A disease-associated gene desert directs macrophage inflammation through ETS2

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22—which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu’s arteritis3–6—we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities

Social Acceptability of Forest Conditions and Management Practices: A Problem Analysis

The purpose of this report is to improve understanding of the complex sociopolitical processes related to resource management and to help structure management response to conflict and contentiousness, misunderstanding among participants, and failed citizen-agency interactions. Public acceptance is essential to every resource management decision public agencies must make. Regardless of the issue—forest health, fuels management, riparian restoration, recreation impacts, or threatened and endangered species—the political environment surrounding most decisions is never about just single questions, nor is it about just ecological questions. Social acceptability involves many diverse factors that are only now beginning to be understood and given credence by resource professionals. In this analysis, we describe the social acceptability concept and identify 10 key problem areas needing indepth consideration for durable decisions to be made about forest conditions and practices on federal lands. A central conclusion is that public judgments are always provisional, never absolute or final. Each situation, each context, produces a unique set of circumstances affecting the formation of public acceptance. By its nature, social acceptability is a process rather than an end product.We conclude by presenting five basic strategies to help guide resource professionals and citizens toward more integrated solution

Factors That Can Undermine the Psychological Benefits of Coastal Environments: Exploring the Effect of Tidal State, Presence, and Type of Litter

The beneficial effects of blue environments have been well documented; however, we do not know how marine litter might modify these effects. Three studies adopted a picture-rating task to examine the influence of litter on preference, perceived restorative quality, and psychological impacts. Photographs varied the presence of marine litter (Study 1) and the type of litter (Studies 2 and 3). The influence of tide and the role of connectedness were also explored. Using both quantitative and qualitative methods, it was shown that litter can undermine the psychological benefits that the coast ordinarily provides, thus demonstrating that, in addition to environmental costs of marine litter, there are also costs to people. Litter stemming from the public had the most negative impact. This research extends our understanding of the psychological benefits from natural coastal environments and the threats to these benefits from abundant and increasing marine litter