Innate immunity is critically dependent on the rapid production of interferon in response to intruding viruses. The intracellular pathogen recognition receptors RIG-I and MDA5 are essential for interferon induction by viral RNAs containing 5′ triphosphates or double-stranded structures, respectively. Viruses with a negative-stranded RNA genome are an important group of pathogens causing emerging and re-emerging diseases. We investigated the ability of genomic RNAs from substantial representatives of this virus group to induce interferon via RIG-I or MDA5. RNAs isolated from particles of Ebola virus, Nipah virus, Lassa virus, and Rift Valley fever virus strongly activated the interferon-beta promoter. Knockdown experiments demonstrated that interferon induction depended on RIG-I, but not MDA5, and phosphatase treatment revealed a requirement for the RNA 5′ triphosphate group. In contrast, genomic RNAs of Hantaan virus, Crimean-Congo hemorrhagic fever virus and Borna disease virus did not trigger interferon induction. Sensitivity of these RNAs to a 5′ monophosphate-specific exonuclease indicates that the RIG-I-activating 5′ triphosphate group was removed post-transcriptionally by a viral function. Consequently, RIG-I is unable to bind the RNAs of Hantaan virus, Crimean-Congo hemorrhagic fever virus and Borna disease virus. These results establish RIG-I as a major intracellular recognition receptor for the genome of most negative-strand RNA viruses and define the cleavage of triphosphates at the RNA 5′ end as a strategy of viruses to evade the innate immune response.

The prerequisites for evidence-based practice were assessed as good, but ways to make evidence-based practice time efficient, easy to access and relevant to clinical practice need to be continuously supported at the management level, so that research evidence becomes linked to work-flow in a way that does not adversely affect productivity and the flow of patients.

Little is known about common factors (e.g., macronutrients and energy supply) regulating the protein secretory function of adipose tissue. We therefore compared the effects of randomly assigned 10-week hypoenergetic (؊600 kcal/day) diets with moderate-fat/moderate-carbohydrate or low-fat/high-carbohydrate content on circulating levels and production of proteins (using radioimmunoassays and enzyme-linked immunosorbent assays) from subcutaneous adipose tissue in 40 obese but otherwise healthy women. Similar results were obtained by the two diets. Body weight decreased by ϳ7.5%. The secretion rate of leptin decreased by ϳ40%, as did that of tumor necrosis factor-␣ (TNF-␣), and interleukin (IL)-6 and -8 decreased by 25-30%, whereas the secretion of plasminogen activator inhibitor 1 (PAI-1) and adiponectin did not show any changes. Regarding mRNA expression (by real-time PCR), only that of leptin and IL-6 decreased significantly. Circulating levels of leptin and PAI-1 decreased by 30 and 40%, respectively, but there were only minor changes in circulating TNF-␣, IL-6, or adiponectin. In conclusion, moderate caloric restriction but not macronutrient composition influences the production and secretion of adipose tissue-derived proteins during weight reduction, leptin being the most sensitive and adiponectin and PAI-1 the least sensitive. Diabetes 53: 1966 -1971, 2004 A dipose tissue secretes a number of proteins with auto-, para-, and endocrine actions, such as tumor necrosis factor-␣ (TNF-␣), interleukin (IL)-6 and -8, plasminogen activator inhibitor 1 (PAI-1), leptin, and adiponectin (1,2). Little is known about the regulation of the protein secretory function of human adipose tissue except for leptin (3). The effect of energy restriction is of particular importance for obesity treatment (4). Dietary-induced weight loss normalizes plasma levels and adipose tissue gene expression of several adipocyte-derived proteins (5-12). Whether the same is true for protein secretion is unknown, except for TNF-␣ (5,10). Furthermore, the relative roles of loss of body fat, energy restriction per se, and changes in macronutrient supply are not known. It is also unknown which proteins are more or less sensitive to nutritional changes regarding their production by adipose tissue. These questions were investigated by studying the release of leptin, adiponectin, IL-6 and -8, TNF-␣, and PAI-1 in subcutaneous adipose tissue of 40 obese women before and after 10 weeks on moderate hypoenergetic diets with either low-fat/highcarbohydrate content or moderate-fat/moderate-carbohydrate content. RESEARCH DESIGN AND METHODSAll subjects participated in a European multicenter study termed NutrientGene Interactions in Human Obesity: Implications for Dietary Guidelines (NUGENOB, www.nugenob.com), which examines the interaction between hypoenergetic diets and genes. Our Swedish center included 40 obese women aged 21-49 years with a BMI of 30.9 -47.7 kg/m 2 who were otherwise healthy and free of regular medication, except 1 woman who was treated wit...