1. P. Bastiaens, M. R. Birtwistle, N. Bluthgen, F. J. Bruggeman, K.-H. Cho, C. Cosentino, A. de la Fuente, J. B. Hoek, A. Kiyatkin, S. Klamt, W. Kolch, S. Legewie, P. Mendes, T. Naka, T. Santra, E.D. Sontag, H. V. Westerhoff, and B. N. Kholodenko. Silence on the relevant literature and errors in implementation. Nature Biotech, 33:336-339, 2015. [PDF] Keyword(s): modular response analysis, systems biology, biochemical networks, reverse engineering, gene and protein networks, protein networks, gene networks, systems identification. Abstract:

   This letter discusses a paper in the same journal which reported a method for reconstructing network topologies. Here we show that the method is a variant of a previously published method, modular response analysis. We also demonstrate that the implementation of the algorithm in that paper using statistical similarity measures as a proxy for global network responses to perturbations is erroneous and its performance is overestimated.




2. M. Andrec, B.N. Kholodenko, R.M. Levy, and E.D. Sontag. Inference of signaling and gene regulatory networks by steady-state perturbation experiments: structure and accuracy. J. Theoret. Biol., 232(3):427-441, 2005. Note: Supplementary materials are here: http://sontaglab.org/FTPDIR/andrec-kholodenko-levy-sontag-JTB04-supplementary.pdf. [PDF] Keyword(s): systems biology, biochemical networks, gene and protein networks, systems identification, reverse engineering, modular response analysis, systems biology, biochemical networks, reverse engineering, gene and protein networks, protein networks, gene networks, systems identification. Abstract:

   One of the fundamental problems of cell biology is the understanding of complex regulatory networks. Such networks are ubiquitous in cells, and knowledge of their properties is essential for the understanding of cellular behavior. This paper studies the effect of experimental uncertainty on the accuracy of the inferred structure of the networks determined using the method in "Untangling the wires: a novel strategy to trace functional interactions in signaling and gene networks".




3. E.D. Sontag, A. Kiyatkin, and B.N. Kholodenko. Inferring dynamic architecture of cellular networks using time series of gene expression, protein and metabolite data. Bioinformatics, 20(12):1877-1886, 2004. Note: Supplementary materials are here: http://sontaglab.org/FTPDIR/sontag-kiyatkin-kholodenko-informatics04-supplement.pdf. [PDF] [doi:http://dx.doi.org/10.1093/bioinformatics/bth173] Keyword(s): modular response analysis, systems biology, biochemical networks, reverse engineering, gene and protein networks, protein networks, gene networks, systems identification. Abstract:

   High-throughput technologies have facilitated the acquisition of large genomics and proteomics data sets. However, these data provide snapshots of cellular behavior, rather than help us reveal causal relations. Here, we propose how these technologies can be utilized to infer the topology and strengths of connections among genes, proteins, and metabolites by monitoring time-dependent responses of cellular networks to experimental interventions. We show that all connections leading to a given network node, e.g., to a particular gene, can be deduced from responses to perturbations none of which directly influences that node, e.g., using strains with knock-outs to other genes. To infer all interactions from stationary data, each node should be perturbed separately or in combination with other nodes. Monitoring time series provides richer information and does not require perturbations to all nodes.




4. B.N. Kholodenko, A. Kiyatkin, F.J. Bruggeman, E.D. Sontag, H.V. Westerhoff, and J. Hoek. Untangling the wires: a novel strategy to trace functional interactions in signaling and gene networks. Proceedings of the National Academy of Sciences USA, 99:12841-12846, 2002. [PDF] Keyword(s): modular response analysis, MAPK cascades, systems biology, biochemical networks, reverse engineering, gene and protein networks, protein networks, gene networks, systems identification. Abstract:

   Emerging technologies have enabled the acquisition of large genomics and proteomics data sets. This paper proposes a novel quantitative method for determining functional interactions in cellular signaling and gene networks. It can be used to explore cell systems at a mechanistic level, or applied within a modular framework, which dramatically decreases the number of variables to be assayed. The topology and strength of network connections are retrieved from experimentally measured network responses to successive perturbations of all modules. In addition, the method can reveal functional interactions even when the components of the system are not all known, in which case some connections retrieved by the analysis will not be direct but correspond to the interaction routes through unidentified elements. The method is tested and illustrated using computer-generated responses of a modeled MAPK cascade and gene network.

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