Homodimerization Is Essential for the Receptor for Advanced Glycation End Products (RAGE)-mediated Signal Transduction

The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor that binds to diverse ligands and initiates a downstream proinflammatory signaling cascade. RAGE activation has been linked to diabetic complications, Alzheimer disease, infections, and cancers. RAGE is known to mediate cell signaling and downstream proinflammatory gene transcription activation, although the precise mechanism surrounding receptor-ligand interactions is still being elucidated. Recent fluorescence resonance energy transfer evidence indicates that RAGE may form oligomers on the cell surface and that this could be related to signal transduction. To investigate whether RAGE forms oligomers, protein-protein interaction assays were carried out. Here, we demonstrate the interaction between RAGE molecules via their N-terminal V domain, which is an important region involved in ligand recognition. By protein cross-linking using water-soluble and membrane-impermeable cross-linker bis(sulfosuccinimidyl) suberate and nondenaturing gels, we show that RAGE forms homodimers at the plasma membrane, a process potentiated by S100B and advanced glycation end products. Soluble RAGE, the RAGE inhibitor, is also capable of binding to RAGE, similar to V peptide, as shown by surface plasmon resonance. Incubation of cells with soluble RAGE or RAGE V domain peptide inhibits RAGE dimerization, subsequent phosphorylation of intracellular MAPK proteins, and activation of NF-kappa B pathways. Thus, the data indicate that dimerization of RAGE represents an important component of RAGE-mediated cell signaling.

Regression analysis of spatial data

Many of the most interesting questions ecologists ask lead to analyses of spatial data. Yet, perhaps confused by the large number of statistical models and fitting methods available, many ecologists seem to believe this is best left to specialists. Here, we describe the issues that need consideration when analysing spatial data and illustrate these using simulation studies. Our comparative analysis involves using methods including generalized least squares, spatial filters, wavelet revised models, conditional autoregressive models and generalized additive mixed models to estimate regression coefficients from synthetic but realistic data sets, including some which violate standard regression assumptions. We assess the performance of each method using two measures and using statistical error rates for model selection. Methods that performed well included generalized least squares family of models and a Bayesian implementation of the conditional auto-regressive model. Ordinary least squares also performed adequately in the absence of model selection, but had poorly controlled Type I error rates and so did not show the improvements in performance under model selection when using the above methods. Removing large-scale spatial trends in the response led to poor performance. These are empirical results; hence extrapolation of these findings to other situations should be performed cautiously. Nevertheless, our simulation-based approach provides much stronger evidence for comparative analysis than assessments based on single or small numbers of data sets, and should be considered a necessary foundation for statements of this type in future.

A roadmap for marine spatial planning: A critical examination of the European Commission's guiding principles based on their application in the Clyde MSP Pilot Project

The European Commission has developed a set of common principles for marine spatial planning in the European Union. A critical examination of these principles in practice is undertaken through an evaluation of the Clyde Marine Spatial Planning Pilot Project. The principles are found to be lacking in specificity and somewhat inconsistent with the ecosystem based approach, which they advocate. Lessons for new marine spatial planning initiatives, relating particularly to stakeholder participation, governance, data requirements, objective setting, and skills and knowledge needs, are derived from the Clyde Pilot. © 2011.

Marine spatial planning from the perspective of a small seaside community in Ireland

Marine spatial planning (MSP) is advocated as a means of managing human uses of the sea in a manner that is consistent with the maintenance of the ecological goods and services of the marine environment. Support for the process is evident at international and national levels but the degree to which it is acceptable to local level stakeholders is not clear. An Daingean (formely Dingle) is a small sea-oriented town situated on the southwest coast of Ireland in which marine-based tourism and other relatively new uses of the sea are pursued along side traditional fishing activities. Stakeholders in An Daingean are found to be positively disposed to a local process of MSP that incorporates meaningful local involvement.