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      Extension of Life Span by Impaired Glucose Metabolism in Caenorhabditis elegans Is Accompanied by Structural Rearrangements of the Transcriptomic Network

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          Abstract

          Glucose restriction mimicked by feeding the roundworm Caenorhabditis elegans with 2-deoxy-D-glucose (DOG) - a glucose molecule that lacks the ability to undergo glycolysis - has been found to increase the life span of the nematodes considerably. To facilitate understanding of the molecular mechanisms behind this life extension, we analyzed transcriptomes of DOG-treated and untreated roundworms obtained by RNA-seq at different ages. We found that, depending on age, DOG changes the magnitude of the expression values of about 2 to 24 percent of the genes significantly, although our results reveal that the gross changes introduced by DOG are small compared to the age-induced changes. We found that 27 genes are constantly either up- or down-regulated by DOG over the whole life span, among them several members of the cytochrome P450 family. The monotonic change with age of the temporal expression patterns of the genes was investigated, leading to the result that 21 genes reverse their monotonic behaviour under impaired glycolysis. Put simply, the DOG-treatment reduces the gross transcriptional activity but increases the interconnectedness of gene expression. However, a detailed analysis of network parameters discloses that the introduced changes differ remarkably between individual signalling pathways. We found a reorganization of the hubs of the mTOR pathway when standard diet is replaced by DOG feeding. By constructing correlation based difference networks, we identified those signalling pathways that are most vigorously changed by impaired glycolysis. Taken together, we have found a number of genes and pathways that are potentially involved in the DOG-driven extension of life span of C. elegans. Furthermore, our results demonstrate how the network structure of ageing-relevant signalling pathways is reorganised under impaired glycolysis.

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          Emergence of scaling in random networks

          Systems as diverse as genetic networks or the world wide web are best described as networks with complex topology. A common property of many large networks is that the vertex connectivities follow a scale-free power-law distribution. This feature is found to be a consequence of the two generic mechanisms that networks expand continuously by the addition of new vertices, and new vertices attach preferentially to already well connected sites. A model based on these two ingredients reproduces the observed stationary scale-free distributions, indicating that the development of large networks is governed by robust self-organizing phenomena that go beyond the particulars of the individual systems.
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            Error and attack tolerance of complex networks

            Many complex systems, such as communication networks, display a surprising degree of robustness: while key components regularly malfunction, local failures rarely lead to the loss of the global information-carrying ability of the network. The stability of these complex systems is often attributed to the redundant wiring of the functional web defined by the systems' components. In this paper we demonstrate that error tolerance is not shared by all redundant systems, but it is displayed only by a class of inhomogeneously wired networks, called scale-free networks. We find that scale-free networks, describing a number of systems, such as the World Wide Web, Internet, social networks or a cell, display an unexpected degree of robustness, the ability of their nodes to communicate being unaffected by even unrealistically high failure rates. However, error tolerance comes at a high price: these networks are extremely vulnerable to attacks, i.e. to the selection and removal of a few nodes that play the most important role in assuring the network's connectivity.
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              Ensembl 2012

              The Ensembl project (http://www.ensembl.org) provides genome resources for chordate genomes with a particular focus on human genome data as well as data for key model organisms such as mouse, rat and zebrafish. Five additional species were added in the last year including gibbon (Nomascus leucogenys) and Tasmanian devil (Sarcophilus harrisii) bringing the total number of supported species to 61 as of Ensembl release 64 (September 2011). Of these, 55 species appear on the main Ensembl website and six species are provided on the Ensembl preview site (Pre!Ensembl; http://pre.ensembl.org) with preliminary support. The past year has also seen improvements across the project.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                30 October 2013
                : 8
                : 10
                : e77776
                Affiliations
                [1 ]Systems Biology and Bioinformatics Group, Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knoell-Institute, Jena, Germany
                [2 ]Department of Human Nutrition, Institute of Nutrition, University of Jena, Jena, Germany
                [3 ]Genome Analysis Group, Leibniz Institute for Age Research - Fritz-Lipmann-Institute, Jena, Germany
                University of Erlangen-Nuremberg, Germany
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MR MP RG. Performed the experiments: KZ. Analyzed the data: SP UM MG. Wrote the paper: SP UM.

                Article
                PONE-D-13-20886
                10.1371/journal.pone.0077776
                3813781
                24204961
                dda4117f-2cba-481d-93f0-9d370a07cb1e
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 May 2013
                : 5 September 2013
                Page count
                Pages: 14
                Funding
                This work is part of the research program of the Jena Centre for Systems Biology of Ageing funded by the German Ministry for Education and Research (Bundesministerium fur Bildung und Forschung - BMBF; support code BMBF 0315581). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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