ASU Scholarship Showcase

The apolipoprotein E (APOE) e4 genotype is a powerful risk factor for late-onset Alzheimer’s disease (AD). In the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, we previously reported significant baseline structural differences in APOE e4 carriers relative to non-carriers, involving the left hippocampus more than the right—a difference more pronounced in e4 homozygotes than heterozygotes. We now examine the longitudinal effects of APOE genotype on hippocampal morphometry at 6-, 12- and 24-months, in the ADNI cohort. We employed a new automated surface registration system based on conformal geometry and tensor-based morphometry. Among different hippocampal surfaces, we computed high-order correspondences, using a novel inverse-consistent surface-based fluid registration method and multivariate statistics consisting of multivariate tensor-based morphometry (mTBM) and radial distance. At each time point, using Hotelling’s T² test, we found significant morphological deformation in APOE e4 carriers relative to non-carriers in the full cohort as well as in the non-demented (pooled MCI and control) subjects at each follow-up interval. In the complete ADNI cohort, we found greater atrophy of the left hippocampus than the right, and this asymmetry was more pronounced in e4 homozygotes than heterozygotes. These findings, combined with our earlier investigations, demonstrate an e4 dose effect on accelerated hippocampal atrophy, and support the enrichment of prevention trial cohorts with e4 carriers.

The development of non-volatile logic through direct coupling of spontaneous ferroelectric polarization with semiconductor charge carriers is nontrivial, with many issues, including epitaxial ferroelectric growth, demonstration of ferroelectric switching and measurable semiconductor modulation. Here we report a true ferroelectric field effect—carrier density modulation in an underlying Ge(001) substrate by switching of the ferroelectric polarization in epitaxial c-axis-oriented BaTiO₃ grown by molecular beam epitaxy. Using the density functional theory, we demonstrate that switching of BaTiO₃ polarization results in a large electric potential change in Ge. Aberration-corrected electron microscopy confirms BaTiO₃ tetragonality and the absence of any low-permittivity interlayer at the interface with Ge. The non-volatile, switchable nature of the single-domain out-of-plane ferroelectric polarization of BaTiO₃ is confirmed using piezoelectric force microscopy. The effect of the polarization switching on the conductivity of the underlying Ge is measured using microwave impedance microscopy, clearly demonstrating a ferroelectric field effect.

To address the need to study frozen clinical specimens using next-generation RNA, DNA, chromatin immunoprecipitation (ChIP) sequencing and protein analyses, we developed a biobank work flow to prospectively collect biospecimens from patients with renal cell carcinoma (RCC). We describe our standard operating procedures and work flow to annotate pathologic results and clinical outcomes. We report quality control outcomes and nucleic acid yields of our RCC submissions (N=16) to The Cancer Genome Atlas (TCGA) project, as well as newer discovery platforms, by describing mass spectrometry analysis of albumin oxidation in plasma and 6 ChIP sequencing libraries generated from nephrectomy specimens after histone H3 lysine 36 trimethylation (H3K36me3) immunoprecipitation. From June 1, 2010, through January 1, 2013, we enrolled 328 patients with RCC. Our mean (SD) TCGA RNA integrity numbers (RINs) were 8.1 (0.8) for papillary RCC, with a 12.5% overall rate of sample disqualification for RIN <7. Banked plasma had significantly less albumin oxidation (by mass spectrometry analysis) than plasma kept at 25°C (P<.001). For ChIP sequencing, the FastQC score for average read quality was at least 30 for 91% to 95% of paired-end reads. In parallel, we analyzed frozen tissue by RNA sequencing; after genome alignment, only 0.2% to 0.4% of total reads failed the default quality check steps of Bowtie2, which was comparable to the disqualification ratio (0.1%) of the 786-O RCC cell line that was prepared under optimal RNA isolation conditions. The overall correlation coefficients for gene expression between Mayo Clinic vs TCGA tissues ranged from 0.75 to 0.82. These data support the generation of high-quality nucleic acids for genomic analyses from banked RCC. Importantly, the protocol does not interfere with routine clinical care. Collections over defined time points during disease treatment further enhance collaborative efforts to integrate genomic information with outcomes.

Many children born preterm exhibit frontal executive dysfunction, behavioral problems including attentional deficit/hyperactivity disorder and attention related learning disabilities. Anomalies in regional specificity of cortico-striato-thalamo-cortical circuits may underlie deficits in these disorders. Nonspecific volumetric deficits of striatal structures have been documented in these subjects, but little is known about surface deformation in these structures. For the first time, here we found regional surface morphological differences in the preterm neonatal ventral striatum. We performed regional group comparisons of the surface anatomy of the striatum (putamen and globus pallidus) between 17 preterm and 19 term-born neonates at term-equivalent age. We reconstructed striatal surfaces from manually segmented brain magnetic resonance images and analyzed them using our in-house conformal mapping program. All surfaces were registered to a template with a new surface fluid registration method. Vertex-based statistical comparisons between the two groups were performed via four methods: univariate and multivariate tensor-based morphometry, the commonly used medial axis distance, and a combination of the last two statistics. We found statistically significant differences in regional morphology between the two groups that are consistent across statistics, but more extensive for multivariate measures. Differences were localized to the ventral aspect of the striatum. In particular, we found abnormalities in the preterm anterior/inferior putamen, which is interconnected with the medial orbital/prefrontal cortex and the midline thalamic nuclei including the medial dorsal nucleus and pulvinar. These findings support the hypothesis that the ventral striatum is vulnerable, within the cortico-stiato-thalamo-cortical neural circuitry, which may underlie the risk for long-term development of frontal executive dysfunction, attention deficit hyperactivity disorder and attention-related learning disabilities in preterm neonates.

Insulin-like growth factor 1 (IGF1) is an important biomarker for the management of growth hormone disorders. Recently there has been rising interest in deploying mass spectrometric (MS) methods of detection for measuring IGF1. However, widespread clinical adoption of any MS-based IGF1 assay will require increased throughput and speed to justify the costs of analyses, and robust industrial platforms that are reproducible across laboratories. Presented here is an MS-based quantitative IGF1 assay with performance rating of >1,000 samples/day, and a capability of quantifying IGF1 point mutations and posttranslational modifications. The throughput of the IGF1 mass spectrometric immunoassay (MSIA) benefited from a simplified sample preparation step, IGF1 immunocapture in a tip format, and high-throughput MALDI-TOF MS analysis. The Limit of Detection and Limit of Quantification of the resulting assay were 1.5 μg/L and 5 μg/L, respectively, with intra- and inter-assay precision CVs of less than 10%, and good linearity and recovery characteristics. The IGF1 MSIA was benchmarked against commercially available IGF1 ELISA via Bland-Altman method comparison test, resulting in a slight positive bias of 16%. The IGF1 MSIA was employed in an optimized parallel workflow utilizing two pipetting robots and MALDI-TOF-MS instruments synced into one-hour phases of sample preparation, extraction and MSIA pipette tip elution, MS data collection, and data processing. Using this workflow, high-throughput IGF1 quantification of 1,054 human samples was achieved in approximately 9 hours. This rate of assaying is a significant improvement over existing MS-based IGF1 assays, and is on par with that of the enzyme-based immunoassays. Furthermore, a mutation was detected in ∼1% of the samples (SNP: rs17884626, creating an A→T substitution at position 67 of the IGF1), demonstrating the capability of IGF1 MSIA to detect point mutations and posttranslational modifications.

Serum Amyloid A (SAA) is an acute phase protein complex consisting of several abundant isoforms. The N- terminus of SAA is critical to its function in amyloid formation. SAA is frequently truncated, either missing an arginine or an arginine-serine dipeptide, resulting in isoforms that may influence the capacity to form amyloid. However, the relative abundance of truncated SAA in diabetes and chronic kidney disease is not known.

Methods: Using mass spectrometric immunoassay, the abundance of SAA truncations relative to the native variants was examined in plasma of 91 participants with type 2 diabetes and chronic kidney disease and 69 participants without diabetes.

Results: The ratio of SAA 1.1 (missing N-terminal arginine) to native SAA 1.1 was lower in diabetics compared to non-diabetics (p = 0.004), and in males compared to females (p<0.001). This ratio was negatively correlated with glycated hemoglobin (r = −0.32, p<0.001) and triglyceride concentrations (r = −0.37, p<0.001), and positively correlated with HDL cholesterol concentrations (r = 0.32, p<0.001).

Conclusion: The relative abundance of the N-terminal arginine truncation of SAA1.1 is significantly decreased in diabetes and negatively correlates with measures of glycemic and lipid control.

Background: Cysteine sulfenic acid (Cys-SOH) plays important roles in the redox regulation of numerous proteins. As a relatively unstable posttranslational protein modification it is difficult to quantify the degree to which any particular protein is modified by Cys-SOH within a complex biological environment. The goal of these studies was to move a step beyond detection and into the relative quantification of Cys-SOH within specific proteins found in a complex biological setting--namely, human plasma.

Results: This report describes the possibilities and limitations of performing such analyses based on the use of thionitrobenzoic acid and dimedone-based probes which are commonly employed to trap Cys-SOH. Results obtained by electrospray ionization-based mass spectrometric immunoassay reveal the optimal type of probe for such analyses as well as the reproducible relative quantification of Cys-SOH within albumin and transthyretin extracted from human plasma--the latter as a protein previously unknown to be modified by Cys-SOH.

Conclusions: The relative quantification of Cys-SOH within specific proteins in a complex biological setting can be accomplished, but several analytical precautions related to trapping, detecting, and quantifying Cys-SOH must be taken into account prior to pursuing its study in such matrices.

In this paper, we report on the highly conductive layer formed at the crystalline γ-alumina/SrTiO₃ interface, which is attributed to oxygen vacancies. We describe the structure of thin γ-alumina layers deposited by molecular beam epitaxy on SrTiO3 (001) at growth temperatures in the range of 400–800 °C, as determined by reflection-high-energy electron diffraction, x-ray diffraction, and high-resolution electron microscopy. In situ x-ray photoelectron spectroscopy was used to confirm the presence of the oxygen-deficient layer. Electrical characterization indicates sheet carrier densities of ∼1013 cm−2 at room temperature for the sample deposited at 700 °C, with a maximum electron Hall mobility of 3100 cm²V^-1s^-1 at 3.2 K and room temperature mobility of 22 cm²V^-1s^-1. Annealing in oxygen is found to reduce the carrier density and turn a conductive sample into an insulator.

In this paper, we develop a new automated surface registration system based on surface conformal parameterization by holomorphic 1-forms, inverse consistent surface fluid registration, and multivariate tensor-based morphometty (mTBM). First, we conformally map a surface onto a planar rectangle space with holomorphic 1-forms. Second, we compute surface conformal representation by combining its local conformal factor and mean curvature and linearly scale the dynamic range of the conformal representation to form the feature image of the surface. Third, we align the feature image with a chosen template image via the fluid image registration algorithm, which has been extended into the curvilinear coordinates to adjust for the distortion introduced by surface parameterization. The inverse consistent image registration algorithm is also incorporated in the system to jointly estimate the forward and inverse transformations between the study and template images. This alignment induces a corresponding deformation on the surface. We tested the system on Alzheimer's Disease Neuroimaging Initiative (ADNI) baseline dataset to study AD symptoms on hippocampus. In our system, by modeling a hippocampus as a 3D parametric surface, we nonlinearly registered each surface with a selected template surface. Then we used mTBM to analyze the morphometry difference between diagnostic groups. Experimental results show that the new system has better performance than two publicly available subcortical surface registration tools: FIRST and SPHARM. We also analyzed the genetic influence of the Apolipoprotein E(is an element of)4 allele (ApoE4), which is considered as the most prevalent risk factor for AD. Our work successfully detected statistically significant difference between ApoE4 carriers and non-carriers in both patients of mild cognitive impairment (MCI) and healthy control subjects. The results show evidence that the ApoE genotype may be associated with accelerated brain atrophy so that our work provides a new MRI analysis tool that may help presymptomatic AD research.

This paper reports the molecular beam epitaxial growth and characterization of high-reflectivity and broad-bandwidth distributed Bragg reflectors (DBRs) made of ZnTe/GaSb quarter-wavelength (lambda/4) layers for optoelectronic applications in the midwave infrared spectral range (2-5 mu m). A series of ZnTe/GaSb DBRs has been successfully grown on GaSb (001) substrates using molecular beam epitaxy (MBE). During the MBE growth, a temperature ramp was applied to the initial growth of GaSb layers on ZnTe to protect the ZnTe underneath from damage due to thermal evaporation. Post-growth characterization using high-resolution x-ray diffraction, atomic force microscopy, and transmission electron microscopy reveals smooth surface morphology, low defect density, and coherent interfaces. Reflectance spectroscopy results show that a DBR sample of seven lambda/4 pairs has a peak reflectance as high as 99.0% centered at 2.56 mu m with a bandwidth of 517 nm.