Simvastatin inhibits TLR8 signaling in primary human monocytes and spontaneous TNF production from rheumatoid synovial membrane cultures

Simvastatin has been shown to have anti-inflammatory effects that are independent of its serum cholesterol lowering action, but the mechanisms by which these anti-inflammatory effects are mediated have not been elucidated. To explore the mechanism involved, the effect of simvastatin on Toll-like receptor (TLR) signalling in primary human monocytes was investigated. A short pre-treatment with simvastatin dose-dependently inhibited the production of tumor necrosis factor-α (TNF) in response to TLR8 (but not TLRs 2, 4, or 5) activation. Statins are known inhibitors of the cholesterol biosynthetic pathway, but intriguingly TLR8 inhibition could not be reversed by addition of mevalonate or geranylgeranyl pyrophosphate; downstream products of cholesterol biosynthesis. TLR8 signalling was examined in HEK 293 cells stably expressing TLR8, where simvastatin inhibited IKKα/β phosphorylation and subsequent NF-κB activation without affecting the pathway to AP-1. Since simvastatin has been reported to have anti-inflammatory effects in RA patients and TLR8 signalling contributes to TNF production in human RA synovial tissue in culture, simvastatin was tested in these cultures. Simvastatin significantly inhibited the spontaneous release of TNF in this model which was not reversed by mevalonate. Together, these results demonstrate a hitherto unrecognized mechanism of simvastatin inhibition of TLR8 signalling that may in part explain its beneficial anti-inflammatory effects

A genome-wide association study identifies risk alleles in plasminogen and P4HA2 associated with giant cell arteritis

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analysed in 2,134 cases and 9,125 unaffected controls from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, P = 1.94E-54, per-allele OR = 1.79; and rs9275592, P = 1.14E-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, P = 1.23E-10, OR = 1.28; and rs128738, P = 4.60E-09, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis

Adult fathead minnow, Pimephales promelas, partial life‐cycle reproductive and gonadal histopathology study with bisphenol A

Bisphenol A (BPA) is an intermediate used to produce epoxy resins and polycarbonate plastics. Although BPA degrades rapidly in the environment with aquatic half‐lives from 0.5 to 6 d, it can be found in aquatic systems because of widespread use. To evaluate potential effects from chronic exposure, fathead minnows were exposed for 164 d to nominal concentrations of 1, 16, 64, 160, and 640 µg/L BPA. Population‐level endpoints of survival, growth, and reproduction were assessed with supplemental endpoints (e.g., vitellogenin, gonad histology), including gonad cell type assessment and quantification. No statistically significant changes in growth, gonad weight, gonadosomatic index, or reproduction variables (e.g., number of eggs and spawns, hatchability) were observed; however, there was a significant impact on male survival at 640 µg/L. Vitellogenin increased in both sexes at 64 µg/L or higher. Gonad cell type frequencies were significantly different from controls at 160 µg/L or higher in males with a slight decrease in spermatocytes compared with less mature cell types, and at 640 µg/L in females with a slight decrease in early vitellogenic cells compared with less mature cells. The decrease in spermatocytes did not correspond to a decrease in the most mature sex cell type (spermatozoa) and did not impair male fertility, as hatchability was not impacted. Overall, marginal shifts in gametogenic cell maturation were not associated with any statistically significant effects on population‐relevant reproductive endpoints (growth, fecundity, and hatchability) at any concentration tested.publishe

The genome of Tetranychus urticae reveals herbivorous pest adaptations

The spider mite Tetranychus urticae is a cosmopolitan agricultural pest with an extensive host plant range and an extreme record of pesticide resistance. Here we present the completely sequenced and annotated spider mite genome, representing the first complete chelicerate genome. At 90 megabases T. urticae has the smallest sequenced arthropod genome. Compared with other arthropods, the spider mite genome shows unique changes in the hormonal environment and organization of the Hox complex, and also reveals evolutionary innovation of silk production. We find strong signatures of polyphagy and detoxification in gene families associated with feeding on different hosts and in new gene families acquired by lateral gene transfer. Deep transcriptome analysis of mites feeding on different plants shows how this pest responds to a changing host environment. The T. urticae genome thus offers new insights into arthropod evolution and plant–herbivore interactions, and provides unique opportunities for developing novel plant protection strategies

Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases

Objective I mmune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies. Methods We meta-analysed similar to 6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases. Results Our analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study. Conclusions We have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs

Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases

Funded by EU/EFPIA Innovative Medicines Initiative Joint Undertaking PRECISESADS (115565), The Spanish Ministry of Economy Industry and Competitiveness (SAF2015-66761-P), The Regional Ministry of Innovation, Science and Technologies of the Andalusian Regional Government (P12-BIO-1395) and Juan de la Cierva fellowship (FJCI-2015-24028). This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences