The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol

C99 is the transmembrane carboxyl-terminal domain of the amyloid precursor protein that is cleaved by γ-secretase to release the amyloid-β polypeptides, which are associated with Alzheimer's disease. Nuclear magnetic resonance and electron paramagnetic resonance spectroscopy show that the extracellular amino terminus of C99 includes a surface-embedded "N-helix" followed by a short "N-loop" connecting to the transmembrane domain (TMD). The TMD is a flexibly curved α helix, making it well suited for processive cleavage by γ-secretase. Titration of C99 reveals a binding site for cholesterol, providing mechanistic insight into how cholesterol promotes amyloidogenesis. Membrane-buried GXXXG motifs (G, Gly; X, any amino acid), which have an established role in oligomerization, were also shown to play a key role in cholesterol binding. The structure and cholesterol binding properties of C99 may aid in the design of Alzheimer's therapeutics.     

Multiyear prediction of monthly mean Atlantic Meridional Overturning Circulation at 26.5°N

Attempts to predict changes in Atlantic Meridional Overturning Circulation (AMOC) have yielded little success to date. Here, we demonstrate predictability for monthly mean AMOC strength at 26.5°N for up to 4 years in advance. This AMOC predictive skill arises predominantly from the basin-wide upper-mid-ocean geostrophic transport, which in turn can be predicted because we have skill in predicting the upper-ocean zonal density difference. Ensemble forecasts initialized between January 2008 and January 2011 indicate a stable AMOC at 26.5°N until at least 2014, despite a brief wind-induced weakening in 2010. Because AMOC influences many aspects of climate, our results establish AMOC as an important potential carrier of climate predictability.     

Clovis age Western Stemmed projectile points and human coprolites at the Paisley Caves

The Paisley Caves in Oregon record the oldest directly dated human remains (DNA) in the Western Hemisphere. More than 100 high-precision radiocarbon dates show that deposits containing artifacts and coprolites ranging in age from 12,450 to 2295 (14)C years ago are well stratified. Western Stemmed projectile points were recovered in deposits dated to 11,070 to 11,340 (14)C years ago, a time contemporaneous with or preceding the Clovis technology. There is no evidence of diagnostic Clovis technology at the site. These two distinct technologies were parallel developments, not the product of a unilinear technological evolution. "Blind testing" analysis of coprolites by an independent laboratory confirms the presence of human DNA in specimens of pre-Clovis age. The colonization of the Americas involved multiple technologically divergent, and possibly genetically divergent, founding groups.     

Detergents modify proteinase K resistance of PrP Sc in different transmissible spongiform encephalopathies (TSEs)

Prion diseases are diagnosed by the detection of their proteinase K-resistant prion protein fragment (PrP(Sc)). Various biochemical protocols use different detergents for the tissue preparation. We found that the resistance of PrP(Sc) against proteinase K may vary strongly with the detergent used. In our study, we investigated the influence of the most commonly used detergents on eight different TSE agents derived from different species and distinct prion disease forms. For a high throughput we used a membrane adsorption assay to detect small amounts of prion aggregates, as well as Western blotting. Tissue lysates were prepared using DOC, SLS, SDS or Triton X-100 in different concentrations and these were digested with various amounts of proteinase K. Detergents are able to enhance or diminish the detectability of PrP(Sc) after proteinase K digestion. Depending on the kind of detergent, its concentration - but also on the host species that developed the TSE and the disease form or prion type - the detectability of PrP(Sc) can be very different. The results obtained here may be helpful during the development or improvement of a PrP(Sc) detection method and they point towards a detergent effect that can be additionally used for decontamination purposes. A plausible explanation for the detergent effects described in this article could be an interaction with the lipids associated with PrP(Sc) that may stabilize the aggregates.     

Sub-lethal levels of carvacrol reduce Salmonella Typhimurium motility and invasion of porcine epithelial cells

The European ban on the use of antibiotic growth promotors has increased the search for new alternatives to prevent pig intestinal microbial diseases and to stimulate growth. The addition of essential oils or components thereof, such as carvacrol, to pig feed is a promising alternative. In this report we determined the effect of sub-lethal concentrations of carvacrol on Salmonella Typhimurium. At concentrations where growth of Salmonella was not inhibited, carvacrol completely inhibited motility of the bacterium. This loss of motility was not due to the loss of the flagellum or to ATP shortage upon carvacrol treatment. Adhesion of Salmonella to IPEC-J2, porcine intestinal epithelial cells, was not affected by carvacrol but invasion was significantly reduced. In addition, the epithelial gene expression of porcine β-defensin 2, an innate immune response to Salmonella infection, was reduced when Salmonella was exposed to carvacrol. This indicates that invasion but not adhesion of Salmonella triggers the porcine β-defensin 2 expression of porcine epithelial cells.     

Effect of detomidine on visceral and somatic nociception and duodenal motility in conscious adult horses

ObjectiveTo evaluate the effects of detomidine on visceral and somatic nociception, heart and respiratory rates, sedation, and duodenal motility and to correlate these effects with serum detomidine concentrations.Study designNonrandomized, experimental trial.AnimalsFive adult horses, each with a permanent gastric cannula weighing 534 ± 46 kg.MethodsVisceral nociception was evaluated by colorectal (CRD) and duodenal distension (DD). The duodenal balloon was used to assess motility. Somatic nociception was assessed via thermal threshold (TT). Nose–to–ground (NTG) height was used as a measure of sedation. Serum was collected for pharmacokinetic analysis. Detomidine (10 or 20 μg kg^?1) was administered intravenously. Data were analyzed by means of a three–factor anova with fixed factors of treatment and time and random factor of horse. When a significant time × treatment interaction was detected, differences were compared with a simple t–test or Bonferroni t–test. Significance was set at p < 0.05.ResultsDetomidine produced a significant, dose–dependent decrease in NTG height, heart rate, and skin temperature and a significant, nondose–dependent decrease in respiratory rate. Colorectal distension threshold was significantly increased with 10 μg kg^?1 for 15 minutes and for at least 165 minutes with 20 μg kg^?1. Duodenal distension threshold was significantly increased at 15 minutes for the 20 μg kg^?1 dose. A significant change in TT was not observed at either dose. A marked, immediate decrease in amplitude of duodenal contractions followed detomidine administration at both doses for 50 minutes.Conclusions and clinical relevanceDetomidine caused a longer period of visceral anti–nociception as determined by CRD but a shorter period of anti–nociception as determined by DD than has been previously reported. The lack of somatic anti–nociception as determined by TT testing may be related to the marked decrease in skin temperature, likely caused by peripheral vasoconstriction and the low temperature cut–off of the testing device.     

Ethyl tert-butyl ether (ETBE) and tert-amyl methyl ether (TAME) can affect distribution pattern of inorganic N in soil

Ethyl tert-butyl ether (ETBE) and tert-amyl methyl ether (TAME) are synthetic compounds that are used as gasoline additives in order to reduce emissions from vehicles. In the present study, effects of these compounds were investigated on the dynamics of inorganic N in soil. Therefore, soil samples with different water contents were contaminated with ETBE and TAME, respectively. It could be shown that in the presence of TAME and ETBE, NH₄⁺–N accumulated; moreover, ETBE addition to soil resulted in increased NO₂⁻–N concentrations. These results indicated for the first time that ETBE and TAME can affect nitrification in soil. Thus, their impact on soil ecology should be investigated more intensively.