A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP

The innate immune system responds to unique molecular signatures that are widely conserved among microbes but that are not normally present in host cells. Compounds that stimulate innate immune pathways may be valuable in the design of novel adjuvants, vaccines, and other immunotherapeutics. The cyclic dinucleotide cyclic-di–guanosine monophosphate (c-di-GMP) is a recently appreciated second messenger that plays critical regulatory roles in many species of bacteria but is not produced by eukaryotic cells. In vivo and in vitro studies have previously suggested that c-di-GMP is a potent immunostimulatory compound recognized by mouse and human cells. We provide evidence that c-di-GMP is sensed in the cytosol of mammalian cells via a novel immunosurveillance pathway. The potency of cytosolic signaling induced by c-di-GMP is comparable to that induced by cytosolic delivery of DNA, and both nucleic acids induce a similar transcriptional profile, including triggering of type I interferons and coregulated genes via induction of TBK1, IRF3, nuclear factor κB, and MAP kinases. However, the cytosolic pathway that senses c-di-GMP appears to be distinct from all known nucleic acid–sensing pathways. Our results suggest a novel mechanism by which host cells can induce an inflammatory response to a widely produced bacterial ligand

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Fisheries 9RO1R1RYHPEHUZZZÀVKHULHVRUJ GUIDELINES AND REVIEWS AFS Completes Assessment, Issues New Guidance Regarding Hatchery Operation and the Use of Hatchery-Origin Fish

BACKGROUND The American Fisheries Society (AFS) is the oldest, larg-HVW DQGPRVW LQÀXHQWLDOSURIHVVLRQDORUJDQL]DWLRQGHYRWHG WR ¿VKHULHVFRQVHUYDWLRQDQGLQWKLVFDSDFLW\WKH$)6KDVURXWLQH-ly assessed the contributions of hatcheries to natural resource management and issued recommendations to guide natural re-VRXUFHPDQDJHUV LQEHVW XVHVRI KDWFKHU\RULJLQ¿VK)RU WKH past several decades, the Society has explored these issues in a formalized process conducted at approximately 10-year in-tervals to assess contemporary issues related to hatcheries and management of aquatic resources. Representatives of the Fish Culture and Fisheries Management Sections came together in WRDQVZHUWKHTXHVWLRQ)LVKFXOWXUH¿VKPDQDJHPHQW¶V ally? ” in a symposium entitled “The Role of Fish Culture in Fisheries Management. ” In 1994, AFS reexamined the issue