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  • 1
    Publication Date: 2015-10-10
    Description: Lysosomal dysfunction plays a central role in the pathogenesis of several neurodegenerative disorders, including Parkinson's disease (PD). Several genes linked to genetic forms of PD, including leucine-rich repeat kinase 2 ( LRRK2 ), functionally converge on the lysosomal system. While mutations in LRRK2 are commonly associated with autosomal-dominant PD, the physiological and pathological functions of this kinase remain poorly understood. Here, we demonstrate that LRRK2 regulates lysosome size, number and function in astrocytes, which endogenously express high levels of LRRK2. Expression of LRRK2 G2019S, the most common pathological mutation, produces enlarged lysosomes and diminishes the lysosomal capacity of these cells. Enlarged lysosomes appears to be a common phenotype associated with pathogenic LRRK2 mutations, as we also observed this effect in cells expressing other LRRK2 mutations; R1441C or Y1699C. The lysosomal defects associated with these mutations are dependent on both the catalytic activity of the kinase and autophosphorylation of LRRK2 at serine 1292. Further, we demonstrate that blocking LRRK2’s kinase activity, with the potent and selective inhibitor PF-06447475, rescues the observed defects in lysosomal morphology and function. The present study also establishes that G2019S mutation leads to a reduction in lysosomal pH and increased expression of the lysosomal ATPase ATP13A2, a gene linked to a parkinsonian syndrome (Kufor–Rakeb syndrome), in brain samples from mouse and human LRRK2 G2019S carriers. Together, these results demonstrate that PD-associated LRRK2 mutations perturb lysosome function in a kinase-dependent manner, highlighting the therapeutic promise of LRRK2 kinase inhibitors in the treatment of PD.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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  • 2
    Publication Date: 2012-11-14
    Description: The effective ice-particle density, parametrized through a mass–dimension relation, is widely used in ice microphysical schemes for weather and climate models. In this study, we use aircraft-based observations in mid-latitude cirrus taken during the Constrain field programme in 2010. The low temperatures and a humidity often close to ice saturation meant that the typical ice particles observed were small (maximum dimension 20–800 µm) and ice water contents were low (0.001–0.05 g m −3 ). Two new instruments are included in this study: the Small Ice Detector Mark-2 (SID-2) and the deep-cone Nevzorov Total Water Content probe. SID-2 is a new single-particle light-scattering instrument and was used to identify and size small ice particles (10–150 µm). The deep-cone Nevzorov probe is shown to be able to collect small ice masses with sufficient sensitivity. The focus of this article is on the effective density of small ice particles (both pristine ice crystals and small aggregates up to 600 µm maximum dimension). Due to instrument limitations in previous studies, the effective density of small ice particles is questionable. Aircraft flights in six cirrus cases provided ice-particle measurements throughout the depth of the cirrus. The particle size distribution (PSD) was mostly bimodal. The smaller ice-crystal mode dominated the PSD near cloud top and the larger ice-aggregate mode dominated near cloud base. A mass–dimension relation valid for both ice crystals and aggregates was found that provided a best fit to the observations. For small ice particles (less than 70 µm diameter) the density is constant (700 kg m −3 ), while for larger ice crystals or aggregates the mass–dimension relation is m ( D ) = 0.0257 D 2.0 . These measurements allow testing of the diagnostic split between ice crystals and aggregates used in the Met Office Unified Model. Copyright © 2012 Royal Meteorological Society and British Crown Copyright, the Met Office
    Print ISSN: 0035-9009
    Electronic ISSN: 1477-870X
    Topics: Geography , Physics
    Published by Wiley
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  • 3
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 1979-11-02
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hirst, E -- New York, N.Y. -- Science. 1979 Nov 2;206(4418):513.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17759410" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 1979-08-17
    Description: In 1977, heating, cooling, lighting, and other operations in residential and commercial buildings used 27 quads (1 quad = 10(15) British thermal units) of energy. This is more than one-third of the nation's total energy budget. Future trends in energy use in buildings are likely to depend strongly on fuel prices and government policies designed to save energy. Three scenarios are examined: (i) a base line in which fuel prices rise as projected by the Department of Energy; (ii) a conservation case that includes higher gas and oil prices plus the regulatory, financial incentive, and information programs authorized by the 94th Congress and proposed in the April 1977 National Energy Plan; and (iii) another conservation case that also includes new technologies (more efficient equipment, appliances, and structures). These scenarios are analyzed for changes in energy use, costs, and employment by means of detailed engineering-economic models of energy use in residential and commercial buildings developed at the Oak Ridge National Laboratory and input-output analyses developed at the University of Illinois.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hirst, E -- Hannon, B -- New York, N.Y. -- Science. 1979 Aug 17;205(4407):656-61.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17781246" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 1978-02-24
    Description: We used a detailed engineering-economic simulation model of residential energy use to evaluate the effects of nine different residential energy-use "futures." These "futures" are described in terms of annual and cumulative energy use from 1977 through 2000 by fuel, end use, and in aggregate. Outputs from the model also include economic information on the costs to households of fuels, equipment, and thermal improvements to new and existing structures. The major outputs from these nine cases are shown in Tables 1 and 2 and Figs. 6 and 7.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hirst, E -- Carney, J -- New York, N.Y. -- Science. 1978 Feb 24;199(4331):845-51.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17757569" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 1980-11-14
    Description: In fiscal year 1980, the Department of Energy awarded grants for state energy conservation programs that totaled more than $400 million; the proposed figure for fiscal year 1981 is almost $600 million. Many states provide additional funds to implement conservation programs. This suggests that state governments play a major role in delivering conservation services to their citizens and are key agents in the nation's conservation efforts. This article discusses the energy conservation activities and responsibilities of one state energy office, the Minnesota Energy Agency, and the obstacles and constraints it faces in delivering its services. Suggestions are presented for resolving these difficulties and for improving the efficiency with which the agency manages its programs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hirst, E -- Armstrong, J R -- New York, N.Y. -- Science. 1980 Nov 14;210(4471):740-4.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17739533" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    Journal of the American Chemical Society 55 (1933), S. 1084-1090 
    ISSN: 1520-5126
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    Journal of the American Chemical Society 75 (1953), S. 253-256 
    ISSN: 1520-5126
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Environment and Resources 16 (1991), S. 91-121 
    ISSN: 1056-3466
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Environment and Resources 20 (1995), S. 535-555 
    ISSN: 1056-3466
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Type of Medium: Electronic Resource
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