Secreted Amyloid β-Proteins in a Cell Culture Model Include N-Terminally Extended Peptides That Impair Synaptic Plasticity

Evidence for a central role of amyloid β-protein (Aβ) in the genesis of Alzheimer’s disease (AD) has led to advanced human trials of Aβ-lowering agents. The “amyloid hypothesis” of AD postulates deleterious effects of small, soluble forms of Aβ on synaptic form and function. Because selectively targeting synaptotoxic forms of soluble Aβ could be therapeutically advantageous, it is important to understand the full range of soluble Aβ derivatives. We previously described a Chinese hamster ovary (CHO) cell line (7PA2 cells) that stably expresses mutant human amyloid precursor protein (APP). Here, we extend this work by purifying an sodium dodecyl sulfate (SDS)-stable, ∼8 kDa Aβ species from the 7PA2 medium. Mass spectrometry confirmed its identity as a noncovalently bonded Aβ40 homodimer that impaired hippocampal long-term potentiation (LTP) in vivo. We further report the detection of Aβ-containing fragments of APP in the 7PA2 medium that extend N-terminal from Asp1 of Aβ. These N-terminally extended Aβ-containing monomeric fragments are distinct from soluble Aβ oligomers formed from Aβ1-40/42 monomers and are bioactive synaptotoxins secreted by 7PA2 cells. Importantly, decreasing β-secretase processing of APP elevated these alternative synaptotoxic APP fragments. We conclude that certain synaptotoxic Aβ-containing species can arise from APP processing events N-terminal to the classical β-secretase cleavage site

Planetary Nebulae as standard candles XI. Application to Spiral Galaxies

We report the results of an [O III] lambda 5007 survey for planetary nebulae (PN) in three spiral galaxies: M101 (NGC 5457), M51 (NGC 5194/5195) and M96 (NGC 3368). By comparing on-band/off-band [O III] lambda 5007 images with images taken in H-alpha and broadband R, we identify 65, 64 and 74 PN candidates in each galaxy, respectively. From these data, an adopted M31 distance of 770 kpc, and the empirical planetary nebula luminosity function (PNLF), we derive distances to M101, M51, and M96 of 7.7 +/- 0.5, 8.4 +/- 0.6, and 9.6 +/- 0.6 Mpc. These observations demonstrate that the PNLF technique can be successfully applied to late-type galaxies, and provide an important overlap between the Population I and Population II distance scales. We also discuss some special problems associated with using the PNLF in spiral galaxies, including the effects of dust and the possible presence of [O III] bright supernova remnants.Comment: 38 pages, TeX, with tables included but not figures. Uses epsf.tex and kpnobasic.tex. To be published in the Astophysical Journal. Full paper is available at http://www.astro.psu.edu/users/johnf/Text/research.htm

Meeting the health and social needs of pregnant asylum seekers; midwifery students’ perspectives. Part 2; Dominant discourses and approaches to care

YesPregnant women seeking asylum in the United Kingdom appear particularly vulnerable, having complex health and social care needs and could benefit from a woman centred approach to midwifery care. This article is the second of three parts and reports on the findings from one objective of a wider doctorate study. It focuses on exploring midwifery students' perceptions of how to approach the care of pregnant women seeking asylum. Although the design of the study is explored in article one, in this context, the data was subject to critical discourse analysis to meet this objective. Key words and phrases were highlighted which appeared to reveal power and ideology implicit in the language used when discussing midwifery care of the pregnant woman seeking asylum. Dominant discourses were identified which appeared to influence the way in which care was approached and the possible sources of these discourses critically analysed. The findings suggest an underpinning ideology around following policies and guidelines to meet the physical needs of the woman at the expense of her other holistic needs. Despite learning to adopt a woman centred approach in theory, once in practice some students appear to be socialised into (re)producing these dominant medical and managerial discourses with “midwifery discourse” being marginalised. In addition, some students appeared to have difficulty understanding how to adopt a woman centred approach and the importance of considering the woman's context and its impact on care. These findings have implications for midwifery educators and this article identifies that the recent Nursing and Midwifery Council requirement for students to undertake a caseloading activity could provide the opportunity for them to adopt a consistent woman centred approach in practice, rejecting dominant medical and managerial discourses. However, these discourses appear to influence midwives caring for women more widely and will be difficult to challenge

Super star clusters in Haro 11: Properties of a very young starburst and evidence for a near-infrared flux excess

We have used multi-band imaging to investigate the nature of the extreme starburst environment in Haro 11 galaxy. The central starburst region has been observed in 8 HST wavebands and at 2.16 micron at the ESO-VLT. We constructed integrated spectral energy distributions (SEDs) for about 200 star clusters and compared them with single stellar population models in order to derive ages, masses and extinctions of thestar clusters. The present starburst has lasted for 40 Myr, and shows a peak of cluster formation only 3.5 Myr old. With such an extremely young cluster population, Haro 11 represents a unique opportunity to investigate the youngest phase of the cluster formation process and evolution in starburst systems. Extinction tends to diminish as function of the cluster age, but the spread is large and for clusters in partial embedded phases ( 10^4 Msun), very young (1-3 Myr) clusters is missing, either because they are embedded inthe parental molecular cloud and heavily extinguished, or because of blending. Almost half of the cluster sample is affected by flux excesses at wavelengths 8000 \AA which cannot be explained by simple stellar evolutionary models. Fitting SED models over all wavebands leads to systematic overestimates of cluster ages and incorrect masses for the stellar population supplying the light in these clusters. We show that the red excess affects also the HST F814W filter, which is typically used to constrain cluster physical properties. The clusters which show the red excess are younger than 40 Myr; we propose possible physical explanations for the phenomenon. Finally, we estimate that Haro 11 hasproduced bound clusters at a rate almost a factor of 10 higher than the massive and regular spirals, like the Milky Way. (Abriged)Comment: Accepted for publication in MNRAS. 23 pages, 23 figure

The Hubble Constant

I review the current state of determinations of the Hubble constant, which gives the length scale of the Universe by relating the expansion velocity of objects to their distance. There are two broad categories of measurements. The first uses individual astrophysical objects which have some property that allows their intrinsic luminosity or size to be determined, or allows the determination of their distance by geometric means. The second category comprises the use of all-sky cosmic microwave background, or correlations between large samples of galaxies, to determine information about the geometry of the Universe and hence the Hubble constant, typically in a combination with other cosmological parameters. Many, but not all, object-based measurements give $H_0$ values of around 72-74km/s/Mpc , with typical errors of 2-3km/s/Mpc. This is in mild discrepancy with CMB-based measurements, in particular those from the Planck satellite, which give values of 67-68km/s/Mpc and typical errors of 1-2km/s/Mpc. The size of the remaining systematics indicate that accuracy rather than precision is the remaining problem in a good determination of the Hubble constant. Whether a discrepancy exists, and whether new physics is needed to resolve it, depends on details of the systematics of the object-based methods, and also on the assumptions about other cosmological parameters and which datasets are combined in the case of the all-sky methods.Comment: Extensively revised and updated since the 2007 version: accepted by Living Reviews in Relativity as a major (2014) update of LRR 10, 4, 200

Exosomes neutralize synaptic-plasticity-disrupting activity of Aβ assemblies in vivo

Background: Exosomes, small extracellular vesicles of endosomal origin, have been suggested to be involved in both the metabolism and aggregation of Alzheimer’s disease (AD)-associated amyloid β-protein (Aβ). Despite their ubiquitous presence and the inclusion of components which can potentially interact with Aβ, the role of exosomes in regulating synaptic dysfunction induced by Aβ has not been explored. Results: We here provide in vivo evidence that exosomes derived from N2a cells or human cerebrospinal fluid can abrogate the synaptic-plasticity-disrupting activity of both synthetic and AD brain-derived Aβ. Mechanistically, this effect involves sequestration of synaptotoxic Aβ assemblies by exosomal surface proteins such as PrPC rather than Aβ proteolysis. Conclusions: These data suggest that exosomes can counteract the inhibitory action of Aβ, which contributes to perpetual capability for synaptic plasticity

Detector Description and Performance for the First Coincidence Observations between LIGO and GEO

For 17 days in August and September 2002, the LIGO and GEO interferometer gravitational wave detectors were operated in coincidence to produce their first data for scientific analysis. Although the detectors were still far from their design sensitivity levels, the data can be used to place better upper limits on the flux of gravitational waves incident on the earth than previous direct measurements. This paper describes the instruments and the data in some detail, as a companion to analysis papers based on the first data.Comment: 41 pages, 9 figures 17 Sept 03: author list amended, minor editorial change

Atmospheric impact of Arctic Sea ice loss in a coupled ocean–atmosphere simulation

The atmospheric response to an idealized decline in Arctic sea ice is investigated in a novel fully coupled climate model experiment. In this experiment two ensembles of single-year model integrations are performed starting on 1 April, the approximate start of the ice melt season. By perturbing the initial conditions of sea ice thickness (SIT), declines in both sea ice concentration and SIT, which result in sea ice distributions that are similar to the recent sea ice minima of 2007 and 2012, are induced. In the ice loss regions there are strong (~3 K) local increases in sea surface temperature (SST); additionally, there are remote increases in SST in the central North Pacific and subpolar gyre in the North Atlantic. Over the central Arctic there are increases in surface air temperature (SAT) of ~8 K due to increases in ocean–atmosphere heat fluxes. There are increases in SAT over continental North America that are in good agreement with recent changes as seen by reanalysis data. It is estimated that up to two-thirds of the observed increase in SAT in this region could be related to Arctic sea ice loss. In early summer there is a significant but weak atmospheric circulation response that projects onto the summer North Atlantic Oscillation (NAO). In early summer and early autumn there is an equatorward shift of the eddy-driven jet over the North Atlantic as a result of a reduction in the meridional temperature gradients. In winter there is no projection onto a particular phase of the NAO

Modelling galaxy spectra in presence of interstellar dust. II. From the UV to the far infrared

In this paper, we present spectrophotometric models for galaxies of different morphological type whose spectral energy distributions (SEDs) take into account the effect of dust in absorbing UV-optical light and re-emitting it in the infrared (IR). The models contain three main components: (i) the diffuse interstellar medium (ISM) composed of gas and dust, (ii) the large complexes of molecular clouds (MCs) in which new stars are formed and (iii) the stars of any age and chemical composition. The galaxy models stand on a robust model of chemical evolution taylored in such a way to match the gross properties of galaxies of different morphological type. A simple geometrical model is adopted for each type of galaxy. The total gas and star mass provided by the chemical model are distributed over the whole volume by means of suitable density profiles, one for each component and depending on the galaxy type (spheroidal, disk and disk plus bulge). The galaxy is then split in suitable volume elements to each of which the appropriate amounts of stars, MCs and ISM are assigned. We derive the SEDs of galaxies of different morphological type. First the the basic relations driving the interaction between the physical components of the galaxy are presented. Second, the main parameters are examined and their effects on the SED of three prototype galaxies (a disk, an elliptical and a starburster) are highlighted. The final part of the paper is devoted to assess the ability of our galaxy models in reproducing the SEDs of a few real galaxies of the Local Universe.Comment: 28 pages, 23 figures and 1 table. Accepted by MNRA