62,559 research outputs found
Enhancing the functional content of protein interaction networks
Protein interaction networks are a promising type of data for studying
complex biological systems. However, despite the rich information embedded in
these networks, they face important data quality challenges of noise and
incompleteness that adversely affect the results obtained from their analysis.
Here, we explore the use of the concept of common neighborhood similarity
(CNS), which is a form of local structure in networks, to address these issues.
Although several CNS measures have been proposed in the literature, an
understanding of their relative efficacies for the analysis of interaction
networks has been lacking. We follow the framework of graph transformation to
convert the given interaction network into a transformed network corresponding
to a variety of CNS measures evaluated. The effectiveness of each measure is
then estimated by comparing the quality of protein function predictions
obtained from its corresponding transformed network with those from the
original network. Using a large set of S. cerevisiae interactions, and a set of
136 GO terms, we find that several of the transformed networks produce more
accurate predictions than those obtained from the original network. In
particular, the measure proposed here performs particularly well for
this task. Further investigation reveals that the two major factors
contributing to this improvement are the abilities of CNS measures, especially
, to prune out noisy edges and introduce new links between
functionally related proteins
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
Pathways and gene networks mediating the regulatory effects of cannabidiol, a nonpsychoactive cannabinoid, in autoimmune T cells.
BackgroundOur previous studies showed that the non-psychoactive cannabinoid, cannabidiol (CBD), ameliorates the clinical symptoms in mouse myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis model of multiple sclerosis (MS) as well as decreases the memory MOG35-55-specific T cell (TMOG) proliferation and cytokine secretion including IL-17, a key autoimmune factor. The mechanisms of these activities are currently poorly understood.MethodsHerein, using microarray-based gene expression profiling, we describe gene networks and intracellular pathways involved in CBD-induced suppression of these activated memory TMOG cells. Encephalitogenic TMOG cells were stimulated with MOG35-55 in the presence of spleen-derived antigen presenting cells (APC) with or without CBD. mRNA of purified TMOG was then subjected to Illumina microarray analysis followed by ingenuity pathway analysis (IPA), weighted gene co-expression network analysis (WGCNA) and gene ontology (GO) elucidation of gene interactions. Results were validated using qPCR and ELISA assays.ResultsGene profiling showed that the CBD treatment suppresses the transcription of a large number of proinflammatory genes in activated TMOG. These include cytokines (Xcl1, Il3, Il12a, Il1b), cytokine receptors (Cxcr1, Ifngr1), transcription factors (Ier3, Atf3, Nr4a3, Crem), and TNF superfamily signaling molecules (Tnfsf11, Tnfsf14, Tnfrsf9, Tnfrsf18). "IL-17 differentiation" and "IL-6 and IL-10-signaling" were identified among the top processes affected by CBD. CBD increases a number of IFN-dependent transcripts (Rgs16, Mx2, Rsad2, Irf4, Ifit2, Ephx1, Ets2) known to execute anti-proliferative activities in T cells. Interestingly, certain MOG35-55 up-regulated transcripts were maintained at high levels in the presence of CBD, including transcription factors (Egr2, Egr1, Tbx21), cytokines (Csf2, Tnf, Ifng), and chemokines (Ccl3, Ccl4, Cxcl10) suggesting that CBD may promote exhaustion of memory TMOG cells. In addition, CBD enhanced the transcription of T cell co-inhibitory molecules (Btla, Lag3, Trat1, and CD69) known to interfere with T/APC interactions. Furthermore, CBD enhanced the transcription of oxidative stress modulators with potent anti-inflammatory activity that are controlled by Nfe2l2/Nrf2 (Mt1, Mt2a, Slc30a1, Hmox1).ConclusionsMicroarray-based gene expression profiling demonstrated that CBD exerts its immunoregulatory effects in activated memory TMOG cells via (a) suppressing proinflammatory Th17-related transcription, (b) by promoting T cell exhaustion/tolerance, (c) enhancing IFN-dependent anti-proliferative program, (d) hampering antigen presentation, and (d) inducing antioxidant milieu resolving inflammation. These findings put forward mechanism by which CBD exerts its anti-inflammatory effects as well as explain the beneficial role of CBD in pathological memory T cells and in autoimmune diseases
The BioGRID Interaction Database: 2011 update
The Biological General Repository for Interaction Datasets (BioGRID) is a public database that archives and disseminates genetic and protein
interaction data from model organisms and humans
(http://www.thebiogrid.org). BioGRID currently holds 347 966
interactions (170 162 genetic, 177 804 protein) curated from both
high-throughput data sets and individual focused studies, as derived
from over 23 000 publications in the primary literature. Complete
coverage of the entire literature is maintained for budding yeast
(Saccharomyces cerevisiae), fission yeast (Schizosaccharomyces pombe)
and thale cress (Arabidopsis thaliana), and efforts to expand curation
across multiple metazoan species are underway. The BioGRID houses 48
831 human protein interactions that have been curated from 10 247
publications. Current curation drives are focused on particular areas
of biology to enable insights into conserved networks and pathways that
are relevant to human health. The BioGRID 3.0 web interface contains
new search and display features that enable rapid queries across
multiple data types and sources. An automated Interaction Management
System (IMS) is used to prioritize, coordinate and track curation
across international sites and projects. BioGRID provides interaction
data to several model organism databases, resources such as Entrez-Gene
and other interaction meta-databases. The entire BioGRID 3.0 data
collection may be downloaded in multiple file formats, including PSI MI
XML. Source code for BioGRID 3.0 is freely available without any
restrictions
Dysregulation of microtubule stability impairs morphofunctional connectivity in primary neuronal networks
Functionally related neurons assemble into connected networks that process and transmit electrochemical information. To do this in a coordinated manner, the number and strength of synaptic connections is tightly regulated. Synapse function relies on the microtubule (MT) cytoskeleton, the dynamics of which are in turn controlled by a plethora of MT-associated proteins, including the MT-stabilizing protein Tau. Although mutations in the Tau-encodingMAPT gene underlie a set of neurodegenerative disorders, termed tauopathies, the exact contribution of MT dynamics and the perturbation thereof to neuronal network connectivity has not yet been scrutinized. Therefore, we investigated the impact of targeted perturbations of MT stability on morphological (e.g., neurite- and synapse density) and functional (e.g., synchronous calcium bursting) correlates of connectivity in networks of primary hippocampal neurons. We found that treatment with MT-stabilizing or -destabilizing compounds impaired morphofunctional connectivity in a reversible manner. We also discovered that overexpression of MAPT induced significant connectivity defects, which were accompanied by alterations in MT dynamics and increased resistance to pharmacological MT depolymerization. Overexpression of a MAPT variant harboring the P301L point mutation in the MT-binding domain did far less, directly linking neuronal connectivity with Tau's MT binding affinity. Our results show that MT stability is a vulnerable node in tauopathies and that its precise pharmacological tuning may positively affect neuronal network connectivity. However, a critical balance in MT turnover causes it to be a difficult therapeutic target with a narrow operating window
Scaling laws in bacterial genomes: A side-effect of selection of mutational robustness?
In the past few years, numerous research projects have focused on identifying and understanding scaling properties in the gene content of prokaryote genomes and the intricacy of their regulation networks. Yet, and despite the increasing amount of data available, the origins of these scalings remain an open question. The RAevol model, a digital genetics model, provides us with an insight into the mechanisms involved in an evolutionary process. The results we present here show that (i) our model reproduces qualitatively these scaling laws and that (ii) these laws are not due to differences in lifestyles but to differences in the spontaneous rates of mutations and rearrangements. We argue that this is due to an indirect selective pressure for robustness that constrains the genome size
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