ASU Scholarship Showcase

Evolutionary dynamical models for cyclic competitions of three species (e.g., rock, paper, and scissors, or RPS) provide a paradigm, at the microscopic level of individual interactions, to address many issues in coexistence and biodiversity. Real ecosystems often involve competitions among more than three species. By extending the RPS game model to five (rock-paper-scissors-lizard-Spock, or RPSLS) mobile species, we uncover a fundamental type of mesoscopic interactions among subgroups of species. In particular, competitions at the microscopic level lead to the emergence of various local groups in different regions of the space, each involving three species. It is the interactions among the groups that fundamentally determine how many species can coexist. In fact, as the mobility is increased from zero, two transitions can occur: one from a five- to a three-species coexistence state and another from the latter to a uniform, single-species state. We develop a mean-field theory to show that, in order to understand the first transition, group interactions at the mesoscopic scale must be taken into account. Our findings suggest, more broadly, the importance of mesoscopic interactions in coexistence of great many species.

Background: Cancer diagnosis in both dogs and humans is complicated by the lack of a non-invasive diagnostic test. To meet this clinical need, we apply the recently developed immunosignature assay to spontaneous canine lymphoma as clinical proof-of-concept. Here we evaluate the immunosignature as a diagnostic for spontaneous canine lymphoma at both at initial diagnosis and evaluating the disease free interval following treatment.

Methods: Sera from dogs with confirmed lymphoma (B cell n = 38, T cell n = 11) and clinically normal dogs (n = 39) were analyzed. Serum antibody responses were characterized by analyzing the binding pattern, or immunosignature, of serum antibodies on a non-natural sequence peptide microarray. Peptides were selected and tested for the ability to distinguish healthy dogs from those with lymphoma and to distinguish lymphoma subtypes based on immunophenotype. The immunosignature of dogs with lymphoma were evaluated for individual signatures. Changes in the immunosignatures were evaluated following treatment and eventual relapse.

Results: Despite being a clonal disease, both an individual immunosignature and a generalized lymphoma immunosignature were observed in each dog. The general lymphoma immunosignature identified in the initial set of dogs (n = 32) was able to predict disease status in an independent set of dogs (n = 42, 97% accuracy). A separate immunosignature was able to distinguish the lymphoma based on immunophenotype (n = 25, 88% accuracy). The individual immunosignature was capable of confirming remission three months following diagnosis. Immunosignature at diagnosis was able to predict which dogs with B cell lymphoma would relapse in less than 120 days (n = 33, 97% accuracy).

Conclusion: We conclude that the immunosignature can serve as a multilevel diagnostic for canine, and potentially human, lymphoma.

Adaptation requires genetic variation, but founder populations are generally genetically depleted. Here we sequence two populations of an inbred ant that diverge in phenotype to determine how variability is generated. Cardiocondyla obscurior has the smallest of the sequenced ant genomes and its structure suggests a fundamental role of transposable elements (TEs) in adaptive evolution. Accumulations of TEs (TE islands) comprising 7.18% of the genome evolve faster than other regions with regard to single-nucleotide variants, gene/exon duplications and deletions and gene homology. A non-random distribution of gene families, larvae/adult specific gene expression and signs of differential methylation in TE islands indicate intragenomic differences in regulation, evolutionary rates and coalescent effective population size. Our study reveals a tripartite interplay between TEs, life history and adaptation in an invasive species.

We investigate high-dimensional nonlinear dynamical systems exhibiting multiple resonances under adiabatic parameter variations. Our motivations come from experimental considerations where time-dependent sweeping of parameters is a practical approach to probing and characterizing the bifurcations of the system. The question is whether bifurcations so detected are faithful representations of the bifurcations intrinsic to the original stationary system. Utilizing a harmonically forced, closed fluid flow system that possesses multiple resonances and solving the Navier-Stokes equation under proper boundary conditions, we uncover the phenomenon of the early effect. Specifically, as a control parameter, e.g., the driving frequency, is adiabatically increased from an initial value, resonances emerge at frequency values that are lower than those in the corresponding stationary system. The phenomenon is established by numerical characterization of physical quantities through the resonances, which include the kinetic energy and the vorticity field, and a heuristic analysis based on the concept of instantaneous frequency. A simple formula is obtained which relates the resonance points in the time-dependent and time-independent systems. Our findings suggest that, in general, any true bifurcation of a nonlinear dynamical system can be unequivocally uncovered through adiabatic parameter sweeping, in spite of a shift in the bifurcation point, which is of value to experimental studies of nonlinear dynamical systems.

Antigen-antibody complexes are central players in an effective immune response. However, finding those interactions relevant to a particular disease state can be arduous. Nonetheless many paths to discovery have been explored since deciphering these interactions can greatly facilitate the development of new diagnostics, therapeutics, and vaccines. In silico B cell epitope mapping approaches have been widely pursued, though success has not been consistent. Antibody mixtures in immune sera have been used as handles for biologically relevant antigens, but these and other experimental approaches have proven resource intensive and time consuming. In addition, these methods are often tailored to individual diseases or a specific proteome, rather than providing a universal platform. Most of these methods are not able to identify the specific antibody’s epitopes from unknown antigens, such as un-annotated neo antigens in cancer. Alternatively, a peptide library comprised of sequences unrestricted by naturally-found protein space provides for a universal search for mimotopes of an antibody’s epitope. Here we present the utility of such a non-natural random sequence library of 10,000 peptides physically addressed on a microarray for mimotope discovery without sequence information of the specific antigen. The peptide arrays were probed with serum from an antigen-immunized rabbit, or alternatively probed with serum pre-absorbed with the same immunizing antigen. With this positive and negative screening scheme, we identified the library-peptides as the mimotopes of the antigen. The unique library peptides were successfully used to isolate antigen-specific antibodies from complete immune serum. Sequence analysis of these peptides revealed the epitopes in the immunized antigen. We present this method as an inexpensive, efficient method for identifying mimotopes of any antibody’s targets. These mimotopes should be useful in defining both components of the antigen-antibody complex.

Background: The success of new sequencing technologies and informatic methods for identifying genes has made establishing gene product function a critical rate limiting step in progressing the molecular sciences. We present a method to functionally mine genomes for useful activities in vivo, using an unusual property of a member of the poxvirus family to demonstrate this screening approach.

Results: The genome of Parapoxvirus ovis (Orf virus) was sequenced, annotated, and then used to PCR-amplify its open-reading-frames. Employing a cloning-independent protocol, a viral expression-library was rapidly built and arrayed into sub-library pools. These were directly delivered into mice as expressible cassettes and assayed for an immune-modulating activity associated with parapoxvirus infection. The product of the B2L gene, a homolog of vaccinia F13L, was identified as the factor eliciting immune cell accumulation at sites of skin inoculation. Administration of purified B2 protein also elicited immune cell accumulation activity, and additionally was found to serve as an adjuvant for antigen-specific responses. Co-delivery of the B2L gene with an influenza gene-vaccine significantly improved protection in mice. Furthermore, delivery of the B2L expression construct, without antigen, non-specifically reduced tumor growth in murine models of cancer.

Conclusion: A streamlined, functional approach to genome-wide screening of a biological activity in vivo is presented. Its application to screening in mice for an immune activity elicited by the pathogen genome of Parapoxvirus ovis yielded a novel immunomodulator. In this inverted discovery method, it was possible to identify the adjuvant responsible for a function of interest prior to a mechanistic study of the adjuvant. The non-specific immune activity of this modulator, B2, is similar to that associated with administration of inactivated particles to a host or to a live viral infection. Administration of B2 may provide the opportunity to significantly impact host immunity while being itself only weakly recognized. The functional genomics method used to pinpoint B2 within an ORFeome may be more broadly applicable to screening for other biological activities in an animal.

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: High-throughput technologies such as DNA, RNA, protein, antibody and peptide microarrays are often used to examine differences across drug treatments, diseases, transgenic animals, and others. Typically one trains a classification system by gathering large amounts of probe-level data, selecting informative features, and classifies test samples using a small number of features. As new microarrays are invented, classification systems that worked well for other array types may not be ideal. Expression microarrays, arguably one of the most prevalent array types, have been used for years to help develop classification algorithms. Many biological assumptions are built into classifiers that were designed for these types of data. One of the more problematic is the assumption of independence, both at the probe level and again at the biological level. Probes for RNA transcripts are designed to bind single transcripts. At the biological level, many genes have dependencies across transcriptional pathways where co-regulation of transcriptional units may make many genes appear as being completely dependent. Thus, algorithms that perform well for gene expression data may not be suitable when other technologies with different binding characteristics exist. The immunosignaturing microarray is based on complex mixtures of antibodies binding to arrays of random sequence peptides. It relies on many-to-many binding of antibodies to the random sequence peptides. Each peptide can bind multiple antibodies and each antibody can bind multiple peptides. This technology has been shown to be highly reproducible and appears promising for diagnosing a variety of disease states. However, it is not clear what is the optimal classification algorithm for analyzing this new type of data.

Results: We characterized several classification algorithms to analyze immunosignaturing data. We selected several datasets that range from easy to difficult to classify, from simple monoclonal binding to complex binding patterns in asthma patients. We then classified the biological samples using 17 different classification algorithms. Using a wide variety of assessment criteria, we found ‘Naïve Bayes’ far more useful than other widely used methods due to its simplicity, robustness, speed and accuracy.

Conclusions: ‘Naïve Bayes’ algorithm appears to accommodate the complex patterns hidden within multilayered immunosignaturing microarray data due to its fundamental mathematical properties.

It is known that in classical fluids turbulence typically occurs at high Reynolds numbers. But can turbulence occur at low Reynolds numbers? Here we investigate the transition to turbulence in the classic Taylor-Couette system in which the rotating fluids are manufactured ferrofluids with magnetized nanoparticles embedded in liquid carriers. We find that, in the presence of a magnetic field transverse to the symmetry axis of the system, turbulence can occur at Reynolds numbers that are at least one order of magnitude smaller than those in conventional fluids. This is established by extensive computational ferrohydrodynamics through a detailed investigation of transitions in the flow structure, and characterization of behaviors of physical quantities such as the energy, the wave number, and the angular momentum through the bifurcations. A finding is that, as the magnetic field is increased, onset of turbulence can be determined accurately and reliably. Our results imply that experimental investigation of turbulence may be feasible by using ferrofluids. Our study of transition to and evolution of turbulence in the Taylor-Couette ferrofluidic flow system provides insights into the challenging problem of turbulence control.

We present a phylogeographic study of at least six reproductively isolated lineages of new world harvester ants within the Pogonomyrmex barbatus and P. rugosus species group. The genetic and geographic relationships within this clade are complex: Four of the identified lineages show genetic caste determination (GCD) and are divided into two pairs. Each pair has evolved under a mutualistic system that necessitates sympatry. These paired lineages are dependent upon one another because their GCD requires interlineage matings for the production of F1 hybrid workers, and intralineage matings are required to produce queens. This GCD system maintains genetic isolation among these interdependent lineages, while simultaneously requiring co-expansion and emigration as their distributions have changed over time. It has also been demonstrated that three of these four GCD lineages have undergone historical hybridization, but the narrower sampling range of previous studies has left questions on the hybrid parentage, breadth, and age of these groups. Thus, reconstructing the phylogenetic and geographic history of this group allows us to evaluate past insights and hypotheses and to plan future inquiries in a more complete historical biogeographic context. Using mitochondrial DNA sequences sampled across most of the morphospecies’ ranges in the U.S.A. and Mexico, we conducted a detailed phylogeographic study. Remarkably, our results indicate that one of the GCD lineage pairs has experienced a dramatic range expansion, despite the genetic load and fitness costs of the GCD system. Our analyses also reveal a complex pattern of vicariance and dispersal in Pogonomyrmex harvester ants that is largely concordant with models of late Miocene, Pliocene, and Pleistocene range shifts among various arid-adapted taxa in North America.