription Regulator 1 (TAZ) tumor suppressor pathway. This study therefore analyzed the involvement of the Hippo/YAP1/TAZ pathway in p53-mediated breast cancer cell invasion. From an RNA-seq screen in MCF10A cell lines harboring different TP53 missense mutations, each with a differing invasive phenotype, components of the Hippo pathway were found to correlate with cell invasion. To this end, the active and inactive forms of YAP1 and TAZ were studied. Phosphorylated (inactive) YAP1 and TAZ are retained in the cytoplasm and eventually degraded. Unphosphorylated (active) YAP1 and TAZ translocate to the nucleus to activate TEAD-family transcription factors, inducing cell survival and proliferation genes leading to increased cell invasion. Using quantitative western blot analysis, it was found that inactive TAZ expression was lower in the most invasive cell lines and higher in the least invasive cell lines (p = 0.003). Moreover, the ratio of inactive TAZ protein to total TAZ protein was also shown to be predominantly lower in the invasive cell lines compared to the non-invasive lines (p = 0.04). Finally, active TAZ expression was primarily higher in p53-mutant invasive cell lines and lower in non-invasive p53 mutant cells. Additionally, although YAP1 and TAZ are thought to be functionally redundant, the pattern seen in TAZ was not seen in the YAP1 protein. Taken together, the results demonstrated here suggest that TAZ holds a more dominant role in governing TNBC cell invasion compared to YAP1 and further highlights TAZ as a potential therapeutic target in TNBC.
ContributorsGrief, Dustin (Author) / LaBaer, Joshua (Thesis advisor) / Anderson, Karen (Committee member) / Nikkhah, Mehdi (Committee member) / Arizona State University (Publisher)
Created2022
Description
Glioblastoma (GBM), the most common and aggressive primary brain tumor affecting adults, is characterized by an aberrant yet druggable epigenetic landscape. The Histone Deacetylases (HDACs), a major family of epigenetic regulators, favor transcriptional repression by mediating chromatin compaction and are frequently overexpressed in human cancers, including GBM. Hence, over the last decade there has been considerable interest in using HDAC inhibitors (HDACi) for the treatment of malignant primary brain tumors. However, to date most HDACi tested in clinical trials have failed to provide significant therapeutic benefit to patients with GBM. This is because current HDACi have poor or unknown pharmacokinetic profiles, lack selectivity towards the different HDAC isoforms, and have narrow therapeutic windows. Isoform selectivity for HDACi is important given that broad inhibition of all HDACs results in widespread toxicity across different organs. Moreover, the functional roles of individual HDAC isoforms in GBM are still not well understood. Here, I demonstrate that HDAC1 expression increases with brain tumor grade and is correlated with decreased survival in GBM. I find that HDAC1 is the essential HDAC isoform in glioma stem cells and its loss is not compensated for by its paralogue HDAC2 or other members of the HDAC family. Loss of HDAC1 alone has profound effects on the glioma stem cell phenotype in a p53-dependent manner and leads to significant suppression of tumor growth in vivo. While no HDAC isoform-selective inhibitors are currently available, the second-generation HDACi quisinostat harbors high specificity for HDAC1. I show that quisinostat exhibits potent growth inhibition in multiple patient-derived glioma stem cells. Using a pharmacokinetics- and pharmacodynamics-driven approach, I demonstrate that quisinostat is a brain-penetrant molecule that reduces tumor burden in flank and orthotopic models of GBM and significantly extends survival both alone and in combination with radiotherapy. The work presented in this thesis thereby unveils the non-redundant functions of HDAC1 in therapy- resistant glioma stem cells and identifies a brain-penetrant HDACi with higher selectivity towards HDAC1 as a potent radiosensitizer in preclinical models of GBM. Together, these results provide a rationale for developing quisinostat as a potential adjuvant therapy for the treatment of GBM.
ContributorsLo Cascio, Costanza (Author) / LaBaer, Joshua (Thesis advisor) / Mehta, Shwetal (Committee member) / Mirzadeh, Zaman (Committee member) / Mangone, Marco (Committee member) / Paek, Andrew (Committee member) / Arizona State University (Publisher)
Created2022
Description
Transient Receptor Potential Vanilloid-1 (TRPV1) is an integral membrane polymodal cation channel involved in various essential biological functions, including thermosensing, thermoregulation, and nociception. Discrete TRPV1 activation modes such as ligand, heat, and proton have been challenging to disentangle. However, dissecting the polymodal nature of TRPV1 is essential for therapeutic development. The human TRPV1 (hTRPV1) voltage-sensing like domain (VSLD; transmembrane helices S1-S4) contains the canonical vanilloid ligand binding site and significantly contributes to thermosensing. Nuclear magnetic resonance (NMR)-detected studies probe the role of the hTRPV1-VSLD in TRPV1 polymodal function. The hTRPV1-VSLD is identified as an allosteric hub for all three primary TRPV1 activation modes and demonstrates plasticity in chemical ligand modulation. The presented results underscore molecular features in the VSLD that dictate TRPV1 function, highlighting important considerations for future therapeutic design.
ContributorsOwens, Aerial M. (Author) / Van Horn, Wade D. (Thesis advisor) / Levitus, Marcia (Committee member) / LaBaer, Joshua (Committee member) / Arizona State University (Publisher)
Created2023
Description
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic, declared in March 2020 resulted in an unprecedented scientific effort that led to the deployment in less than a year of several vaccines to prevent severe disease, hospitalizations, and death from coronavirus disease 2019 (COVID-19). Most vaccine models focus on the production of neutralizing antibodies against the spike (S) to prevent infection. As the virus evolves, new variants emerge that evade neutralizing antibodies produced by natural infection and vaccination, while memory T cell responses are long-lasting and resilient to most of the changes found in variants of concern (VOC). Several lines of evidence support the study of T cell-mediated immunity in SARS-CoV-2 infections. First, T cell reactivity against SARS-CoV-2 is found in both (cluster of differentiation) CD4+ and CD8+ T cell compartments in asymptomatic, mild, and severe recovered COVID-19 patients. Second, an early and stronger CD8+ T cell response correlates with less severe COVID-19 disease [1-4]. Third, both CD4+ and CD8+ T cells that are reactive to SARS-CoV-2 viral antigens are found in healthy unexposed individuals suggesting that cross-reactive and conserved epitopes may be protective against infection.
The current study is focused on the T cell-mediated response, with special attention to conserved, non-spike-cross-reactive epitopes that may be protective against SARS-CoV-2. The first chapter reviews the importance of epitope prediction in understanding the T cell-mediated responses to a pathogen. The second chapter centers on the validation of SARS-CoV-2 CD8+ T cell predicted peptides to find conserved, immunodominant, and immunoprevalent epitopes that can be incorporated into the next generation of vaccines against severe COVID-19 disease. The third chapter explores pre-existing immunity to SARS-CoV-2 in a pre-pandemic cohort and finds two highly immunogenic epitopes that are conserved among human common cold coronaviruses (HCoVs). To end, the fourth chapter explores the concept of T cell receptor (TCR) cross-reactivity by isolating SARS-CoV-2-reactive TCRs to elucidate the mechanisms of cross-reactivity to SARS-CoV-2 and other human coronaviruses (HCoVs).
ContributorsCarmona, Jacqueline (Author) / Anderson, Karen S (Thesis advisor) / Lake, Douglas (Thesis advisor) / Maley, Carlo (Committee member) / Mangone, Marco (Committee member) / LaBaer, Joshua (Committee member) / Arizona State University (Publisher)
Created2023