Found In Translation: a machine learning model for mouse-to-human inference.

Cross-species differences form barriers to translational research that ultimately hinder the success of clinical trials, yet knowledge of species differences has yet to be systematically incorporated in the interpretation of animal models. Here we present Found In Translation (FIT; http://www.mouse2man.org ), a statistical methodology that leverages public gene expression data to extrapolate the results of a new mouse experiment to expression changes in the equivalent human condition. We applied FIT to data from mouse models of 28 different human diseases and identified experimental conditions in which FIT predictions outperformed direct cross-species extrapolation from mouse results, increasing the overlap of differentially expressed genes by 20-50%. FIT predicted novel disease-associated genes, an example of which we validated experimentally. FIT highlights signals that may otherwise be missed and reduces false leads, with no experimental cost.

Immune-centric network of cytokines and cells in disease context identified by computational mining of PubMed.

Cytokines are signaling molecules secreted and sensed by immune and other cell types, enabling dynamic intercellular communication. Although a vast amount of data on these interactions exists, this information is not compiled, integrated or easily searchable. Here we report immuneXpresso, a text-mining engine that structures and standardizes knowledge of immune intercellular communication. We applied immuneXpresso to PubMed to identify relationships between 340 cell types and 140 cytokines across thousands of diseases. The method is able to distinguish between incoming and outgoing interactions, and it includes the effect of the interaction and the cellular function involved. These factors are assigned a confidence score and linked to the disease. By leveraging the breadth of this network, we predicted and experimentally verified previously unappreciated cell-cytokine interactions. We also built a global immune-centric view of diseases and used it to predict cytokine-disease associations. This standardized knowledgebase (http://www.immunexpresso.org) opens up new directions for interpretation of immune data and model-driven systems immunology.

Development of a Functional Biomarker for Use in Cell-Based Therapy Studies in Seropositive Rheumatoid Arthritis.

UNLABELLED: Cell-based therapy has potential therapeutic value in autoimmune diseases such as rheumatoid arthritis (RA). In RA, reduction of disease activity has been associated with improvement in the function of regulatory T cells (Treg) and attenuated responses of proinflammatory effector T cells (Teff). Mesenchymal stem cells (MSCs) and related multipotent adult progenitor cells (MAPC) have strong anti-inflammatory and immunomodulatory properties and may be able to "reset" the immune system to a pre-RA state. MAPC are MSC-like cells that are slightly earlier in lineage, have greater expansion capacity, and can be used as "off-the-shelf" therapy. Assessment of cell-based therapy to treat arthritis and related diseases is limited by the lack of available biological correlates that can be measured early on and indicate treatment response. We set out to develop a functional measure that could be used ex vivo as a biomarker of response. We were able to demonstrate that MAPC products could inhibit Teff responses from patients with active RA and that Treg from RA patients suppressed Teff. This assay used ex vivo can be used with MAPC or Treg alone or in combination and reflects the overall level of Teff suppression. Use of a novel functional biomarker as an exploratory endpoint in trials of cell-based therapy should be of value to detect biological outcomes at a point prior to the time that clinical response might be observed. SIGNIFICANCE: Therapy with mesenchymal stem cells and related multipotent adult progenitor cells is immune modifying in a variety of diseases. There is interest in using cell-based therapy in rheumatoid arthritis (RA) to induce tolerance and "reset" the immune system to its pre-RA state. In a clinical trial, it should be known as soon as possible if there is a chance of response. A biomarker has been developed that permits measurement of the effects of cell-based therapy on effector T cell function.

A cyanobacterial AbrB-like protein affects the apparent photosynthetic affinity for CO2 by modulating low-CO2-induced gene expression.

In Synechocystis sp. strain PCC 6803, over 450 genes are upregulated following transfer of the cells from a high (1-5% CO(2) in air, HC) to a low level of CO(2) (as in air or lower, LC). This includes sbtA, ndhF3 and cmpA involved in inorganic carbon (Ci) uptake. Earlier studies implicated NdhR in the regulation of LC-induced genes but there are indications that additional components are involved. Following extraction of proteins from cells grown under HC and (NH4)(2)SO(4) fractionation, we have identified LexA and two AbrB-like proteins, Sll0359 and Sll0822, which bind to a fragment of the sbtA promoter. Using extracts prepared from LC-grown cells, Sll0822 did not bind to the sbtA promoter despite its presence in the cells, suggesting that it may serve as a repressor of LC-induced genes. This is supported by the fact that sbtA, ndhF3 and cmpA normally expressed only under LC in the wild-type are transcribed under both HC and LC in a Deltasll0822 mutant. When grown under HC this mutant exhibits an elevated apparent photosynthetic affinity to Ci, typically observed in the wild-type only under LC. Clearly, expression of genes essential for Ci uptake was sufficient to raise the apparent photosynthetic affinity for external Ci.

An AbrB-like protein might be involved in the regulation of cylindrospermopsin production by Aphanizomenon ovalisporum.

Certain filamentous cyanobacteria, including Aphanizomenon ovalisporum, are potentially toxic owing to the formation of the hepatotoxin cylindrospermopsin. We previously identified a gene cluster in A. ovalisporum likely to be involved in cylindrospermopsin biosynthesis, including amidinotransferase (aoaA) and polyketide-synthase (aoaC), transcribed on the reverse strands. Analysis of the genomic region between aoaA and aoaC identified two transcription start points for each of these genes, differentially expressed under nitrogen and light stress conditions. The transcript abundances of these genes and the cylindrospermopsin level were both affected by nitrogen availability and light intensity. Gel shift assays and DNA affinity columns isolated a protein that specifically binds to a 150 bp DNA fragment from the region between aoaA and aoaC, and MS/MS analyses identified similarity to AbrB in other cyanobacteria and in Bacillus sp. Comparison of the native AbrB isolated from A. ovalisporum with that obtained after cloning and overexpression of abrB in Escherichia coli identified specific post-translational modifications in the native cyanobacterial protein. These modifications, which are missing in the protein expressed in E. coli, include N-acetylation and methylation of specific residues. We discuss the possible role of these modifications in the regulation of cylindrospermopsin production in Aphanizomenon.