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...the gene ontologies (GO) that occur more frequently are presented in larger font. Clicking on a GO term in this cloud links to the relevant record in the GO database [http:// amigo.geneontology.org/; =-=(30)-=-]. In addition the data are presented in a tabular format containing columns for GO accession number, term name, definition and P value to facilitate further downstream analysis. TF Analysis—presents ...

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...- or down-regulation. The pre-processing of the array data was platform- and array design-specific. Raw data from Affimetrix arrays were normalized using the Robust Multi-array Averaging (RMA) method =-=(23)-=-, which consisted of three steps: background adjustment, quantile normalization (24) and summarization (25). For some experiments, only processed data were available, and these data were only used if ...

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...esign-specific. Raw data from Affimetrix arrays were normalized using the Robust Multi-array Averaging (RMA) method (23), which consisted of three steps: background adjustment, quantile normalization =-=(24)-=- and summarization (25). For some experiments, only processed data were available, and these data were only used if they had been processed and normalized using RMA, GeneChip RMA (GCRMA) or MicroArray...

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...a from Affimetrix arrays were normalized using the Robust Multi-array Averaging (RMA) method (23), which consisted of three steps: background adjustment, quantile normalization (24) and summarization =-=(25)-=-. For some experiments, only processed data were available, and these data were only used if they had been processed and normalized using RMA, GeneChip RMA (GCRMA) or MicroArray Suite (MAS5) methods. ...

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...ated samples with appropriate controls. All data were log2 transformed before analysis. The statistical significance of any differences in gene expression was tested using a paired or unpaired t-test =-=(28,29)-=-. The Welch t-test was adopted to avoid any assumption of equal variance; previous analysis had indicated that the Welch t-test tended to be more conservative and so less likely to return false than o...

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...d in different physiological and pathological circumstances, thus identifying a role for IFNs in such diverse diseases as autoimmunity, cancer, diabetes, neurodegeneration and developmental anomalies =-=(19)-=-. It remains unclear how IFN contributes to the pathogenesis of these diseases. The existence of genomic technologies such as microarrays has enabled the genome-wide assessment of changes in gene expr...

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...on to the 75th percentile was performed to remove technical variations between individual arrays. Data from two-colour arrays were normalized applying normalizeWithinArrays and normalizeBetweenArrays =-=(26,27)-=-. Data from any replicated probes were averaged to provide a single measure for each probe in the array. All Agilent control probes were removed. Normalized probes from both microarray platforms were ...

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...on to the 75th percentile was performed to remove technical variations between individual arrays. Data from two-colour arrays were normalized applying normalizeWithinArrays and normalizeBetweenArrays =-=(26,27)-=-. Data from any replicated probes were averaged to provide a single measure for each probe in the array. All Agilent control probes were removed. Normalized probes from both microarray platforms were ...

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...nase, MAP kinase and others (13). The activation of these many signal transduction pathways leads to activated transcription factors binding to promoters and regulating the expression of sets of IRGs =-=(14)-=-. It is the nature of the genes, their magnitude, duration and cellular context that will determine the outcome of the IFN response. This response will vary from cell to cell and can be beneficial or ...

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...ated samples with appropriate controls. All data were log2 transformed before analysis. The statistical significance of any differences in gene expression was tested using a paired or unpaired t-test =-=(28,29)-=-. The Welch t-test was adopted to avoid any assumption of equal variance; previous analysis had indicated that the Welch t-test tended to be more conservative and so less likely to return false than o...

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...ctivate STATs 1, 2, 3, 4, 5 and 6 depending on the type of IFN and the target cell (12). In addition, there are non-STAT signalling pathways also activated including PI3 kinase, MAP kinase and others =-=(13)-=-. The activation of these many signal transduction pathways leads to activated transcription factors binding to promoters and regulating the expression of sets of IRGs (14). It is the nature of the ge...

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...subtypes), type II (a single IFNg) and type III (IFN; also called IL28 and IL29), which are distinguished by having distinct genetic loci, amino acid sequence homology and specific cognate receptors =-=(3)-=-. All IFNs can have numerous effects on cells, including the ability to modulate growth, differentiation, proliferation, survival/ apoptosis and motility. In the immune system, these basic properties ...

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...e, there are clinical trials of reagents to block IFN activity in diseases such as Systemic Lupus Erythematosus (9). Administration of IFN also has side effects associated with dose-limiting toxicity =-=(10)-=-. As a consequence, there is considerable interest in understanding the regulation of IFN signalling: how each signal transduction pathway is activated or suppressed; what biological effects are attri...

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...n the Interferome, has highlighted the association of pathways activated by IFNs in a broad range of diseases, including influenza outbreaks (32), hepatitis (33), HIV (34), Mycobacterium tuberculosis =-=(35)-=-, breast cancer metastases (36) and autoimmune disorders (37). Annotation of these pathways holds considerable promise for the development of refined diagnostics and new therapies and vaccines. Databa...

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... expression of IRGs in their resting, unstimulated state, across various tissues and cells. The human and mouse expression data were obtained from the tissues and cell lines data in the BioGPS portal =-=(31)-=-. The IRG list resulting from the search is plotted against expression in these tissues and cells, with red indicating high expression and blue low expression. All ‘Secondary Search’ results can be do...

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... biological effects are attributed to which pathways; and how they can be differentially modulated. Once an IFN has engaged its cognate receptor, a series of events are activated to transduce signals =-=(11)-=-. The IFN receptors are pre-associated with pairs of JAK kinases which, once activated by the ligand binding to its receptor, phosphorylate tyrosine residues on each other and on the intracellular dom...

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...er elements], the range of signals that are generated from ligated receptors is far more complex. In fact, IFNs can activate STATs 1, 2, 3, 4, 5 and 6 depending on the type of IFN and the target cell =-=(12)-=-. In addition, there are non-STAT signalling pathways also activated including PI3 kinase, MAP kinase and others (13). The activation of these many signal transduction pathways leads to activated tran...

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...ntiation, proliferation, survival/ apoptosis and motility. In the immune system, these basic properties result in the ability of IFNs to regulate the development and activities of most effector cells =-=(4,5)-=-. They can affect most cells in the body that express the cognate receptors, albeit differently. Consequently, they have wide ranging effects on homeostasis and pathology. IFNs are involved in the hos...

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...ivated, we embarked on a project to collect and annotate a comprehensive list of IFN-regulated genes, associated data and pathway predictions and established the Interferome DB (www. interferome.org) =-=(20)-=-. Since its publication in 2009, it has received >2 million hits, has 48 citations in eminent journals and we have had considerable feedback requesting additional functionality or access; refer databa...

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... analysis. Data pre-processing For the storage, management and statistical analysis of microarray experiments from different platforms, the BioArray Software Environment (BASE) server was established =-=(22)-=-. This processing represents a significant improvement in Interferome v2.0 compared with the original Interferome (‘v1.0’) which included only qualitative up- or down-regulation. The pre-processing of...

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...ar context that will determine the outcome of the IFN response. This response will vary from cell to cell and can be beneficial or harmful to the host. IFNs are produced in a variety of circumstances =-=(15)-=-. In recent years, there has been a revolution in understanding the innate immune system, which evolved to recognize bacteria, viruses and other pathogens, and then to mount an immediate response and ...

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...fication of gene signatures of importance in the pathogenesis of these diseases. INTRODUCTION Interferon (IFN) was discovered and defined as a protein with the ability to protect cells from infection =-=(1,2)-=-. It has been subsequently realized that there is a large family of IFN proteins that have pleiotrophic effects. There are three types of IFNs, namely type I (composed of a, b, k, e and o subtypes), t...

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...Ns varies over 1000-fold. Because IFNs may also contribute to the pathogenesis of disease, there are clinical trials of reagents to block IFN activity in diseases such as Systemic Lupus Erythematosus =-=(9)-=-. Administration of IFN also has side effects associated with dose-limiting toxicity (10). As a consequence, there is considerable interest in understanding the regulation of IFN signalling: how each ...

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...s, such as those made available in the Interferome, has highlighted the association of pathways activated by IFNs in a broad range of diseases, including influenza outbreaks (32), hepatitis (33), HIV =-=(34)-=-, Mycobacterium tuberculosis (35), breast cancer metastases (36) and autoimmune disorders (37). Annotation of these pathways holds considerable promise for the development of refined diagnostics and n...

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...ation in 2009, it has received >2 million hits, has 48 citations in eminent journals and we have had considerable feedback requesting additional functionality or access; refer database statistics and =-=(21)-=-. We herein describe an update of the Interferome DB called v2.0 (http://interferome.its. monash.edu.au/interferome/). In summary, there has been a significant improvement in computational infrastruct...

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...s activated by IFNs in a broad range of diseases, including influenza outbreaks (32), hepatitis (33), HIV (34), Mycobacterium tuberculosis (35), breast cancer metastases (36) and autoimmune disorders =-=(37)-=-. Annotation of these pathways holds considerable promise for the development of refined diagnostics and new therapies and vaccines. Databases such as the Interferome with related sites together with ...

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...fication of gene signatures of importance in the pathogenesis of these diseases. INTRODUCTION Interferon (IFN) was discovered and defined as a protein with the ability to protect cells from infection =-=(1,2)-=-. It has been subsequently realized that there is a large family of IFN proteins that have pleiotrophic effects. There are three types of IFNs, namely type I (composed of a, b, k, e and o subtypes), t...

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...ntiation, proliferation, survival/ apoptosis and motility. In the immune system, these basic properties result in the ability of IFNs to regulate the development and activities of most effector cells =-=(4,5)-=-. They can affect most cells in the body that express the cognate receptors, albeit differently. Consequently, they have wide ranging effects on homeostasis and pathology. IFNs are involved in the hos...

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...ments in analytical methods, such as those made available in the Interferome, has highlighted the association of pathways activated by IFNs in a broad range of diseases, including influenza outbreaks =-=(32)-=-, hepatitis (33), HIV (34), Mycobacterium tuberculosis (35), breast cancer metastases (36) and autoimmune disorders (37). Annotation of these pathways holds considerable promise for the development of...

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...cal methods, such as those made available in the Interferome, has highlighted the association of pathways activated by IFNs in a broad range of diseases, including influenza outbreaks (32), hepatitis =-=(33)-=-, HIV (34), Mycobacterium tuberculosis (35), breast cancer metastases (36) and autoimmune disorders (37). Annotation of these pathways holds considerable promise for the development of refined diagnos...

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...ted the association of pathways activated by IFNs in a broad range of diseases, including influenza outbreaks (32), hepatitis (33), HIV (34), Mycobacterium tuberculosis (35), breast cancer metastases =-=(36)-=- and autoimmune disorders (37). Annotation of these pathways holds considerable promise for the development of refined diagnostics and new therapies and vaccines. Databases such as the Interferome wit...