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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 28 October 2014, Vol.111(43), pp.15573-8
    Description: Mutations within the lysosomal enzyme β-glucocerebrosidase (GC) result in Gaucher disease and represent a major risk factor for developing Parkinson disease (PD). Loss of GC activity leads to accumulation of its substrate glucosylceramide and α-synuclein. Since lysosomal activity of GC is tightly linked to expression of its trafficking receptor, the lysosomal integral membrane protein type-2 (LIMP-2), we studied α-synuclein metabolism in LIMP-2-deficient mice. These mice showed an α-synuclein dosage-dependent phenotype, including severe neurological impairments and premature death. In LIMP-2-deficient brains a significant reduction in GC activity led to lipid storage, disturbed autophagic/lysosomal function, and α-synuclein accumulation mediating neurotoxicity of dopaminergic (DA) neurons, apoptotic cell death, and inflammation. Heterologous expression of LIMP-2 accelerated clearance of overexpressed α-synuclein, possibly through increasing lysosomal GC activity. In surviving DA neurons of human PD midbrain, LIMP-2 levels were increased, probably to compensate for lysosomal GC deficiency. Therefore, we suggest that manipulating LIMP-2 expression to increase lysosomal GC activity is a promising strategy for the treatment of synucleinopathies.
    Keywords: Amrf ; C57/Bl6-J ; Gd ; Pme ; Scarb2 ; Glucosylceramidase -- Metabolism ; Lysosome-Associated Membrane Glycoproteins -- Metabolism ; Alpha-Synuclein -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    In: Journal of Analytical Atomic Spectrometry, 2011, Vol.26(6), pp.1265-1272
    Description: The valence shell electron configurations within a few electron volts above the Fermi level in cerium, ytterbium, europium and samarium compounds were probed by resonant X-ray emission spectroscopy (RXES) at the L 3 absorption pre-edge. The rare earth systems show distinct spectral signatures depending on the f-electron configuration. The high energy resolution experimental results reported here are well reproduced by atomic multiplet calculations confirming the localized character of the 4f electrons. The magnitude of the electron–electron interactions within the 4f shell and between 3d and 4f electrons is analyzed. The present technique is a powerful tool for the study of the 4f valence electron configuration that, unlike L 3 absorption spectroscopy at the main edge, is little influenced by valence electron relaxation following core hole creation.
    Keywords: Fermi Level ; Europium Compounds ; Fermi Surfaces ; Ytterbium ; Shells ; Tools ; Rare Earth Metals ; Mathematical Analysis ; Instruments and Measurements (So);
    ISSN: 0267-9477
    E-ISSN: 1364-5544
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  • 3
    Language: English
    In: Clinical Cancer Research, 12/01/2010, Vol.16(23), pp.5781-5795
    Description: PURPOSE: Glioblastomas are the most common and most deadly primary brain tumors. Here, we evaluated the chemotherapeutic effect of the natural polyphenol curcumin on glioma cells in vitro and in vivo using an immunocompetent orthotopic mouse model.EXPERIMENTAL DESIGN: Curcumin's effects on proliferation, cell cycle, migration, invasion, JAK/STAT3 signaling, STAT3 target gene expression, and STAT3C rescue experiments were determined in murine glioma cell lines in vitro. Therapeutic effects of curcumin in vivo were evaluated in tumor-bearing mice fed a Western-type diet fortified with curcumin (0.05%, w/w) and in control animals. Tumor growth patterns and survival were evaluated by immunohistochemistry, morphometric analyses, and Kaplan-Meier plots.RESULTS: In vitro, curcumin inhibited JAK1,2/STAT3 tyrosine-phosphorylation in a dose-dependent fashion in murine glioma cell lines. Real-time RT-PCR revealed that curcumin downregulated transcription of the STAT3 target genes c-Myc, MMP-9, Snail, and Twist, and of the proliferation marker Ki67. Curcumin dose-dependently suppressed cell proliferation by inducing a G2/M phase arrest. In wound healing and Matrigel invasion assays, curcumin treatment resulted in a dose-dependent attenuation of the glioma cells' migratory and invasive behavior, which could be rescued by constitutively active STAT3C. In vivo, curcumin intake reduced the growth and midline crossing of intracranially implanted tumors and proliferation of tumor cells ensuing in significant long-term survival compared with control diet.CONCLUSION: This preclinical study shows that curcumin is capable of suppressing malignant glioma growth in vitro and in vivo. Our data suggest that the pharmacologically safe agent curcumin holds promise for clinical application in glioma therapy.
    Keywords: Medicine;
    ISSN: 1078-0432
    E-ISSN: 1557-3265
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  • 4
    Language: English
    In: Inorganic chemistry, 19 July 2010, Vol.49(14), pp.6468-73
    Description: The electronic structure and ligand environment of sulfur was investigated in various sulfur-containing compounds with different structures and chemical states by using X-ray emission spectroscopy (XES). Calculations were performed using density functional theory (DFT) as implemented in the StoBe code. The sulfur chemical state and atomic environment is discussed in terms of the molecular orbitals and partial charges that are obtained from the calculations. The main spectral features can be modeled using our calculational approach. The sensitivity of the Kbeta emission to the cation and the local symmetry is discussed.
    Keywords: Natural Sciences ; Naturvetenskap ; Natural Sciences ; Naturvetenskap;
    ISSN: 00201669
    E-ISSN: 1520-510X
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  • 5
    Language: English
    In: Alternative Medicine Review, Dec, 2010, Vol.15(4), p.380(1)
    Keywords: Head And Neck Cancer -- Care And Treatment ; Head And Neck Cancer -- Patient Outcomes ; Radiotherapy -- Complications And Side Effects ; Selenium (Chemical element) -- Analysis
    ISSN: 1089-5159
    E-ISSN: 21691509
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  • 6
    Language: English
    In: Genetics, 03/01/2013, Vol.193(3), pp.865-876
    Description: Intraneuronal deposition of aggregated proteins in tauopathies, Parkinson disease, or familial encephalopathy with neuroserpin inclusion bodies (FENIB) leads to impaired protein homeostasis (proteostasis). FENIB represents a conformational dementia, caused by intraneuronal polymerization of mutant variants of the serine protease inhibitor neuroserpin. In contrast to the aggregation process, the kinetic relationship between neuronal proteostasis and aggregation are poorly understood. To address aggregate formation dynamics, we studied FENIB in Caenorhabditis elegans and mice. Point mutations causing FENIB also result in aggregation of the neuroserpin homolog SRP-2 most likely within the ER lumen in worms, recapitulating morphological and biochemical features of the human disease. Intriguingly, we identified conserved protein quality control pathways to modulate protein aggregation both in worms and mice. Specifically, downregulation of the unfolded protein response (UPR) pathways in the worm favors mutant SRP-2 accumulation, while mice overexpressing a polymerizing mutant of neuroserpin undergo transient induction of the UPR in young but not in aged mice. Thus, we find that perturbations of proteostasis through impairment of the heat shock response or altered UPR signaling enhance neuroserpin accumulation in vivo. Moreover, accumulation of neuroserpin polymers in mice is associated with an age-related induction of the UPR suggesting a novel interaction between aging and ER overload. These data suggest that targets aimed at increasing UPR capacity in neurons are valuable tools for therapeutic intervention.
    Keywords: Biology;
    ISSN: 0016-6731
    ISSN: 19432631
    E-ISSN: 19432631
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  • 7
    Language: English
    In: Intermetallics, May, 2014, Vol.48, p.3(7)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.intermet.2013.08.017 Byline: C. Hochmuth, D. Schliephake, R. Volkl, M. Heilmaier, U. Glatzel Abstract: Mo-Si-B alloys with a molybdenum solid solution accompanied by two intermetallic phases and Mo.sub.5SiB.sub.2 are a prominent example for a potential new high temperature structural material. In this study the influence of 1, 2 and 4 at.% zirconium on microstructure and creep properties of Mo-9Si-8B (at.%) alloys produced by spark plasma sintering is investigated. Creep experiments have been carried out at temperatures of 1100 [degrees]C up to 1250 [degrees]C in vacuum. The samples exhibit sub-micron grain sizes as small as 450 nm due to the chosen production route. With addition of 1 at.% zirconium, formation of SiO.sub.2 on the grain boundaries can be prevented, thereby enhancing grain boundary strength and creep properties significantly. Moreover ZrO.sub.2 particles also enhance creep resistance of the molybdenum solid solution. Creep deformation is a combination of dislocation creep in the grains including dislocation-particle interaction and grain boundary sliding leading to intergranular fracture surfaces. It is promising to use grain size adjustments in order to balance the creep and oxidation resistance of the investigated material. Author Affiliation: (a) Metallische Werkstoffe, Universitat Bayreuth, Ludwig-Thoma-Str. 36b, 95447 Bayreuth, Germany (b) Institut fur Angewandte Materialien - Werkstoffkunde, Karlsruher Institut fur Technologie, Engelbert-Arnold-Str. 4, 76131 Karlsruhe, Germany Article History: Received 10 April 2013; Revised 20 August 2013; Accepted 27 August 2013
    Keywords: Intermetallic Compounds -- Analysis ; Zirconium -- Analysis ; Building Materials -- Analysis ; Molybdenum Alloys -- Analysis ; Molybdenum -- Analysis ; Fracture (Materials) -- Analysis
    ISSN: 0966-9795
    Source: Cengage Learning, Inc.
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  • 8
    In: Rheumatology, 2004, Vol.43(4), pp.524-526
    Keywords: Vip; Rheumatoid Arthritis; Cxcl8; Ccl2; Tnf-; Il-6; Synoviocytes
    ISSN: 1462-0324
    E-ISSN: 1462-0332
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  • 9
    Language: English
    In: Journal of Neuroscience, 08/07/2013, Vol.33(32), pp.12915-12928
    Description: The metalloproteinase ADAM10 is of importance for Notch-dependent cortical brain development. The protease is tightly linked with alpha -secretase activity toward the amyloid precursor protein (APP) substrate. Increasing ADAM10 activity is suggested as a therapy to prevent the production of the neurotoxic amyloid beta (A beta ) peptide in Alzheimer's disease. To investigate the function of ADAM10 in postnatal brain, we generated Adam10 conditional knock-out (A10cKO) mice using a CaMKII alpha -Cre deleter strain. The lack of ADAM10 protein expression was evident in the brain cortex leading to a reduced generation of sAPP alpha and increased levels of sAPP beta and endogenous A beta peptides. The A10cKO mice are characterized by weight loss and increased mortality after weaning associated with seizures. Behavioral comparison of adult mice revealed that the loss of ADAM10 in the A10cKO mice resulted in decreased neuromotor abilities and reduced learning performance, which were associated with altered in vivo network activities in the hippocampal CA1 region and impaired synaptic function. Histological and ultrastructural analysis of ADAM10-depleted brain revealed astrogliosis, microglia activation, and impaired number and altered morphology of postsynaptic spine structures. A defect in spine morphology was further supported by a reduction of the expression of NMDA receptors subunit 2A and 2B. The reduced shedding of essential postsynaptic cell adhesion proteins such as N-Cadherin, Nectin-1, and APP may explain the postsynaptic defects and the impaired learning, altered network activity, and synaptic plasticity of the A10cKO mice. Our study reveals that ADAM10 is instrumental for synaptic and neuronal network function in the adult murine brain.
    Keywords: Nectin ; N-Methyl-D-Aspartic Acid Receptors ; Learning ; Chromium ; Neural Networks ; Alzheimer'S Disease ; Seizures ; Brain ; Plasticity (Synaptic) ; Glutamic Acid Receptors (Ionotropic) ; Cell Adhesion ; Amyloid Precursor Protein ; Neurodegenerative Diseases ; Cortex ; N-Cadherin ; Neurotoxicity ; Adam10 Protein ; Secretase ; Beta -Amyloid ; Developmental Neuroscience;
    ISSN: 0270-6474
    E-ISSN: 1529-2401
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  • 10
    Language: English
    In: Blood, 11/01/2012, Vol.120(18), pp.3793-3802
    Description: The devastating effect of ischemic stroke is attenuated in mice lacking conventional and unconventional T cells, suggesting that inflammation enhances tissue damage in cerebral ischemia. We explored the functional role of αβ and γδ T cells in a murine model of stroke and distinguished 2 different T cell-dependent proinflammatory pathways in ischemia-reperfusion injury. IFN-γ produced by CD4(+) T cells induced TNF-α production in macrophages, whereas IL-17A secreted by γδ T cells led to neutrophil recruitment. The synergistic effect of TNF-α and IL-17A on astrocytes resulted in enhanced secretion of CXCL-1, a neutrophil chemoattractant. Application of an IL-17A-blocking antibody within 3 hours after stroke induction decreased infarct size and improved neurologic outcome in the murine model. In autoptic brain tissue of patients who had a stroke, we detected IL-17A-positive lymphocytes, suggesting that this aspect of the inflammatory cascade is also relevant in the human brain. We propose that selective targeting of IL-17A signaling might provide a new therapeutic option for the treatment of stroke.
    Keywords: Medicine ; Biology ; Chemistry ; Anatomy & Physiology;
    ISSN: 0006-4971
    E-ISSN: 1528-0020
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