Grantee Research Project Results
2008 Progress Report: Environmental Bioinformatics and Computational Toxicology Center
EPA Grant Number: R832721Center: New Jersey Research Center for Environmental Bioinformatics and Computational Toxicology
Center Director: Welsh, William J.
Title: Environmental Bioinformatics and Computational Toxicology Center
Investigators: Welsh, William J. , Georgopoulos, Panos G. , I, Androulakis , Floudas, Christodoulos , Rabitz, H , Ierapetritou, M , Tong, Weida
Current Investigators: Welsh, William J. , Georgopoulos, Panos G.
Institution: University of Medicine and Dentistry of New Jersey , Rutgers , Princeton University
Current Institution: University of Medicine and Dentistry of New Jersey , Princeton University , Rutgers
EPA Project Officer: Hahn, Intaek
Project Period: October 1, 2005 through September 30, 2010
Project Period Covered by this Report: October 1, 2007 through September 30,2008
Project Amount: $5,422,135
RFA: Computational Toxicology: Environmental Bioinformatics Research Center (2004) RFA Text | Recipients Lists
Research Category: Safer Chemicals , Human Health , Computational Toxicology
Objective:
The Environmental Bioinformatics Computational Toxicology Center (ebCTC) brings together a team of computational scientists, with diverse backgrounds in bioinformatics, cheminformatics, and enviroinformatics, from UMDNJ, Rutgers, and Princeton Universities, and the USFDA’s Center for Toxicoinformatics. This team is addressing, in a systematic and integrative manner, multiple elements of the toxicant Source-to-Outcome sequence as well as developing cheminformatics tools for toxicant characterization. The computational tools being developed through this effort are extensively evaluated and refined through collaborative applications involving ebCTC scientists as well as colleagues from the three universities, USFDA, and USEPA; particular emphasis is on methods that enhance current quantitative risk assessment practices and reduce uncertainties.Progress Summary:
During the third year of Center activities, the team: (a) took further steps towards integrating developmental efforts from the various ongoing research projects of the Center, and (b) established new collaborations involving scientists from other institutions and EPA, to enhance research in critical areas. A representative sample of specific accomplishments includes:
Data Analysis Methods and Computational Tools
- Continued progress in expanding the framework of ArrayTrack to ebTrack and in the development of new analysis components for incorporation into ebTrack. Evaluation and design of interfaces to open source databases (e.g., PostgreSQL) and to various “external” modeling tools for enabling wider deployment of the ebTrack/ArrayTrack system for integrative analyses of various types of genomic, proteomic, and metabonomic data. Development and demonstration of novel computational tools for peptide identification from tandem mass spectrometry data; development and demonstration of novel, optimized statistical and pattern recognition methods for clustering of gene expression data (these tools are being implemented as modules that can be incorporated into ebTrack).
- Application of novel techniques for analysis of time-series gene expression data and identification of informative genes to support risk analysis tasks: application to exposures to phthalates with identification of critical gene expression motifs, associated gene ontology functions, maximally affected pathways and subsequent cross-species extrapolation conservation of protein sequences between rat and human.
Diagnostic Analysis Methods and Computational Tools·
- Enhancements to the Random-Sampling High Dimensional Model Representation (RS-HDMR) algorithm for sensitivity and uncertainty analysis: Application to (a) toxicokinetic modeling of Arsenic and of aromatic hydrocarbon mixtures; (b) allosteric regulation of aspartate transcarbamoylase (AtCase) by all four ribonucleotide triphosphates (NTPs).
-
Optimization and refinement of sensitivity analysis techniques for usage with PBPK modeling: Application to novel models for aging organisms and populations.
- Development and evaluation of a Bayesian computational framework for exposure reconstruction from biomarker data using toxicokinetic models and numerical inversion methods: Applications to the NHEXAS and NHANES datasets.
-
Development of a strategy for efficiently optimizing the substituent combinations by iterative rounds of compound sampling, and property estimation over the landscape of molecular discovery. Application of this approach to a large pharmaceutical compound library demonstrating its ability to find active compounds.
Molecular Modeling Methods and Computational Tools
- Ongoing development of computational tools for de novo protein design and high resolution protein structure determination: Applications to prediction of interhelical restraints for alpha helical proteins.
- Ongoing development, enhancement, and application of the Shape Signatures QSAR technology for chemical hazard identification: (a) Demonstrations with applications involving conazoles, (b) Development of a Shape Signatures database of ligands extracted from the Protein Data Bank (PDB), and (c) Application of a multi-step screening procedure using Shape Signatures and clustering to identify previously unrecognized antiestrogenic chemicals.
- Molecular modeling studies of ligand-PXR interactions: Applications to binding of conazoles, azoles, steroids and various other structural families to the AF-2 site.
Bionetwork Modeling Methods and Tools
-
Development of customized metabolic engineering tools for identifying important pathways within the overall hepatocyte metabolism, and experimental verification of modeling results.
-
Development and demonstration of novel computational procedures for quantifying the structure of molecular bionetworks via the S-space Network Identification Protocol (SNIP) and the Closed-Loop Identification Protocol (CLIP).
Integrative Toxicokinetic/Toxicodynamic Modeling for Biologically Based Dose-Response Analysis
-
Development of algorithms for rapid assessment of risks from chronic and multiscale exposures to mixtures of contaminants: Applications to halogenated organics.
- Progress in designing/implementing and demonstrating the modular multiscale DORIAN (Dose-
- Response Information Analysis) framework to support mechanistic toxicity and - in conjunction with the Modeling Environment for Total Risk (MENTOR) - comprehensive risk assessment studies: Selected preliminary applications use Arsenic, TCDD, and TCE as “prototype” toxicants.
Future Activities:
Currently planned and ongoing activities include the following:- Continue implementation of existing and design new ebTrack interfaces to open source databases (e.g., PostgreSQL) and to various “external” and Center-developed modeling tools for facilitating wider deployment and applicability of the ebTrack/ArrayTrack system for integrative analyses of various types of genomic, proteomic, and metabonomic data. This will be pursued through further incorporation of novel, optimized statistical and pattern recognition methods for clustering of gene expression data as ebTrack components, and through further analysis of ongoing applications and initiation of additional applications of ArrayTrack for environmentally relevant toxicants (e.g., dibutyl phthalate, TCE, Arsenic, etc.) and component-by-component evaluations of ArrayTrack applications. Specific focus will be on chemicals from EPAs ToxCast database.
- Refine the environmental bioinformatics Knowledge Base (ebKB) and make a public beta version of ebKB available.
- Continue development and implementation of new techniques for incorporating biochemical data into the optimization and parameter estimation components of MENTOR-3P (Modeling Environment for Total Risk with Physiologically based Pharmacokinetic modules for Populations), focusing on Bayesian tools in conjunction with optimization techniques.
- Refine the framework for DORIAN (Dose-Response Information Analysis) modules representing different scales of biological complexity ranging from molecule-molecule interactions to biochemical networks to virtual organs and systems.
- Implement a modular “Virtual Liver” with alternative levels of detail in describing physical structure of the liver with respect to toxicokinetic and toxicodynamic processes with case studies focusing on environmentally-relevant chemicals.
- Implement algorithms as DORIAN modules for rapid assessment of risks from chronic and multiscale exposures to mixtures of contaminants.
-
Continue development and incorporation of diagnostic tools as DORIAN modules for sensitivity and stability analysis of mechanistic models, and demonstrate with case studies focusing on chemicals from EPA’s ToxCast database.
- Pursue experimental verification of modeling results from network models of hepatocyte metabolism, and integration of regulatory rules within metabolic network models and constrain the model such that cell capabilities in the models become more realistic.
- Define metabonomic case studies focusing on (a) pathways involved in steroidogenesis pathways due to in utero exposure to phthalate esters, (b) hepatocarcinogenic potential of exposure to triazole conazoles, and (c) experimental verification of the interactions between ethanol and other central hepatic pathways and xenobiotic pathways.
- Apply SNIP (S-space Network Identification Protocol) and CLIP (Closed-Loop Identification Protocol) to larger networks with higher complexity and optimal design of perturbation experiments for improved efficiency and reliability of SNIP. Additional applications to other realistic bionetworks (e.g., metabolic networks) and optimize the performance.
- Pursue further application of the RS-HDMR (Random-Sampling High Dimensional Model Representation) analysis of the mechanism of action on the cooperative inhibition of aspartate transcarbamoylase, which potentially can enable deeper understanding of many biological processes in which this enzyme is involved.
-
Pursue further incorporation of cheminformatic data in Shape Signatures classification models. Ongoing case studies focus on a blood-brain barrier model.
-
Continue development of structural models for liver nuclear receptors: PXR, FXR, LXR, VDR, etc., and, molecular modeling studies of xenobiotic-NR interactions, with emphasis on chemicals from the ToxCast database and nuclear receptors found in the liver. Ongoing case studies focus on the computational structural model of FXR for Ciona (sea squirt), for comparison with x-ray structural data of FXR for other species.
- Study new approaches, including hybrid methods, for (a) de novo protein design, (b) understanding biological coherence in gene clustering, and (c) peptide identification.
- Define specific case studies for comprehensive source-to-outcome modeling and analysis, and further evaluation of approaches developed at the Center through collaborative efforts with external researchers.
Journal Articles: 118 Displayed | Download in RIS Format
| Other center views: | All 330 publications | 132 publications in selected types | All 118 journal articles |
|---|
| Type | Citation | ||
|---|---|---|---|
|
|
Ai N, Krasowski MD, Welsh WJ, Ekins S. Understanding nuclear receptors using computational methods. Drug Discovery Today 2009;14(9-10):486-494. |
R832721 (2008) |
Exit |
|
|
Almon RR, Yang E, Lai W, Androulakis IP, Ghimbovschi S, Hoffman EP, Jusko WJ, DuBois DC. Relationships between circadian rhythms and modulation of gene expression by glucocorticoids in skeletal muscle. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 2008;295(4):R1031-R1047. |
R832721 (2008) |
Exit Exit Exit |
|
|
Almon RR, Yang E, Lai W, Androulakis IP, DuBois DC, Jusko WJ. Circadian variations in rat liver gene expression: relationships to drug actions. Journal of Pharmacology and Experimental Therapeutics 2008;326(3):700-716. |
R832721 (2008) |
Exit Exit Exit |
|
|
Androulakis IP, Yang E, Almon RR. Analysis of time-series gene expression data:methods, challenges, and opportunities. Annual Review of Biomedical Engineering 2007;9:205-228. |
R832721 (2007) |
Exit |
|
|
Arora S, Wang X, Keenan S, Andaya C, Zhang Q, Peng Y, Welsh W. Novel Microtubule Polymerization Inhibitor with Potent Antiproliferative and Antitumor Activity. CANCER RESEARCH 2009;69(5):1910-1915 |
R832721 (Final) |
Exit |
|
|
Baliban RC, DiMaggio PA, Plazas-Mayorca MD, Young NL, Garcia BA, Floudas CA. A novel approach for untargeted post-translational modification identification using integer linear optimization and tandem mass spectrometry. Molecular and Cellular Proteomics 2010;9(5):764-779. |
R832721 (Final) |
Exit Exit Exit |
|
|
Bellows ML, Fung HK, Taylor MS, Floudas CA, Lopez de Victoria A, Morikis D. New compstatin variants through two de novo protein design frameworks. Biophysical Journal 2010;98(10):2337-2346. |
R832721 (Final) |
Exit |
|
|
Bellows M, Floutas C. Computational Methods for De novo Protein Design and its Applications to the Human Immunodeficiency Vir 1, Purine Nucleoside Phosphorylase, Ubiquitin Specific Protease 7, and Histone Demethylases. CURRENT DRUG TARGETS 2010;11(3):264-278. |
R832721 (Final) |
|
|
|
Brell G, Li G, Rabitz H. An efficient algorithm to accelerate the discovery of complex material formulations. The Journal of Chemical Physics 2010;132(17):174103-174110. |
R832721 (Final) |
Exit |
|
|
Chekmarev DS, Kholodovych V, Balakin KV, Ivanenkov Y, Ekins S, Welsh WJ. Shape signatures: new descriptors for predicting cardiotoxicity in silico. Chemical Research in Toxicology 2008;21(6):1304-1314. |
R832721 (2008) |
Exit |
|
|
Chekmarev D, Kholodovych V, Kortagere S, Welsh WJ, Ekins S. Predicting inhibitors of acetylcholinesterase by regression and classification machine learning approaches with combinations of molecular descriptors. Pharmaceutical Research 2009;26(9):2216-2224. |
R832721 (2008) |
Exit |
|
|
Chen M, Martin J, Fang H, Isukapalli S, Georgopoulos PG, Welsh WJ, Tong W. ebTrack: an environmental bioinformatics system built upon ArrayTrackTM. BMC Proceedings 2009;3(Suppl 2):S5. |
R832721 (2008) |
Exit Exit Exit |
|
|
Cohen Hubal EA, Richard A, Aylward L, Edwards S, Gallagher J, Goldsmith M-R, Isukapalli S, Tornero-Velez R, Weber E, Kavlock R. Advancing exposure characterization for chemical evaluation and risk assessment. Journal of Toxicology and Environmental Health-Part B-Critical Reviews 2010;13(2-4):299-313. |
R832721 (Final) |
Exit |
|
|
Davis E, Ierapetritou M. A kriging method for the solution of nonlinear programs with black-box functions. AIChE Journal 2007;53(8):2001-2012. |
R832721 (2007) |
Exit Exit |
|
|
Davis E, Ierapetritou M. A kriging based method for the solution of mixed-integer nonlinear programs containing black-box functions. JOURNAL OF GLOBAL OPTIMIZATION 2009;43(2-3):191-205. |
R832721 (Final) |
Exit Exit |
|
|
Davis E, Ierapetritou M. A centroid-based sampling strategy for kriging global modeling and optimization. AIChE Journal 2010;56(1):220-240. |
R832721 (2008) |
Exit |
|
|
DiMaggio Jr PA, Floudas CA. De novo peptide identification via tandem mass spectrometry and integer linear optimization. Analytical Chemistry 2007;79(4):1433-1446. |
R832721 (2007) |
|
|
|
DiMaggio Jr PA, Floudas CA. A mixed-integer optimization framework for de novo peptide identification. AIChE Journal 2007;53(1):160-173. |
R832721 (2007) R832721C005 (2006) |
|
|
|
DiMaggio Jr. PA, Floudas CA, Lu B, Yates III JR. A hybrid method for peptide identification using integer linear optimization, local database search, and quadrupole time-of-flight or OrbiTrap tandem mass spectrometry. Journal of Proteome Research 2008;7(4):1584-1593. |
R832721 (2008) |
Exit |
|
|
DiMaggio Jr PA, McAllister SR, Floudas CA, Feng X-J, Rabinowitz JD, Rabitz HA. Optimal methods for re-ordering data matrices in systems biology and drug discovery applications. Biophysical Reviews and Letters 2008;3(1-2):19-42. |
R832721 (2008) |
Exit |
|
|
DiMaggio Jr PA, McAllister SR, Floudas CA, Feng X-J, Rabinowitz JD, Rabitz HA. Biclustering via optimal re-ordering of data matrices in systems biology: rigorous methods and comparative studies. BMC Bioinformatics 2008;9:458-473. |
R832721 (2008) |
Exit Exit Exit |
|
|
DiMaggio Jr. PA, McAllister SR, Floudas CA, Feng X-J, Rabinowitz JD, Rabitz HA. Enhancing molecular discovery using descriptor-free rearrangement clustering techniques for sparse data sets. AIChE Journal 2010;56(2):405-418. |
R832721 (Final) |
Exit |
|
|
DiMaggio Jr PA, McAllister SR, Floudas CA, Feng X-J, Rabinowitz JD, Rabitz HA. A network flow model for biclustering via optimal re-ordering of data matrices. Journal of Global Optimization 2010;47(3):343-354. |
R832721 (2008) R832721 (Final) |
Exit Exit |
|
|
DiMaggio Jr. PA, Subramani A, Judson RS, Floudas CA. A novel framework for predicting in vivo toxicities from in vitro data using optimal methods for dense and sparse matrix re-ordering and logistic regression. Toxicological Sciences 2010;118(1):251-265. |
R832721 (Final) |
Exit Exit Exit |
|
|
DiMaggio Jr. PA, Young NL, Baliban RC, Garcia BA, Floudas CA. A mixed integer linear optimization framework for the identification and quantification of targeted post-translational modifications of highly modified proteins using multiplexed electron transfer dissociation tandem mass spectrometry. Molecular and Cellular Proteomics 2009;8(11):2527-2543. |
R832721 (Final) |
Exit Exit Exit |
|
|
Dong X, Foteinou PT, Calvano SE, Lowry SF, Androulakis IP. Agent-based modeling of endotoxin-induced acute inflammatory response in human blood leukocytes. PLoS One 2010;5(2):e9249. |
R832721 (Final) |
Exit Exit Exit |
|
|
Efstathiou C, Isukapalli S, Georgopoulos P. A mechanistic modeling system for estimating large scale emissions and transport of pollen and co-allergens. Atmospheric Environment 2011;45(13):2260-2276. |
R832721 (Final) R834547 (2010) R834547 (Final) |
Exit Exit Exit |
|
|
Ekins S, Chang C, Mani S, Krasowski MD, Reschly EJ, Iyer M, Kholodovych V, Ai N, Welsh WJ, Sinz M, Swaan PW, Patel R, Bachmann K. Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites. Molecular Pharmacology 2007;72(3):592-603. |
R832721 (2007) |
|
|
|
Ekins S, Kholodovych V, Ai N, Sinz M, Gal J, Gera L, Welsh WJ, Bachmann K, Mani S. Computational discovery of novel low micromolar human pregnane X receptor antagonists. Molecular Pharmacology 2008;74(3):662-672. |
R832721 (2008) |
Exit Exit Exit |
|
|
Feng X, Sanchis J, Reetz MT, Rabitz H. Enhancing the efficiency of directed evolution in focused enzyme libraries by the adaptive substituent reordering algorithm. Chemistry-A European Journal 2012;18(18):5646-5654. |
R832721 (Final) |
Exit |
|
|
Floudas CA. Computational methods in protein structure prediction. Biotechnology and Bioengineering 2007;97(2):207-213. |
R832721 (2007) |
Exit Exit |
|
|
Foteinou PT, Yang E, Androulakis IP. Networks, biology and systems engineering: a case study in inflammation. Computers & Chemical Engineering 2009;33(12):2028-2041. |
R832721 (Final) |
Exit Exit |
|
|
Foteinou PT, Calvano SE, Lowry SF, Androulakis IP. Translational potential of systems-based models of inflammation. Clinical and Translational Science 2009;2(1):85-89. |
R832721 (2008) |
Exit |
|
|
Foteinou PT, Calvano SE, Lowry SF, Androulakis IP. Modeling endotoxin-induced systemic inflammation using an indirect response approach. Mathematical Biosciences 2009;217(1):27-42. |
R832721 (2008) |
Exit |
|
|
Foteinou PT, Calvano SE, Lowry SF, Androulakis IP. In silico simulation of corticosteroids effect on an NFkB-dependent physicochemical model of systemic inflammation. PLoS One 2009;4(3):e4706. |
R832721 (2008) |
Exit Exit Exit |
|
|
Foteinou PT, Yang E, Saharidis GK, Ierapetritou MG, Androulakis IP. A mixed-integer optimization framework for the synthesis and analysis of regulatory networks. Journal of Global Optimization 2009;43(2-3):263-276. |
R832721 (2008) |
Exit |
|
|
Foteinou PT, Calvano SE, Lowry SF, Androulakis IP. Multiscale model for the assessment of autonomic dysfunction in human endotoxemia. Physiological Genomics 2010;42(1):5-19. |
R832721 (Final) |
Exit Exit Exit |
|
|
Foteinou P, Calvano S, Lowry S, Androulakis I. A physiological model for autonomic heart rate regulation in human endotoxemia. SHOCK 2011;35(3):229-239. |
R832721 (Final) |
Exit |
|
|
Fung HK, Welsh WJ, Floudas CA. Computational de novo peptide and protein design: rigid templates versus flexible templates. Industrial & Engineering Chemistry Research 2008;47(4):993-1001. |
R832721 (2007) R832721 (2008) |
Exit Exit |
|
|
Fung HK, Floudas CA, Taylor MS, Zhang L, Morikis D. Toward full-sequence de novo protein design with flexible templates for human beta-defensin-2. Biophysical Journal 2008;94(2):584-599. |
R832721 (2008) |
Exit Exit Exit |
|
|
Georgopoulos PG. A multiscale approach for assessing the interactions of environmental and biological systems in a holistic health risk assessment framework. Water, Air, & Soil Pollution: Focus 2008;8(1):3-21. |
R832721 (2007) R832721 (2008) R832721C001 (2006) R832721C001 (2007) |
Exit Exit |
|
|
Georgopoulos PG, Sasso AF, Isukapalli SS, Lioy PJ, Vallero DA, Okino M, Reiter L. Response to "µg/kg-day or µg/day? A commentary on Georgopoulos et al., JESEE 2008." Journal of Exposure Science & Environmental Epidemiology 2008;18(6):536-537 (author reply). |
R832721 (2008) |
Exit Exit |
|
|
Georgopoulos PG, Wang S-W, Yang Y-C, Xue J, Zartarian VG, McCurdy T, Ozkaynak H. Biologically based modeling of multimedia, multipathway, multiroute population exposures to arsenic. Journal of Exposure Science & Environmental Epidemiology 2008;18(5):462-476. |
R832721 (2008) |
Exit Exit Exit |
|
|
Georgopoulos PG, Sasso AF, Isukapalli SS, Lioy PJ, Vallero DA, Okino M, Reiter L. Reconstructing population exposures to environmental chemicals from biomarkers: challenges and opportunities. Journal of Exposure Science & Environmental Epidemiology 2009;19(2):149-171. |
R832721 (2008) |
Exit Exit Exit |
|
|
Gerecke DR, Chen M, Isukapalli SS, Gordon MK, Chang Y-C, Tong W, Androulakis IP, Georgopoulos PG. Differential gene expression profiling of mouse skin after sulfur mustard exposure: extended time response and inhibitor effect. Toxicology and Applied Pharmacology 2009;234(2):156-165. |
R832721 (2008) |
Exit Exit Exit |
|
|
Halai R, Bellows-Peterson M, Branchett W, Smadbeck J, Kieslich C, Croker D, Cooper M, Morikis D, Woodruff T, Floudas C, Monk P. Derivation of ligands for the complement C3a receptor from the C-termin of C5a. EUROPEAN JOURNAL OF PHARMACOLOGY 2014;745:176-181. |
R832721 (Final) |
Exit Exit |
|
|
Isukapalli SS, Lioy PJ, Georgopoulos PG. Mechanistic modeling of emergency events: assessing the impact of hypothetical releases of anthrax. Risk Analysis 2008;28(3):723-740. |
R832721 (2008) |
Exit |
|
|
Iyer VV, Ovacik MA, Androulakis IP, Roth CM, Ierapetritou MG. Transcriptional and metabolic flux profiling of triadimefon effects on cultured hepatocytes. Toxicology and Applied Pharmacology 2010;248(3):165-177. |
R832721 (Final) |
Exit Exit |
|
|
Iyer VV, Yang H, Ierapetritou MG, Roth CM. Effects of glucose and insulin on HepG2-C3A cell metabolism. Biotechnology and Bioengineering 2010;107(2):347-356. |
R832721 (2008) R832721 (Final) |
Exit |
|
|
Izmailov S, Feng XJ, Li G, Rabitz H. A scalable algorithm for molecular property estimation in high dimensional scaffold-based libraries. Journal of Mathematical Chemistry 2012;50(7):1765-1790. |
R832721 (Final) |
Exit |
|
|
Jiao Y, Su M, Chen M, Jia W, Chou Y, Huang Z, Yang N, Tong W. LC/ESI-MS method for the determination of trimetazidine in human plasma: application to a bioequivalence study on Chinese volunteers. Journal of Pharmaceutical and Biomedical Analysis 2007;43(5):1804-1807. |
R832721 (2007) |
Exit Exit |
|
|
Jornsten R, Ouyang M, Wang H-Y. A meta-data based method for DNA microarray imputation. BMC Bioinformatics 2007;8:109. |
R832721 (2007) |
|
|
|
Jornsten R, Keles S. Mixture models with multiple levels, with application to the analysis of multifactor gene expression data. Biostatistics 2008;9(3):540-554. |
R832721 (2008) |
Exit Exit Exit |
|
|
Jornsten R. Simultaneous model selection via rate-distortion theory, with applications to cluster and significance analysis of gene expression data. Journal of Computational & Graphical Statistics 2009;18(3):613-639. |
R832721 (2007) |
Exit |
|
|
Kortagere S, Chekmarev D, Welsh W, Ekins S. Hybrid Scoring and Classification Approaches to Predict Human Pregnane X Receptor Activators. PHARMACEUTICAL RESEARCH 2008;26(4):1001-1011 |
R832721 (Final) |
Exit |
|
|
Kortagere S, Chekmarev D, Welsh WJ, Ekins S. New predictive models for blood-brain barrier permeability of drug-like molecules. Pharmaceutical Research 2008;25(8):1836-1845. |
R832721 (2008) |
Exit |
|
|
Kortagere S, Ekins S, Welsh WJ. Halogenated ligands and their interactions with amino acids: implications for structure-activity and structure-toxicity relationships. Journal of Molecular Graphics and Modelling 2008;27(2):170-177. |
R832721 (2008) |
Exit |
|
|
Kortagere S, Welsh W, Morrisey J, Daly T, Ejigiri I, Sinnis P, Vaidya A, Bergman L. Structure-based Design of Novel Small-Molecule Inhibitors of Plasmodium falciparum. JOURNAL OF CHEMICAL INFORMATION AND MODELING 2010;50(5):840-849 |
R832721 (Final) |
Exit |
|
|
Lerapetritou MG, Georgopoulos PG, Roth CM, Androulakis IP. Tissue-level modeling of xenobiotic metabolism in liver: an emerging tool for enabling clinical translational research. Clinical and Translational Science 2009;2(3):228-237. |
R832721 (2008) |
Exit |
|
|
Li C, Ai N, Dinh G, Welsh W, Chen J. Human ADA3 regulates RARα transcriptional activity through direct contact between LxxLL motifs and the receptor coactivator pocket. NUCLEIC ACIDS RESEARCH 2010;38(16):5291-5303 |
R832721 (Final) |
Exit |
|
|
Li C-W, Ai N, Dinh GK, Welsh WJ, Chen JD. Human ADA3 regulates RARα transcriptional activity through direct contact between LxxLL motifs and the receptor coactivator pocket. Nucleic Acids Research 2010;38(16):5291-5303. |
R832721 (2008) R832721 (Final) |
Exit Exit Exit |
|
|
Li G, Rabitz H, Hu J, Chen Z, Ju Y. Regularized random-sampling high dimensional model representation (RS-HDMR). Journal of Mathematical Chemistry 2008;43(3):1207-1232. |
R832721 (2007) R832721 (2008) |
Exit |
|
|
Li G, Rabitz H, Yelvington PE, Oluwole OO, Bacon F, Kolb CE, Schoendorf J. Global sensitivity analysis for systems with independent and/or correlated inputs. Journal of Physical Chemistry A 2010;114(19):6022-6032. |
R832721 (2008) R832721 (Final) R835826 (Final) |
Exit Exit |
|
|
Li G, Rabitz H. D-MORPH regression: application to modeling with unknown parameters more than observation data. Journal of Mathematical Chemistry 2010;48(4):1010-1035. |
R832721 (Final) |
Exit |
|
|
Lin Y, Yassuda K, Assem M, Cline C, Barber J, Li C, Kholodovych V, Ai N, Chen J, Welsh W, Ekins S, Schuetz E. The Major Human Pregnane X Receptor PXR Splice Variant, PXR.2, Exhibits Significantly Diminished Ligand-Activated Transcriptional Regulation. DRUG METABOLISM AND DISPOSITION 2009;37(6):1295-1304. |
R832721 (Final) |
Exit Exit Exit |
|
|
McAllister SR, Mickus BE, Klepeis JL, Floudas CA. Novel approach for α-helical topology prediction in globular proteins:generation of interhelical restraints. Proteins:Structure, Function, and Bioinformatics 2006;65(4):930-952. |
R832721 (2007) |
|
|
|
McAllister SR, Floudas CA. α-helical topology prediction and generation of distance restraints in membrane proteins. Biophysical Journal 2008;95(11):5281-5295. |
R832721 (2008) R832721 (Final) |
Exit Exit Exit |
|
|
McAllister SR, Rajgaria R, Floudas CA. A path selection approach to global pairwise sequence alignment using integer linear optimization. Optimization: A Journal of Mathematical Programming and Operations Research 2008;57(1):101-111. |
R832721 (2008) |
Exit |
|
|
McAllister SR, Feng X-J, DiMaggio Jr PA, Floudas CA, Rabinowitz JD, Rabitz H. Descriptor-free molecular discovery in large libraries by adaptive substituent reordering. Bioorganic & Medicinal Chemistry Letters 2008;18(22):5967-5970. |
R832721 (2008) |
Exit Exit |
|
|
McAllister SR, Floudas CA. Enhanced bounding techniques to reduce the protein conformational search space. Optimization Methods & Software 2009;24(4-5):837-855. |
R832721 (2008) |
Exit |
|
|
McAllister SR, DiMaggio Jr PA, Floudas CA. Mathematical modeling and efficient optimization methods for the distance-dependent rearrangement clustering problem. Journal of Global Optimization 2009;45(1):111-129. |
R832721 (2008) |
Exit |
|
|
McAllister SR, Floudas CA. An improved hybrid global optimization method for protein tertiary structure prediction. Computational Optimization and Applications 2010;45(2):377-413. |
R832721 (2008) R832721 (Final) |
Exit |
|
|
Nguyen TT, Nowakowski RS, Androulakis IP. Unsupervised selection of highly coexpressed and noncoexpressed genes using a consensus clustering approach. OMICS 2009;13(3):219-237. |
R832721 (2008) |
Exit |
|
|
Nguyen TT, Almon RR, DuBois DC, Jusko WJ, Androulakis IP. Importance of replication in analyzing time-series gene expression data: corticosteroid dynamics and circadian patterns in rat liver. BMC Bioinformatics 2010;11:279. |
R832721 (Final) |
Exit Exit Exit |
|
|
Nguyen TT, Foteinou PT, Calvano SE, Lowry SF, Androulakis IP. Computational identification of transcriptional regulators in human endotoxemia. PLoS One 2011;6(5):e18889. |
R832721 (Final) |
Exit Exit Exit |
|
|
Nguyen T, Almon R, DuBOis D, Jko W, Androulakis I. Comparative analysis of acute and chronic corticosteroid pharmacogenomic effects in rat liver:Transcriptional dynamics and regulatory structures. BMC BIOINFORMATICS 2010;11:515. |
R832721 (Final) |
Exit Exit |
|
|
Oelschlaeger P, Ai N, DuPrez KT, Welsh WJ, Toney JH. Evolving carbapenemases: can medicinal chemists advance one step ahead of the coming storm? Journal of Medicinal Chemistry 2010;53(8):3013-3027. |
R832721 (Final) |
Exit |
|
|
Orman M, Arai K, Yarmush M, Androulakis I, Berthiaume F, Ierapetritou M. Metabolic flux determination in perfused livers by mass balance analysis: Effect of fasting. BIOTECHNOLOGY AND BIOENGINEERING 2010;107(5):825-835 |
R832721 (Final) |
Exit |
|
|
Ovacik MA, Androulakis IP. On the potential for integrating gene expression and metabolic flux data. Current Bioinformatics 2008;3(3):142-148. |
R832721 (2008) |
Exit Exit |
|
|
Ovacik MA, Sukumaran S, Almon RR, DuBois DC, Jusko WJ, Androulakis IP. Circadian signatures in rat liver: from gene expression to pathways. BMC Bioinformatics 2010;11:540. |
R832721 (2008) R832721 (Final) |
Exit Exit Exit |
|
|
Ovacik MA, Androulakis IP. Enzyme sequence similarity improves the reaction alignment method for cross-species pathway comparison. Toxicology and Applied Pharmacology 2013;271(3):363-371. |
R832721 (2008) R832721 (Final) |
Exit Exit Exit |
|
|
Ovacik MA, Sen B, Euling SY, Gaido KW, Ierapetritou MG, Androulakis IP. Pathway modeling of microarray data: a case study of pathway activity changes in the testis following in utero exposure to dibutyl phthalate (DBP). Toxicology and Applied Pharmacology 2013;271(3):386-394. |
R832721 (Final) |
Exit Exit |
|
|
Piazza M, Feng X-J, Rabinowitz JD, Rabitz H. Diverse metabolic model parameters generate similar methionine cycle dynamics. Journal of Theoretical Biology 2008;251(4):628-639. |
R832721 (2008) |
Exit Exit Exit |
|
|
Rabinowitz JD, Hsiao JJ, Gryncel KR, Kantrowitz ER, Feng X-J, Li G, Rabitz H. Dissecting enzyme regulation by multiple allosteric effectors: nucleotide regulation of aspartate transcarbamoylase. Biochemistry 2008;47(21):5881-5888. |
R832721 (2008) |
Exit |
|
|
Rajgaria R, McAllister SR, Floudas CA. A novel high resolution Cα—Cα distance dependent force field based on a high quality decoy set. Proteins 2006;65(3):726-741. |
R832721 (2007) R832721C005 (2006) R832721C005 (2007) |
Exit Exit |
|
|
Rajgaria R, McAllister SR, Floudas CA. Distance dependent centroid to centroid force fields using high resolution decoys. Proteins: Structure, Function, Bioinformatics 2008;70(3):950-970. |
R832721 (2008) |
Exit |
|
|
Rajgaria R, McAllister SR, Floudas CA. Towards accurate residue-residue hydrophobic contact prediction for α helical proteins via integer linear optimization. Proteins: Structure, Function, Bioinformatics 2009;74(4):929-947. |
R832721 (2008) R832721 (Final) |
Exit |
|
|
Rajgaria R, Wei Y, Floudas CA. Contact prediction for beta and alpha-beta proteins using integer linear optimization and its impact on the first principles 3D structure prediction method ASTRO-FOLD. Proteins 2010;78(8):1825-1846. |
R832721 (Final) |
Exit |
|
|
Reschly EJ, Ai N, Ekins S, Welsh WJ, Hagey LR, Hofmann AF, Krasowski MD. Evolution of the bile salt nuclear receptor FXR in vertebrates. Journal of Lipid Research 2008;49(7):1577-1587. |
R832721 (2008) |
Exit Exit Exit |
|
|
Reschly EJ, Ai N, Welsh WJ, Ekins S, Hagey LR, Krasowski MD. Ligand specificity and evolution of liver X receptors. Journal of Steroid Biochemistry and Molecular Biology 2008;110(1-2):83-94. |
R832721 (2008) |
Exit |
|
|
Saharidis GK, Ierapetritou MG. Resolution method for mixed integer bi-level linear problems based on decomposition technique. Journal of Global Optimization 2009;44(1):29-51. |
R832721 (2008) |
Exit Exit |
|
|
Saharidis G, Androulakis I, Ierapetritou M. Model building using bi-level optimization. JOURNAL OF GLOBAL OPTIMIZATION 2011;49(1):49-67. |
R832721 (Final) |
Exit Exit |
|
|
Sasso AF, Isukapalli SS, Georgopoulos PG. A generalized physiologically-based toxicokinetic modeling system for chemical mixtures containing metals. Theoretical Biology and Medical Modelling 2010;7:17. |
R832721 (Final) |
Exit Exit Exit |
|
|
Sasso AF, Georgopoulos PG, Isukapalli SS, Krishnan K. Bayesian analysis of a lipid-based physiologically based toxicokinetic model for a mixture of PCBs in rats. Journal of Toxicology 2012;2012:895391, doi:10.1155/2012/895391. |
R832721 (2008) |
Exit Exit Exit |
|
|
Scheff JD, Almon RR, DuBois DC, Jusko WJ, Androulakis IP. A new symbolic representation for the identification of informative genes in replicated microarray experiments. OMICS–A Journal of Integrative Biology 2010;14(3):239-248. |
R832721 (Final) |
Exit |
|
|
Schnackenberg LK, Chen M, Sun J, Holland RD, Dragan Y, Tong W, Welsh W, Beger RD. Evaluations of the trans-sulfuration pathway in multiple liver toxicity studies. Toxicology and Applied Pharmacology 2009;235(1):25-32. |
R832721 (2008) |
Exit Exit Exit |
|
|
Stamatelos SK, Brinkerhoff CJ, Isukapalli SS, Georgopoulos PG. Mathematical model of uptake and metabolism of arsenic(III) in human hepatocytes – incorporation of cellular antioxidant response and threshold-dependent behavior. BMC Systems Biology 2011;5:16. |
R832721 (Final) |
Exit Exit Exit |
|
|
Stamatelos S, Androulakis I, Kong A, Georgopoulos P. A semi-mechanistic integrated toxicokinetic-toxicodynamic (TK/TD) model for arsenic(III) in hepatocytes. JOURNAL OF THEORETICAL BIOLOGY 2013;317:244-256 |
R832721 (Final) |
Exit |
|
|
Subramani A, DiMaggio P, Floudas C. Selecting High Quality Protein Structures from Diverse Conformational Ensembles. BIOPHYSICAL JOURNAL 2009;97(6):1728-1736. |
R832721 (Final) |
Exit Exit |
|
|
Sun JJ, Abdeljabbar DM, Clarke N, Bellows ML, Floudas CA, Link AJ. Reconstitution and engineering of apoptotic protein interactions on the bacterial cell surface. Journal of Molecular Biology 2009;394(2):297-305. |
R832721 (Final) |
Exit |
|
|
Tan MP, Smith EN, Broach JR, Floudas CA. Microarray data mining: a novel optimization-based approach to uncover biologically coherent structures. BMC Bioinformatics 2008;9:268-289. |
R832721 (2008) |
Exit Exit Exit |
|
|
Taylor MS, Fung HK, Rajgaria R, Filizola M, Weinstein H, Floudas CA. Mutations affecting the oligomerization interface of G-protein-coupled receptors revealed by a novel de novo protein design framework. Biophysical Journal 2008;94(7):2470-2481. |
R832721 (2008) |
Exit Exit Exit |
|
|
Wang CY, Ai N, Arora S, Erenrich E, Nagarajan K, Zauhar R, Young D, Welsh WJ. Identification of previously unrecognized antiestrogenic chemicals using a novel virtual screening approach. Chemical Research in Toxicology 2006;19(12):1595-1601. |
R832721C004 (2006) R832721C004 (2007) |
not available |
|
|
Xue J, Zartarian V, Wang S-W, Liu SV, Georgopoulos P. Probabilistic modeling of dietary arsenic exposure and dose and evaluation with 2003-2004 NHANES data. Environmental Health Perspectives 2010;118(3):345-350. |
R832721 (Final) |
|
|
|
Yang EH, Almon RR, Dubois DC, Jusko WJ, Androulakis IP. Identification of global transcriptional dynamics. PLoS One 2009;10;4(7):e5992. |
R832721 (2008) |
Exit Exit Exit |
|
|
Yang E, Maguire T, Yarmush ML, Berthiaume F, Androulakis IP. Bioinformatics analysis of the early inflammatory response in a rat thermal injury model. BMC Bioinformatics 2007;8:10. |
R832721 (2007) |
|
|
|
Yang E, Simcha D, Almon RR, Dubois DC, Jusko WJ, Androulakis IP. Context specific transcription factor prediction. Annals of Biomedical Engineering 2007;35(6):1053-1067. |
R832721 (2007) |
Exit Exit |
|
|
Yang E, Foteinou PT, King KR, Yarmush ML, Androulakis IP. A novel non-overlapping bi-clustering algorithm for network generation using living cell array data. Bioinformatics 2007;23(17):2306-2313. |
R832721 (2007) |
Exit Exit |
|
|
Yang E, Maguire T, Yarmush ML, Androulakis IP. Informative gene selection and design of regulatory networks using integer optimization. Computers & Chemical Engineering 2008;32(4-5):633-649. |
R832721 (2007) R832721 (2008) |
Exit Exit |
|
|
Yang E, Maguire TJ, Yarmush ML, Berthiaume F, Androulakis IP. Identification of regulatory mechanisms of the hepatic response to thermal injury. Computers & Chemical Engineering 2008;32(1-2):356-369. |
R832721 (2007) R832721 (2008) |
Exit Exit |
|
|
Yang E, Almon RR, DuBois DC, Jusko WJ, Androulakis IP. Extracting global system dynamics of corticosteroid genomic effects in rat liver. Journal of Pharmacology and Experimental Therapeutics 2008;324(3):1243-1254. |
R832721 (2007) R832721 (2008) |
Exit Exit Exit |
|
|
Yang E, Androulakis IP. Assessing and selecting gene expression signals based upon the quality of the measured dynamics. BMC Bioinformatics 2009;10:55-67. |
R832721 (2008) |
Exit Exit Exit |
|
|
Yang E, Yarmush ML, Androulakis IP. Transcription factor network reconstruction using the living cell array. Journal of Theoretical Biology 2009;256(3):393-407. |
R832721 (2008) |
Exit Exit Exit |
|
|
Yang H, Roth CM, Ierapetritou MG. A rational design approach for amino acid supplementation in hepatocyte culture. Biotechnology and Bioengineering 2009;103(6):1176-1191. |
R832721 (2008) R832721 (Final) |
Exit Exit |
|
|
Yang H, Ierapetritou MG, Roth CM. Effects of amino acid transport limitations on cultured hepatocytes. Biophysical Chemistry 2010;152(1-3):89-98. |
R832721 (2008) R832721 (Final) |
Exit |
|
|
Yang H, Roth CM, Ierapetritou MG. Analysis of amino acid supplementation effects on hepatocyte cultures using flux balance analysis. OMICS 2011;15(7-8):449-460. |
R832721 (2008) |
Exit |
|
|
Yang Y, Xu X, Georgopoulos PG. A Bayesian population PBPK model for multiroute chloroform exposure. Journal of Exposure Science & Environmental Epidemiology 2010;20(4):326-341. |
R832721 (2008) R832721 (Final) |
Exit |
|
|
Yuan J, Doucette C, Fowler W, Feng X, Piazza M, Rabitz H, Wingreen N, Rabinowitz J. Metabolomics-driven quantitative analysis of ammonia assimilation in E. coli. MOLECULAR SYSTEMS BIOLOGY 2009;5(302). |
R832721 (Final) |
Exit Exit |
Supplemental Keywords:
computational toxicology, toxicogenomics, bioinformatics, toxicoinformatics, proteomics, metabonomics, physiomics, cytomics, genomics, transcriptomics, enviroinformatics, cheminformatics, biologically based dose-response modeling, cross-species extrapolation, risk assessment, Health, Scientific Discipline, Geographic Area, State, Risk Assessments, Biochemistry, Environmental Monitoring, Biology, ecological risk assessment, computational toxicology, toxicology, dose-response, environmental risks, biopollution, outreach and training, chemical composition, New Jersey (NJ), human exposure, bioinformatics, biochemical researchRelevant Websites:
http://ebctc.org
|
Progress and Final Reports:
Original Abstract Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R832721C001 Development and Application of the DORIAN (Dose-Response Information Analysis) System
R832721C002 Hepatocyte Metabolism Model for Xenobiotics
R832721C003 Development of Computational Tools for Optimal Identification of Biological Networks
R832721C004 Cheminformatics Tools for Toxicant Characterization
R832721C005 Optimization Tools for In Silico Structural Proteomics
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.