ABSTRACT
Thiopurines are commonly used drugs in the therapy of Crohn's disease, but unfortunately only show a 30% response rate. The biological basis for the thiopurine response is unclear, thus hampering patient selection prior to treatment. A genetic risk factor associated specifically with Crohn's disease is a variant in ATG16L1 that reduces autophagy. We have previously shown that autophagy is involved in dendritic cell (DC)-T-cell interactions and cytoskeletal regulation. Here we further investigated the role of autophagy in DC cytoskeletal modulation and cellular trafficking. Autophagy-deficient DC displayed loss of filopodia, altered podosome distribution, and increased membrane ruffling, all consistent with increased cellular adhesion. Consequently, autophagy-deficient DC showed reduced migration. The cytoskeletal aberrations were mediated through hyperactivation of Rac1, a known thiopurine target. Indeed thiopurines restored the migratory defects in autophagy-deficient DC. Clinically, the ATG16L1 risk variant associated with increased response to thiopurine treatment in patients with Crohn's disease but not ulcerative colitis. These results suggest that the association between ATG16L1 and Crohn's disease is mediated at least in part through Rac1 hyperactivation and subsequent defective DC migration. As this phenotype can be corrected using thiopurines, ATG16L1 genotyping may be useful in the identification of patients that will benefit most from thiopurine treatment.
Subject(s)
Autophagy-Related Proteins/metabolism , Autophagy , Crohn Disease/immunology , Dendritic Cells/physiology , rac1 GTP-Binding Protein/metabolism , Alleles , Animals , Autophagy/genetics , Autophagy-Related Proteins/genetics , Cell Membrane Structures/pathology , Cell Movement , Cells, Cultured , Colitis, Ulcerative/drug therapy , Crohn Disease/drug therapy , Crohn Disease/genetics , Cytoskeleton/metabolism , Dendritic Cells/pathology , Female , Genetic Predisposition to Disease , Humans , Mercaptopurine/therapeutic use , Mice , Mice, Inbred C57BL , Mice, Knockout , Polymorphism, Genetic , RNA, Small Interfering/genetics , RiskABSTRACT
Surrogates, such as umbrella species, are commonly used to reduce the complexity of quantifying biodiversity for conservation purposes. The presence of umbrella species is often indicative of high taxonomic diversity; however, functional diversity is now recognized as an important metric for biodiversity and thus should be considered when choosing umbrella species. We identified umbrella species associated with high taxonomic and functional biodiversity in urban areas in Switzerland. We analyzed 39,752 individuals of 574 animal species from 96 study plots and 1397 presences of 262 plant species from 58 plots. Thirty-one biodiversity measures of 7 taxonomic groups (plants, spiders, bees, ground beetles, lady bugs, weevils and birds) were included in within- and across-taxa analyses. Sixteen measures were taxonomical (species richness and species diversity), whereas 15 were functional (species traits including mobility, resource use, and reproduction). We used indicator value analysis to identify umbrella species associated with single or multiple biodiversity measures. Many umbrella species were indicators of high biodiversity within their own taxonomic group (from 33.3% in weevils to 93.8% in birds), to a lesser extent they were indicators across taxa. Principal component analysis revealed that umbrella species for multiple measures of biodiversity represented different aspects of biodiversity, especially with respect to measures of taxonomic and functional diversity. Thus, even umbrella species for multiple measures of biodiversity were complementary in the biodiversity aspects they represented. Thus, the choice of umbrella species based solely on taxonomic diversity is questionable and may not represent biodiversity comprehensively. Our results suggest that, depending on conservation priorities, managers should choose multiple and complementary umbrella species to assess the state of biodiversity.
Subject(s)
Arthropods , Biodiversity , Birds , Cities , Plants , Animals , Conservation of Natural Resources , SwitzerlandABSTRACT
Emission spectrophotometry was used to measure the levels of titanium, aluminum, and vanadium in the blood, urine, and hair of 30 patients with total hip arthroplasties. The patients were divided into three groups of ten; one group was studied two years after total hip replacement, one at four years, and one at six years. High levels of titanium and aluminum were found in the hair, especially in the group studied six years after implantation, while the levels of the three ions in the blood and urine were not significant.
