InnateDB: facilitating systems-level analyses of the mammalian innate immune response.

Although considerable progress has been made in dissecting the signaling pathways involved in the innate immune response, it is now apparent that this response can no longer be productively thought of in terms of simple linear pathways. InnateDB (www.innatedb.ca) has been developed to facilitate systems-level analyses that will provide better insight into the complex networks of pathways and interactions that govern the innate immune response. InnateDB is a publicly available, manually curated, integrative biology database of the human and mouse molecules, experimentally verified interactions and pathways involved in innate immunity, along with centralized annotation on the broader human and mouse interactomes. To date, more than 3500 innate immunity-relevant interactions have been contextually annotated through the review of 1000 plus publications. Integrated into InnateDB are novel bioinformatics resources, including network visualization software, pathway analysis, orthologous interaction network construction and the ability to overlay user-supplied gene expression data in an intuitively displayed molecular interaction network and pathway context, which will enable biologists without a computational background to explore their data in a more systems-oriented manner.

Curating the innate immunity interactome.

BACKGROUND: The innate immune response is the first line of defence against invading pathogens and is regulated by complex signalling and transcriptional networks. Systems biology approaches promise to shed new light on the regulation of innate immunity through the analysis and modelling of these networks. A key initial step in this process is the contextual cataloguing of the components of this system and the molecular interactions that comprise these networks. InnateDB (http://www.innatedb.com) is a molecular interaction and pathway database developed to facilitate systems-level analyses of innate immunity. RESULTS: Here, we describe the InnateDB curation project, which is manually annotating the human and mouse innate immunity interactome in rich contextual detail, and present our novel curation software system, which has been developed to ensure interactions are curated in a highly accurate and data-standards compliant manner. To date, over 13,000 interactions (protein, DNA and RNA) have been curated from the biomedical literature. Here, we present data, illustrating how InnateDB curation of the innate immunity interactome has greatly enhanced network and pathway annotation available for systems-level analysis and discuss the challenges that face such curation efforts. Significantly, we provide several lines of evidence that analysis of the innate immunity interactome has the potential to identify novel signalling, transcriptional and post-transcriptional regulators of innate immunity. Additionally, these analyses also provide insight into the cross-talk between innate immunity pathways and other biological processes, such as adaptive immunity, cancer and diabetes, and intriguingly, suggests links to other pathways, which as yet, have not been implicated in the innate immune response. CONCLUSIONS: In summary, curation of the InnateDB interactome provides a wealth of information to enable systems-level analysis of innate immunity.

In vivo monitoring of hepatic oxygenation changes in chronically ethanol-treated rats by functional magnetic resonance imaging.

In this study, functional magnetic resonance imaging (fMRI) was used to evaluate in vivo hepatic oxygenation changes in chronically ethanol (CE)-treated and pair-fed (PF) control rats. Male Wistar rats were pair-fed an all-liquid diet containing 36% of total calories as either ethanol or dextrin-maltose for 8 weeks. The rats were initially examined under normoxic conditions, and then subjected to 100% oxygen (hyperoxia), 10% oxygen (hypoxia), 5% carbon dioxide (hypercapnia), or an acute dose of ethanol (1.4 g/kg bw intraperitoneally). A T(2)-weighted spin-echo sequence, which may be more selective for sinusoidal (capillary bed) changes, was performed before, during, and after the four challenges. During hyperoxia, both the CE and PF rats showed a statistically significant increase in signal intensity (22% +/- 5% and 48% +/- 6%, respectively, P < 0.05) relative to normoxia, while hypoxic challenge decreased the signal intensity (9% +/- 4%, p>0.05 and 15% +/- 3%, P < 0.05, respectively). The hypercapnic challenge, which causes vasodilation, resulted in a small increase in signal intensity in CE-fed rats (5% +/- 3%, P > 0.05) and a significant increase in the PF rats (15% +/- 4%, P < 0.05), again consistent with expected changes in deoxyhemoglobin. With all three physiological challenges, the degree of change was less in CE rats compared to PF controls. An acute dose of ethanol that causes vasodilation also increased signal intensity, with no significant difference between the two groups. The signal intensity changes seen with fMRI were highly correlated with pulse oximeter readings (r(2) = 0.95; P < 0.05). In conclusion, fMRI was shown to be a good noninvasive indicator of tissue deoxyhemoglobin changes in the liver. In addition, fMRI was able to detect subtle, early effects of CE administration (manifested as an impaired ability of the liver to respond adequately to oxygenation challenges), consistent with microvascular dysfunction.