Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms

The ε4-allele variant of apolipoprotein E (ApoE4) is the strongest genetic risk factor for Alzheimer\u27s disease, although it only differs from its neutral counterpart ApoE3 by a single amino acid substitution. While ApoE4 influences the formation of plaques and neurofibrillary tangles, the structural determinants of pathogenicity remain undetermined due to limited structural information. Previous studies have led to conflicting models of the C-terminal region positioning with respect to the N-terminal domain across isoforms largely because the data are potentially confounded by the presence of heterogeneous oligomers. Here, we apply a combination of single-molecule spectroscopy and molecular dynamics simulations to construct an atomically detailed model of monomeric ApoE4 and probe the effect of lipid association. Importantly, our approach overcomes previous limitations by allowing us to work at picomolar concentrations where only the monomer is present. Our data reveal that ApoE4 is far more disordered and extended than previously thought and retains significant conformational heterogeneity after binding lipids. Comparing the proximity of the N- and C-terminal domains across the three major isoforms (ApoE4, ApoE3, and ApoE2) suggests that all maintain heterogeneous conformations in their monomeric form, with ApoE2 adopting a slightly more compact ensemble. Overall, these data provide a foundation for understanding how ApoE4 differs from nonpathogenic and protective variants of the protein

Do the Health Benefits of Cycling Outweigh the Risks?

BACKGROUND: Although from a societal point of view a modal shift from car to bicycle may have beneficial health effects due to decreased air pollution emissions, decreased greenhouse gas emissions, and increased levels of physical activity, shifts in individual adverse health effects such as higher exposure to air pollution and risk of a traffic accident may prevail.Objective: We describe whether the health benefits from the increased physical activity of a modal shift for urban commutes outweigh the health risks. DATA SOURCES AND EXTRACTION: We have summarized the literature for air pollution, traffic accidents, and physical activity using systematic reviews supplemented with recent key studies. DATA SYNTHESIS: We quantified the impact on all-cause mortality when 500,000 people would make a transition from car to bicycle for short trips on a daily basis in the Netherlands. We have expressed mortality impacts in life-years gained or lost, using life table calculations. For individuals who shift from car to bicycle, we estimated that beneficial effects of increased physical activity are substantially larger (3-14 months gained) than the potential mortality effect of increased inhaled air pollution doses (0.8-40 days lost) and the increase in traffic accidents (5-9 days lost). Societal benefits are even larger because of a modest reduction in air pollution and greenhouse gas emissions and traffic accidents. CONCLUSIONS: On average, the estimated health benefits of cycling were substantially larger than the risks relative to car driving for individuals shifting their mode of transport

Ethanol exposure increases mutation rate through error-prone polymerases

International audienceEthanol is a ubiquitous environmental stressor that is toxic to all lifeforms. Here, we use the model eukaryote Saccharomyces cerevisiae to show that exposure to sublethal ethanol concentrations causes DNA replication stress and an increased mutation rate. Specifically, we find that ethanol slows down replication and affects localization of Mrc1, a conserved protein that helps stabilize the replisome. In addition, ethanol exposure also results in the recruitment of error-prone DNA polymerases to the replication fork. Interestingly, preventing this recruitment through mutagenesis of the PCNA/Pol30 polymerase clamp or deleting specific error-prone polymerases abolishes the mutagenic effect of ethanol. Taken together, this suggests that the mutagenic effect depends on a complex mechanism, where dysfunctional replication forks lead to recruitment of error-prone polymerases. Apart from providing a general mechanistic framework for the mutagenic effect of ethanol, our findings may also provide a route to better understand and prevent ethanol-associated carcinogenesis in higher eukaryotes

Perturbed Angular Correlation Study of Fe/Cr (100) and Fe/Co (1-10) Multilayers

Recently we completed the very first and detailed perturbed angular correlation investigation on MBE-grown very thin film multilayers. The present paper aims to show that otherwise rather unaccessible but unique information on the (interface) magnetism could be obtained. For the Fe/Cr(1 0 0) multilayer system we observe, below a critical Cr thickness of 5.0 nm, a collapse of the spin-density-wave ordering in chromium. While the magnetization in the Fe-layer is in-plane, the Cr magnetization in thicker layers is out-of-plane. In the Fe/Co (1 -1 0) system, the observation of transferred magnetic hyperfine field satellites and their temperature dependence leads to the determination of an oscillating magnetic moment profile at the Fe/Co interface as well as a structure model for the superlattice

NACA Advanced Restricted Reports

Report presenting a dual-rotation axial-flow fan composed of two oppositely rotating 24-blade rotors. The fan was tested with various combinations of front and rear blade angles and with two combinations of front and rear solidities. For quantity coefficients above 0.3 the greatest pressure rise was obtained from 24 blades in each rotor with the blades adjusted to absorb equal torque at maximum pressure

NACA Advanced Restricted Reports

Report presenting an investigation of the characteristics of air scoops in the NACA propeller-research tunnel. The investigation showed that, at inlet-velocity ratios equal to or greater than 0.3, scoops in a forward position on the fuselage gave total pressures in the inlet nearly equal to free-stream total pressure

NACA Advanced Restricted Reports

Report presenting an axial flow fan tested with 5, 9, 12, 18, and 24 blades and with two different blade sections. The range of contravane angle and blade angle without contravanes was extended past results published for the same fan previously