IntroductionRheumatoid arthritis (RA) is a chronic inflammatory and destructive joint disease characterized by overexpression of pro-inflammatory/pro-destructive genes and other activating genes (for example, proto-oncogenes) in the synovial membrane (SM). The gene expression in disease is often characterized by significant inter-individual variances via specific synchronization/desynchronization of gene expression. To elucidate the contribution of the variance to the pathogenesis of disease, expression variances were tested in SM samples of RA patients, osteoarthritis (OA) patients, and normal controls (NCs).MethodAnalysis of gene expression in RA, OA, and NC samples was carried out using Affymetrix U133A/B oligonucleotide arrays, and the results were validated by real-time reverse transcription-polymerase chain reaction. For the comparison between RA and NC, 568 genes with significantly different variances in the two groups (P ≤ 0.05; Bonferroni/Holm corrected Brown-Forsythe version of the Levene test) were selected. For the comparison between RA and OA, 333 genes were selected. By means of the Kyoto Encyclopedia of Genes and Genomes, the pathways/complexes significantly affected by higher gene expression variances were identified in each group.ResultsTen pathways/complexes significantly affected by higher gene expression variances were identified in RA compared with NC, including cytokine–cytokine receptor interactions, the transforming growth factor-beta pathway, and anti-apoptosis. Compared with OA, three pathways with significantly higher variances were identified in RA (for example, B-cell receptor signaling and vascular endothelial growth factor signaling). Functionally, the majority of the identified pathways are involved in the regulation of inflammation, proliferation, cell survival, and angiogenesis.ConclusionIn RA, a number of disease-relevant or even disease-specific pathways/complexes are characterized by broad intra-group inter-individual expression variances. Thus, RA pathogenesis in different individuals may depend to a lesser extent on common alterations of the expression of specific key genes, and rather on individual-specific alterations of different genes resulting in common disturbances of key pathways.

These authors contributed equally to this work. SUMMARYInduced defenses are thought to be economical: growth and fitness-limiting resources are only invested into defenses when needed. To date, this putative growth-defense trade-off has not been quantified in a common currency at the level of individual compounds. Here, a quantification method for 15 N-labeled proteins enabled a direct comparison of nitrogen (N) allocation to proteins, specifically, ribulose-1,5-bisposphate carboxylase/ oxygenase (RuBisCO), as proxy for growth, with that to small N-containing defense metabolites (nicotine and phenolamides), as proxies for defense after herbivory. After repeated simulated herbivory, total N decreased in the shoots of wild-type (WT) Nicotiana attenuata plants, but not in two transgenic lines impaired in jasmonate defense signaling (irLOX3) and phenolamide biosynthesis (irMYB8). N was reallocated among different compounds within elicited rosette leaves: in the WT, a strong decrease in total soluble protein (TSP) and RuBisCO was accompanied by an increase in defense metabolites, irLOX3 showed a similar, albeit attenuated, pattern, whereas irMYB8 rosette leaves were the least responsive to elicitation, with overall higher levels of RuBisCO. Induced defenses were higher in the older compared with the younger rosette leaves, supporting the hypothesis that tissue developmental stage influences defense investments. We propose that MYB8, probably by regulating the production of phenolamides, indirectly mediates protein pool sizes after herbivory. Although the decrease in absolute N invested in TSP and RuBisCO elicited by simulated herbivory was much larger than the N-requirements of nicotine and phenolamide biosynthesis, 15 N flux studies revealed that N for phenolamide synthesis originates from recently assimilated N, rather than from RuBisCO turnover.

The polymorphic fungus Candida albicans can live as an aggressive pathogen that causes a wide variety of diseases in humans. Host resistance against these infections is mediated predominantly by phagocytes, namely neutrophils and macrophages. This report provides two game theoretical models of ingested C. albicans cells in macrophages. Two strategies are available for each pathogenic yeast cell: avoiding lysis transiently (called silencing) or forming hyphae and escaping (called piercing because the macrophage is pierced from inside). In dependence on parameter values, two different outcomes can be derived from the model: when the difference of the costs of the two strategies is low, all fungal cells inside a macrophage will play the piercing strategy, while in the high-cost case, a mixed population of piercing and silencing cells is the only stable solution. Further, the role of the SAP gene family encoding secreted proteinases and the Sap proteins is investigated with the help of known studies and is put in relation to the costs of the strategies, the most important parameter of this model. Our results are in agreement with wet-lab results presented by other groups and the model parameters can be estimated from experimental data.

Gene duplication represents an evolutionary mechanism for expanding metabolic potential. Here we analysed the evolutionary relatedness of isocitrate and methylisocitrate lyases, which are key enzymes of the glyoxylate and methylcitrate cycle respectively. Phylogenetic analyses imply that ancient eukaryotes acquired an isocitrate lyase gene from a prokaryotic source, but it was lost in some eukaryotic lineages. However, protists, oomycetes and most fungi maintained this gene and successfully integrated the corresponding enzyme into the glyoxylate cycle. A second gene, encoding a highly related enzyme, is present in fungi, but absent from other eukaryotes. This methylisocitrate lyase is specifically involved in propionyl-CoA degradation via the methylcitrate cycle. Although bacteria possess methylisocitrate lyases with a structural fold similar to that of isocitrate lyases, their sequence identity to fungal methylisocitrate lyases is low. Phylogenetic analyses imply that fungal methylisocitrate lyases arose from gene duplication of an ancient isocitrate lyase gene from the basidiomycete lineage. Mutagenesis of active-site residues of a bacterial and fungal isocitrate lyase, which have been predicted to direct the substrate specificity of iso- and methylisocitrate lyases, experimentally confirmed the possibility of direct evolution of methylisocitrate lyases from isocitrate lyases. Thus, gene duplication has increased the metabolic capacity of fungi.