Effects of Heparin and Enoxaparin on APP Processing and Aβ Production in Primary Cortical Neurons from Tg2576 Mice

BACKGROUND Alzheimer's disease (AD) is caused by accumulation of Aβ, which is produced through sequential cleavage of β-amyloid precursor protein (APP) by the β-site APP cleaving enzyme (BACE1) and γ-secretase. Enoxaparin, a low molecular weight form of the glycosaminoglycan (GAG) heparin, has been reported to lower Aβ plaque deposition and improve cognitive function in AD transgenic mice. METHODOLOGY/PRINCIPAL FINDINGS We examined whether heparin and enoxaparin influence APP processing and inhibit Aβ production in primary cortical cell cultures. Heparin and enoxaparin were incubated with primary cortical cells derived from Tg2576 mice, and the level of APP and proteolytic products of APP (sAPPα, C99, C83 and Aβ) was measured by western blotting. Treatment of the cells with heparin or enoxaparin had no significant effect on the level of total APP. However, both GAGs decreased the level of C99 and C83, and inhibited sAPPα and Aβ secretion. Heparin also decreased the level of β-secretase (BACE1) and α-secretase (ADAM10). In contrast, heparin had no effect on the level of ADAM17. CONCLUSIONS/SIGNIFICANCE The data indicate that heparin and enoxaparin decrease APP processing via both α- and β-secretase pathways. The possibility that GAGs may be beneficial for the treatment of AD needs further study.This work was funded by a project grant (490031) from the National Health and Medical Research Council of Australia (http://www.nhmrc.gov.au). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Magnetic circuit for hall effect plasma accelerator

A Hall effect plasma accelerator includes inner and outer electromagnets, circumferentially surrounding the inner electromagnet along a thruster centerline axis and separated therefrom, inner and outer magnetic conductors, in physical connection with their respective inner and outer electromagnets, with the inner magnetic conductor having a mostly circular shape and the outer magnetic conductor having a mostly annular shape, a discharge chamber, located between the inner and outer magnetic conductors, a magnetically conducting back plate, in magnetic contact with the inner and outer magnetic conductors, and a combined anode electrode/gaseous propellant distributor, located at a bottom portion of the discharge chamber. The inner and outer electromagnets, the inner and outer magnetic conductors and the magnetically conducting back plate form a magnetic circuit that produces a magnetic field that is largely axial and radially symmetric with respect to the thruster centerline

Unitarity and the Hilbert space of quantum gravity

Under the premises that physics is unitary and black hole evaporation is complete (no remnants, no topology change), there must exist a one-to-one correspondence between states on future null and timelike infinity and on any earlier spacelike Cauchy surface (e.g., slices preceding the formation of the hole). We show that these requirements exclude a large set of semiclassical spacetime configurations from the Hilbert space of quantum gravity. In particular, the highest entropy configurations, which account for almost all of the volume of semiclassical phase space, would not have quantum counterparts, i.e. would not correspond to allowed states in a quantum theory of gravity.Comment: 7 pages, 3 figures, revtex; minor changes in v2 (version published in Class. Quant. Grav.

The effect on photochemical smog of converting the U.S. fleet of gasoline vehicles to modern diesel vehicles

With the increased use of particle traps and nitrogen oxide (NO_x) control devices to reduce air pollution, “modern” diesel vehicles are being encouraged over gasoline vehicles globally as a central method of slowing global warming. Data to date, though, suggest that the NO_2:NO ratio from modern diesel may exceed that of gasoline, and it is difficult to reduce diesel NO_x below gasoline NO_x without increasing particle emissions. Here, it is calculated that, unless the diesel NO_2:NO ratio and total NO_x are reduced to those of gasoline, modern diesel, which should have lower hydrocarbon (HC) and carbon monoxide (CO) emissions than gasoline, may still enhance photochemical smog at the surface and aloft, on average, over the U.S. relative to gasoline. The reason is that vehicle-produced smog in the U.S. depends more on NO_x and the NO_2:NO ratio than on HCs or CO. It is also found that vehicle NO_x controls may be more effective than NO_2:NO ratio controls at reducing ozone

High-Power Krypton Hall Thruster Technology Being Developed for Nuclear-Powered Applications

The NASA Glenn Research Center has been performing research and development of moderate specific impulse, xenon-fueled, high-power Hall thrusters for potential solar electric propulsion applications. These applications include Mars missions, reusable tugs for low-Earth-orbit to geosynchronous-Earth-orbit transportation, and missions that require transportation to libration points. This research and development effort resulted in the design and fabrication of the NASA-457M Hall thruster that has been tested at input powers up to 95 kW. During project year 2003, NASA established Project Prometheus to develop technology in the areas of nuclear power and propulsion, which are enabling for deep-space science missions. One of the Project-Prometheus-sponsored Nuclear Propulsion Research tasks is to investigate alternate propellants for high-power Hall thruster electric propulsion. The motivation for alternate propellants includes the disadvantageous cost and availability of xenon propellant for extremely large scale, xenon-fueled propulsion systems and the potential system performance benefits of using alternate propellants. The alternate propellant krypton was investigated because of its low cost relative to xenon. Krypton propellant also has potential performance benefits for deep-space missions because the theoretical specific impulse for a given voltage is 20 percent higher than for xenon because of krypton's lower molecular weight. During project year 2003, the performance of the high-power NASA-457M Hall thruster was measured using krypton as the propellant at power levels ranging from 6.4 to 72.5 kW. The thrust produced ranged from 0.3 to 2.5 N at a discharge specific impulse up to 4500 sec

Toward an Integrated Model for Raised-Bog Development: Theory and Field Evidence

The development and distribution of Northern mires, including minerotrophic fens and ombrotrophic raised bogs, frequently are presumed to be strongly controlled by the interplay of regional climate and site geomorphology and history. Investigations of these relationships provide insights into long-term trends in ecosystem development by linking geological and landscape-scale processes. In this study, a theoretical model for raised-bog development integrates internal bog hydrodynamics with external factors, including local substrate characteristics, and regional temperature and moisture conditions. The model is used to interpret the development of raised bogs in the Bergslagen region, which coincides with the modern northern distributional limit of those mires in central Sweden. The development of minerotrophic fens that precede bog formation is also considered. Basal radiocarbon dates along surveyed transects are used to assess the pattern and timing of peatland formation and rates of lateral expansion. Previous palynological and lake-level studies from the same region provide independent evidence for changes in Holocene climate. Fen initiation in the region occurred throughout the Holocene under a broad range of environmental conditions. Once established, fens appear to expand faster during moister periods. Locally, substrate slope is an important mediator of fen development, with slopes >0.5% inhibiting lateral expansion. Accumulation of Sphagnum peat, an indicator of raisedbog initiation, occurred from -4000 to 5000 yr BP during relatively dry phases. Rates of lateral expansion were not significantly affected by increasing moisture or by decreasing temperatures until at least 2000 yr BP However, modern geographic trends in cross sectional shape of mires suggest that, at the northern limit of their range today, raised bogs are limited by low temperatures.Organismic and Evolutionary Biolog

Impact-induced melting during accretion of the Earth

Because of the high energies involved, giant impacts that occur during planetary accretion cause large degrees of melting. The depth of melting in the target body after each collision determines the pressure and temperature conditions of metal-silicate equilibration and thus geochemical fractionation that results from core-mantle differentiation. The accretional collisions involved in forming the terrestrial planets of the inner Solar System have been calculated by previous studies using N-body accretion simulations. Here we use the output from such simulations to determine the volumes of melt produced and thus the pressure and temperature conditions of metal-silicate equilibration, after each impact, as Earth-like planets accrete. For these calculations a parametrised melting model is used that takes impact velocity, impact angle and the respective masses of the impacting bodies into account. The evolution of metal-silicate equilibration pressures (as defined by evolving magma ocean depths) during Earth's accretion depends strongly on the lifetime of impact-generated magma oceans compared to the time interval between large impacts. In addition, such results depend on starting parameters in the N-body simulations, such as the number and initial mass of embryos. Thus, there is the potential for combining the results, such as those presented here, with multistage core formation models to better constrain the accretional history of the Earth

On the response of a particle detector in Anti-de Sitter spacetime

We consider the vacuum response of a particle detector in Anti-de Sitter spacetime, and in particular analyze how spacetime features such as curvature and dimensionality affect the response spectrum of an accelerated detector. We calculate useful limits on Wightman functions, analyze the dynamics of the detector in terms of vacuum fluctuations and radiation reactions, and discuss the thermalization process for the detector. We also present a generalization of the GEMS approach and obtain the Gibbons-Hawking temperature of de Sitter spacetime as an embedded Unruh temperature in a curved Anti-de Sitter spacetime.Comment: 13 pages, no figures, accepted for publication in Class. Quantum Gra