Network analysis identifies protein clusters of functional importance in juvenile idiopathic arthritis

Introduction

Our objective was to utilise network analysis to identify protein clusters of greatest potential functional relevance in the pathogenesis of oligoarticular and rheumatoid factor negative (RF-ve) polyarticular juvenile idiopathic arthritis (JIA).

Methods

JIA genetic association data were used to build an interactome network model in BioGRID 3.2.99. The top 10% of this protein:protein JIA Interactome was used to generate a minimal essential network (MEN). Reactome FI Cytoscape 2.83 Plugin and the Disease Association Protein-Protein Link Evaluator (Dapple) algorithm were used to assess the functionality of the biological pathways within the MEN and to statistically rank the proteins. JIA gene expression data were integrated with the MEN and clusters of functionally important proteins derived using MCODE.

Results

A JIA interactome of 2,479 proteins was built from 348 JIA associated genes. The MEN, representing the most functionally related components of the network, comprised of seven clusters, with distinct functional characteristics. Four gene expression datasets from peripheral blood mononuclear cells (PBMC), neutrophils and synovial fluid monocytes, were mapped onto the MEN and a list of genes enriched for functional significance identified. This analysis revealed the genes of greatest potential functional importance to be PTPN2 and STAT1 for oligoarticular JIA and KSR1 for RF-ve polyarticular JIA. Clusters of 23 and 14 related proteins were derived for oligoarticular and RF-ve polyarticular JIA respectively.

Conclusions

This first report of the application of network biology to JIA, integrating genetic association findings and gene expression data, has prioritised protein clusters for functional validation and identified new pathways for targeted pharmacological intervention.     

Symbiont choice in a fungus-growing ant (Attini, Formicidae)

Cultivars of fungus-growing (attine) ants are vertically transmittedthrough inheritance from parent to offspring nest, but horizontalcultivar transfer between ant nests occurs occasionally, resultingin cultivar replacement within ant lineages. Two mechanismscould theoretically prevent the invasion of suboptimal cultivarstrains and thus stabilize ant–cultivar coevolution: first,partner feedback inherent in vertical cultivar transmissionand second, partner (symbiont) choice if the ants differentiatebetween productive and inferior cultivars during replacements.To elucidate the nature of symbiont choice, we presented workersof Cyphomyrmex muelleri with novel cultivars representing aphylogenetic cline of close and distant relatives of the nativeC. muelleri cultivar. Workers invariably preferred their nativecultivar, discriminating against even very close relatives ofthe native cultivar. When given a choice between two non-nativecultivar strains, workers accepted the strain most closely relatedto their native cultivar. Two conclusions emerge. First, colonyswitches to distantly related cultivars are behaviorally unlikelyand may not be preference-based; rather, distant switches mayoccur under constrained choice, such as pathogen-related gardenlosses that force colonies to import novel cultivars. Second,the ability of attine ants to differentiate between closelyrelated cultivar strains suggests that the ant–fungusmutualism is stabilized evolutionarily not only by partner feedbackinherent in vertical cultivar transmission, but possibly alsoby symbiont choice through which the ants select against unwanted,presumably inferior, cultivars. The efficacy of symbiont choicenow needs to be tested experimentally. Such research may benefitfrom application of theory and experimental paradigms that havebeen developed within the areas of mate choice and sexual selection.     

Structure and solution properties of tamarind-seed polysaccharide.

The major polysaccharide in tamarind seed is a galactoxyloglucan for which the ratios galactose:xylose:glucose are 1:2:25:2.8. A minor polysaccharide (2-3%) contains branched (1----5)-alpha-L-arabinofuranan and unbranched (1----4)-beta-D-galactopyranan features. Small-angle X-ray scattering experiments gave values for the cross-sectional radius of the polymer in aqueous solution that were typical of single-stranded molecules. Marked stiffness of the chain (C infinity 110) was deduced from static light-scattering studies and is ascribed partially to the restriction of the motion of the (1----4)-beta-D-glucan backbone by its extensive (approximately 80%) glycosylation. The rigidity of the polymer caused significant draining effects which heavily influenced the hydrodynamic behaviour. The dependence of "zero-shear" viscosity on concentration was used to characterise "dilute" and "semi-dilute" concentration regimes. The marked dependence on concentration in the "semi-dilute" region was similar to that for other stiff neutral polysaccharide systems, ascribed to "hyper-entanglements", and it is suggested that these may have arisen through a tenuous alignment of stiffened chains.     

The farming ant Sericomyrmex amabilis nutritionally manages its fungal symbiont and its social parasite

1. When parasites exploit mutualisms involving food exchange, they can destabilise the partnership with costs to interacting partners. For instance, the ant Sericomyrmex amabilis farms fungal symbionts to produce food, but, in so doing, attracts parasitic Megalomyrmex symmetochus guest ants that infiltrate fungus‐farming ant societies and live with their hosts their entire lives. 2. The present study examined whether host foraging in parasitised colonies shifts towards nutritional requirements of the parasitic guest ants as inferred from the parasite's elemental content (%C, %N, and C:N). 3. Laboratory feeding experiments with nutritionally defined diets indicated that S. amabilis ants harvest protein‐biased substrate, and more total substrate when hosting M. symmetochus relative to when provisioning their fungus gardens and nestmates. 4. Field surveys further showed that parasitised colonies incur reductions in fungus garden nutritional quality and quantity, brood mass, and host worker body condition. And yet these costs appear manageable across growing seasons, as parasitised fungal cultivars appear to provide sufficient nutrition for stable populations of host ants. 5. The approach developed here shows how behavioural strategies for nutrient regulation can extend beyond the needs of the individual to entire fungus‐farming systems, and implies that S. amabilis dynamically adjusts collective foraging strategies when parasitised to enhance long‐term symbiotic stability.     

Effect of monomer composition on proton dissociation of weak polyacids

The study of the proton dissociation process of weak polyacids (eg α carboxylic poly(monoprotic)acid) is based on the knowledge of the change in electrostatic free energy, G(el), as a function of the variation of the number of charges on the polymer chain. The original treatment proposed by Manning can be used to describe the proton dissociation process of weak poly(monoprotic)acids, in the absence of pH-induced conformational transitions. In order to describe the alpha dependence of pKa of weak co-poly(monoprotic)acids containing two different acidic groups in different amounts along the polymer chain, a simple modification of the model is proposed. Abbreviations used: Due to the difficulty of using non-ASCI characters in the main text, we have used the following abbreviations: G(el) Gel 10-pH 10-pH pKa pKa alpha α alphan αn dG(el)/dalpha δGel/δα KA and KB KA and KB CA and CB CA and CB βA and βB βA and βB δpK δpK §max ξmax This revised version was published online in November 2006 with corrections to the Cover Date.     

Synthesis and evaluation of 5,6-disubstituted thiopyrimidine aryl aminothiazoles as inhibitors of the calcium-activated chloride channel TMEM16A/Ano1

Transmembrane protein 16A (TMEM16A), also called Ano1, is a Ca²⁺ activated Cl^? channel expressed widely in mammalian epithelia, as well as in vascular smooth muscle and some tumors and electrically excitable cells. TMEM16A inhibitors have potential utility for treatment of disorders of epithelial fluid and mucus secretion, hypertension, some cancers and other diseases. 4-Aryl-2-amino thiazole T16A_inh-01 was previously identified by high-throughput screening. Here, a library of 47 compounds were prepared that explored the 5,6-disubstituted pyrimidine scaffold found in T16A_inh-01. TMEM16A inhibition activity was measured using fluorescence plate reader and short-circuit current assays. We found that very little structural variation of T16A_inh-01 was tolerated, with most compounds showing no activity at 10?μM. The most potent compound in the series, 9bo, which substitutes 4-methoxyphenyl in T16A_inh-01 with 2-thiophene, had IC₅₀ ～1?μM for inhibition of TMEM16A chloride conductance.     

Morphological and Biochemical Changes in Myelin Subfractions of Developing Rats Fed Microbial Lipids

Morphological, biochemical, and physicochemical studies of myelin subfractions were undertaken on the progeny of Sprague-Dawley rats fed diets containing lipids either extracted from yeasts grown on n-alkanes or from margarine. Myelin subfractions obtained from pooled brain homogenates of littermates by sucrose density gradient centrifugation at 7, 14, and 21 days postnatally were subjected to electron microscopy, sodium dodecylsulfate polyacrylamide gel electrophoresis and assayed for 2', 3' cyclic nucleotide 3'-phosphohydrolase activity (CNPase; EC 3.1.4.37). Additionally, surface pressure measurements were made of lipid monolayers derived from myelin subfractions, which were subsequently injected with myelin basic proteins. The myelin subfractions of test animals, when compared with those of controls, show an earlier increase in the specific activity of CNPase, the earlier appearance of low-molecular-weight proteins, and an increase in the affinity of basic proteins for lipids derived from the myelin light fraction. This biochemistry suggests the presence of a more mature myelin between 7 and 14 days in the experimental group. The morphological studies, however, do not seem to concur with the biochemical data. The observed changes are discussed in relation to the influence of dietary lipids on myelinogenesis.