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  • 1
    ISSN: 1432-0649
    Keywords: 42.10 ; 42.80
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract The validity of 2-D coupled-wave theory is investigated for the case of Bragg diffraction of a Gaussian beam by a thick unslanted phase grating in transmission mode. Fourier plane wave decomposition theory, as presented in a companion article, is used to test 2-D coupled-wave theory under circumstances when its validity is in question, namely when the incident distribution is very narrow or fast-varying, or when the parameterv o, due to Kogelnik (1969), which is proportional to the product of coupling rate and grating thickness, is very large. Numerical evaluations of the field patterns at output from the grating, obtained using plane-wave decomposition, are used to explore the effect of the gradual violation of the conditions (from the previous article) under which 2-D coupled-wave theory is valid.
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  • 2
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    Springer
    Applied physics 26 (1981), S. 37-42 
    ISSN: 1432-0649
    Keywords: 42.80 ; 42.82 ; 42.10
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract Novel thick grating focussing and de-focussing devices are described which employ uniform phase gratings with special boundary shapes. The analysis used is based upon an eigenmodal approach to Kogelnik's coupled-wave equations, akin to the dynamical theory of x-ray diffraction. The relationship between the direction of phase progression of the coupled-waves at Bragg incidence, and the direction of the Poynting vector is carefully delineated. As a consequence, a new technique-Poynting Vector Optics — is suggested as potentially an important means of designing thick gratings to fulfil certain beam processing roles, especially in integrated optics applications. The two-dimensional coupled-wave equations are briefly employed to illustrate the effectiveness of a particular focussing device.
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Applied physics 26 (1981), S. 89-98 
    ISSN: 1432-0649
    Keywords: 42.80 ; 42.82 ; 42.10
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract The two-dimensional analysis of a recently reported thick grating Bragg diffraction focussing device is carried out using Solymar's coupled-wave approach. It is shown that the device is capable of operating as a non-divergent lens with beam contraction ratios of better than 100:1, and conversion efficiencies of nearly 100%. It is also shown that it can operate as a novel kind of Fourier spectrum analyser, the focussed diffracted intensity being proportional (as a function of Bragg condition violation) to the modulus squared of the Fourier transform of the incident finite beam. The focussing properties are studied as functions of incident beam profile, width and position, grating strength and Bragg condition violation. Poynting vector optics is used successfully to predict (in conjunction with the dispersion surfaces of x-ray dynamical theory) the off-Bragg behaviour in the focal plane. It is likely that the device could be used as avariable ratio beam contractor in integrated optics, where the grating strength could be controlled (interdigital electrode system) electrooptically.
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  • 4
    Electronic Resource
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    Springer
    Applied physics 39 (1986), S. 231-246 
    ISSN: 1432-0649
    Keywords: 42.10 ; 42.80
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract The behavior of light in dielectric gratings is discussed in terms of the optical Floquet-Bloch waves (or modes). The emphasis is on the development of a good physical understanding of the nature of these waves, using the wavevector diagram to summarize their spatial dispersion and spectra. It is shown that Floquet-Bloch theory offers some advantages conceptually over the commonly used coupled-wave theory, because the rays of the Floquet-Bloch waves (given by their group velocities) play the same role in a periodic medium as do those of plane waves in isotropic or graded-index media. The effect on power conservation of truncating the Floquet expansions for the Floquet-Bloch waves is considered in detail. Using the greater intuitive power of Floquet-Bloch theory, it is shown (in contrast to recent claims to the contrary) how rigorous coupled-wave theory can be applied to symmetrical reflection gratings, and secondly how the light in these gratings can be viewed in terms of the multiple-beam interference of Floquet-Bloch waves, leading to behavior reminiscent of a low-finesse Fabry-Perot cavity.
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  • 5
    Electronic Resource
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    Applied physics 22 (1980), S. 335-353 
    ISSN: 1432-0630
    Keywords: 42.30 ; 42.10 ; 42.80
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: Abstract In this review, a surgey of the evidence for the appearance in volume holography of certain anomalous effects (akin to the Borrmann effect in x-ray crystallography) is conducted, with reference to both experimental observations and theoretical models. The main part of the paper is devoted to the application of a recently-developed two-dimensional coupled-wave theory (an extension of Kogelnik's one-dimensional theory) to the modelling of such anomalous phenomena. Extensive calculations based upon this theory, for the case of Gaussian wave incidence on a uniform mixed grating for various boundary conditions, are presented in a unified two-dimensional description of Borrmann-like effects in volume holography. In particular, certain qualitative predictions of the dynamical theory of x-ray diffraction are expressed quantitatively in the two-dimensional theory.
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  • 6
    ISSN: 1432-0649
    Keywords: 42.10 ; 42.80
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract Two rival techniques used in the analysis of Bragg diffraction of two-dimensional light beams by thick unslanted phase gratings, namely Fourier plane wave decomposition and 2-D coupled-wave theory, are compared. The advantages and regions of applicability of each are discussed, and the conditions found under which they yield identical results. In particular, the results of plane-wave decomposition are used to provide quantitative conditions for validity of 2-D coupled-wave theory. These conditions are not easily derived using any other technique, and set quantitative limits to how narrow or fast-varying the incident distribution may be before 2-D coupled-wave theory fails. It is also shown that 2-D coupled-wave theory is inadequate when the parameterv 0, due to Kogelnik (1969), which is proportional to the product of coupling rate and grating thickness, is very large.
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  • 7
    Publication Date: 2013-07-13
    Description: Cell-surface receptors frequently use scaffold proteins to recruit cytoplasmic targets, but the rationale for this is uncertain. Activated receptor tyrosine kinases, for example, engage scaffolds such as Shc1 that contain phosphotyrosine (pTyr)-binding (PTB) domains. Using quantitative mass spectrometry, here we show that mammalian Shc1 responds to epidermal growth factor (EGF) stimulation through multiple waves of distinct phosphorylation events and protein interactions. After stimulation, Shc1 rapidly binds a group of proteins that activate pro-mitogenic or survival pathways dependent on recruitment of the Grb2 adaptor to Shc1 pTyr sites. Akt-mediated feedback phosphorylation of Shc1 Ser 29 then recruits the Ptpn12 tyrosine phosphatase. This is followed by a sub-network of proteins involved in cytoskeletal reorganization, trafficking and signal termination that binds Shc1 with delayed kinetics, largely through the SgK269 pseudokinase/adaptor protein. Ptpn12 acts as a switch to convert Shc1 from pTyr/Grb2-based signalling to SgK269-mediated pathways that regulate cell invasion and morphogenesis. The Shc1 scaffold therefore directs the temporal flow of signalling information after EGF stimulation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Yong -- Zhang, Cunjie -- Croucher, David R -- Soliman, Mohamed A -- St-Denis, Nicole -- Pasculescu, Adrian -- Taylor, Lorne -- Tate, Stephen A -- Hardy, W Rod -- Colwill, Karen -- Dai, Anna Yue -- Bagshaw, Rick -- Dennis, James W -- Gingras, Anne-Claude -- Daly, Roger J -- Pawson, Tony -- MOP-13466-6849/Canadian Institutes of Health Research/Canada -- England -- Nature. 2013 Jul 11;499(7457):166-71. doi: 10.1038/nature12308.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G 1X5, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23846654" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast/cytology ; Cell Line ; Epidermal Growth Factor/*metabolism ; Epithelial Cells/cytology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Feedback, Physiological ; GRB2 Adaptor Protein/deficiency/genetics/metabolism ; Humans ; Mice ; Multiprotein Complexes/chemistry/metabolism ; Phosphorylation ; Protein Binding ; Protein-Tyrosine Kinases ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Receptor, Epidermal Growth Factor/agonists/metabolism ; Shc Signaling Adaptor Proteins/deficiency/genetics/*metabolism ; *Signal Transduction ; Time Factors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2011-02-26
    Description: Metarhizium anisopliae infects mosquitoes through the cuticle and proliferates in the hemolymph. To allow M. anisopliae to combat malaria in mosquitoes with advanced malaria infections, we produced recombinant strains expressing molecules that target sporozoites as they travel through the hemolymph to the salivary glands. Eleven days after a Plasmodium-infected blood meal, mosquitoes were treated with M. anisopliae expressing salivary gland and midgut peptide 1 (SM1), which blocks attachment of sporozoites to salivary glands; a single-chain antibody that agglutinates sporozoites; or scorpine, which is an antimicrobial toxin. These reduced sporozoite counts by 71%, 85%, and 90%, respectively. M. anisopliae expressing scorpine and an [SM1](8):scorpine fusion protein reduced sporozoite counts by 98%, suggesting that Metarhizium-mediated inhibition of Plasmodium development could be a powerful weapon for combating malaria.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153607/" 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/PMC4153607/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fang, Weiguo -- Vega-Rodriguez, Joel -- Ghosh, Anil K -- Jacobs-Lorena, Marcelo -- Kang, Angray -- St Leger, Raymond J -- 5R21A1079429-02/PHS HHS/ -- R01 AI031478/AI/NIAID NIH HHS/ -- R21 AI079429/AI/NIAID NIH HHS/ -- R21 AI088033/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2011 Feb 25;331(6020):1074-7. doi: 10.1126/science.1199115.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Entomology, University of Maryland, 4112 Plant Sciences Building, College Park, MD 20742, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21350178" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anopheles gambiae/*microbiology/*parasitology/physiology ; Antibodies, Protozoan/immunology ; Base Sequence ; Cloning, Molecular ; Defensins/genetics/metabolism ; Feeding Behavior ; Female ; Hemolymph/metabolism/microbiology/parasitology ; Humans ; Insect Vectors/*microbiology/*parasitology/physiology ; Malaria, Falciparum/transmission ; Metarhizium/*genetics/physiology ; Molecular Sequence Data ; Oligopeptides/genetics/metabolism ; Organisms, Genetically Modified ; Pest Control, Biological ; Plasmodium falciparum/*physiology ; Protozoan Proteins/immunology ; Salivary Glands/metabolism/parasitology ; Spores, Fungal/physiology ; Sporozoites/physiology ; Transformation, Genetic ; Transgenes
    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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  • 9
    Publication Date: 2013-12-18
    Description: Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case-control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer's disease in seven independent case-control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer's disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer's disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer's disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-beta precursor protein (APP) and extracellular Abeta42 and Abeta40 (the 42- and 40-residue isoforms of the amyloid-beta peptide), and knockdown of PLD3 leads to a significant increase in extracellular Abeta42 and Abeta40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050701/" 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/PMC4050701/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cruchaga, Carlos -- Karch, Celeste M -- Jin, Sheng Chih -- Benitez, Bruno A -- Cai, Yefei -- Guerreiro, Rita -- Harari, Oscar -- Norton, Joanne -- Budde, John -- Bertelsen, Sarah -- Jeng, Amanda T -- Cooper, Breanna -- Skorupa, Tara -- Carrell, David -- Levitch, Denise -- Hsu, Simon -- Choi, Jiyoon -- Ryten, Mina -- UK Brain Expression Consortium -- Hardy, John -- Trabzuni, Daniah -- Weale, Michael E -- Ramasamy, Adaikalavan -- Smith, Colin -- Sassi, Celeste -- Bras, Jose -- Gibbs, J Raphael -- Hernandez, Dena G -- Lupton, Michelle K -- Powell, John -- Forabosco, Paola -- Ridge, Perry G -- Corcoran, Christopher D -- Tschanz, Joann T -- Norton, Maria C -- Munger, Ronald G -- Schmutz, Cameron -- Leary, Maegan -- Demirci, F Yesim -- Bamne, Mikhil N -- Wang, Xingbin -- Lopez, Oscar L -- Ganguli, Mary -- Medway, Christopher -- Turton, James -- Lord, Jenny -- Braae, Anne -- Barber, Imelda -- Brown, Kristelle -- Alzheimer's Research UK Consortium -- Passmore, Peter -- Craig, David -- Johnston, Janet -- McGuinness, Bernadette -- Todd, Stephen -- Heun, Reinhard -- Kolsch, Heike -- Kehoe, Patrick G -- Hooper, Nigel M -- Vardy, Emma R L C -- Mann, David M -- Pickering-Brown, Stuart -- Kalsheker, Noor -- Lowe, James -- Morgan, Kevin -- David Smith, A -- Wilcock, Gordon -- Warden, Donald -- Holmes, Clive -- Pastor, Pau -- Lorenzo-Betancor, Oswaldo -- Brkanac, Zoran -- Scott, Erick -- Topol, Eric -- Rogaeva, Ekaterina -- Singleton, Andrew B -- Kamboh, M Ilyas -- St George-Hyslop, Peter -- Cairns, Nigel -- Morris, John C -- Kauwe, John S K -- Goate, Alison M -- 081864/Wellcome Trust/United Kingdom -- 089698/Wellcome Trust/United Kingdom -- 089703/Wellcome Trust/United Kingdom -- 100140/Wellcome Trust/United Kingdom -- 1R01AG041797/AG/NIA NIH HHS/ -- 5U24AG026395/AG/NIA NIH HHS/ -- AG005133/AG/NIA NIH HHS/ -- AG023652/AG/NIA NIH HHS/ -- AG030653/AG/NIA NIH HHS/ -- AG041718/AG/NIA NIH HHS/ -- AG07562/AG/NIA NIH HHS/ -- G0802189/Medical Research Council/United Kingdom -- G0802462/Medical Research Council/United Kingdom -- G0901254/Medical Research Council/United Kingdom -- G1100695/Medical Research Council/United Kingdom -- K01 AG046374/AG/NIA NIH HHS/ -- MC_G1000734/Medical Research Council/United Kingdom -- NIH P50 AG05681/AG/NIA NIH HHS/ -- NIH R01039700/PHS HHS/ -- P01 AG003991/AG/NIA NIH HHS/ -- P01 AG026276/AG/NIA NIH HHS/ -- P01 AG03991/AG/NIA NIH HHS/ -- P30 NS069329/NS/NINDS NIH HHS/ -- P30-NS069329/NS/NINDS NIH HHS/ -- P50 AG005133/AG/NIA NIH HHS/ -- P50 AG005681/AG/NIA NIH HHS/ -- R01 AG011380/AG/NIA NIH HHS/ -- R01 AG030653/AG/NIA NIH HHS/ -- R01 AG035083/AG/NIA NIH HHS/ -- R01 AG039700/AG/NIA NIH HHS/ -- R01 AG041718/AG/NIA NIH HHS/ -- R01 AG041797/AG/NIA NIH HHS/ -- R01 AG042611/AG/NIA NIH HHS/ -- R01 AG044546/AG/NIA NIH HHS/ -- R01-AG035083/AG/NIA NIH HHS/ -- R01-AG042611/AG/NIA NIH HHS/ -- R01-AG044546/AG/NIA NIH HHS/ -- R01-AG11380/AG/NIA NIH HHS/ -- R01-AG18712/AG/NIA NIH HHS/ -- R01-AG21136/AG/NIA NIH HHS/ -- R01AG21136/AG/NIA NIH HHS/ -- R25 DA027995/DA/NIDA NIH HHS/ -- U24 AG021886/AG/NIA NIH HHS/ -- U24 AG026395/AG/NIA NIH HHS/ -- U24AG21886/AG/NIA NIH HHS/ -- WT089698/Wellcome Trust/United Kingdom -- ZIA AG000950-11/Intramural NIH HHS/ -- ZO1 AG000950-10/AG/NIA NIH HHS/ -- ZO1AG000950-11/AG/NIA NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2014 Jan 23;505(7484):550-4. doi: 10.1038/nature12825. Epub 2013 Dec 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [2] Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University 425 South Euclid Avenue, St. Louis, Missouri 63110, USA. ; 1] Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [2] Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [3]. ; 1] Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [2]. ; Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA. ; 1] Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK [2] Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35 Room 1A1014, 35 Lincoln Drive, Bethesda, Maryland 20892, USA. ; Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. ; Department of Medical and Molecular Genetics, King's College London, 16 De Crespigny Park, London SE5 8AF UK. ; MRC Sudden Death Brain Bank Project, University of Edinburgh, South Bridge, Edinburgh EH8 9YL UK. ; 1] Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, UK [2] Neuroimaging Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland 4006, Australia. ; Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, UK. ; Istituto di Genetica delle Popolazioni - CNR, Trav. La Crucca, 3 - Reg. Baldinca - 07100 Li Punti, Sassari, Italy. ; Department of Biology, Brigham Young University, Provo, Utah 84602, USA. ; 1] Department of Mathematics and Statistics, Utah State University, Logan, Utah 84322, USA [2] Center for Epidemiologic Studies, Utah State University, Logan, Utah 84322, USA. ; 1] Center for Epidemiologic Studies, Utah State University, Logan, Utah 84322, USA [2] Department of Psychology, Utah State University, Logan, Utah 84322, USA. ; 1] Center for Epidemiologic Studies, Utah State University, Logan, Utah 84322, USA [2] Department of Psychology, Utah State University, Logan, Utah 84322, USA [3] Department of Family Consumer and Human Development, Utah State University, Logan, Utah 84322, USA. ; 1] Department of Family Consumer and Human Development, Utah State University, Logan, Utah 84322, USA [2] Department of Nutrition, Dietetics, and Food Sciences, Utah State University, Logan, Utah 84322, USA. ; Department of Human Genetics, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA. ; 1] Alzheimer's Disease Research Center, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA [2] Department of Neurology, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA. ; Department of Psychiatry, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA. ; Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK. ; Queen's University Belfast, University Road, Belfast BT7 1NN, UK. ; Royal Derby Hospital, Uttoxeter Road, Derby, DE22 3NE, UK. ; University of Bonn, Regina-Pacis-Weg 3, 53113 Bonn, Germany. ; University of Bristol, Tyndall Avenue, Bristol, City of Bristol BS8 1TH, UK. ; University of Leeds, Woodhouse Lane, Leeds, West Yorkshire LS2 9JT, UK. ; University of Newcastle, Newcastle upon Tyne, Tyne and Wear NE1 7RU, UK. ; University of Manchester, Oxford Road, Manchester, Greater Manchester M13 9PL, UK. ; University of Oxford (OPTIMA), Wellington Square, Oxford OX1 2JD, UK. ; 1] Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Avenida Pio XII, 55. 31008 Pamplona, Navarra, Spain [2] Department of Neurology, Clinica Universidad de Navarra, School of Medicine, University of Navarra Avenida Pio XII, 36. 31008 Pamplona, Spain [3] CIBERNED, Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain. ; Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Avenida Pio XII, 55. 31008 Pamplona, Navarra, Spain. ; University of Washington, 325 Ninth Avenue, Seattle, Washington 98104-2499, USA. ; The Scripps Research Institute, La Jolla, California 3344 North Torrey Pines Court, La Jolla, California 92037, USA. ; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, Toronto, Ontario M5T 2S8, Canada. ; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35 Room 1A1014, 35 Lincoln Drive, Bethesda, Maryland 20892, USA. ; 1] Department of Human Genetics, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA [2] Alzheimer's Disease Research Center, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA [3] Department of Neurology, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA. ; 1] Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, Toronto, Ontario M5T 2S8, Canada [2] Cambridge Institute for Medical Research, and the Department of Clinical Neurosciences, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK. ; 1] Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [2] Pathology and Immunology, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA. ; 1] Pathology and Immunology, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [2] Department of Neurology, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [3] Knight ADRC, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA. ; 1] Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [2] Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [3] Department of Neurology, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [4] Knight ADRC, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [5] Department of Genetics, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24336208" target="_blank"〉PubMed〈/a〉
    Keywords: African Americans/genetics ; Age of Onset ; Aged ; Aged, 80 and over ; Alzheimer Disease/*genetics/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Brain/metabolism ; Case-Control Studies ; Europe/ethnology ; Exome/genetics ; Female ; Genetic Predisposition to Disease/*genetics ; Genetic Variation/*genetics ; Humans ; Male ; Peptide Fragments/metabolism ; Phospholipase D/deficiency/*genetics/metabolism ; Protein Processing, Post-Translational/genetics ; Proteolysis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2013-11-15
    Description: Glucose homeostasis is a vital and complex process, and its disruption can cause hyperglycaemia and type II diabetes mellitus. Glucokinase (GK), a key enzyme that regulates glucose homeostasis, converts glucose to glucose-6-phosphate in pancreatic beta-cells, liver hepatocytes, specific hypothalamic neurons, and gut enterocytes. In hepatocytes, GK regulates glucose uptake and glycogen synthesis, suppresses glucose production, and is subject to the endogenous inhibitor GK regulatory protein (GKRP). During fasting, GKRP binds, inactivates and sequesters GK in the nucleus, which removes GK from the gluconeogenic process and prevents a futile cycle of glucose phosphorylation. Compounds that directly hyperactivate GK (GK activators) lower blood glucose levels and are being evaluated clinically as potential therapeutics for the treatment of type II diabetes mellitus. However, initial reports indicate that an increased risk of hypoglycaemia is associated with some GK activators. To mitigate the risk of hypoglycaemia, we sought to increase GK activity by blocking GKRP. Here we describe the identification of two potent small-molecule GK-GKRP disruptors (AMG-1694 and AMG-3969) that normalized blood glucose levels in several rodent models of diabetes. These compounds potently reversed the inhibitory effect of GKRP on GK activity and promoted GK translocation both in vitro (isolated hepatocytes) and in vivo (liver). A co-crystal structure of full-length human GKRP in complex with AMG-1694 revealed a previously unknown binding pocket in GKRP distinct from that of the phosphofructose-binding site. Furthermore, with AMG-1694 and AMG-3969 (but not GK activators), blood glucose lowering was restricted to diabetic and not normoglycaemic animals. These findings exploit a new cellular mechanism for lowering blood glucose levels with reduced potential for hypoglycaemic risk in patients with type II diabetes mellitus.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lloyd, David J -- St Jean, David J Jr -- Kurzeja, Robert J M -- Wahl, Robert C -- Michelsen, Klaus -- Cupples, Rod -- Chen, Michelle -- Wu, John -- Sivits, Glenn -- Helmering, Joan -- Komorowski, Renee -- Ashton, Kate S -- Pennington, Lewis D -- Fotsch, Christopher -- Vazir, Mukta -- Chen, Kui -- Chmait, Samer -- Zhang, Jiandong -- Liu, Longbin -- Norman, Mark H -- Andrews, Kristin L -- Bartberger, Michael D -- Van, Gwyneth -- Galbreath, Elizabeth J -- Vonderfecht, Steven L -- Wang, Minghan -- Jordan, Steven R -- Veniant, Murielle M -- Hale, Clarence -- England -- Nature. 2013 Dec 19;504(7480):437-40. doi: 10.1038/nature12724. Epub 2013 Nov 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. ; Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. ; Department of Comparative Biology & Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24226772" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing ; Animals ; Blood Glucose/metabolism ; Carrier Proteins/*antagonists & inhibitors/metabolism ; Cell Nucleus/enzymology ; Crystallography, X-Ray ; Diabetes Mellitus, Type 2/blood/*drug therapy/enzymology ; Disease Models, Animal ; Hepatocytes ; Humans ; Hyperglycemia/blood/drug therapy/enzymology ; Hypoglycemic Agents/chemistry/*pharmacology/*therapeutic use ; Liver/cytology/enzymology/metabolism ; Male ; Models, Molecular ; Organ Specificity ; Phosphorylation/drug effects ; Piperazines/chemistry/metabolism/pharmacology/therapeutic use ; Protein Binding/drug effects ; Protein Transport/drug effects ; Rats ; Rats, Wistar ; Sulfonamides/chemistry/metabolism/pharmacology/therapeutic use
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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