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T cell large granular lymphocyte (T-LGL) leukemia features a clonal expansion of antigen-primed, competent, cytotoxic T lymphocytes (CTL). To systematically understand signaling components that determine the survival of CTL in T-LGL leukemia, we constructed a T-LGL survival signaling network by integrating the signaling pathways involved in normal CTL activation and the known deregulations of survival signaling in leukemic T-LGL. This network was subsequently translated into a predictive, discrete, dynamic model. Our model suggests that the persistence of IL-15 and PDGF is sufficient to reproduce all known deregulations in leukemic T-LGL. This finding leads to the following predictions: (i) Inhibiting PDGF signaling induces apoptosis in leukemic T-LGL. (ii) Sphingosine kinase 1 and NF[kappa]B are essential for the long-term survival of CTL in T-LGL leukemia. (iii) NF[kappa]B functions downstream of PI3K and prevents apoptosis through maintaining the expression of myeloid cell leukemia sequence 1. (iv) T box expressed in T cells (T-bet) should be constitutively activated concurrently with NF[kappa]B activation to reproduce the leukemic T-LGL phenotype. We validated these predictions experimentally. Our study provides a model describing the signaling network involved in maintaining the long-term survival of competent CTL in humans. The model will be useful in identifying potential therapeutic targets for T-LGL leukemia and generating long-term competent CTL necessary for tumor and cancer vaccine development. discrete dynamic model | nuclear factor kappa-B | signal transduction network | T box expressed in T cells | T cell large granular lymphocyte leukemia

Author(s): Réka Albert; Hawoong Jeong; Albert-László Barabási (corresponding author) Many complex systems display a surprising degree of tolerance against errors. For example, relatively simple organisms grow, persist and reproduce despite [...]

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 was found to be a consequence of two generic mechanisms: (i) networks expand continuously by the addition of new vertices, and (ii) new vertices attach preferentially to sites that are already well connected. A model based on these two ingredients reproduces the observed stationary scale-free distributions, which indicates that the development of large networks is governed by robust self-organizing phenomena that go beyond the particulars of the individual systems., The inability of contemporary science to describe systems composed of nonidentical elements that have diverse and nonlocal inter-actions currently limits advances in many disciplines, ranging from molecular biology to computer [...]

The huge size of the World Wide Web, estimated to be at least 8X10(8), makes it difficult to determine its local connectivity and distribution of links. A robot has been constructed which adds to its database all links found on each HTML document and follows these to retrieve the related documents. Despite its increasing size, it is found that the average diameter of the web is only 19 links.

Author(s): Réka Albert; Jeong; Barabasi Nature 406, 378-382 (2000). In this paper, the error tolerance curves for the exponential network were affected by a software error. This did not impact [...]