Systems Biology Commons^™

Effect Of Arginine On Oligomerization And Stability Of N-Acetylglutamate Synthase., N Haskins, A Mumo, P H Brown, Mendel Tuchman, Hiroki Morizono, L Caldovic

Genomics and Precision Medicine Faculty Publications

N-acetylglutamate synthase (NAGS; E.C.2.3.1.1) catalyzes the formation of N-acetylglutamate (NAG) from acetyl coenzyme A and glutamate. In microorganisms and plants, NAG is the first intermediate of the L-arginine biosynthesis; in animals, NAG is an allosteric activator of carbamylphosphate synthetase I and III. In some bacteria bifunctional N-acetylglutamate synthase-kinase (NAGS-K) catalyzes the first two steps of L-arginine biosynthesis. L-arginine inhibits NAGS in bacteria, fungi, and plants and activates NAGS in mammals. L-arginine increased thermal stability of the NAGS-K from Maricaulis maris (MmNAGS-K) while it destabilized the NAGS-K from Xanthomonas campestris (XcNAGS-K). Analytical gel chromatography and ultracentrifugation indicated tetrameric structure of the …

Zombies, Predatory Wasps And Consciousness, James K. Peterson

Annual Symposium on Biomathematics and Ecology Education and Research

No abstract provided.

Muscle Myeloid Type I Interferon Gene Expression May Predict Therapeutic Responses To Rituximab In Myositis Patients., Kanneboyina Nagaraju, Svetlana Ghimbovschi, Sree Rayavarapu, Aditi Phadke, Lisa G. Rider, Eric P. Hoffman, Frederick Miller

Genomics and Precision Medicine Faculty Publications

Objective. To identify muscle gene expression patterns that predict rituximab responses and assess the effects of rituximab on muscle gene expression in PM and DM.

Methods. In an attempt to understand the molecular mechanism of response and non-response to rituximab therapy, we performed Affymetrix gene expression array analyses on muscle biopsy specimens taken before and after rituximab therapy from eight PM and two DM patients in the Rituximab in Myositis study. We also analysed selected muscle-infiltrating cell phenotypes in these biopsies by immunohistochemical staining. Partek and Ingenuity pathway analyses assessed the gene pathways and networks.

Results. Myeloid type I IFN …

Identification Of Pathway-Specific Serum Biomarkers Of Response To Glucocorticoid And Infliximab Treatment In Children With Inflammatory Bowel Disease, Christopher R. Heier, Alyson A. Fiorillo, Ellen Chaisson, Heather A. Gordish-Dressman, Yetrib Hathout, Jesse M. Damsker, Eric P. Hoffman, Laurie S. Conklin

Genomics and Precision Medicine Faculty Publications

Objective:

Serum biomarkers may serve to predict early response to therapy, identify relapse, and facilitate drug development in inflammatory bowel disease (IBD). Biomarkers are particularly important in children, in whom achieving early remission and minimizing procedures are especially beneficial.

Methods:

We profiled protein and micro RNA (miRNA) in serum from patients pre- and post-therapy, to identify molecular markers of pharmacodynamic effect. Serum was obtained from children with IBD before and after treatment with either corticosteroids (prednisone; n=12) or anti-tumor necrosis factor-α biologic (infliximab; n=7). Over 1,100 serum proteins were assayed using aptamer-based SOMAscan proteomics, and 22 miRNAs analyzed …

Global Intron Retention Mediated Gene Regulation During Cd4+ T Cell Activation., Ting Ni, Wenjing Yang, Miao Han, Yubo Zhang, Ting Shen, Hongbo Nie, Zhihui Zhou, Yalei Dai, Yanqin Yang, Poching Liu, Kairong Cui, Zhouhao Zeng, Yi Tian, Bin Zhou, Gang Wei, Keji Zhao, Weiqun Peng, Jun Zhu

Genomics and Precision Medicine Faculty Publications

T cell activation is a well-established model for studying cellular responses to exogenous stimulation. Using strand-specific RNA-seq, we observed that intron retention is prevalent in polyadenylated transcripts in resting CD4(+) T cells and is significantly reduced upon T cell activation. Several lines of evidence suggest that intron-retained transcripts are less stable than fully spliced transcripts. Strikingly, the decrease in intron retention (IR) levels correlate with the increase in steady-state mRNA levels. Further, the majority of the genes upregulated in activated T cells are accompanied by a significant reduction in IR. Of these 1583 genes, 185 genes are predominantly regulated at …

Nasp: An Accurate, Rapid Method For The Identification Of Snps In Wgs Datasets That Supports Flexible Input And Output Formats, Jason Sahl, Darrin Lemmer, Jason Travis, James Schupp, John Gillece, Maliha Aziz, +Several Additional Authors

Environmental and Occupational Health Faculty Publications

Whole-genome sequencing (WGS) of bacterial isolates has become standard practice in many laboratories. Applications for WGS analysis include phylogeography and molecular epidemiology, using single nucleotide polymorphisms (SNPs) as the unit of evolution. NASP was developed as a reproducible method that scales well with the hundreds to thousands of WGS data typically used in comparative genomics applications. In this study, we demonstrate how NASP compares with other tools in the analysis of two real bacterial genomics datasets and one simulated dataset. Our results demonstrate that NASP produces similar, and often better, results in comparison with other pipelines, but is much more …

Opn-A Induces Muscle Inflammation By Increasing Recruitment And Activation Of Pro-Inflammatory Macrophages., Gina M Many, Yasuyuki Yokosaki, Kitipong Uaesoontrachoon, Peter P Nghiem, Luca Bello, Sherry Dadgar, Ying Yin, Jesse M Damsker, Heather B Cohen, Joe N Kornegay, Marcas M Bamman, David M Mosser, Kanneboyina Nagaraju, Eric P Hoffman

Genomics and Precision Medicine Faculty Publications

New Findings

• What is the central question of this study? What is the functional relevance of OPN isoform expression in muscle pathology?
• What is the main finding and its importance? The full‐length human OPN‐a isoform is the most pro‐inflammatory isoform in the muscle microenvironment, acting on macrophages and myoblasts in an RGD‐integrin‐dependent manner. OPN‐a upregulates expression of tenascin‐C (TNC), a known Toll‐like receptor 4 (TLR4) agonist. Blocking TLR4 signalling inhibits the pro‐inflammatory effects of OPN‐a, suggesting that a potential mechanism of OPN action is by promoting TNC–TLR4 signalling.

Although osteopontin (OPN) is an important mediator of muscle remodelling in health …

Histological And Molecular Analysis Of A Progressive Diffuse Intrinsic Pontine Glioma And Synchronous Metastatic Lesions: A Case Report., Javad Nazarian, Gary E Mason, Cheng Ying Ho, Eshini Panditharatna, Madhuri Kambhampati, Louis Gilbert Vezina, Roger J. Packer, Eugene I Hwang

Genomics and Precision Medicine Faculty Publications

There is no curative treatment for patients with diffuse intrinsic pontine glioma (DIPG). However, with the recent availability of biopsy and autopsy tissue, new data regarding the biologic behavior of this tumor have emerged, allowing greater molecular characterization and leading to investigations which may result in improved therapeutic options. Treatment strategies must address both primary disease sites as well as any metastatic deposits, which may be variably sensitive to a particular approach.In this case report, we present a patient with DIPG treated with irradiation and serial investigational agents. The clinical, pathological and molecular phenotypes of both the progressive primary tumor …

Ocean Acidification And Predator-Prey Relations: Correlating Disruption Of Predator Avoidance With Chemosensory Deficits, Alexandra Fw Sidun, William G. Wright

Student Scholar Symposium Abstracts and Posters

One of the most destructive effects of global climate change is the increased carbon sequestering and consequential acidification of our world’s oceans. The impacts of ocean acidification on marine organisms are still relatively unknown, especially effects on behavioral ecology. Avoiding predation has emerged from recent behavioral ecology literature as a critical feature in the life history of a wide array of animal species; experiments on marine fishes suggest acidic water compromises their predator-avoidance abilities. Recent assays in our lab suggest predator-induced behavior is reduced by weakly acidic water. These experiments do not address the potential factor of generalized malaise caused …

Effect Of The Il-1 Receptor Antagonist Kineret® On Disease Phenotype In Mdx Mice., Margaret E. Benny Klimek, Arpana Sali, Sree Rayavarapu, Jack Van Der Meulen, Kanneboyina Nagaraju

Genomics and Precision Medicine Faculty Publications

Duchenne muscular dystrophy (DMD) is an X-linked muscle disease caused by mutations in the dystrophin gene. The pathology of DMD manifests in patients with progressive muscle weakness, loss of ambulation and ultimately death. One of the characteristics of DMD is muscle inflammation, and dystrophin-deficient skeletal muscles produce higher levels of the pro-inflammatory cytokine interleukin 1β (IL-1β) in response to toll like receptor (TLR) stimulation compared to controls; therefore, blocking the IL-1β pathway could improve the disease phenotype in mdx mice, a mouse model of DMD. Kineret® or IL-1Ra is a recombinant IL-1 receptor antagonist approved by the FDA for treating …

Glucocorticoid Receptor (Nr3c1) Variants Associate With The Muscle Strength And Size Response To Resistance Training., Garrett I Ash, Matthew A Kostek, Harold Lee, Theodore J Angelopoulos, Priscilla M Clarkson, Paul M Gordon, Niall M Moyna, Paul S Visich, Robert F Zoeller, Thomas B Price, Joseph M. Devaney, Heather Gordish-Dressman, Paul D Thompson, Eric P. Hoffman, Linda S Pescatello

Genomics and Precision Medicine Faculty Publications

Glucocorticoid receptor (NR3C1) polymorphisms associate with obesity, muscle strength, and cortisol sensitivity. We examined associations among four NR3C1 polymorphisms and the muscle response to resistance training (RT). European-American adults (n = 602, 23.8±0.4yr) completed a 12 week unilateral arm RT program. Maximum voluntary contraction (MVC) assessed isometric strength (kg) and MRI assessed biceps size (cm2) pre- and post-resistance training. Subjects were genotyped for NR3C1 -2722G>A, -1887G>A, -1017T>C, and +363A>G. Men carrying the -2722G allele gained less relative MVC (17.3±1.2vs33.5±6.1%) (p = 0.010) than AA homozygotes; men with -1887GG gained greater relative MVC than A allele carriers …

Effects On Muscle Tissue Remodeling And Lipid Metabolism In Muscle Tissue From Adult Patients With Polymyositis Or Dermatomyositis Treated With Immunosuppressive Agents., Ingela Loell, Joan Raouf, Yi-Wen Chen, Rongye Shi, Inger Nennesmo, Helene Alexanderson, Maryam Dastmalchi, Kanneboyina Nagaraju, Marina Korotkova, Ingrid E Lundberg

Genomics and Precision Medicine Faculty Publications

BACKGROUND: Polymyositis (PM) and dermatomyositis (DM) are autoimmune muscle diseases, conventionally treated with high doses of glucocorticoids in combination with immunosuppressive drugs. Treatment is often dissatisfying, with persisting muscle impairment. We aimed to investigate molecular mechanisms that might contribute to the persisting muscle impairment despite immunosuppressive treatment in adult patients with PM or DM using gene expression profiling of repeated muscle biopsies.

METHODS: Paired skeletal muscle biopsies from six newly diagnosed adult patients with DM or PM taken before and after conventional immunosuppressive treatment were examined by gene expression microarray analysis. Selected genes that displayed changes in expression were analyzed …

Are Immune Modulating Single Nucleotide Polymorphisms Associated With Necrotizing Enterocolitis?, Ashanti L Franklin, Mariam Said, Clint D Cappiello, Heather Gordish-Dressman, Zohreh Tatari-Calderone, Stanislav Vukmanovic, Khodayar Rais-Bahrami, Naomi L C Luban, Joseph M Devaney, Anthony D Sandler

Genomics and Precision Medicine Faculty Publications

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal emergency. The purpose of this study is to determine if functional single nucleotide polymorphisms (SNPs) in immune-modulating genes pre-dispose infants to NEC. After Institutional Review Board approval and parental consent, buccal swabs were collected for DNA extraction. TaqMan allelic discrimination assays and BglII endonuclease digestion were used to genotype specific inflammatory cytokines and TRIM21. Statistical analysis was completed using logistic regression. 184 neonates were analyzed in the study. Caucasian neonates with IL-6 (rs1800795) were over 6 times more likely to have NEC (p = 0.013; OR = 6.61, 95% CI 1.48-29.39), and over …

Effect Of Genetic Background On The Dystrophic Phenotype In Mdx Mice., William D Coley, Laurent Bogdanik, Maria Candida Vila, Qing Yu, Terence A Partridge, Kanneboyina Nagaraju, +12 Additional Authors

Genomics and Precision Medicine Faculty Publications

Genetic background significantly affects phenotype in multiple mouse models of human diseases, including muscular dystrophy. This phenotypic variability is partly attributed to genetic modifiers that regulate the disease process. Studies have demonstrated that introduction of the γ-sarcoglycan null allele onto the DBA/2J background confers a more severe muscular dystrophy phenotype than the original strain, demonstrating the presence of genetic modifier loci in the DBA/2J background. To characterize the phenotype of dystrophin deficiency on the DBA/2J background, we created and phenotyped DBA/2J-congenic Dmdmdx mice (D2-mdx) and compared them to the original, C57BL/10ScSn-Dmdmdx (B10-mdx) model. These strains were compared to their respective …

Age-Associated Methylation Suppresses Spry1, Leading To A Failure Of Re-Quiescence And Loss Of The Reserve Stem Cell Pool In Elderly Muscle., Anne Bigot, William J Duddy, Zamalou G Ouandaogo, Elisa Negroni, Virginie Mariot, Svetlana Ghimbovschi, Brennan Harmon, Aurore Wielgosik, Camille Loiseau, Joseph Devaney, Julie Dumonceaux, Gillian Butler-Browne, Vincent Mouly, Stéphanie Duguez

Genomics and Precision Medicine Faculty Publications

The molecular mechanisms by which aging affects stem cell number and function are poorly understood. Murine data have implicated cellular senescence in the loss of muscle stem cells with aging. Here, using human cells and by carrying out experiments within a strictly pre-senescent division count, we demonstrate an impaired capacity for stem cell self-renewal in elderly muscle. We link aging to an increased methylation of the SPRY1 gene, a known regulator of muscle stem cell quiescence. Replenishment of the reserve cell pool was modulated experimentally by demethylation or siRNA knockdown of SPRY1. We propose that suppression of SPRY1 by age-associated …

Bioregulatory Systems Medicine: An Innovative Approach To Integrating The Science Of Molecular Networks, Inflammation, And Systems Biology With The Patient's Autoregulatory Capacity?, Alyssa W Goldman, Yvonne Burmeister, Konstantin Cesnulevicius, Martha Herbert, Mary Kane, David Lescheid, Timothy Mccaffrey, Myron Schultz, Bernd Seilheimer, Alta Smit, Georges St Laurent, Brian Berman

Medicine Faculty Publications

Bioregulatory systems medicine (BrSM) is a paradigm that aims to advance current medical practices. The basic scientific and clinical tenets of this approach embrace an interconnected picture of human health, supported largely by recent advances in systems biology and genomics, and focus on the implications of multi-scale interconnectivity for improving therapeutic approaches to disease. This article introduces the formal incorporation of these scientific and clinical elements into a cohesive theoretical model of the BrSM approach. The authors review this integrated body of knowledge and discuss how the emergent conceptual model offers the medical field a new avenue for extending the …

Targeted Single Molecule Sequencing Methodology For Ovarian Hyperstimulation Syndrome., Funda Orkunoglu-Suer, Arthur F. Harralson, David Frankfurter, Paul Gindoff, Travis J. O'Brien

Genomics and Precision Medicine Faculty Publications

BACKGROUND: One of the most significant issues surrounding next generation sequencing is the cost and the difficulty assembling short read lengths. Targeted capture enrichment of longer fragments using single molecule sequencing (SMS) is expected to improve both sequence assembly and base-call accuracy but, at present, there are very few examples of successful application of these technologic advances in translational research and clinical testing. We developed a targeted single molecule sequencing (T-SMS) panel for genes implicated in ovarian response to controlled ovarian hyperstimulation (COH) for infertility.

RESULTS: Target enrichment was carried out using droplet-base multiplex polymerase chain reaction (PCR) technology (RainDance®) …

Genetic Modifiers Of Duchenne Muscular Dystrophy And Dilated Cardiomyopathy., Andrea Barp, Luca Bello, Luisa Politano, Paola Melacini, Chiara Calore, Eric P. Hoffman, +16 Additional Authors

Genomics and Precision Medicine Faculty Publications

OBJECTIVE: Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4) also modify DCM onset.

METHODS: A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction < 50% and/or end diastolic volume > 70 mL/m2 as …

Transcriptional Pathways Associated With Skeletal Muscle Changes After Spinal Cord Injury And Treadmill Locomotor Training., Celine Baligand, Yi-Wen Chen, Fan Ye, Sachchida Nand Pandey, San-Huei Lai, Min Liu, Krista Vandenborne

Genomics and Precision Medicine Faculty Publications

The genetic and molecular events associated with changes in muscle mass and function after SCI and after the implementation of candidate therapeutic approaches are still not completely known. The overall objective of this study was to identify key molecular pathways activated with muscle remodeling after SCI and locomotor training. We implemented treadmill training in a well-characterized rat model of moderate SCI and performed genome wide expression profiling on soleus muscles at multiple time points: 3, 8, and 14 days after SCI. We found that the activity of the protein ubiquitination and mitochondrial function related pathways was altered with SCI and …

Population Differentiation And Habitat Selection Of A Montane Red Fox Population In The Greater Yellowstone Ecosystem, Patrick Cross

Graduate Student Theses, Dissertations, & Professional Papers

Montane red fox (Vulpes vulpes) populations across the western United States are genetically and morphologically distinct from foxes at lower elevations. These montane populations also share a preference for subalpine forest habitats. One hypothesis is that they stem from boreal forest-associated ancestors that expanded during the Pleistocene when boreal forests extended farther south than they do today. Forest habitat selection may therefore aid the persistence of native populations surrounded by non-native conspecifics. Alternatively, this behavior may be an avoidance mechanism in response to competition with larger coyotes (Canis latrans), or a product of the fox's natural adaptability. The red fox …

Phylogenetic Search Through Partial Tree Mixing., Kenneth Sundberg, Mark Clement, Quinn Snell, Dan Ventura, Michael Whiting, Keith Crandall

Computational Biology Institute

BACKGROUND: Recent advances in sequencing technology have created large data sets upon which phylogenetic inference can be performed. Current research is limited by the prohibitive time necessary to perform tree search on a reasonable number of individuals. This research develops new phylogenetic algorithms that can operate on tens of thousands of species in a reasonable amount of time through several innovative search techniques.

RESULTS: When compared to popular phylogenetic search algorithms, better trees are found much more quickly for large data sets. These algorithms are incorporated in the PSODA application available at http://dna.cs.byu.edu/psoda

CONCLUSIONS: The use of Partial Tree Mixing …

From Energy Gradient And Natural Selection To Biodiversity And Stability Of Ecosystems, Bo Deng

Department of Mathematics: Faculty Publications

The purpose of this paper is to incorporate well-established ecological principles into a foodweb model consisting of four trophic levels --- abiotic resources, plants, herbivores, and carnivores. The underlining principles include Kimura's neutral theory of genetic evolution, Liebig's Law of the Minimum for plant growth, Holling's functionals for herbivore foraging and carnivore predation, the One-Life Rule for all organisms, and Lotka-Volterra's model for intraand interspecific competitions. Numerical simulations of the model led to the following statistical findings: (a) particular foodwebs can give contradicting observations on biodiversity and productivity, in particular, all known functional forms -- - positive, negative, sigmoidal, and …