Physiologically regulated transgenic ABCA1 does not reduce amyloid burden or amyloid‐beta peptide levels in vivo

J Lipid Res. 2007 Apr;48(4):914-23. Epub 2007 Jan 18. Physiologically regulated transgenic ABCA1 does not reduce amyloid burden or amyloid-beta peptide levels in vivo. Hirsch-Reinshagen V, Chan JY, Wilkinson A, Tanaka T, Fan J, Ou G, Maia LF, Singaraja RR, Hayden MR, Wellington CL. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada. Abstract ABCA1-deficient mice have low levels of poorly lipidated apolipoprotein E (apoE) and exhibit increased amyloid load. To test whether excess ABCA1 protects from amyloid deposition, we crossed APP/PS1 mice to ABCA1 bacterial artificial chromosome (BAC) transgenic mice. Compared with wild-type animals, the ABCA1 BAC led to a 50% increase in cortical ABCA1 protein and a 15% increase in apoE abundance, demonstrating that this BAC supports modest ABCA1 overexpression in brain. However, this was observed only in animals that do not deposit amyloid. Comparison of ABCA1/APP/PS1 mice with APP/PS1 controls revealed no differences in levels of brain ABCA1 protein, amyloid, Abeta, or apoE, despite clear retention of ABCA1 overexpression in the livers of these animals. To further investigate ABCA1 expression in the amyloid-containing brain, we then compared ABCA1 mRNA and protein levels in young and aged cortex and cerebellum of APP/PS1 and ABCA1/APP/PS1 animals. Compared with APP/PS1 controls, aged ABCA1/APP/PS1 mice exhibited increased ABCA1 mRNA, but not protein, selectively in cortex. Additionally, ABCA1 mRNA levels were not increased before amyloid deposition but were induced only in the presence of extensive Abeta and amyloid levels. These data suggest that an induction of ABCA1 expression may be associated with late-stage Alzheimer's neuropathology. PMID: 17235115 [PubMed - indexed for MEDLINE

Robust optimization strategies for sheet metal springback compensation

.Sheet metal forming is a major industrial process, mainly due to its cost efficiency after the establishment of the processdesign. However, the process design from tools geometry to load conditions is not straightforward, as a consequence of the side effects associated with sheet metal forming. The emphas is in this area goes to the springback effect or elastic recovery,which is one of the main causes of part’s inaccuracy,demanding tool compensation.This work proposes to compare different robust opti-mization strategies to sheet metal forming springback compensation.The methodology adopted resorts to Response SurfaceMethod(RSM),as well as to Finite Element Model Updating (FEMU) strategies, to adjust the design variables.These include the tools’surfaces,which are parametrised with NURBS.These strategies are then compared using theU-Rail benchmark. The results achieved reveal a reduction of 99% on the geometrical error of the final piece for the best methodology

GD1a modulates GM-CSF-induced cell proliferation

AbstractGangliosides have been extensively described to be involved in the proliferation and differentiation of various cell types, such including hematopoietic cells. Our previous studies on murine models of stroma-mediated myelopoiesis have shown that gangliosides are required for optimal capacity of stromal cells to support proliferation of myeloid precursor cells, being shed to the supernatant and selectively incorporated into myeloid cell membranes. Here we describe the effect of gangliosides on the specific granulocyte–macrophage colony-stimulating factor (GM-CSF)-induced proliferation. For that, we used the monocytic FDC-P1 cell line, which is dependent upon GM-CSF for survival and proliferation. Cells were cultured in the presence of GM-CSF and exogenous gangliosides (GM3, GD1a or GM1) or in the absence of endogenous ganglioside synthesis by the use of a ceramide-synthase inhibitor, d-PDMP. We observed that exogenous addition of GD1a enhanced the GM-CSF-induced proliferation of the FDC-P1 cells. Also, we detected an increase in the expression of the α isoform of the GM-CSF receptor (GMRα) as well as of the transcription factor C/EBPα. On the contrary, inhibition of glucosylceramide synthesis was accompanied by a decrease in cell proliferation, which was restored upon the addition of exogenous GD1a. We also show a co-localization of GD1a and GMR by immunocytochemistry. Taken together, our results suggest for the first time that ganglioside GD1a play a role on the modulation of GM-CSF-mediated proliferative response, which might be of great interest not only in hematopoiesis, but also in other immunological processes, Alzheimer disease, alveolar proteinosis and wherever GM-CSF exerts its effects

Gravitons and Lightcone Fluctuations

Gravitons in a squeezed vacuum state, the natural result of quantum creation in the early universe or by black holes, will introduce metric fluctuations. These metric fluctuations will introduce fluctuations of the lightcone. It is shown that when the various two-point functions of a quantized field are averaged over the metric fluctuations, the lightcone singularity disappears for distinct points. The metric averaged functions remain singular in the limit of coincident points. The metric averaged retarded Green's function for a massless field becomes a Gaussian which is nonzero both inside and outside of the classical lightcone. This implies some photons propagate faster than the classical light speed, whereas others propagate slower. The possible effects of metric fluctuations upon one-loop quantum processes are discussed and illustrated by the calculation of the one-loop electron self-energy.Comment: 18pp, LATEX, TUTP-94-1

The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease.

J Biol Chem. 2005 Dec 30;280(52):43243-56. Epub 2005 Oct 5. The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease. Hirsch-Reinshagen V, Maia LF, Burgess BL, Blain JF, Naus KE, McIsaac SA, Parkinson PF, Chan JY, Tansley GH, Hayden MR, Poirier J, Van Nostrand W, Wellington CL. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V4Z 5H5, Canada. Abstract ABCA1, a cholesterol transporter expressed in the brain, has been shown recently to be required to maintain normal apoE levels and lipidation in the central nervous system. In addition, ABCA1 has been reported to modulate beta-amyloid (Abeta) production in vitro. These observations raise the possibility that ABCA1 may play a role in the pathogenesis of Alzheimer disease. Here we report that the deficiency of ABCA1 does not affect soluble or guanidine-extractable Abeta levels in Tg-SwDI/B or amyloid precursor protein/presenilin 1 (APP/PS1) mice, but rather is associated with a dramatic reduction in soluble apoE levels in brain. Although this reduction in apoE was expected to reduce the amyloid burden in vivo, we observed that the parenchymal and vascular amyloid load was increased in Tg-SwDI/B animals and was not diminished in APP/PS1 mice. Furthermore, we observed an increase in the proportion of apoE retained in the insoluble fraction, particularly in the APP/PS1 model. These data suggested that ABCA1-mediated effects on apoE levels and lipidation influenced amyloidogenesis in vivo. PMID: 16207707 [PubMed - indexed for MEDLINE

The HERMES Dual-Radiator Ring Imaging Cerenkov Detector

The construction and use of a dual radiator Ring Imaging Cerenkov(RICH) detector is described. This instrument was developed for the HERMES experiment at DESY which emphasizes measurements of semi-inclusive deep-inelastic scattering. It provides particle identification for pions, kaons, and protons in the momentum range from 2 to 15 GeV, which is essential to these studies. The instrument uses two radiators, C4F10, a heavy fluorocarbon gas, and a wall of silica aerogel tiles. The use of aerogel in a RICH detector has only recently become possible with the development of clear, large homogeneous and hydrophobic aerogel. A lightweight mirror was constructed using a newly perfected technique to make resin-coated carbon-fiber surfaces of optical quality. The photon detector consists of 1934 photomultiplier tubes for each detector half, held in a soft steel matrix to provide shielding against the residual field of the main spectrometer magnet.Comment: 25 pages, 23 figure