ASU Scholarship Showcase

Five immunocompetent C57BL/6-cBrd/cBrd/Cr (albino C57BL/6) mice were injected with GL261-luc2 cells, a cell line sharing characteristics of human glioblastoma multiforme (GBM). The mice were imaged using magnetic resonance (MR) at five separate time points to characterize growth and development of the tumor. After 25 days, the final tumor volumes of the mice varied from 12 mm³ to 62 mm³, even though mice were inoculated from the same tumor cell line under carefully controlled conditions. We generated hypotheses to explore large variances in final tumor size and tested them with our simple reaction-diffusion model in both a 3-dimensional (3D) finite difference method and a 2-dimensional (2D) level set method. The parameters obtained from a best-fit procedure, designed to yield simulated tumors as close as possible to the observed ones, vary by an order of magnitude between the three mice analyzed in detail. These differences may reflect morphological and biological variability in tumor growth, as well as errors in the mathematical model, perhaps from an oversimplification of the tumor dynamics or nonidentifiability of parameters. Our results generate parameters that match other experimental in vitro and in vivo measurements. Additionally, we calculate wave speed, which matches with other rat and human measurements.

Background:
Data assimilation refers to methods for updating the state vector (initial condition) of a complex spatiotemporal model (such as a numerical weather model) by combining new observations with one or more prior forecasts. We consider the potential feasibility of this approach for making short-term (60-day) forecasts of the growth and spread of a malignant brain cancer (glioblastoma multiforme) in individual patient cases, where the observations are synthetic magnetic resonance images of a hypothetical tumor.

Results:
We apply a modern state estimation algorithm (the Local Ensemble Transform Kalman Filter), previously developed for numerical weather prediction, to two different mathematical models of glioblastoma, taking into account likely errors in model parameters and measurement uncertainties in magnetic resonance imaging. The filter can accurately shadow the growth of a representative synthetic tumor for 360 days (six 60-day forecast/update cycles) in the presence of a moderate degree of systematic model error and measurement noise.

Conclusions:
The mathematical methodology described here may prove useful for other modeling efforts in biology and oncology. An accurate forecast system for glioblastoma may prove useful in clinical settings for treatment planning and patient counseling.

In spite of well-documented health benefits of vegetarian diets, less is known regarding the effects of these diets on athletic performance. In this cross-sectional study, we compared elite vegetarian and omnivore adult endurance athletes for maximal oxygen uptake (VO2 max) and strength. Twenty-seven vegetarian (VEG) and 43 omnivore (OMN) athletes were evaluated using VO2 max testing on the treadmill, and strength assessment using a dynamometer to determine peak torque for leg extensions. Dietary data were assessed using detailed seven-day food logs. Although total protein intake was lower among vegetarians in comparison to omnivores, protein intake as a function of body mass did not differ by group (1.2 ± 0.3 and 1.4 ± 0.5 g/kg body mass for VEG and OMN respectively, p = 0.220). VO2 max differed for females by diet group (53.0 ± 6.9 and 47.1 ± 8.6 mL/kg/min for VEG and OMN respectively, p < 0.05) but not for males (62.6 ± 15.4 and 55.7 ± 8.4 mL/kg/min respectively). Peak torque did not differ significantly between diet groups. Results from this study indicate that vegetarian endurance athletes’ cardiorespiratory fitness was greater than that for their omnivorous counterparts, but that peak torque did not differ between diet groups. These data suggest that vegetarian diets do not compromise performance outcomes and may facilitate aerobic capacity in athletes.

Background: Obesity is a metabolic disease caused by environmental and genetic factors. However, the epigenetic mechanisms of obesity are incompletely understood. The aim of our study was to investigate the role of skeletal muscle DNA methylation in combination with transcriptomic changes in obesity.

Results: Muscle biopsies were obtained basally from lean (n = 12; BMI = 23.4 ± 0.7 kg/m[superscript 2]) and obese (n = 10; BMI = 32.9 ± 0.7 kg/m[superscript 2]) participants in combination with euglycemic-hyperinsulinemic clamps to assess insulin sensitivity. We performed reduced representation bisulfite sequencing (RRBS) next-generation methylation and microarray analyses on DNA and RNA isolated from vastus lateralis muscle biopsies. There were 13,130 differentially methylated cytosines (DMC; uncorrected P < 0.05) that were altered in the promoter and untranslated (5' and 3'UTR) regions in the obese versus lean analysis. Microarray analysis revealed 99 probes that were significantly (corrected P < 0.05) altered. Of these, 12 genes (encompassing 22 methylation sites) demonstrated a negative relationship between gene expression and DNA methylation. Specifically, sorbin and SH3 domain containing 3 (SORBS3) which codes for the adapter protein vinexin was significantly decreased in gene expression (fold change −1.9) and had nine DMCs that were significantly increased in methylation in obesity (methylation differences ranged from 5.0 to 24.4 %). Moreover, differentially methylated region (DMR) analysis identified a region in the 5'UTR (Chr.8:22,423,530–22,423,569) of SORBS3 that was increased in methylation by 11.2 % in the obese group. The negative relationship observed between DNA methylation and gene expression for SORBS3 was validated by a site-specific sequencing approach, pyrosequencing, and qRT-PCR. Additionally, we performed transcription factor binding analysis and identified a number of transcription factors whose binding to the differentially methylated sites or region may contribute to obesity.

Conclusions: These results demonstrate that obesity alters the epigenome through DNA methylation and highlights novel transcriptomic changes in SORBS3 in skeletal muscle.

The early indications of vitamin C deficiency are unremarkable (fatigue, malaise, depression) and may manifest as a reduced desire to be physically active; moreover, hypovitaminosis C may be associated with increased cold duration and severity. This study examined the impact of vitamin C on physical activity and respiratory tract infections during the peak of the cold season. Healthy non-smoking adult men (18–35 years; BMI <34 kg/m²; plasma vitamin C<45 µmol/L) received either 1000 mg of vitamin C daily (n = 15) or placebo (n = 13) in a randomized, double-blind, eight-week trial. All participants completed the Wisconsin Upper Respiratory Symptom Survey-21 daily and the Godin Leisure-Time Exercise Questionnaire weekly. In the final two weeks of the trial, the physical activity score rose modestly for the vitamin C group vs. placebo after adjusting for baseline values: +39.6% (95% CI [−4.5,83.7]; p = 0.10). The number of participants reporting cold episodes was 7 and 11 for the vitamin C and placebo groups respectively during the eight-week trial (RR = 0.55; 95% CI [0.33,0.94]; p = 0.04) and cold duration was reduced 59% in the vitamin C versus placebo groups (−3.2 days; 95% CI [−7.0,0.6]; p = 0.06). These data suggest measurable health advantages associated with vitamin C supplementation in a population with adequate-to-low vitamin C status.

Background: Our publication of the BitTorious portal [1] demonstrated the ability to create a privatized distributed data warehouse of sufficient magnitude for real-world bioinformatics studies using minimal changes to the standard BitTorrent tracker protocol. In this second phase, we release a new server-side specification to accept anonymous philantropic storage donations by the general public, wherein a small portion of each user’s local disk may be used for archival of scientific data. We have implementated the server-side announcement and control portions of this BitTorrent extension into v3.0.0 of the BitTorious portal, upon which compatible clients may be built.

Results: Automated test cases for the BitTorious Volunteer extensions have been added to the portal’s v3.0.0 release, supporting validation of the “peer affinity” concept and announcement protocol introduced by this specification. Additionally, a separate reference implementation of affinity calculation has been provided in C++ for informaticians wishing to integrate into libtorrent-based projects.

Conclusions: The BitTorrent “affinity” extensions as provided in the BitTorious portal reference implementation allow data publishers to crowdsource the extreme storage prerequisites for research in “big data” fields. With sufficient awareness and adoption of BitTorious Volunteer-based clients by the general public, the BitTorious portal may be able to provide peta-scale storage resources to the scientific community at relatively insignificant financial cost.

Background: Centralized silos of genomic data are architecturally easier to initially design, develop and deploy than distributed models. However, as interoperability pains in EHR/EMR, HIE and other collaboration-centric life sciences domains have taught us, the core challenge of networking genomics systems is not in the construction of individual silos, but the interoperability of those deployments in a manner embracing the heterogeneous needs, terms and infrastructure of collaborating parties. This article demonstrates the adaptation of BitTorrent to private collaboration networks in an authenticated, authorized and encrypted manner while retaining the same characteristics of standard BitTorrent.

Results: The BitTorious portal was sucessfully used to manage many concurrent domestic Bittorrent clients across the United States: exchanging genomics data payloads in excess of 500GiB using the uTorrent client software on Linux, OSX and Windows platforms. Individual nodes were sporadically interrupted to verify the resilience of the system to outages of a single client node as well as recovery of nodes resuming operation on intermittent Internet connections.

Conclusions: The authorization-based extension of Bittorrent and accompanying BitTorious reference tracker and user management web portal provide a free, standards-based, general purpose and extensible data distribution system for large ‘omics collaborations.

Background: Omnivorous diets are high in arachidonic acid (AA) compared to vegetarian diets. Research shows that high intakes of AA promote changes in brain that can disturb mood. Omnivores who eat fish regularly increase their intakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), fats that oppose the negative effects of AA in vivo. In a recent cross-sectional study, omnivores reported significantly worse mood than vegetarians despite higher intakes of EPA and DHA. This study investigated the impact of restricting meat, fish, and poultry on mood.

Findings: Thirty-nine omnivores were randomly assigned to a control group consuming meat, fish, and poultry daily (OMN); a group consuming fish 3-4 times weekly but avoiding meat and poultry (FISH), or a vegetarian group avoiding meat, fish, and poultry (VEG). At baseline and after two weeks, participants completed a food frequency questionnaire, the Profile of Mood States questionnaire and the Depression Anxiety and Stress Scales. After the diet intervention, VEG participants reduced their EPA, DHA, and AA intakes, while FISH participants increased their EPA and DHA intakes. Mood scores were unchanged for OMN or FISH participants, but several mood scores for VEG participants improved significantly after two weeks.

Conclusions: Restricting meat, fish, and poultry improved some domains of short-term mood state in modern omnivores. To our knowledge, this is the first trial to examine the impact of restricting meat, fish, and poultry on mood state in omnivores.

Background: Immunosignaturing is a new peptide microarray based technology for profiling of humoral immune responses. Despite new challenges, immunosignaturing gives us the opportunity to explore new and fundamentally different research questions. In addition to classifying samples based on disease status, the complex patterns and latent factors underlying immunosignatures, which we attempt to model, may have a diverse range of applications.

Methods: We investigate the utility of a number of statistical methods to determine model performance and address challenges inherent in analyzing immunosignatures. Some of these methods include exploratory and confirmatory factor analyses, classical significance testing, structural equation and mixture modeling.

Results: We demonstrate an ability to classify samples based on disease status and show that immunosignaturing is a very promising technology for screening and presymptomatic screening of disease. In addition, we are able to model complex patterns and latent factors underlying immunosignatures. These latent factors may serve as biomarkers for disease and may play a key role in a bioinformatic method for antibody discovery.

Conclusion: Based on this research, we lay out an analytic framework illustrating how immunosignatures may be useful as a general method for screening and presymptomatic screening of disease as well as antibody discovery.

Background: The physical health status of vegetarians has been extensively reported, but there is limited research regarding the mental health status of vegetarians, particularly with regard to mood. Vegetarian diets exclude fish, the major dietary source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), critical regulators of brain cell structure and function. Omnivorous diets low in EPA and DHA are linked to impaired mood states in observational and experimental studies.

Methods: We examined associations between mood state and polyunsaturated fatty acid intake as a result of adherence to a vegetarian or omnivorous diet in a cross-sectional study of 138 healthy Seventh Day Adventist men and women residing in the Southwest. Participants completed a quantitative food frequency questionnaire, Depression Anxiety Stress Scale (DASS), and Profile of Mood States (POMS) questionnaires.

Results: Vegetarians (VEG:n = 60) reported significantly less negative emotion than omnivores (OMN:n = 78) as measured by both mean total DASS and POMS scores (8.32 ± 0.88 vs 17.51 ± 1.88, p = .000 and 0.10 ± 1.99 vs 15.33 ± 3.10, p = .007, respectively). VEG reported significantly lower mean intakes of EPA (p < .001), DHA (p < .001), as well as the omega-6 fatty acid, arachidonic acid (AA; p < .001), and reported higher mean intakes of shorter-chain α-linolenic acid (p < .001) and linoleic acid (p < .001) than OMN. Mean total DASS and POMS scores were positively related to mean intakes of EPA (p < 0.05), DHA (p < 0.05), and AA (p < 0.05), and inversely related to intakes of ALA (p < 0.05), and LA (p < 0.05), indicating that participants with low intakes of EPA, DHA, and AA and high intakes of ALA and LA had better mood.

Conclusions: The vegetarian diet profile does not appear to adversely affect mood despite low intake of long-chain omega-3 fatty acids.