Modeling Amyloid Beta Peptide Insertion into Lipid Bilayers

Inspired by recent suggestions that the Alzheimer's amyloid beta peptide (A beta) can insert into cell membranes and form harmful ion channels, we model insertion of the 40 and 42 residue forms of the peptide into cell membranes using a Monte Carlo code which is specific at the amino acid level. We examine insertion of the regular A-beta peptide as well as mutants causing familial Alzheimer's disease, and find that all but one of the mutants change the insertion behavior by causing the peptide to spend more simulation steps in only one leaflet of the bilayer. We also find that A-beta 42, because of the extra hydrophobic residues relative to A-beta 40, is more likely to adopt this conformation than A-beta 40 in both wild-type and mutant forms. We argue qualitatively why these effects happen. Here, we present our results and develop the hypothesis that this partial insertion increases the probability of harmful channel formation. This hypothesis can partly explain why these mutations are neurotoxic simply due to peptide insertion behavior. We further apply this model to various artificial A-beta mutants which have been examined experimentally, and offer testable experimental predictions contrasting the roles of aggregation and insertion with regard to toxicity of A-beta mutants. These can be used through further experiments to test our hypothesis.Comment: 14 pages; 8 figures; 2nd revisio

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

Data delen: een vloek of een zegen?

Data delen, dat is niet iets waar veel schippers voor warmlopen. Maar het kan veel opleveren door bepaalde gegevens van een schip te delen. Wat zijn de beste snel-heden om op welke waterwegen mee te varen? Die informatie kan door data te delen gebrui-kt worden door minder ervaren schippers. Ook kan een motor langer in bedrijf blijven als je er meer over weet

Onderscheidende kenmerken van brandstoftypen als alternatief voor diesel

De gemeente Amsterdam heeft een aanbestedingsprocedure uitgevaardigd voor de inkoop van brandstof voor dieselvoertuigen. De gunningscriteria op basis waarvan een aanbieder zal worden geselecteerd, zijn de prijs en het effect op luchtvervuiling. Tijdens de aanbestedingsprocedure zijn er in raadscommissievergaderingen vragen gesteld over de gehanteerde duurzaamheidsdoelstellingen. Hierop heeft de gemeente Amsterdam TNO verzocht om meer inzicht te verschaffen in

Electric shipping in the city of Amsterdam

In November 2013, a policy paper for clean shipping has been adopted by the City Council of Amsterdam. This policy prescribes that every commercial ship needs to be zero-emission in 2020 or 2025, depending on its size, on the canals of Amsterdam

New EGR technology retains HD diesel economy with 21st century emissions

An EGR system for turbocharged (and aftercooled) heavy-duty diesel engines have been demonstrated on a 12 litre 315 kW engine with 4 valves per cyclinder head and high pressure injection system. In the EGR system exhaust gas is tapped of before the turbine, run through a cooler and mixed with the intake air after the compressor and aftercooler. This is done with a minimum of disturbance to the pressure balance across the engine by combining a very efficient venturi-mixer unit with a VGT turbocharger. The venturi-mixer is positioned between the aftercooler and the intake manifold and provides a suction power to the EGR gas. Optimization of EGR quantity and injection timing reduced the NOx emission over the European 13-mode test by almost 60% to 2.4 g/kWh. Particulate emissions were 0.107 g/kWh and the BSFC penalty 2,5%. Initial tests demonstrate acceptable transient behaviour when using a dedicated control strategy. The expected EURO4 emission requirements are 3 g/kWh NOx and 0.10 g/kWh particulates (approximate time of implementation is 2004)

DAF Euro-4 heavy-duty diesel engine with TNO EGR system and CRT particulates filter

This paper reports on a study of the TNO venturi EGR system and the Johnson Matthey CRT particulates trap on a DAF 355 kW engine. The results obtained indicate that this EGR-CRT combination is an effective means to achieve EURO-4 emission level, while maintaining good fuel economy. EGR strategy, injection timing and air-fuel ratio were optimized in such a way that good regeneration conditions were obtained across most of the engine operating map. Also transient EGR control is optimised to combine low NOx emission during the ETC with good driveability and good engine out particulates emission. The size of the oxidation catalyst in the CRT was investigated. It appeared that the larger oxidation catalyst showed a better regeneration performance during a low temperature duty-cycle. Negative aspects of a larger oxidation catalyst are increased costs and increased NOemission (because of the catalyst ability to oxidize more NO into NO). In order to secure regeneration under all circumstances it was found necessary to develop an active regeneration control strategy. This strategy will temporarily increase exhaust temperature and NOx-PM ratio when a high back pressure is detected. The EGR-CRT system is installed in a truck to investigate its performance and durability in practise