Matching Items (5)
Filtering by
- Genre: Doctoral Dissertation
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
While exercising mammalian muscle increasingly relies on carbohydrates for fuel as aerobic exercise intensity rises above the moderate range, flying birds are extraordinary endurance athletes and fuel flight, a moderate-high intensity exercise, almost exclusively with lipid. In addition, Aves have long lifespans compared to weight-matched mammals. As skeletal muscle mitochondria account for the majority of oxygen consumption during aerobic exercise, the primary goal was to investigate differences in isolated muscle mitochondria between these species and to examine to what extent factors intrinsic to mitochondria may account for the behavior observed in the intact tissue and whole organism. First, maximal enzyme activities were assessed in sparrow and rat mitochondria. Citrate synthase and aspartate aminotransferase activity were higher in sparrow compared to rat mitochondria, while glutamate dehydrogenase activity was lower. Sparrow mitochondrial NAD-linked isocitrate dehydrogenase activity was dependent on phosphate, unlike the mammalian enzyme. Next, the rate of oxygen consumption (JO), electron transport chain (ETC) activity, and reactive oxygen species (ROS) production were assessed in intact mitochondria. Maximal rates of fat oxidation were lower than for carbohydrate in rat but not sparrow mitochondria. ETC activity was higher in sparrows, but no differences were found in ROS production between species. Finally, fuel selection and control of respiration at three rates between rest and maximum were assessed. Mitochondrial fuel oxidation and selection mirrored that of the whole body; in rat mitochondria the reliance on carbohydrate increased as the rate of oxygen consumption increased, whereas fat dominated under all conditions in the sparrow. These data indicate fuel selection, at least in part, can be modulated at the level of the mitochondrial matrix when multiple substrates are present at saturating levels. As an increase in matrix oxidation-reduction potential has been linked to a suppression of fat oxidation and high ROS production, the high ETC activity relative to dehydrogenase activity in avian compared to mammalian mitochondria may result in lower matrix oxidation-reduction potential, allowing fatty acid oxidation to proceed while also resulting in low ROS production in vivo.
ContributorsKuzmiak, Sarah (Author) / Willis, Wayne T (Thesis advisor) / Mandarino, Lawrence (Committee member) / Sweazea, Karen (Committee member) / Harrison, Jon (Committee member) / Gadau, Juergen (Committee member) / Arizona State University (Publisher)
Created2012
Description
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by progressive autoimmune destruction of insulin-producing pancreatic β-cells. Genetic, immunological and environmental factors contribute to T1D development. The focus of this dissertation is to track the humoral immune response in T1D by profiling autoantibodies (AAbs) and anti-viral antibodies using an innovative protein array platform called Nucleic Acid Programmable Protein Array (NAPPA).
AAbs provide value in identifying individuals at risk, stratifying patients with different clinical courses, improving our understanding of autoimmune destructions, identifying antigens for cellular immune response and providing candidates for prevention trials in T1D. A two-stage serological AAb screening against 6,000 human proteins was performed. A dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) was validated with 36% sensitivity at 98% specificity by an orthogonal immunoassay. This is the first systematic screening for novel AAbs against large number of human proteins by protein arrays in T1D. A more comprehensive search for novel AAbs was performed using a knowledge-based approach by ELISA and a screening-based approach against 10,000 human proteins by NAPPA. Six AAbs were identified and validated with sensitivities ranged from 16% to 27% at 95% specificity. These two studies enriched the T1D “autoantigenome” and provided insights into T1D pathophysiology in an unprecedented breadth and width.
The rapid rise of T1D incidence suggests the potential involvement of environmental factors including viral infections. Sero-reactivity to 646 viral antigens was assessed in new-onset T1D patients. Antibody positive rate of EBV was significantly higher in cases than controls that suggested a potential role of EBV in T1D development. A high density-NAPPA platform was demonstrated with high reproducibility and sensitivity in profiling anti-viral antibodies.
This dissertation shows the power of a protein-array based immunoproteomics approach to characterize humoral immunoprofile against human and viral proteomes. The identification of novel T1D-specific AAbs and T1D-associated viruses will help to connect the nodes in T1D etiology and provide better understanding of T1D pathophysiology.
AAbs provide value in identifying individuals at risk, stratifying patients with different clinical courses, improving our understanding of autoimmune destructions, identifying antigens for cellular immune response and providing candidates for prevention trials in T1D. A two-stage serological AAb screening against 6,000 human proteins was performed. A dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) was validated with 36% sensitivity at 98% specificity by an orthogonal immunoassay. This is the first systematic screening for novel AAbs against large number of human proteins by protein arrays in T1D. A more comprehensive search for novel AAbs was performed using a knowledge-based approach by ELISA and a screening-based approach against 10,000 human proteins by NAPPA. Six AAbs were identified and validated with sensitivities ranged from 16% to 27% at 95% specificity. These two studies enriched the T1D “autoantigenome” and provided insights into T1D pathophysiology in an unprecedented breadth and width.
The rapid rise of T1D incidence suggests the potential involvement of environmental factors including viral infections. Sero-reactivity to 646 viral antigens was assessed in new-onset T1D patients. Antibody positive rate of EBV was significantly higher in cases than controls that suggested a potential role of EBV in T1D development. A high density-NAPPA platform was demonstrated with high reproducibility and sensitivity in profiling anti-viral antibodies.
This dissertation shows the power of a protein-array based immunoproteomics approach to characterize humoral immunoprofile against human and viral proteomes. The identification of novel T1D-specific AAbs and T1D-associated viruses will help to connect the nodes in T1D etiology and provide better understanding of T1D pathophysiology.
ContributorsBian, Xiaofang (Author) / LaBaer, Joshua (Thesis advisor) / Mandarino, Lawrence (Committee member) / Chang, Yung (Committee member) / Arizona State University (Publisher)
Created2015
Description
Energy use within urban building stocks is continuing to increase globally as populations expand and access to electricity improves. This projected increase in demand could require deployment of new generation capacity, but there is potential to offset some of this demand through modification of the buildings themselves. Building stocks are quasi-permanent infrastructures which have enduring influence on urban energy consumption, and research is needed to understand: 1) how development patterns constrain energy use decisions and 2) how cities can achieve energy and environmental goals given the constraints of the stock. This requires a thorough evaluation of both the growth of the stock and as well as the spatial distribution of use throughout the city. In this dissertation, a case study in Los Angeles County, California (LAC) is used to quantify urban growth, forecast future energy use under climate change, and to make recommendations for mitigating energy consumption increases. A reproducible methodological framework is included for application to other urban areas.
In LAC, residential electricity demand could increase as much as 55-68% between 2020 and 2060, and building technology lock-in has constricted the options for mitigating energy demand, as major changes to the building stock itself are not possible, as only a small portion of the stock is turned over every year. Aggressive and timely efficiency upgrades to residential appliances and building thermal shells can significantly offset the projected increases, potentially avoiding installation of new generation capacity, but regulations on new construction will likely be ineffectual due to the long residence time of the stock (60+ years and increasing). These findings can be extrapolated to other U.S. cities where the majority of urban expansion has already occurred, such as the older cities on the eastern coast. U.S. population is projected to increase 40% by 2060, with growth occurring in the warmer southern and western regions. In these growing cities, improving new construction buildings can help offset electricity demand increases before the city reaches the lock-in phase.
In LAC, residential electricity demand could increase as much as 55-68% between 2020 and 2060, and building technology lock-in has constricted the options for mitigating energy demand, as major changes to the building stock itself are not possible, as only a small portion of the stock is turned over every year. Aggressive and timely efficiency upgrades to residential appliances and building thermal shells can significantly offset the projected increases, potentially avoiding installation of new generation capacity, but regulations on new construction will likely be ineffectual due to the long residence time of the stock (60+ years and increasing). These findings can be extrapolated to other U.S. cities where the majority of urban expansion has already occurred, such as the older cities on the eastern coast. U.S. population is projected to increase 40% by 2060, with growth occurring in the warmer southern and western regions. In these growing cities, improving new construction buildings can help offset electricity demand increases before the city reaches the lock-in phase.
ContributorsReyna, Janet Lorel (Author) / Chester, Mikhail V (Thesis advisor) / Gurney, Kevin (Committee member) / Reddy, T. Agami (Committee member) / Rey, Sergio (Committee member) / Arizona State University (Publisher)
Created2016
Description
Fossil fuel CO2 (FFCO2) emissions are recognized as the dominant greenhouse gas driving climate change (Enting et. al., 1995; Conway et al., 1994; Francey et al., 1995; Bousquet et. al., 1999). Transportation is a major component of FFCO2 emissions, especially in urban areas. An improved understanding of on-road FFCO2 emission at high spatial resolution is essential to both carbon science and mitigation policy. Though considerable research has been accomplished within a few high-income portions of the planet such as the United States and Western Europe, little work has attempted to comprehensively quantify high-resolution on-road FFCO2 emissions globally. Key questions for such a global quantification are: (1) What are the driving factors for on-road FFCO2 emissions? (2) How robust are the relationships? and (3) How do on-road FFCO2 emissions vary with urban form at fine spatial scales?
This study used urban form/socio-economic data combined with self-reported on-road FFCO2 emissions for a sample of global cities to estimate relationships within a multivariate regression framework based on an adjusted STIRPAT model. The on-road high-resolution (whole-city) regression FFCO2 model robustness was evaluated by introducing artificial error, conducting cross-validation, and assessing relationship sensitivity under various model specifications. Results indicated that fuel economy, vehicle ownership, road density and population density were statistically significant factors that correlate with on-road FFCO2 emissions. Of these four variables, fuel economy and vehicle ownership had the most robust relationships.
A second regression model was constructed to examine the relationship between global on-road FFCO2 emissions and urban form factors (described by population
ii
density, road density, and distance to activity centers) at sub-city spatial scales (1 km2). Results showed that: 1) Road density is the most significant (p<2.66e-037) predictor of on-road FFCO2 emissions at the 1 km2 spatial scale; 2) The correlation between population density and on-road FFCO2 emissions for interstates/freeways varies little by city type. For arterials, on-road FFCO2 emissions show a stronger relationship to population density in clustered cities (slope = 0.24) than dispersed cities (slope = 0.13). FFCO2 3) The distance to activity centers has a significant positive relationship with on-road FFCO2 emission for the interstate and freeway toad types, but an insignificant relationship with the arterial road type.
This study used urban form/socio-economic data combined with self-reported on-road FFCO2 emissions for a sample of global cities to estimate relationships within a multivariate regression framework based on an adjusted STIRPAT model. The on-road high-resolution (whole-city) regression FFCO2 model robustness was evaluated by introducing artificial error, conducting cross-validation, and assessing relationship sensitivity under various model specifications. Results indicated that fuel economy, vehicle ownership, road density and population density were statistically significant factors that correlate with on-road FFCO2 emissions. Of these four variables, fuel economy and vehicle ownership had the most robust relationships.
A second regression model was constructed to examine the relationship between global on-road FFCO2 emissions and urban form factors (described by population
ii
density, road density, and distance to activity centers) at sub-city spatial scales (1 km2). Results showed that: 1) Road density is the most significant (p<2.66e-037) predictor of on-road FFCO2 emissions at the 1 km2 spatial scale; 2) The correlation between population density and on-road FFCO2 emissions for interstates/freeways varies little by city type. For arterials, on-road FFCO2 emissions show a stronger relationship to population density in clustered cities (slope = 0.24) than dispersed cities (slope = 0.13). FFCO2 3) The distance to activity centers has a significant positive relationship with on-road FFCO2 emission for the interstate and freeway toad types, but an insignificant relationship with the arterial road type.
ContributorsSong, Yang (Author) / Gurney, Kevin (Thesis advisor) / Kuby, Michael (Committee member) / Golub, Aaron (Committee member) / Chester, Mikhail (Committee member) / Selover, Nancy (Committee member) / Arizona State University (Publisher)
Created2018