44,326 research outputs found
A Systemic Receptor Network Triggered by Human cytomegalovirus Entry
Virus entry is a multistep process that triggers a variety of cellular
pathways interconnecting into a complex network, yet the molecular complexity
of this network remains largely unsolved. Here, by employing systems biology
approach, we reveal a systemic virus-entry network initiated by human
cytomegalovirus (HCMV), a widespread opportunistic pathogen. This network
contains all known interactions and functional modules (i.e. groups of
proteins) coordinately responding to HCMV entry. The number of both genes and
functional modules activated in this network dramatically declines shortly,
within 25 min post-infection. While modules annotated as receptor system, ion
transport, and immune response are continuously activated during the entire
process of HCMV entry, those for cell adhesion and skeletal movement are
specifically activated during viral early attachment, and those for immune
response during virus entry. HCMV entry requires a complex receptor network
involving different cellular components, comprising not only cell surface
receptors, but also pathway components in signal transduction, skeletal
development, immune response, endocytosis, ion transport, macromolecule
metabolism and chromatin remodeling. Interestingly, genes that function in
chromatin remodeling are the most abundant in this receptor system, suggesting
that global modulation of transcriptions is one of the most important events in
HCMV entry. Results of in silico knock out further reveal that this entire
receptor network is primarily controlled by multiple elements, such as EGFR
(Epidermal Growth Factor) and SLC10A1 (sodium/bile acid cotransporter family,
member 1). Thus, our results demonstrate that a complex systemic network, in
which components coordinating efficiently in time and space contributes to
virus entry.Comment: 26 page
Uniformly curated signaling pathways reveal tissue-specific cross-talks and support drug target discovery
Motivation: Signaling pathways control a large variety of cellular processes.
However, currently, even within the same database signaling pathways are often
curated at different levels of detail. This makes comparative and cross-talk
analyses difficult. Results: We present SignaLink, a database containing 8
major signaling pathways from Caenorhabditis elegans, Drosophila melanogaster,
and humans. Based on 170 review and approx. 800 research articles, we have
compiled pathways with semi-automatic searches and uniform, well-documented
curation rules. We found that in humans any two of the 8 pathways can
cross-talk. We quantified the possible tissue- and cancer-specific activity of
cross-talks and found pathway-specific expression profiles. In addition, we
identified 327 proteins relevant for drug target discovery. Conclusions: We
provide a novel resource for comparative and cross-talk analyses of signaling
pathways. The identified multi-pathway and tissue-specific cross-talks
contribute to the understanding of the signaling complexity in health and
disease and underscore its importance in network-based drug target selection.
Availability: http://SignaLink.orgComment: 9 pages, 4 figures, 2 tables and a supplementary info with 5 Figures
and 13 Table
Finding undetected protein associations in cell signaling by belief propagation
External information propagates in the cell mainly through signaling cascades
and transcriptional activation, allowing it to react to a wide spectrum of
environmental changes. High throughput experiments identify numerous molecular
components of such cascades that may, however, interact through unknown
partners. Some of them may be detected using data coming from the integration
of a protein-protein interaction network and mRNA expression profiles. This
inference problem can be mapped onto the problem of finding appropriate optimal
connected subgraphs of a network defined by these datasets. The optimization
procedure turns out to be computationally intractable in general. Here we
present a new distributed algorithm for this task, inspired from statistical
physics, and apply this scheme to alpha factor and drug perturbations data in
yeast. We identify the role of the COS8 protein, a member of a gene family of
previously unknown function, and validate the results by genetic experiments.
The algorithm we present is specially suited for very large datasets, can run
in parallel, and can be adapted to other problems in systems biology. On
renowned benchmarks it outperforms other algorithms in the field.Comment: 6 pages, 3 figures, 1 table, Supporting Informatio
NaviCell: a web-based environment for navigation, curation and maintenance of large molecular interaction maps
Molecular biology knowledge can be systematically represented in a
computer-readable form as a comprehensive map of molecular interactions. There
exist a number of maps of molecular interactions containing detailed
description of various cell mechanisms. It is difficult to explore these large
maps, to comment their content and to maintain them. Though there exist several
tools addressing these problems individually, the scientific community still
lacks an environment that combines these three capabilities together. NaviCell
is a web-based environment for exploiting large maps of molecular interactions,
created in CellDesigner, allowing their easy exploration, curation and
maintenance. NaviCell combines three features: (1) efficient map browsing based
on Google Maps engine; (2) semantic zooming for viewing different levels of
details or of abstraction of the map and (3) integrated web-based blog for
collecting the community feedback. NaviCell can be easily used by experts in
the field of molecular biology for studying molecular entities of their
interest in the context of signaling pathways and cross-talks between pathways
within a global signaling network. NaviCell allows both exploration of detailed
molecular mechanisms represented on the map and a more abstract view of the map
up to a top-level modular representation. NaviCell facilitates curation,
maintenance and updating the comprehensive maps of molecular interactions in an
interactive fashion due to an imbedded blogging system. NaviCell provides an
easy way to explore large-scale maps of molecular interactions, thanks to the
Google Maps and WordPress interfaces, already familiar to many users. Semantic
zooming used for navigating geographical maps is adopted for molecular maps in
NaviCell, making any level of visualization meaningful to the user. In
addition, NaviCell provides a framework for community-based map curation.Comment: 20 pages, 5 figures, submitte
Correlated fragile site expression allows the identification of candidate fragile genes involved in immunity and associated with carcinogenesis
Common fragile sites (cfs) are specific regions in the human genome that are
particularly prone to genomic instability under conditions of replicative
stress. Several investigations support the view that common fragile sites play
a role in carcinogenesis. We discuss a genome-wide approach based on graph
theory and Gene Ontology vocabulary for the functional characterization of
common fragile sites and for the identification of genes that contribute to
tumour cell biology. CFS were assembled in a network based on a simple measure
of correlation among common fragile site patterns of expression. By applying
robust measurements to capture in quantitative terms the non triviality of the
network, we identified several topological features clearly indicating
departure from the Erdos-Renyi random graph model. The most important outcome
was the presence of an unexpected large connected component far below the
percolation threshold. Most of the best characterized common fragile sites
belonged to this connected component. By filtering this connected component
with Gene Ontology, statistically significant shared functional features were
detected. Common fragile sites were found to be enriched for genes associated
to the immune response and to mechanisms involved in tumour progression such as
extracellular space remodeling and angiogenesis. Our results support the
hypothesis that fragile sites serve a function; we propose that fragility is
linked to a coordinated regulation of fragile genes expression.Comment: 18 pages, accepted for publication in BMC Bioinformatic
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