ASU Scholarship Showcase

Human protein diversity arises as a result of alternative splicing, single nucleotide polymorphisms (SNPs) and posttranslational modifications. Because of these processes, each protein can exists as multiple variants in vivo. Tailored strategies are needed to study these protein variants and understand their role in health and disease. In this work we utilized quantitative mass spectrometric immunoassays to determine the protein variants concentration of beta-2-microglobulin, cystatin C, retinol binding protein, and transthyretin, in a population of 500 healthy individuals. Additionally, we determined the longitudinal concentration changes for the protein variants from four individuals over a 6 month period. Along with the native forms of the four proteins, 13 posttranslationally modified variants and 7 SNP-derived variants were detected and their concentration determined. Correlations of the variants concentration with geographical origin, gender, and age of the individuals were also examined. This work represents an important step toward building a catalog of protein variants concentrations and examining their longitudinal changes.

The apolipoprotein E (APOE) e4 allele is the most prevalent genetic risk factor for Alzheimer's disease (AD). Hippocampal volumes are generally smaller in AD patients carrying the e4 allele compared to e4 noncarriers. Here we examined the effect of APOE e4 on hippocampal morphometry in a large imaging database—the Alzheimer's Disease Neuroimaging Initiative (ADNI). We automatically segmented and constructed hippocampal surfaces from the baseline MR images of 725 subjects with known APOE genotype information including 167 with AD, 354 with mild cognitive impairment (MCI), and 204 normal controls. High-order correspondences between hippocampal surfaces were enforced across subjects with a novel inverse consistent surface fluid registration method. Multivariate statistics consisting of multivariate tensor-based morphometry (mTBM) and radial distance were computed for surface deformation analysis. Using Hotelling's T2 test, we found significant morphological deformation in APOE e4 carriers relative to noncarriers in the entire cohort as well as in the nondemented (pooled MCI and control) subjects, affecting the left hippocampus more than the right, and this effect was more pronounced in e4 homozygotes than heterozygotes. Our findings are consistent with previous studies that showed e4 carriers exhibit accelerated hippocampal atrophy; we extend these findings to a novel measure of hippocampal morphometry. Hippocampal morphometry has significant potential as an imaging biomarker of early stage AD.

Mild Cognitive Impairment (MCI) is a transitional stage between normal aging and dementia and people with MCI are at high risk of progression to dementia. MCI is attracting increasing attention, as it offers an opportunity to target the disease process during an early symptomatic stage. Structural magnetic resonance imaging (MRI) measures have been the mainstay of Alzheimer's disease (AD) imaging research, however, ventricular morphometry analysis remains challenging because of its complicated topological structure. Here we describe a novel ventricular morphometry system based on the hyperbolic Ricci flow method and tensor-based morphometry (TBM) statistics. Unlike prior ventricular surface parameterization methods, hyperbolic conformal parameterization is angle-preserving and does not have any singularities. Our system generates a one-to-one diffeomorphic mapping between ventricular surfaces with consistent boundary matching conditions. The TBM statistics encode a great deal of surface deformation information that could be inaccessible or overlooked by other methods. We applied our system to the baseline MRI scans of a set of MCI subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI: 71 MCI converters vs. 62 MCI stable). Although the combined ventricular area and volume features did not differ between the two groups, our fine-grained surface analysis revealed significant differences in the ventricular regions close to the temporal lobe and posterior cingulate, structures that are affected early in AD. Significant correlations were also detected between ventricular morphometry, neuropsychological measures, and a previously described imaging index based on fluorodeoxyglucose positron emission tomography (FDG-PET) scans. This novel ventricular morphometry method may offer a new and more sensitive approach to study preclinical and early symptomatic stage AD.

The City of Phoenix (Arizona, USA) developed a Tree and Shade Master Plan and a Cool Roofs initiative to ameliorate extreme heat during the summer months in their arid city. This study investigates the impact of the City's heat mitigation strategies on daytime microclimate for a pre-monsoon summer day under current climate conditions and two climate change scenarios. We assessed the cooling effect of trees and cool roofs in a Phoenix residential neighborhood using the microclimate model ENVI-met. First, using xeric landscaping as a base, we created eight tree planting scenarios (from 0% canopy cover to 30% canopy cover) for the neighborhood to characterize the relationship between canopy cover and daytime cooling benefit of trees. In a second set of simulations, we ran ENVI-met for nine combined tree planting and landscaping scenarios (mesic, oasis, and xeric) with regular roofs and cool roofs under current climate conditions and two climate change projections. For each of the 54 scenarios, we compared average neighborhood mid-afternoon air temperatures and assessed the benefits of each heat mitigation measure under current and projected climate conditions. Findings suggest that the relationship between percent canopy cover and air temperature reduction is linear, with 0.14 °C cooling per percent increase in tree cover for the neighborhood under investigation. An increase in tree canopy cover from the current 10% to a targeted 25% resulted in an average daytime cooling benefit of up to 2.0 °C in residential neighborhoods at the local scale. Cool roofs reduced neighborhood air temperatures by 0.3 °C when implemented on residential homes. The results from this city-specific mitigation project will inform messaging campaigns aimed at engaging the city decision makers, industry, and the public in the green building and urban forestry initiatives.

Proteins can exist as multiple proteoforms in vivo, as a result of alternative splicing and single-nucleotide polymorphisms (SNPs), as well as posttranslational processing. To address their clinical significance in a context of diagnostic information, proteoforms require a more in-depth analysis. Mass spectrometric immunoassays (MSIA) have been devised for studying structural diversity in human proteins. MSIA enables protein profiling in a simple and high-throughput manner, by combining the selectivity of targeted immunoassays, with the specificity of mass spectrometric detection. MSIA has been used for qualitative and quantitative analysis of single and multiple proteoforms, distinguishing between normal fluctuations and changes related to clinical conditions. This mini review offers an overview of the development and application of mass spectrometric immunoassays for clinical and population proteomics studies. Provided are examples of some recent developments, and also discussed are the trends and challenges in mass spectrometry-based immunoassays for the next-phase of clinical applications.

Introduction: Apolipoprotein C-III (apoC-III) regulates triglyceride (TG) metabolism. In plasma, apoC-III exists in non-sialylated (apoC-III_0a without glycosylation and apoC-III[subscript 0b] with glycosylation), monosialylated (apoC-III₁) or disialylated (apoC-III₂) proteoforms. Our aim was to clarify the relationship between apoC-III sialylation proteoforms with fasting plasma TG concentrations.

Methods: In 204 non-diabetic adolescent participants, the relative abundance of apoC-III plasma proteoforms was measured using mass spectrometric immunoassay.

Results: Compared with the healthy weight subgroup (n = 16), the ratios of apoC-III_0a, apoC-III_0b, and apoC-III₁ to apoC-III₂ were significantly greater in overweight (n = 33) and obese participants (n = 155). These ratios were positively correlated with BMI z-scores and negatively correlated with measures of insulin sensitivity (S[subscript i]). The relationship of apoC-III₁ / apoC-III₂ with S_i persisted after adjusting for BMI (p = 0.02). Fasting TG was correlated with the ratio of apoC-III_0a / apoC-III₂ (r = 0.47, p<0.001), apoC-III_0b / apoC-III₂ (r = 0.41, p<0.001), apoC-III₁ / apoC-III₂ (r = 0.43, p<0.001). By examining apoC-III concentrations, the association of apoC-III proteoforms with TG was driven by apoC-III_0a (r = 0.57, p<0.001), apoC-III_0b (r = 0.56. p<0.001) and apoC-III₁ (r = 0.67, p<0.001), but not apoC-III₂ (r = 0.006, p = 0.9) concentrations, indicating that apoC-III relationship with plasma TG differed in apoC-III₂ compared with the other proteoforms.

Conclusion: We conclude that apoC-III_0a, apoC-III_0b, and apoC-III₁, but not apoC-III₂ appear to be under metabolic control and associate with fasting plasma TG. Measurement of apoC-III proteoforms can offer insights into the biology of TG metabolism in obesity.

Shade plays an important role in designing pedestrian-friendly outdoor spaces in hot desert cities. This study investigates the impact of photovoltaic canopy shade and tree shade on thermal comfort through meteorological observations and field surveys at a pedestrian mall on Arizona State University's Tempe campus. During the course of 1 year, on selected clear calm days representative of each season, we conducted hourly meteorological transects from 7:00 a.m. to 6:00 p.m. and surveyed 1284 people about their thermal perception, comfort, and preferences. Shade lowered thermal sensation votes by approximately 1 point on a semantic differential 9-point scale, increasing thermal comfort in all seasons except winter. Shade type (tree or solar canopy) did not significantly impact perceived comfort, suggesting that artificial and natural shades are equally efficient in hot dry climates. Globe temperature explained 51 % of the variance in thermal sensation votes and was the only statistically significant meteorological predictor. Important non-meteorological factors included adaptation, thermal comfort vote, thermal preference, gender, season, and time of day. A regression of subjective thermal sensation on physiological equivalent temperature yielded a neutral temperature of 28.6 °C. The acceptable comfort range was 19.1 °C-38.1 °C with a preferred temperature of 20.8 °C. Respondents exposed to above neutral temperature felt more comfortable if they had been in air-conditioning 5 min prior to the survey, indicating a lagged response to outdoor conditions. Our study highlights the importance of active solar access management in hot urban areas to reduce thermal stress.

This study investigates the impact of urban form and landscaping type on the mid-afternoon microclimate in semi-arid Phoenix, Arizona. The goal is to find effective urban form and design strategies to ameliorate temperatures during the summer months. We simulated near-ground air temperatures for typical residential neighborhoods in Phoenix using the three-dimensional microclimate model ENVI-met. The model was validated using weather observations from the North Desert Village (NDV) landscape experiment, located on the Arizona State University's Polytechnic campus. The NDV is an ideal site to determine the model's input parameters, since it is a controlled environment recreating three prevailing residential landscape types in the Phoenix metropolitan area (mesic, oasis, and xeric). After validation, we designed five neighborhoods with different urban forms that represent a realistic cross-section of typical residential neighborhoods in Phoenix. The scenarios follow the Local Climate Zone (LCZ) classification scheme after Stewart and Oke. We then combined the neighborhoods with three landscape designs and, using ENVI-met, simulated microclimate conditions for these neighborhoods for a typical summer day. Results were analyzed in terms of mid-afternoon air temperature distribution and variation, ventilation, surface temperatures, and shading. Findings show that advection is important for the distribution of within-design temperatures and that spatial differences in cooling are strongly related to solar radiation and local shading patterns. In mid-afternoon, dense urban forms can create local cool islands. Our approach suggests that the LCZ concept is useful for planning and design purposes.

Summer daytime cooling efficiency of various land cover is investigated for the urban core of Phoenix, Arizona, using the Local-Scale Urban Meteorological Parameterization Scheme (LUMPS). We examined the urban energy balance for 2 summer days in 2005 to analyze the daytime cooling-water use tradeoff and the timing of sensible heat reversal at night. The plausibility of the LUMPS model results was tested using remotely sensed surface temperatures from Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) imagery and reference evapotranspiration values from a meteorological station. Cooling efficiency was derived from sensible and latent heat flux differences. The time when the sensible heat flux turns negative (sensible heat flux transition) was calculated from LUMPS simulated hourly fluxes. Results indicate that the time when the sensible heat flux changes direction at night is strongly influenced by the heat storage capacity of different land cover types and by the amount of vegetation. Higher heat storage delayed the transition up to 3 h in the study area, while vegetation expedited the sensible heat reversal by 2 h. Cooling efficiency index results suggest that overall, the Phoenix urban core is slightly more efficient at cooling than the desert, but efficiencies do not increase much with wet fractions higher than 20%. Industrial sites with high impervious surface cover and low wet fraction have negative cooling efficiencies. Findings indicate that drier neighborhoods with heterogeneous land uses are the most efficient landscapes in balancing cooling and water use in Phoenix. However, further factors such as energy use and human vulnerability to extreme heat have to be considered in the cooling-water use tradeoff, especially under the uncertainties of future climate change.

The impetus for discovery and evaluation of protein biomarkers has been accelerated by recent development of advanced technologies for rapid and broad proteome analyses. Mass spectrometry (MS)-based protein assays hold great potential for in vitro biomarker studies. Described here is the development of a multiplex mass spectrometric immunoassay (MSIA) for quantification of apolipoprotein C-I (apoC-I), apolipoprotein C-II (apoC-II), apolipoprotein C-III (apoC-III) and their proteoforms. The multiplex MSIA assay was fast (∼40 min) and high-throughput (96 samples at a time). The assay was applied to a small cohort of human plasma samples, revealing the existence of multiple proteoforms for each apolipoprotein C. The quantitative aspect of the assay enabled determination of the concentration for each proteoform individually. Low-abundance proteoforms, such as fucosylated apoC-III, were detected in less than 20% of the samples. The distribution of apoC-III proteoforms varied among samples with similar total apoC-III concentrations. The multiplex analysis of the three apolipoproteins C and their proteoforms using quantitative MSIA represents a significant step forward toward better understanding of their physiological roles in health and disease.