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Identifying biological themes within lists of genes with EASEIdentifying biological themes within lists of genes with EASE EASE is a customizable software application for rapid biological interpretation of gene lists that result from the analysis of microarray, proteomics, SAGE and other high-throughput genomic data. The biological themes returned by EASE recapitulate manually determined themes in previously published gene lists and are robust to varying methods of normalization, intensity calculation and statistical selection of genes. EASE is a powerful tool for rapidly converting the results of functional genomics studies from 'genes' to 'themes'. AbstractEASE is a customizable software application for rapid biological interpretation of gene lists that result from the analysis of microarray, proteomics, SAGE and other high-throughput genomic data. The biological themes returned by EASE recapitulate manually determined themes in previously published gene lists and are robust to varying methods of normalization, intensity calculation and statistical selection of genes. EASE is a powerful tool for rapidly converting the results of functional genomics studies from 'genes' to 'themes'. RationaleHigh-density microarray and proteomics technologies have enabled the discovery of global patterns of biological responses to experimental or natural perturbations [1]. Much work has addressed the issues of data normalization and statistical selection of the genes that are significantly modulated or clustered on the basis of expression profiles [2]. The net result of these efforts is one or more lists of genes. Unfortunately, little work has addressed the issue of rapidly identifying biological themes in such lists [3]. Most investigators currently annotate genes one-at-a-time using internet-based databases or manual literature searches. After this tedious process, it can still be a struggle to identify the most salient biological themes in order to make sense of the results and researchers have no systematic way to prioritize these themes for further analysis. A parallel issue in interpreting such data is how to exploit the ever-expanding flood of functional genomic data and tools. We developed the Expression Analysis Systematic Explorer (EASE) to automate the process of biological theme determination for lists of genes and to serve as a customizable gateway to online analysis tools. This is the first report to show that the highest-ranking themes derived by a computational method can recapitulate manually derived themes in previously published microarray, proteomics and SAGE results, and to provide evidence that these themes are stable to varying methods of gene selection.EASE performs three basic functions with any list of genes. The first is theme discovery, defined as the identification of terms or phrases that describe a statistically significant number of genes in the list with respect to the number of genes described by the term or phrase in the population of genes from which the list derived. The second is customiza...

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Certain HIV-encoded proteins modify host-cell gene expression in a manner that facilitates viral replication. These activities may contribute to low-level viral replication in nonproliferating cells. Through the use of oligonucleotide microarrays and high-throughput Western blotting we demonstrate that one of these proteins, gp120, induces the expression of cytokines, chemokines, kinases, and transcription factors associated with antigen-specific T cell activation in the absence of cellular proliferation. Examination of transcriptional changes induced by gp120 in freshly isolated peripheral blood mononuclear cells and monocyte-derivedmacrophages reveals a broad and complex transcriptional program conducive to productive infection with HIV. Observations include the induction of nuclear factor of activated T cells, components of the RNA polymerase II complex including TFII D, proteins localized to the plasma membrane, including several syntaxins, and members of the Rho protein family, including Cdc 42. These observations provide evidence that envelope-mediated signaling contributes to the productive infection of HIV in suboptimally activated T cells.H IV preferentially replicates in proliferating CD4 ϩ T cells(1). However recent evidence suggests that, in vivo, resting and suboptimally activated T cells may serve as targets for low-level productive infection in the absence of cellular proliferation (2-5). Infection in this manner may contribute to the establishment and͞or maintenance of persistent viral reservoirs that currently prevent the eradication of virus. To productively infect suboptimally activated CD4 ϩ T cells, HIV must overcome post-entry barriers to replication (6-8).DNA microarrays have been used to characterize the effect of HIV on target cell transcription (9, 10); in one microarray-based study, HIV Nef was shown to diminish barriers to viral replication by mimicking antigen-specific T cell proliferation signals (11,12). It has been suggested that HIV gp120 also facilitates replication in suboptimally activated cells (12-15). Gp120 transduces near-simultaneous signals through CD4 (16), a component of the T cell receptor complex, and CCR5, a chemokine receptor (17)(18)(19). In vivo concentrations of gp120 (20, 21) fall within the range required to induce signaling in vitro (17)(18)(19)22). To provide a more complete picture of the complex cascade of signals induced by gp120, we treated freshly isolated peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDMs) with an envelope derived from a CCR5-using virus and measured temporal changes in the levels of mRNA by using Affymetrix (Santa Clara, CA) U95A oligonucleotide microarrays that include probes encompassing Ϸ12,600 genes. In addition, we used a high-throughput Western blot analysis that allowed us to screen protein lysates with 800 monoclonal antibodies. The gp120 used was derived from JR-FL, a CCR5-tropic molecular clone obtained from a minimally passaged viral isolate (23). We used concentrations of envelope near or bel...

HIV infection leads to decreases in the number of CD4 + T lymphocytes and an increased risk for opportunistic infections and neoplasms. The administration of intermittent cycles of IL-2 to HIV-infected patients can lead to profound increases (often greater than 100%) in CD4 cell number and percentage. Using in vivo labeling with 2 H-glucose and BrdU, we have been able to demonstrate that, although therapy with IL-2 leads to high levels of proliferation of CD4 as well as CD8 lymphocytes, it is a remarkable preferential increase in survival of CD4 cells (with half-lives that can exceed 3 years) that is critical to the sustained expansion of these cells. This increased survival was time-dependent: the median half-life, as determined by semiempirical modeling, of labeled CD4 cells in 6 patients increased from 1.7 weeks following an early IL-2 cycle to 28.7 weeks following a later cycle, while CD8 cells showed no change in the median half-life. Examination of lymphocyte subsets demonstrated that phenotypically naive (CD27 + CD45RO -) as well as central memory (CD27 + CD45RO + ) CD4 cells were preferentially expanded, suggesting that IL-2 can help maintain cells important for host defense against new antigens as well as for long-term memory to opportunistic pathogens.

Background: Molecular experiments using multiplex strategies such as cDNA microarrays or proteomic approaches generate large datasets requiring biological interpretation. Text based data mining tools have recently been developed to query large biological datasets of this type of data. PubMatrix is a web-based tool that allows simple text based mining of the NCBI literature search service PubMed using any two lists of keywords terms, resulting in a frequency matrix of term cooccurrence.

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