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Search Results: 1 - 10 of 463987 matches for " Rebecca A. Baillie "
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Virtual Systems Pharmacology (ViSP) software for mechanistic system-level model simulations
Sergey Ermakov,Peter Forster,Marko Miladinov,Rebecca Baillie,Tarek A. Leil
Frontiers in Pharmacology , 2014, DOI: 10.3389/fphar.2014.00232
Abstract: Multiple software programs are available for designing and running large scale system-level pharmacology models used in the drug development process. Depending on the problem, scientists may be forced to use several modeling tools that could increase model development time, IT costs and so on. Therefore, it is desirable to have a single platform that allows setting up and running large-scale simulations for the models that have been developed with different modeling tools. We developed a workflow and a software platform in which a model file is compiled into a self-contained executable that is no longer dependent on the software that was used to create the model. At the same time the full model specifics is preserved by presenting all model parameters as input parameters for the executable. This platform was implemented as a model agnostic, therapeutic area agnostic and web-based application with a database back-end that can be used to configure, manage and execute large-scale simulations for multiple models by multiple users. The user interface is designed to be easily configurable to reflect the specifics of the model and the user's particular needs and the back-end database has been implemented to store and manage all aspects of the systems, such as Models, Virtual Patients, User Interface Settings, and Results. The platform can be adapted and deployed on an existing cluster or cloud computing environment. Its use was demonstrated with a metabolic disease systems pharmacology model that simulates the effects of two antidiabetic drugs, metformin and fasiglifam, in type 2 diabetes mellitus patients.
Lipidomics Reveals Early Metabolic Changes in Subjects with Schizophrenia: Effects of Atypical Antipsychotics
Joseph McEvoy, Rebecca A. Baillie, Hongjie Zhu, Peter Buckley, Matcheri S. Keshavan, Henry A. Nasrallah, George G. Dougherty, Jeffrey K. Yao, Rima Kaddurah-Daouk
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0068717
Abstract: There is a critical need for mapping early metabolic changes in schizophrenia to capture failures in regulation of biochemical pathways and networks. This information could provide valuable insights about disease mechanisms, trajectory of disease progression, and diagnostic biomarkers. We used a lipidomics platform to measure individual lipid species in 20 drug-na?ve patients with a first episode of schizophrenia (FE group), 20 patients with chronic schizophrenia that had not adhered to prescribed medications (RE group), and 29 race-matched control subjects without schizophrenia. Lipid metabolic profiles were evaluated and compared between study groups and within groups before and after treatment with atypical antipsychotics, risperidone and aripiprazole. Finally, we mapped lipid profiles to n3 and n6 fatty acid synthesis pathways to elucidate which enzymes might be affected by disease and treatment. Compared to controls, the FE group showed significant down-regulation of several n3 polyunsaturated fatty acids (PUFAs), including 20:5n3, 22:5n3, and 22:6n3 within the phosphatidylcholine and phosphatidylethanolamine lipid classes. Differences between FE and controls were only observed in the n3 class PUFAs; no differences where noted in n6 class PUFAs. The RE group was not significantly different from controls, although some compositional differences within PUFAs were noted. Drug treatment was able to correct the aberrant PUFA levels noted in FE patients, but changes in re patients were not corrective. Treatment caused increases in both n3 and n6 class lipids. These results supported the hypothesis that phospholipid n3 fatty acid deficits are present early in the course of schizophrenia and tend not to persist throughout its course. These changes in lipid metabolism could indicate a metabolic vulnerability in patients with schizophrenia that occurs early in development of the disease.
Metabolomics Reveals Amino Acids Contribute to Variation in Response to Simvastatin Treatment
Miles Trupp, Hongjie Zhu, William R. Wikoff, Rebecca A. Baillie, Zhao-Bang Zeng, Peter D. Karp, Oliver Fiehn, Ronald M. Krauss, Rima Kaddurah-Daouk
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038386
Abstract: Statins are widely prescribed for reducing LDL-cholesterol (C) and risk for cardiovascular disease (CVD), but there is considerable variation in therapeutic response. We used a gas chromatography-time-of-flight mass-spectrometry-based metabolomics platform to evaluate global effects of simvastatin on intermediary metabolism. Analyses were conducted in 148 participants in the Cholesterol and Pharmacogenetics study who were profiled pre and six weeks post treatment with 40 mg/day simvastatin: 100 randomly selected from the full range of the LDL-C response distribution and 24 each from the top and bottom 10% of this distribution (“good” and “poor” responders, respectively). The metabolic signature of drug exposure in the full range of responders included essential amino acids, lauric acid (p<0.0055, q<0.055), and alpha-tocopherol (p<0.0003, q<0.017). Using the HumanCyc database and pathway enrichment analysis, we observed that the metabolites of drug exposure were enriched for the pathway class amino acid degradation (p<0.0032). Metabolites whose change correlated with LDL-C lowering response to simvastatin in the full range responders included cystine, urea cycle intermediates, and the dibasic amino acids ornithine, citrulline and lysine. These dibasic amino acids share plasma membrane transporters with arginine, the rate-limiting substrate for nitric oxide synthase (NOS), a critical mediator of cardiovascular health. Baseline metabolic profiles of the good and poor responders were analyzed by orthogonal partial least square discriminant analysis so as to determine the metabolites that best separated the two response groups and could be predictive of LDL-C response. Among these were xanthine, 2-hydroxyvaleric acid, succinic acid, stearic acid, and fructose. Together, the findings from this study indicate that clusters of metabolites involved in multiple pathways not directly connected with cholesterol metabolism may play a role in modulating the response to simvastatin treatment. Trial Registration ClinicalTrials.gov NCT00451828
Enteric Microbiome Metabolites Correlate with Response to Simvastatin Treatment
Rima Kaddurah-Daouk, Rebecca A. Baillie, Hongjie Zhu, Zhao-Bang Zeng, Michelle M. Wiest, Uyen Thao Nguyen, Katie Wojnoonski, Steven M. Watkins, Miles Trupp, Ronald M. Krauss
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025482
Abstract: Although statins are widely prescribed medications, there remains considerable variability in therapeutic response. Genetics can explain only part of this variability. Metabolomics is a global biochemical approach that provides powerful tools for mapping pathways implicated in disease and in response to treatment. Metabolomics captures net interactions between genome, microbiome and the environment. In this study, we used a targeted GC-MS metabolomics platform to measure a panel of metabolites within cholesterol synthesis, dietary sterol absorption, and bile acid formation to determine metabolite signatures that may predict variation in statin LDL-C lowering efficacy. Measurements were performed in two subsets of the total study population in the Cholesterol and Pharmacogenetics (CAP) study: Full Range of Response (FR), and Good and Poor Responders (GPR) were 100 individuals randomly selected from across the entire range of LDL-C responses in CAP. GPR were 48 individuals, 24 each from the top and bottom 10% of the LDL-C response distribution matched for body mass index, race, and gender. We identified three secondary, bacterial-derived bile acids that contribute to predicting the magnitude of statin-induced LDL-C lowering in good responders. Bile acids and statins share transporters in the liver and intestine; we observed that increased plasma concentration of simvastatin positively correlates with higher levels of several secondary bile acids. Genetic analysis of these subjects identified associations between levels of seven bile acids and a single nucleotide polymorphism (SNP), rs4149056, in the gene encoding the organic anion transporter SLCO1B1. These findings, along with recently published results that the gut microbiome plays an important role in cardiovascular disease, indicate that interactions between genome, gut microbiome and environmental influences should be considered in the study and management of cardiovascular disease. Metabolic profiles could provide valuable information about treatment outcomes and could contribute to a more personalized approach to therapy.
A study of Double Pomeron Exchange in ALICE
A. Kirk,O. Villalobos Baillie
Physics , 1998,
Abstract: The non-Abelian nature of QCD suggests that particles that have a gluon constituent, such as glueballs or hybrids, should exist. Experiments WA76, WA91 and WA102 have performed a dedicated search for these states in central production using the CERN Omega Spectrometer. New results from central production show that there is a kinematical filter which can select out glueball candidates from known qqbar states. A further study of this at high energies is essential in order to get information on the M(X0) > 2 GeV region. This paper describes how this could be done using the the ALICE detector at the LHC.
An Integrated Strategy to Study Muscle Development and Myofilament Structure in Caenorhabditis elegans
Barbara Meissner,Adam Warner,Kim Wong,Nicholas Dube,Adam Lorch,Sheldon J. McKay,Jaswinder Khattra,Teresa Rogalski,Aruna Somasiri,Iasha Chaudhry,Rebecca M. Fox,David M. Miller III,David L. Baillie,Robert A. Holt,Steven J. M. Jones,Marco A. Marra,Donald G. Moerman
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000537
Abstract: A crucial step in the development of muscle cells in all metazoan animals is the assembly and anchorage of the sarcomere, the essential repeat unit responsible for muscle contraction. In Caenorhabditis elegans, many of the critical proteins involved in this process have been uncovered through mutational screens focusing on uncoordinated movement and embryonic arrest phenotypes. We propose that additional sarcomeric proteins exist for which there is a less severe, or entirely different, mutant phenotype produced in their absence. We have used Serial Analysis of Gene Expression (SAGE) to generate a comprehensive profile of late embryonic muscle gene expression. We generated two replicate long SAGE libraries for sorted embryonic muscle cells, identifying 7,974 protein-coding genes. A refined list of 3,577 genes expressed in muscle cells was compiled from the overlap between our SAGE data and available microarray data. Using the genes in our refined list, we have performed two separate RNA interference (RNAi) screens to identify novel genes that play a role in sarcomere assembly and/or maintenance in either embryonic or adult muscle. To identify muscle defects in embryos, we screened specifically for the Pat embryonic arrest phenotype. To visualize muscle defects in adult animals, we fed dsRNA to worms producing a GFP-tagged myosin protein, thus allowing us to analyze their myofilament organization under gene knockdown conditions using fluorescence microscopy. By eliminating or severely reducing the expression of 3,300 genes using RNAi, we identified 122 genes necessary for proper myofilament organization, 108 of which are genes without a previously characterized role in muscle. Many of the genes affecting sarcomere integrity have human homologs for which little or nothing is known.
Multiple Potts Models Coupled to Two-Dimensional Quantum Gravity
C. F. Baillie,D. A. Johnston
Physics , 1992, DOI: 10.1016/0370-2693(92)90156-X
Abstract: We perform Monte Carlo simulations using the Wolff cluster algorithm of {\it multiple} $q=2,3,4$ state Potts models on dynamical phi-cubed graphs of spherical topology in order to investigate the $c>1$ region of two-dimensional quantum gravity. Contrary to naive expectation we find no obvious signs of pathological behaviour for $c>1$. We discuss the results in the light of suggestions that have been made for a modified DDK ansatz for $c>1$.
A Numerical Test of KPZ Scaling: Potts Models Coupled to Two-Dimensional Quantum Gravity
C. F. Baillie,D. A. Johnston
Physics , 1992, DOI: 10.1142/S0217732392001191
Abstract: We perform Monte Carlo simulations using the Wolff cluster algorithm of the q=2 (Ising), 3, 4 and q=10 Potts models on dynamical phi-cubed graphs of spherical topology with up to 5000 nodes. We find that the measured critical exponents are in reasonable agreement with those from the exact solution of the Ising model and with those calculated from KPZ scaling for q=3,4 where no exact solution is available. Using Binder's cumulant we find that the q=10 Potts model displays a first order phase transition on a dynamical graph, as it does on a fixed lattice. We also examine the internal geometry of the graphs generated in the simulation, finding a linear relationship between ring length probabilities and the central charge of the Potts model
Spin Models on Thin Graphs
C. F. Baillie,D. A. Johnston
Physics , 1995, DOI: 10.1016/0920-5632(96)00142-9
Abstract: We discuss the utility of analytical and numerical investigation of spin models, in particular spin glasses, on ordinary ``thin'' random graphs (in effect Feynman diagrams) using methods borrowed from the ``fat'' graphs of two dimensional gravity. We highlight the similarity with Bethe lattice calculations and the advantages of the thin graph approach both analytically and numerically for investigating mean field results.
Damaging 2D Quantum Gravity
C. F. Baillie,D. A. Johnston
Physics , 1993, DOI: 10.1016/0370-2693(94)91191-6
Abstract: We investigate numerically the behaviour of damage spreading in a Kauffman cellular automaton with quenched rules on a dynamical $\phi^3$ graph, which is equivalent to coupling the model to discretized 2D gravity. The model is interesting from the cellular automaton point of view as it lies midway between a fully quenched automaton with fixed rules and fixed connectivity and a (soluble) fully annealed automaton with varying rules and varying connectivity. In addition, we simulate the automaton on a fixed $\phi^3$ graph coming from a 2D gravity simulation as a means of exploring the graph geometry.
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