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  • 1
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Microtubule-associated protein τ is abnormally hyperphosphorylated and aggregated in affected neurons of Alzheimer disease brain. This hyperphosphorylated τ can be dephosphorylated at some of the abnormal phosphorylated sites by purified protein phosphatase-1, 2A, and 2B in vitro. In the present study, we have developed an assay to measure protein phosphatase activity toward τ-1 sites (Ser199/Ser202) using the hyperphosphorylated τ isolated from Alzheimer disease brain as substrate. Using this assay, we have identified that in normal brain, protein phosphatase-2A and 2B and, to a lesser extent, 1 are involved in the dephosphorylation of τ. The Km values of dephosphorylation of the hyperphosphorylated τ by protein phosphatase-2A and 2B are similar. The τ phosphatase activity is decreased by ∼30% in brain of Alzheimer disease patients compared with those of age-matched controls. These findings suggest that a defect of protein phosphatase could be the cause of the abnormal hyperphosphorylation of τ in Alzheimer disease.
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  • 2
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abnormal phosphorylation of microtubule-associated protein tau plays a critical role in Alzheimer's disease (AD), together with a distinct decrease of energy metabolism in the affected brain regions. To explore the effect of acute energy crisis on tau phosphorylation and the underlying mechanisms, we incubated rat brain slices in artificial cerebrospinal fluid (aCSF) at 37°C with or without an oxygen supply, or in aCSF with low glucose concentrations. Then, the levels of total, phosphorylated and unphosphorylated tau, as well as the activities and levels of protein phosphatase (PP)-1, PP-2A, glycogen synthase kinase 3 (GSK-3), extracellular signal-regulated protein kinase (ERK) and C-jun amino terminal kinase (JNK), were measured. It was found, unexpectedly, that tau was significantly dephosphorylated at Ser396/Ser404 (PHF-1), Ser422 (R145), Ser199/Ser202 (Tau-1), Thr181 (AT270), Ser202/Thr205 (AT8) and Thr231 (AT180) by acute anoxia for 30 min or 120 min. The activity of PP-2A and the level of dephosphorylated PP-2A catalytic subunit at tyrosine 307 (Tyr307) were simultaneously increased. The active forms of ERK1/2 and JNK1/2 were decreased under anoxic incubation. The PP-2A inhibitor, okadaic acid (OA, 0.75 µm), completely prevented tau from acute anoxia-induced dephosphorylation and restored the active forms of ERK1/2 and JNK1/2 to the control level. The activities and protein levels of GSK-3 and PP-1 showed no change during acute anoxia. These data suggest that acute anoxia induces tau dephosphorylation, and that PP-2A may play a key role in tau dephosphorylation induced by acute anoxia.
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  • 3
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Neurofibrillary tangles (NFTs) consisting of the hyperphosphorylated microtubule-associated protein tau are a defining pathological characteristic of Alzheimer's disease (AD). Hyperphosphorylation of tau is hypothesized to impair the microtubule stabilizing function of tau, leading to the formation of paired helical filaments and neuronal death. Glycogen synthase kinase-3 (GSK-3) has been shown to be one of several kinases that mediate tau hyperphosphorylation in vitro. However, molecular mechanisms underlying overactivation of GSK-3 and its potential linkage to AD-like pathologies in vivo remain unclear. Here, we demonstrate that injection of wortmannin (a specific inhibitor of phosphoinositol-3 kinase) or GF-109203X (a specific inhibitor of protein kinase C) into the left ventricle of rat brains leads to overactivation of GSK-3, hyperphosphorylation of tau at Ser 396/404/199/202 and, most significantly, impaired spatial memory. The effects of wortmannin and GF-109203X are additive. Significantly, specific inhibition of GSK-3 activity by LiCl prevents hyperphosphorylation of tau, and spatial memory impairment resulting from PI3K and PKC inhibition. These results indicate that in vivo inhibition of phosphoinositol-3 kinase and protein kinase C results in overactivation of GSK-3 and tau hyperphosphorylation and support a direct role of GSK-3 in the formation of AD-like cognitive deficits.
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  • 4
    ISSN: 1471-0528
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Objective To determine whether endothelial cell injury would be produced by factor(s) released into the fetal circulation, manifested by altered messenger RNA expression of nitric oxide synthase.Design Case–control study.Setting University teaching hospital.Samples Fetal plasma was collected from 34 normal pregnancies, 44 pregnancies with umbilical placental vascular disease identified by an abnormal umbilical Doppler and 11 pregnancies with maternal pre-eclampsia but with normal umbilical Doppler studies.Methods Aliquots from a common culture of human umbilical vein endothelial cells (HUVECs) were incubated with fetal plasma from the members of the three patient groups. The total RNA was extracted from the endothelial cells and mRNA for nitric oxide synthase was measured by reverse transcription and semi-quantitative polymerase chain reaction (RT-PCR). This was standardised by comparison of the amplified inducible nitric oxide synthase (iNOS) or endothelial constitutive nitric oxide synthase (ecNOS) to glyceraldehyde 3-phosphate dehydrogenase (GAPDH).Main outcome measure Endothelial cell gene expression of iNOS and ecNOS.Results The mRNA expression of iNOS and ecNOS were significantly higher (P 〈 0.05) in HUVECs stimulated by fetal plasma from pregnancies with umbilical placental vascular disease [iNOS 1.12 (0.16); ecNOS 1.78 (0.18)] when compared with normal pregnancies [iNOS 0.56 (0.06); ecNOS 1.06 (0.10)]. In the maternal pre-eclampsia group, the NOS expression [iNOS 0.76 (0.11); ecNOS 1.39 (0.26)] did not differ from normal pregnancy. In the vascular disease group, there was no difference in NOS expression between the subgroups with and without maternal pre-eclampsia.Conclusions Our study demonstrates that umbilical placental vascular disease is associated with a factor(s) in fetal plasma that produces an increase in the expression of iNOS and ecNOS mRNA by endothelial cells. Our findings raise the possibility that the release of factors causing an up-regulation of iNOS and ecNOS in the endothelium in the fetal placenta may occur as part of an inflammatory response of the vascular endothelium to injury.
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  • 5
    ISSN: 1365-2958
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology , Medicine
    Notes: Serogroup A meningococci of subgroups III, IV-1 and IV-2 are probably descended from a common ancestor that existed in the nineteenth century. The 10.5 kb sequences spanning five distinct chromosomal loci, encoding cell-surface antigens, a secreted protease or housekeeping genes and intergenic regions, were almost identical in strains of those subgroups isolated in 1966, 1966 and 1917 respectively. During the subsequent two to three decades, all of these loci varied as a result of mutation, translocation or import of DNA from unrelated neisseriae. Thus, microevolution occurs frequently in naturally transformable bacteria. Many variants were isolated only once or within a single geographical location and disappeared thereafter. Other variants achieved genetic fixation within months or a few years. The speed with which sequence variation is either eliminated or fixed may reflect sequential bottlenecks associated with epidemic spread and contrasts with the results of phylogenetic analyses from bacteria that do not cause epidemics.
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  • 6
    Publication Date: 2011-08-26
    Description: In this paper, we studied the development of hadronic shower in an electromagnetic calorimeter of Alpha Magnetic Spectrometer II. Two parametrized empirical formulae were proposed to describe the hadronic shower shape in calorimeter. Using 100 GeV proton beam incident on the center of the ECAL, detailed plots of lateral and longitudinal hadronic shower behavior were given and we found the formulae can describe the development of the hadronic shower with the test beam data. The possible application of the parametrized formulae including e ± -π ± discrimination and tau jet reconstruction was discussed.
    Print ISSN: 1674-1137
    Topics: Physics
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  • 7
    Publication Date: 2011-03-12
    Description: In the LHC experiment, the neutral pions produced during jet fragmentation are the background sources for all physics channels with high-energy photons in their final state. In this paper, the application of the three-dimensional parametric formula for electromagnetic (EM) showers, which we developed in the Alpha Magnetic Spectrometer II experiment, is presented to distinguish the unconverted photons from the neutral pions. With the constructed electromagnetic calorimeter (ECAL) in a GEANT4 simulation, the parametric formulae were validated and the unconverted γ/π 0 discrimination was performed with the Toolkit for Multivariate Data Analysis (TMVA) package in ROOT for different transverse energies ranging from 15 GeV to 75 GeV, which is the most sensitive region for light Higgs (with mass ~120 GeV) searches with the channel H → γγ. With this discrimination method and the selected transverse energy region, we can reject π 0 with the efficiency from ~40% (65–75...
    Print ISSN: 1674-1137
    Topics: Physics
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  • 8
    Publication Date: 2012-10-19
    Description: In the LHC experiment, the H → γγ channel provides a clean final state with an effective mass peak that is reconstructed with great precision, despite the small branching ratio. As a consequence, the H → γγ channel is one of the most promising channels for the Higgs discovery in the very low mass region. In order to increase the sensitivity of the Higgs search, background rejection rate is very important, so γ/π 0 discrimination is one of the key points in the analysis. At least 40% of photons will convert with the experience of ATLAS and CMS. We constructed electromagnetic calorimeter (ECAL) in GEANT4 simulation, using 6 variables which have different shapes between converted γ and π 0 , with the TMVA (Toolkit for Multivariate Data Analysis) to do the separation. With this method we can get 30% to 60% π 0 rejection efficiency when keeping 90% converted γ efficiency, in the region of transverse momentum 15 GeV to 75 GeV, not only in MC sumulation but...
    Print ISSN: 1674-1137
    Topics: Physics
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  • 9
    Publication Date: 2012-01-18
    Description: The properties of neutron-rich boron isotopes are studied in the relativistic continuum Hartree-Bogoliubov theory in coordinate space with NL-SH, PK1 and TM2 effective interactions. Pairing corrections are taken into account by a density dependent force of zero range. The binding energies calculated for these nuclei agree with the experimental data quite well. The neutron-rich nucleus 17 B has been predicted to have a two-neutron halo structure in its ground state. The halo structure of 17 B is reproduced in a self-consistent way, and this halo is shown to be formed by the valence neutron level 2 s 1/2 .
    Print ISSN: 1674-1137
    Topics: Physics
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  • 10
    Publication Date: 2014-08-14
    Description: During carbon ion therapy, lots of positron emitters such as 11 C, 15 O, 10 C are generated in irradiated tissues by nuclear reactions, and can be used to track the carbon beam in the tissue by a positron emission tomography (PET) scanner. In this study, an dual-plate in-room PET scanner has been designed and evaluated based on the GATE simulation platform to monitor patient dose in carbon ion therapy. The dual-plate PET is designed to avoid interference with the carbon beamline and with patient positioning. Its performance was compared with that of four-head and full-ring PET scanners. The dual-plate, four-head and full-ring PET scanners consisted of 30, 60, 60 detector modules, respectively, with a 36 cm distance between directly opposite detector modules for dose deposition measurements. Each detector module consisted of a 24×24 array of 2 mm×2 mm×18 mm LYSO pixels coupled to a Hamamatsu H8500 PMT. To estimate the production yield of positron emi...
    Print ISSN: 1674-1137
    Topics: Physics
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