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- Genre: Doctoral Dissertation
Description
In an effort to begin validating the large number of discovered candidate biomarkers, proteomics is beginning to shift from shotgun proteomic experiments towards targeted proteomic approaches that provide solutions to automation and economic concerns. Such approaches to validate biomarkers necessitate the mass spectrometric analysis of hundreds to thousands of human samples. As this takes place, a serendipitous opportunity has become evident. By the virtue that as one narrows the focus towards "single" protein targets (instead of entire proteomes) using pan-antibody-based enrichment techniques, a discovery science has emerged, so to speak. This is due to the largely unknown context in which "single" proteins exist in blood (i.e. polymorphisms, transcript variants, and posttranslational modifications) and hence, targeted proteomics has applications for established biomarkers. Furthermore, besides protein heterogeneity accounting for interferences with conventional immunometric platforms, it is becoming evident that this formerly hidden dimension of structural information also contains rich-pathobiological information. Consequently, targeted proteomics studies that aim to ascertain a protein's genuine presentation within disease- stratified populations and serve as a stepping-stone within a biomarker translational pipeline are of clinical interest. Roughly 128 million Americans are pre-diabetic, diabetic, and/or have kidney disease and public and private spending for treating these diseases is in the hundreds of billions of dollars. In an effort to create new solutions for the early detection and management of these conditions, described herein is the design, development, and translation of mass spectrometric immunoassays targeted towards diabetes and kidney disease. Population proteomics experiments were performed for the following clinically relevant proteins: insulin, C-peptide, RANTES, and parathyroid hormone. At least thirty-eight protein isoforms were detected. Besides the numerous disease correlations confronted within the disease-stratified cohorts, certain isoforms also appeared to be causally related to the underlying pathophysiology and/or have therapeutic implications. Technical advancements include multiplexed isoform quantification as well a "dual- extraction" methodology for eliminating non-specific proteins while simultaneously validating isoforms. Industrial efforts towards widespread clinical adoption are also described. Consequently, this work lays a foundation for the translation of mass spectrometric immunoassays into the clinical arena and simultaneously presents the most recent advancements concerning the mass spectrometric immunoassay approach.
ContributorsOran, Paul (Author) / Nelson, Randall (Thesis advisor) / Hayes, Mark (Thesis advisor) / Ros, Alexandra (Committee member) / Williams, Peter (Committee member) / Arizona State University (Publisher)
Created2011
Description
Signal processing techniques have been used extensively in many engineering problems and in recent years its application has extended to non-traditional research fields such as biological systems. Many of these applications require extraction of a signal or parameter of interest from degraded measurements. One such application is mass spectrometry immunoassay (MSIA) which has been one of the primary methods of biomarker discovery techniques. MSIA analyzes protein molecules as potential biomarkers using time of flight mass spectrometry (TOF-MS). Peak detection in TOF-MS is important for biomarker analysis and many other MS related application. Though many peak detection algorithms exist, most of them are based on heuristics models. One of the ways of detecting signal peaks is by deploying stochastic models of the signal and noise observations. Likelihood ratio test (LRT) detector, based on the Neyman-Pearson (NP) lemma, is an uniformly most powerful test to decision making in the form of a hypothesis test. The primary goal of this dissertation is to develop signal and noise models for the electrospray ionization (ESI) TOF-MS data. A new method is proposed for developing the signal model by employing first principles calculations based on device physics and molecular properties. The noise model is developed by analyzing MS data from careful experiments in the ESI mass spectrometer. A non-flat baseline in MS data is common. The reasons behind the formation of this baseline has not been fully comprehended. A new signal model explaining the presence of baseline is proposed, though detailed experiments are needed to further substantiate the model assumptions. Signal detection schemes based on these signal and noise models are proposed. A maximum likelihood (ML) method is introduced for estimating the signal peak amplitudes. The performance of the detection methods and ML estimation are evaluated with Monte Carlo simulation which shows promising results. An application of these methods is proposed for fractional abundance calculation for biomarker analysis, which is mathematically robust and fundamentally different than the current algorithms. Biomarker panels for type 2 diabetes and cardiovascular disease are analyzed using existing MS analysis algorithms. Finally, a support vector machine based multi-classification algorithm is developed for evaluating the biomarkers' effectiveness in discriminating type 2 diabetes and cardiovascular diseases and is shown to perform better than a linear discriminant analysis based classifier.
ContributorsBuddi, Sai (Author) / Taylor, Thomas (Thesis advisor) / Cochran, Douglas (Thesis advisor) / Nelson, Randall (Committee member) / Duman, Tolga (Committee member) / Arizona State University (Publisher)
Created2012
Description
Infrastructure systems are facing non-stationary challenges that stem from climate change and the increasingly complex interactions between the social, ecological, and technological systems (SETSs). It is crucial for transportation infrastructures—which enable residents to access opportunities and foster prosperity, quality of life, and social connections—to be resilient under these non-stationary challenges. Vulnerability assessment (VA) examines the potential consequences a system is likely to experience due to exposure to perturbation or stressors and lack of the capacity to adapt. Post-fire debris flow and heat represent particularly challenging problems for infrastructure and users in the arid U.S. West. Post-fire debris flow, which is manifested with heat and drought, produces powerful runoff threatening physical transportation infrastructures. And heat waves have devastating health effects on transportation infrastructure users, including increased mortality rates. VA anticipates the potential consequences of these perturbations and enables infrastructure stakeholders to improve the system's resilience. The current transportation climate VA—which only considers a single direct climate stressor on the infrastructure—falls short of addressing the wildfire and heat challenges. This work proposes advanced transportation climate VA methods to address the complex and multiple climate stressors and the vulnerability of infrastructure users. Two specific regions were chosen to carry out the progressive transportation climate VA: 1) the California transportation networks’ vulnerability to post-fire debris flows, and 2) the transportation infrastructure user’s vulnerability to heat exposure in Phoenix.
ContributorsLi, Rui (Author) / Chester, Mikhail V. (Thesis advisor) / Middel, Ariane (Committee member) / Hondula, David M. (Committee member) / Pendyala, Ram (Committee member) / Arizona State University (Publisher)
Created2022
Description
Cities globally are experiencing substantial warming due to ongoing urbanization and climate change. However, existing efforts to mitigate urban heat focus mainly on new technologies, exacerbate social injustices, and ignore the need for a sustainability lens that considers environmental, social, and economic perspectives. Heat in urban areas is amplified and urgently needs to be considered as a critical sustainability issue that crosses disciplinary and sectoral (traditional) boundaries. The missing urgency is concerning because urban overheating is a multi-faceted threat to the well-being and performance of individuals as well as the energy efficiency and economy of cities. Urban heat consequences require transformation in ways of thinking by involving the best available knowledge engaging scientists, policymakers, and communities. To do so, effective heat mitigation planning requires a considerable amount of diverse knowledge sources, yet urban planners face multiple barriers to effective heat mitigation, including a lack of usable, policy-relevant science and governance structures. To address these issues, transdisciplinary approaches, such as co-production via partnerships and the creation of usable, policy-relevant science, are necessary to allow for sustainable and equitable heat mitigation that allow cities to work toward multiple Sustainable Development Goals (SDGs) using a systems approach. This dissertation presents three studies that contribute to a sustainability lens on urban heat, improve the holistic and multi-perspective understanding of heat mitigation strategies, provide contextual guidance for reflective pavement as a heat mitigation strategy, and evaluate a multilateral, sustainability-oriented, co-production partnership to foster heat resilience equitably in cities. Results show that science and city practice communicate differently about heat mitigation strategies while both avoid to communicate disservices and trade-offs. Additionally, performance evaluation of heat mitigation strategies for decision-making needs to consider multiple heat metrics, people, and background climate. Lastly, the partnership between science, city practice, and community needs to be evaluated to be accountable and provide a pathway of growth for all partners. The outcomes of this dissertation advance research and awareness of urban heat for science, practice, and community, and provide guidance to improve holistic and sustainable decision-making in cities and partnerships to address SDGs around urban heat.
ContributorsSchneider, Florian Arwed (Author) / Middel, Ariane (Thesis advisor) / Vanos, Jennifer K (Committee member) / Withycombe Keeler, Lauren (Committee member) / Arizona State University (Publisher)
Created2023
Description
Extreme heat and its human impacts are significant public health challenges that disproportionately affect certain populations. Often, people with the least resources to cope with the heat also live in the hottest regions of cities. Previous heat vulnerability research has predominantly been conducted at a coarse geographic scale, yet translating relationships measured at aggregated scales to the individual level can result in ecological fallacy. Prior work has also primarily studied the most severe health outcomes: hospitalization/emergency care and mortality. It is likely that magnitudes more people are experiencing negative health impacts from heat that do not necessarily result in medical care. Such less severe impacts are under-researched in the literature.This dissertation addresses these knowledge gaps by identifying how social characteristics and physical measurements of heat at the individual and household level act independently and in concert to influence human heat-related outcomes, especially less severe outcomes. In the first paper, meta-analysis was used to quantify the summary effects of vulnerability indicators on incidence of heat-related illness. More proximal vulnerability indicators (e.g., residential air conditioning use, indoor heat exposure, etc.) tended to have the strongest impact on odds of experiencing heat-related illness than more distal indicators. In the next paper, indoor air temperature observations were related to the social characteristics of the residents. The strongest predictor of indoor air temperature was the residents’ ideal thermally comfortable temperature, despite affordability. In the final paper, fine scale biometeorological observations of the outdoor thermal environment near residents’ homes were linked to their experience with heat-related illness. The outdoor thermal environment appeared to have a stronger, more consistent impact on heat-related illness among households in a lower income neighborhood compared to a higher income one. These findings affirm the value of employing residential heat mitigation solutions at the individual and household scale, indoors and outdoors. Across all chapters, the indoor thermal environment, and the ability to modify it, had a clear impact on residents’ comfort and health. Solutions that target the most proximal causal factors of heat-related illness will likely have the greatest impact on reducing the burden of heat on human health and well-being.
ContributorsWright, Mary K (Author) / Hondula, David M (Thesis advisor) / Larson, Kelli L (Committee member) / Middel, Ariane (Committee member) / Arizona State University (Publisher)
Created2023
Description
ABSTRACTWith the National Aeronautics and Space Administration (NASA) Psyche Mission, humans will soon have the first opportunity to explore a new kind of planetary body: one composed mostly of metal as opposed to stony minerals or ices. Identifying the composition of asteroids from Earth-based observations has been an ongoing challenge. Although optical reflectance spectra, radar, and orbital dynamics can constrain an asteroid’s mineralogy and bulk density, in many cases there is not a clear or precise match with analogous materials such as meteorites. Additionally, the surfaces of asteroids and other small, airless planetary bodies can be heavily modified over geologic time by exposure to the space environment. To accurately interpret remote sensing observations of metal-rich asteroids, it is therefore necessary to understand how the processes active on asteroid surfaces affect metallic materials. This dissertation represents a first step toward that understanding. In collaboration with many colleagues, I have performed laboratory experiments on iron meteorites to simulate solar wind ion irradiation, surface heating, micrometeoroid bombardment, and high-velocity impacts. Characterizing the meteorite surface’s physical and chemical properties before and after each experiment can constrain the effects of each process on a metal-rich surface in space. While additional work will be needed for a complete understanding, it is nevertheless possible to make some early predictions of what (16) Psyche’s surface regolith might look like when humans observe it up close. Moreover, the results of these experiments will inform future exploration beyond asteroid Psyche as humans attempt to understand how Earth’s celestial neighborhood came to be.
ContributorsChristoph, John Morgan M. (Author) / Elkins-Tanton, Linda (Thesis advisor) / Williams, David (Committee member) / Dukes, Catherine (Committee member) / Sharp, Thomas (Committee member) / Bell III, James (Committee member) / Arizona State University (Publisher)
Created2023
Description
The global increase in urbanization has raised questions about urban sustainability to which multiple research communities have entered. Those communities addressing interest in the urban heat island (UHI) effect and extreme temperatures include land system science, urban/landscape ecology, and urban climatology. General investigations of UHI have focused primarily on land surface and canopy layer air temperatures. The surface temperature is of prime importance to UHI studies because of its central rule in the surface energy balance, direct effects on air temperature, and outdoor thermal comfort. Focusing on the diurnal surface temperature variations in Phoenix, Arizona, especially on the cool (green space) island effect and the surface heat island effect, the dissertation develops three research papers that improve the integration among the abovementioned sub-fields. Specifically, these papers involve: (1) the quantification and modeling of the diurnal cooling benefits of green space; (2) the optimization of green space locations to reduce the surface heat island effect in daytime and nighttime; and, (3) an evaluation of the effects of vertical urban forms on land surface temperature using Google Street View. These works demonstrate that the pattern of new green spaces in central Phoenix could be optimized such that 96% of the maximum daytime and nighttime cooling benefits would be achieved, and that Google Street View data offers an alternative to other data, providing the vertical dimensions of land-cover for addressing surface temperature impacts, increasing the model accuracy over the use of horizontal land-cover data alone. Taken together, the dissertation points the way towards the integration of research directions to better understand the consequences of detailed land conditions on temperatures in urban areas, providing insights for urban designs to alleviate these extremes.
ContributorsZhang, Yujia (Author) / Turner, Billie (Thesis advisor) / Murray, Alan T. (Committee member) / Myint, Soe W (Committee member) / Middel, Ariane (Committee member) / Arizona State University (Publisher)
Created2018
Description
Urban-induced heating is a challenge to the livability and health of city dwellers. It is a complex issue that many cities are facing, and a more urgent hazard in hot urban deserts (HUDs) than elsewhere due to already high temperatures and aridity. The challenge compounds in the absence of more localized heat mitigation understanding. In addition, over-reliance on evidence from temperate regions is disconnected from the actualities of extreme bioclimatic dynamics found in HUDs. This dissertation is an integration of a series of studies that inform urban climate relationships specific to HUDs. This three-paper dissertation demonstrates heat mitigation aspirational goals from actualities, depicts local urban thermal drivers in Kuwait, and then tests morphological sensitivity of selected thermal modulation strategies in one neighborhood in Kuwait City.
The first paper is based on a systematic literature review where evidence from morphological mitigation strategies in HUDs were critically reviewed, synthesized and integrated. Metrics, measurements, and methods were extracted to examine the applicability of the different strategies, and a content synthesis identified the levels of strategy success. Collective challenges and uncertainties were interpreted to compare aspirational goals from actualities of morphological mitigation strategies.
The second paper unpacks the relationship of urban morphological attributes in influencing thermal conditions to assess latent magnitudes of heat amelioration strategies. Mindful of the challenges presented in the first study, a 92-day summer field-measurement campaign captured system dynamics of urban thermal stimuli within sub-diurnal phenomena. A composite data set of sub-hourly air temperature measurements with sub-meter morphological attributes was built, statistically analyzed, and modeled. Morphological mediation effects were found to vary hourly with different patterns under varying weather conditions in non-linear associations. Results suggest mitigation interventions be investigated and later tested on a site- use and time-use basis.
The third paper concludes with a simulation-based study to conform on the collective findings of the earlier studies. The microclimate model ENVI-met 4.4, combined with field measurements, was used to simulate the effect of rooftop shade-sails in cooling the near ground thermal environment. Results showed significant cooling effects and thus presented a novel shading approach that challenges orthodox mitigation strategies in HUDs.
The first paper is based on a systematic literature review where evidence from morphological mitigation strategies in HUDs were critically reviewed, synthesized and integrated. Metrics, measurements, and methods were extracted to examine the applicability of the different strategies, and a content synthesis identified the levels of strategy success. Collective challenges and uncertainties were interpreted to compare aspirational goals from actualities of morphological mitigation strategies.
The second paper unpacks the relationship of urban morphological attributes in influencing thermal conditions to assess latent magnitudes of heat amelioration strategies. Mindful of the challenges presented in the first study, a 92-day summer field-measurement campaign captured system dynamics of urban thermal stimuli within sub-diurnal phenomena. A composite data set of sub-hourly air temperature measurements with sub-meter morphological attributes was built, statistically analyzed, and modeled. Morphological mediation effects were found to vary hourly with different patterns under varying weather conditions in non-linear associations. Results suggest mitigation interventions be investigated and later tested on a site- use and time-use basis.
The third paper concludes with a simulation-based study to conform on the collective findings of the earlier studies. The microclimate model ENVI-met 4.4, combined with field measurements, was used to simulate the effect of rooftop shade-sails in cooling the near ground thermal environment. Results showed significant cooling effects and thus presented a novel shading approach that challenges orthodox mitigation strategies in HUDs.
ContributorsAlKhaled, Saud R A H (Author) / Coseo, Paul (Thesis advisor) / Brazel, Anthony (Thesis advisor) / Middel, Ariane (Committee member) / Cheng, Chingwen (Committee member) / Arizona State University (Publisher)
Created2019
Description
Massive glycerol cluster ions with many charges (~ 106 Da, ~ ±100 charges) have been generated by electrospray to bombard biomolecules and biological sample surfaces. The low impact energy per nucleon facilitates intact sputtering and ionization of biomolecules which can be subsequently imaged. Various lipids, peptides and proteins have been studied. The primary cluster ion source has been coupled with an ion-microscope imaging mass spectrometer (TRIFT-1, Physical Electronics). A lateral resolution of ~3µm has been demonstrated, which is acceptable for sub-cellular imaging of animal cells (e.g. single cancer cell imaging in early diagnosis). Since the available amount of target molecules per pixel is limited in biological samples, the measurement of useful ion yields (ratio of detected molecular ion counts to the sample molecules sputtered) is important to determine whether enough ion counts per pixel can be obtained. The useful ion yields of several lipids and peptides are in the 1-3×10-5 range. A 3×3 µm2lipid bilayer can produce ~260 counts/pixel for a meaningful 3×3 µm2 pixel ion image. This method can probably be used in cell imaging in the future, when there is a change in the lipid contents of the cell membrane (e.g. cancer cells vs. normal cells).
ContributorsZhang, Jitao (Author) / Williams, Peter (Thesis advisor) / Hayes, Mark (Committee member) / Nelson, Randall (Committee member) / Arizona State University (Publisher)
Created2015
Description
Cell heterogeneity is widely present in the biological world and exists even in an isogenic population. Resolving the protein heterogeneity at the single cell level is of enormous biological and clinical relevance. However, single cell protein analysis has proven to be challenging due to extremely low amount of protein in a single cell and the huge complexity of proteome. This requires appropriate sampling and sensitive detection techniques. Here, a new approach, microfluidics combined with MALDI-TOF mass spectrometry was brought forward, for the analysis of proteins in single cells. The detection sensitivity of peptides as low as 300 molecules and of proteins as low as 10^6 molecules has been demonstrated. Furthermore, an immunoassay was successfully integrated in the microfluidic device for capturing the proteins of interest and further identifying them by subsequent enzymatic digestion. Moreover, an improved microfluidic platform was designed with separate chambers and valves, allowing the absolute quantification by employing iTRAQ tags or an isotopically labeled peptide. The study was further extended to analyze a protein in MCF-7 cell lysate. The approach capable of identifying and quantifying protein molecules in MCF-7 cells is promising for future proteomic studies at the single cell level.
ContributorsYang, Mian (Author) / Ros, Alexandra (Thesis advisor) / Hayes, Mark (Committee member) / Nelson, Randall (Committee member) / Arizona State University (Publisher)
Created2016