An approach for the identification of targets specific to bone metastasis using cancer genes interactome and gene ontology analysis

Metastasis is one of the most enigmatic aspects of cancer pathogenesis and is a major cause of cancer-associated mortality. Secondary bone cancer (SBC) is a complex disease caused by metastasis of tumor cells from their primary site and is characterized by intricate interplay of molecular interactions. Identification of targets for multifactorial diseases such as SBC, the most frequent complication of breast and prostate cancers, is a challenge. Towards achieving our aim of identification of targets specific to SBC, we constructed a 'Cancer Genes Network', a representative protein interactome of cancer genes. Using graph theoretical methods, we obtained a set of key genes that are relevant for generic mechanisms of cancers and have a role in biological essentiality. We also compiled a curated dataset of 391 SBC genes from published literature which serves as a basis of ontological correlates of secondary bone cancer. Building on these results, we implement a strategy based on generic cancer genes, SBC genes and gene ontology enrichment method, to obtain a set of targets that are specific to bone metastasis. Through this study, we present an approach for probing one of the major complications in cancers, namely, metastasis. The results on genes that play generic roles in cancer phenotype, obtained by network analysis of 'Cancer Genes Network', have broader implications in understanding the role of molecular regulators in mechanisms of cancers. Specifically, our study provides a set of potential targets that are of ontological and regulatory relevance to secondary bone cancer.Comment: 54 pages (19 pages main text; 11 Figures; 26 pages of supplementary information). Revised after critical reviews. Accepted for Publication in PLoS ON

Bounds for the global cyclicity index of a general network via weighted majorization

n/

Enhanced Astrocytic Nitric Oxide Production and Neuronal Modifications in the Neocortex of a NOS2 Mutant Mouse

BACKGROUND: It has been well accepted that glial cells in the central nervous system (CNS) produce nitric oxide (NO) through the induction of a nitric oxide synthase isoform (NOS2) only in response to various insults. Recently we described rapid astroglial, NOS2-dependent, NO production in the neocortex of healthy mice on a time scale relevant to neuronal activity. To explore a possible role for astroglial NOS2 in normal brain function we investigated a NOS2 knockout mouse (B6;129P2-Nos2(tm1Lau)/J, Jackson Laboratory). Previous studies of this mouse strain revealed mainly altered immune responses, but no compensatory pathways and no CNS abnormalities have been reported. METHODOLOGY/PRINCIPAL FINDINGS: To our surprise, using NO imaging in brain slices in combination with biochemical methods we uncovered robust NO production by neocortical astrocytes of the NOS2 mutant. These findings indicate the existence of an alternative pathway that increases basal NOS activity. In addition, the astroglial mutation instigated modifications of neuronal attributes, shown by changes in the membrane properties of pyramidal neurons, and revealed in distinct behavioral abnormalities characterized by an increase in stress-related parameters. CONCLUSIONS/SIGNIFICANCE: The results strongly indicate the involvement of astrocytic-derived NO in modifying the activity of neuronal networks. In addition, the findings corroborate data linking NO signaling with stress-related behavior, and highlight the potential use of this genetic model for studies of stress-susceptibility. Lastly, our results beg re-examination of previous studies that used this mouse strain to examine the pathophysiology of brain insults, assuming lack of astrocytic nitrosative reaction

Open Babel: An open chemical toolbox

Background: A frequent problem in computational modeling is the interconversion of chemical structures between different formats. While standard interchange formats exist (for example, Chemical Markup Language) and de facto standards have arisen (for example, SMILES format), the need to interconvert formats is a continuing problem due to the multitude of different application areas for chemistry data, differences in the data stored by different formats (0D versus 3D, for example), and competition between software along with a lack of vendorneutral formats. Results: We discuss, for the first time, Open Babel, an open-source chemical toolbox that speaks the many languages of chemical data. Open Babel version 2.3 interconverts over 110 formats. The need to represent such a wide variety of chemical and molecular data requires a library that implements a wide range of cheminformatics algorithms, from partial charge assignment and aromaticity detection, to bond order perception and canonicalization. We detail the implementation of Open Babel, describe key advances in the 2.3 release, and outline a variety of uses both in terms of software products and scientific research, including applications far beyond simple format interconversion. Conclusions: Open Babel presents a solution to the proliferation of multiple chemical file formats. In addition, it provides a variety of useful utilities from conformer searching and 2D depiction, to filtering, batch conversion, and substructure and similarity searching. For developers, it can be used as a programming library to handle chemical data in areas such as organic chemistry, drug design, materials science, and computational chemistry. It is freely available under an open-source license fro