Differential Expression of Soluble Receptor for Advanced Glycation End-products in Mice Susceptible or Resistant to Chronic Colitis.

BACKGROUND: Identifying the factors that contribute to chronicity in inflamed colitic tissue is not trivial. However, in mouse models of colitis, we can investigate at preclinical timepoints. We sought to validate murine Trichuris muris infection as a model for identification of factors that promote development of chronic colitis. METHODS: We compared preclinical changes in mice with a resolving immune response to T. muris (resistant) vs mice that fail to expel the worms and develop chronic colitis (susceptible). Findings were then validated in healthy controls and patients with suspected or confirmed IBD. RESULTS: The receptor for advanced glycation end products (RAGE) was highly dysregulated between resistant and susceptible mice before the onset of any pathological signs. Increased soluble RAGE (sRAGE) in the serum and feces of resistant mice correlated with reduced colitis scores. Mouse model findings were validated in a preliminary clinical study: fecal sRAGE was differentially expressed in patients with active IBD compared with IBD in remission, patients with IBD excluded, or healthy controls. CONCLUSIONS: Preclinical changes in mouse models can identify early pathways in the development of chronic inflammation that human studies cannot. We identified the decoy receptor sRAGE as a potential mechanism for protection against chronic inflammation in colitis in mice and humans. We propose that the RAGE pathway is clinically relevant in the onset of chronic colitis and that further study of sRAGE in IBD may provide a novel diagnostic and therapeutic target.

Integration of Kinase and Calcium Signaling at the Level of Chromatin Underlies Inducible Gene Activation in T Cells.

TCR signaling pathways cooperate to activate the inducible transcription factors NF-κB, NFAT, and AP-1. In this study, using the calcium ionophore ionomycin and/or PMA on Jurkat T cells, we show that the gene expression program associated with activation of TCR signaling is closely related to specific chromatin landscapes. We find that calcium and kinase signaling cooperate to induce chromatin remodeling at ∼2100 chromatin regions, which demonstrate enriched binding motifs for inducible factors and correlate with target gene expression. We found that these regions typically function as inducible enhancers. Many of these elements contain composite NFAT/AP-1 sites, which typically support cooperative binding, thus further reinforcing the need for cooperation between calcium and kinase signaling in the activation of genes in T cells. In contrast, treatment with PMA or ionomycin alone induces chromatin remodeling at far fewer regions (∼600 and ∼350, respectively), which mostly represent a subset of those induced by costimulation. This suggests that the integration of TCR signaling largely occurs at the level of chromatin, which we propose plays a crucial role in regulating T cell activation.

Exploring the Links between Post-Industrial Landscape History and Ecology through Participatory Methods.

There is increasing recognition of the importance for local biodiversity of post-mining sites, many of which lie near communities that have suffered significant social and economic deprivation as the result of mine closures. However, no studies to date have actively used the knowledge of local communities to relate the history and treatment of post-mining sites to their current ecological status. We report a study of two post-mining sites in the Yorkshire coalfield of the UK in which the local community were involved in developing site histories and assessing plant and invertebrate species composition. Site histories developed using participatory GIS revealed that the sites had a mixture of areas of spontaneous succession and technical reclamation, and identified that both planned management interventions and informal activities influenced habitat heterogeneity and ecological diversity. Two groups of informal activity were identified as being of particular importance. Firstly, there has been active protection by the community of flower-rich habitats of conservation value (e.g. calcareous grassland) and distinctive plant species (e.g. orchids) which has also provided important foraging resources for butterfly and bumblebee species. Secondly, disturbance by activities such as use of motorbikes, informal camping, and cutting of trees and shrubs for fuel, as well as planned management interventions such as spreading of brick rubble, has provided habitat for plant species of open waste ground and locally uncommon invertebrate species which require patches of bare ground. This study demonstrates the importance of informal, and often unrecorded, activities by the local community in providing diverse habitats and increased biodiversity within a post-mining site, and shows that active engagement with the local community and use of local knowledge can enhance ecological interpretation of such sites and provide a stronger basis for successful future management.