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  • 1
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    Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-11-22
    Description: Nucleoside reverse transcriptase inhibitors (NRTIs) are mainstay therapeutics for HIV that block retrovirus replication. Alu (an endogenous retroelement that also requires reverse transcriptase for its life cycle)-derived RNAs activate P2X7 and the NLRP3 inflammasome to cause cell death of the retinal pigment epithelium in geographic atrophy, a type of age-related macular degeneration. We found that NRTIs inhibit P2X7-mediated NLRP3 inflammasome activation independent of reverse transcriptase inhibition. Multiple approved and clinically relevant NRTIs prevented caspase-1 activation, the effector of the NLRP3 inflammasome, induced by Alu RNA. NRTIs were efficacious in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease, and sterile liver inflammation. Our findings suggest that NRTIs are ripe for drug repurposing in P2X7-driven diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274127/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274127/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fowler, Benjamin J -- Gelfand, Bradley D -- Kim, Younghee -- Kerur, Nagaraj -- Tarallo, Valeria -- Hirano, Yoshio -- Amarnath, Shoba -- Fowler, Daniel H -- Radwan, Marta -- Young, Mark T -- Pittman, Keir -- Kubes, Paul -- Agarwal, Hitesh K -- Parang, Keykavous -- Hinton, David R -- Bastos-Carvalho, Ana -- Li, Shengjian -- Yasuma, Tetsuhiro -- Mizutani, Takeshi -- Yasuma, Reo -- Wright, Charles -- Ambati, Jayakrishna -- BB/J017345/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- DP1 GM114862/GM/NIGMS NIH HHS/ -- DP1GM114862/DP/NCCDPHP CDC HHS/ -- K99 EY024336/EY/NEI NIH HHS/ -- K99EY024336/EY/NEI NIH HHS/ -- P30EY003040/EY/NEI NIH HHS/ -- R01 EY018350/EY/NEI NIH HHS/ -- R01 EY018836/EY/NEI NIH HHS/ -- R01 EY020672/EY/NEI NIH HHS/ -- R01 EY022238/EY/NEI NIH HHS/ -- R01 EY024068/EY/NEI NIH HHS/ -- R01EY001545/EY/NEI NIH HHS/ -- R01EY018350/EY/NEI NIH HHS/ -- R01EY018836/EY/NEI NIH HHS/ -- R01EY020672/EY/NEI NIH HHS/ -- R01EY022238/EY/NEI NIH HHS/ -- R01EY024068/EY/NEI NIH HHS/ -- T32HL091812/HL/NHLBI NIH HHS/ -- TL1 RR033172/RR/NCRR NIH HHS/ -- TL1 TR000115/TR/NCATS NIH HHS/ -- UL1 RR033173/RR/NCRR NIH HHS/ -- UL1 TR000117/TR/NCATS NIH HHS/ -- UL1RR033173/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2014 Nov 21;346(6212):1000-3. doi: 10.1126/science.1261754.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Department of Physiology, University of Kentucky, Lexington, KY 40536, USA. ; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Department of Microbiology, Immunology, and Human Genetics, University of Kentucky, Lexington, KY 40536, USA. Department of Biomedical Engineering, University of Kentucky, Lexington, KY 40536, USA. ; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. ; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Angiogenesis Lab, Institute of Genetics and Biophysics, CNR, Naples, Italy. ; Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. ; School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK. ; Immunology Research Group, University of Calgary, Calgary, Alberta T2N 4N1, Canada. ; Chapman University School of Pharmacy, 9401 Jeronimo Road, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA. ; Departments of Pathology and Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA. ; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Department of Physiology, University of Kentucky, Lexington, KY 40536, USA. jamba2@email.uky.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25414314" target="_blank"〉PubMed〈/a〉
    Keywords: Alu Elements ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Carrier Proteins/metabolism ; Caspase 1/metabolism ; Choroidal Neovascularization/drug therapy ; Disease Models, Animal ; Geographic Atrophy/drug therapy ; Graft vs Host Disease/drug therapy ; Hepatitis/drug therapy ; Inflammasomes/*drug effects ; Liver/drug effects ; Mice ; Receptors, Purinergic P2X7/metabolism ; Retinal Pigment Epithelium/drug effects/metabolism/physiology ; Reverse Transcriptase Inhibitors/*pharmacology/therapeutic use
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    Agonist binding evokes extensive conformational changes in the extracellular domain of the ATP-gated human P2X1 receptor ion channel (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-03-05
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 3
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    Characterizing Disturbed Desert Soils Using Multiobjective Parameter Optimization (2013)
    Soil Science Society of America (SSSA)
    Details
    Publication Date: 2013-02-22
    Description: Simulating soil moisture dynamics in coarse-textured alluvial soils under high evaporative demand and infrequent rainfall challenges both characterization and numerical methods. For this study, three geomorphically young disturbed soils in the central Mojave Desert were characterized using direct, indirect, and inverse parameter estimation methods for numerical simulations using HYDRUS. Observations of soil water content () and matric head ( h ) were used to formulate our multiobjective framework optimized using the AMALGAM algorithm. Both the direct and indirect parameterization methods reproduced but proved inadequate for h data. Sensitivity analysis found the parameters related to the dry end of the soil hydraulic function—including residual water content ( r ) and pore-size distribution ( n) —most sensitive but often conflicting between the two criteria while soil temperature was effectively simulated but insensitive. At the sites, a large dynamic range of h (1–400 m) was accompanied by a relatively small range of (0.04–0.10 m 3 m –3 ), limiting our ability to resolve the wet-end of the hydraulic functions. Direct parameterization from infiltrometer data and indirect pedotransfer functions had good agreement with but largely underestimated h . Pareto analysis determined the trade-off between fitting both criteria and revealed model structure inadequacies as well as bifurcations into parameter populations, favoring either or h error minimization. The Pareto solutions compensated for the underestimation of h by forcing the α and n parameters to uncharacteristically low values for such coarse textures. This compensation kept the water capacity sufficiently high at lower to maintain conductivity toward the surface. These results are likely a consequence of either the disturbed soil system or hysteresis between measurements of and h.
    Electronic ISSN: 1539-1663
    Topics: Geosciences , Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Published by Soil Science Society of America (SSSA)
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  • 4
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    Cassini in Titan's tail: CAPS observations of plasma escape (2012)
    Wiley
    Details
    Publication Date: 2012-05-23
    Description: We present observations of CAPS electron and ion spectra during Titan distant tail crossings at 5,000–10,000 km altitude by the Cassini spacecraft. In common with closer tail encounters, we identify ionospheric plasma in the tail. Some of the electron spectra indicate a direct magnetic connection to Titan's dayside ionosphere due to the presence of ionospheric photoelectrons. Ion observations reveal heavy (m/q∼ 16 and 28) and light (m/q = 1–2) ion populations streaming into the tail. Using the distant tail encounters T9, T75 and T63, we estimate total plasma loss rates from Titan via this process of (4.2, 0.96 and 2.3) × 1024 ions s−1 respectively for the three encounters, values which are in agreement with some simulations but slightly lower than earlier estimates based on non-differential techniques. Using the mass-separated data, this corresponds to mass loss rates of (8.9, 1.6, 4.0) × 1025 amu s−1 for T9, T75 and T63 respectively, an average loss rate of ∼7 tonnes per Earth day. Remarkably, all of the tail encounters studied here indicate a split tail feature, indicating that this may be a common feature in Titan's interaction with Saturn's magnetosphere.
    Print ISSN: 0148-0227
    Topics: Geosciences , Physics
    Published by Wiley on behalf of American Geophysical Union (AGU).
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  • 5
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    ATP-evoked P2X receptor conformational change [Pharmacology] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-03-21
    Description: P2X receptors for ATP have a wide range of physiological roles and comprise a structurally distinct family of ligand-gated trimeric ion channels. The crystal structure of a P2X4 receptor, in combination with mutagenesis studies, has provided a model of the intersubunit ATP-binding sites and identified an extracellular lateral portal, adjacent to the membrane, that funnels ions to the channel pore. However, little is known about the extent of ATP-induced conformational changes in the extracellular domain of the receptor. To address this issue, we have used MTSEA-biotinylation (N-Biotinoylaminoethyl methanethiosulfonate) to show ATP-sensitive accessibility of cysteine mutants at the human P2X1 receptor. Mapping these data to a P2X1 receptor homology model identifies significant conformational rearrangement. Electron microscopy of purified P2X1 receptors showed marked changes in structure on ATP binding, and introducing disulphide bonds between adjacent subunits to restrict intersubunit movements inhibited channel function. These results are consistent with agonist-induced rotation of the propeller-head domain of the receptor, sliding of adjacent subunits leading to restricted access to the upper vestibule, movement in the ion conducting lateral portals, and gating of the channel pore.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 6
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    Emergent equilibrium in many-body optical bistability (2017)
    American Physical Society (APS)
    Details
    Publication Date: 2017-04-18
    Description: Author(s): M. Foss-Feig, P. Niroula, J. T. Young, M. Hafezi, A. V. Gorshkov, R. M. Wilson, and M. F. Maghrebi Many-body systems constructed of quantum-optical building blocks can now be realized in experimental platforms ranging from exciton-polariton fluids to ultracold Rydberg gases, establishing a fascinating interface between traditional many-body physics and the driven-dissipative, nonequilibrium setti… [Phys. Rev. A 95, 043826] Published Mon Apr 17, 2017
    Keywords: Quantum optics, physics of lasers, nonlinear optics, classical optics
    Print ISSN: 1050-2947
    Electronic ISSN: 1094-1622
    Topics: Physics
    Published by American Physical Society (APS)
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  • 7
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    Airborne lidar on the Alaskan North Slope: Wetlands mapping, lake volumes, and permafrost features (2013)
    Society of Exploration Geophysicists (SEG)
    Details
    Publication Date: 2013-06-29
    Description: Wetlands and shallow, freshwater lakes are common on the Alaskan North Slope, a permafrost-dominated coastal plain above the Arctic Circle. New approaches are needed to augment traditional remote sensing and ground-based field activities that would enable rapid and accurate discrimination of wetlands from uplands and estimation of lake depths and volumes over areas being considered for exploration and production activities. Using a new airborne lidar instrument that combines laser ranging at near-infrared wavelengths for topography and green wavelengths for bathymetry, we flew a pilot study over a 490-km 2 area south of Prudhoe Bay to measure surface topography at a density of about 20 points/m 2 and water-body depths at a density of about 2 points/m 2 . High-resolution digital elevation models, having vertical accuracies of a few centimeters, have been generated from the topographic laser data.
    Print ISSN: 1070-485X
    Electronic ISSN: 1938-3789
    Topics: Geosciences
    Published by Society of Exploration Geophysicists (SEG)
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  • 8
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    Cold ionospheric ions in the magnetic reconnection outflow region (2017)
    Wiley
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    Publication Date: 2017-09-21
    Description: Magnetosheath plasma usually determines properties of asymmetric magnetic reconnection at the subsolar region of Earth's magnetopause. However, cold plasma that originated from the ionosphere can also reach the magnetopause, and modify the kinetic physics of asymmetric reconnection. We present a magnetopause crossing with high-density (10-60 cm −3 ) cold ions and ongoing reconnection from the observation of the Magnetospheric Multiscale (MMS) spacecraft. The magnetopause crossing is estimated to be 300 ion-inertial lengths south of the X line. Two distinct ion populations are observed on the magnetosheath edge of the ion jet. One population with large parallel velocities (200-300 km/s) is identified to be cold ion beams, and the other population is the magnetosheath ions. In the deHoffman-Teller frame, the field-aligned magnetosheath ions are Alfvénic and move towards the jet region, while the field-aligned cold ion beams move towards the magnetosheath boundary layer, with much small speeds. These cold ion beams are suggested to be from the cold ions entering the jet close to the X line. This is the first observation of the cold ionospheric ions in the reconnection outflow region, including the reconnection jet and the magnetosheath boundary layer.
    Print ISSN: 0148-0227
    Topics: Geosciences , Physics
    Published by Wiley on behalf of American Geophysical Union (AGU).
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  • 9
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    Caveolin-1 influences P2X7 receptor expression and localization in mouse lung alveolar epithelial cells (2007)
    Wiley
    Details
    Publication Date: 2007-05-11
    Print ISSN: 1742-464X
    Electronic ISSN: 1742-4658
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Published by Wiley on behalf of Federation of European Biochemical Societies.
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