Functional integration of a metabolic network model and expression data without arbitrary thresholding

Motivation: Flux balance analysis (FBA) has been used extensively to analyze genome-scale, constraint-based models of metabolism in a variety of organisms. The predictive accuracy of such models has recently been improved through the integration of high-throughput expression profiles of metabolic genes and proteins. However, extensions of FBA often require that such data be discretized a […]

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Metabolic network analysis integrated with transcript verification for sequenced genomes

With sequencing of thousands of organisms completed or in progress, there is a growing need to integrate gene prediction with metabolic network analysis. Using Chlamydomonas reinhardtii as a model, we describe a systems-level methodology bridging metabolic network reconstruction with experimental verification of enzyme encoding open reading frames. Our quantitative and predictive metabolic model and its […]

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Functional States of the Genome-Scale Escherichia Coli Transcriptional Regulatory System

A transcriptional regulatory network (TRN) constitutes the collection of regulatory rules that link environmental cues to the transcription state of a cell’s genome. We recently proposed a matrix formalism that quantitatively represents a system of such rules (a transcriptional regulatory system [TRS]) and allows systemic characterization of TRS properties. The matrix formalism not only allows […]

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Proteomic and network analysis characterize stage-specific metabolism in Trypanosoma cruzi

Background: Trypanosoma cruzi is a Kinetoplastid parasite of humans and is the cause of Chagas disease, a potentially lethal condition affecting the cardiovascular, gastrointestinal, and nervous systems of the human host. Constraint-based modeling has emerged in the last decade as a useful approach to integrating genomic and other high-throughput data sets with more traditional, experimental […]

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Dynamic Analysis of Integrated Signaling, Metabolic, and Regulatory Networks

Extracellular cues affect signaling, metabolic, and regulatory processes to elicit cellular responses. Although intracellular signaling, metabolic, and regulatory networks are highly integrated, previous analyses have largely focused on independent processes (e.g., metabolism) without considering the interplay that exists among them. However, there is evidence that many diseases arise from multifunctional components with roles throughout signaling, […]

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Systems analysis of metabolism in the pathogenic trypanosomatid Leishmania major

Systems analyses have facilitated the characterization of metabolic networks of several organisms. We have reconstructed the metabolic network of Leishmania major, a poorly characterized organism that causes cutaneous leishmaniasis in mammalian hosts. This network reconstruction accounts for 560 genes, 1112 reactions, 1101 metabolites and 8 unique subcellular localizations. Using a systems- based approach, we hypothesized […]

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Predicting biological system objectives de novo from internal state measurements

Background: Optimization theory has been applied to complex biological systems to interrogate network properties and develop and refine metabolic engineering strategies. For example, methods are emerging to engineer cells to optimally produce byproducts of commercial value, such as bioethanol, as well as molecular compounds for disease therapy. Flux balance analysis (FBA) is an optimization framework […]

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Multiscale computational analysis of Xenopus laevis morphogenesis reveals key insights of systems-level behavior

Background: Tissue morphogenesis is a complex process whereby tissue structures self-assemble by the aggregate behaviors of independently acting cells responding to both intracellular and extracellular cues in their environment. During embryonic development, morphogenesis is particularly important for organizing cells into tissues, and although key regulatory events of this process are well studied in isolation, a […]

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Systems analyses characterize integrated functions of biochemical networks

Metabolic, regulatory and signaling pathways have been characterized in detail over the past century. As the amount of genomic, proteomic and metabolic data has increased, and the mathematical and analytical capabilities of interrogating these data have advanced, the overlapping roles of pathway constituents have been described. These developments reflect the truly integrated nature of subcellular […]

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Reconstruction of Cellular Signalling Networks and Analysis of Their Properties

The study of cellular signalling over the past 20 years and the advent of high- throughput technologies are enabling the reconstruction of large-scale signalling networks. After careful reconstruction of signalling networks, their properties must be described within an integrative framework that accounts for the complexity of the cellular signalling network and that is amenable to […]

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