Search Results - (Author, Cooperation:G. Thompson)

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  1. 1
    The Brainstorm Consortium, Anttila, V., Bulik-Sullivan, B., Finucane, H. K., Walters, R. K., Bras, J., Duncan, L., Escott-Price, V., Falcone, G. J., Gormley, P., Malik, R., Patsopoulos, N. A., Ripke, S., Wei, Z., Yu, D., Lee, P. H., Turley, P., Grenier-Boley, B., Chouraki, V., Kamatani, Y., Berr, C., Letenneur, L., Hannequin, D., Amouyel, P., Boland, A., Deleuze, J.-F., Duron, E., Vardarajan, B. N., Reitz, C., Goate, A. M., Huentelman, M. J., Kamboh, M. I., Larson, E. B., Rogaeva, E., St George-Hyslop, P., Hakonarson, H., Kukull, W. A., Farrer, L. A., Barnes, L. L., Beach, T. G., Demirci, F. Y., Head, E., Hulette, C. M., Jicha, G. A., Kauwe, J. S. K., Kaye, J. A., Leverenz, J. B., Levey, A. I., Lieberman, A. P., Pankratz, V. S., Poon, W. W., Quinn, J. F., Saykin, A. J., Schneider, L. S., Smith, A. G., Sonnen, J. A., Stern, R. A., Van Deerlin, V. M., Van Eldik, L. J., Harold, D., Russo, G., Rubinsztein, D. C., Bayer, A., Tsolaki, M., Proitsi, P., Fox, N. C., Hampel, H., Owen, M. J., Mead, S., Passmore, P., Morgan, K., Nöthen, M. M., Rossor, M., Lupton, M. K., Hoffmann, P., Kornhuber, J., Lawlor, B., McQuillin, A., Al-Chalabi, A., Bis, J. C., Ruiz, A., Boada, M., Seshadri, S., Beiser, A., Rice, K., van der Lee, S. J., De Jager, P. L., Geschwind, D. H., Riemenschneider, M., Riedel-Heller, S., Rotter, J. I., Ransmayr, G., Hyman, B. T., Cruchaga, C., Alegret, M., Winsvold, B., Palta, P., Farh, K.-H., Cuenca-Leon, E., Furlotte, N., Kurth, T., Ligthart, L., Terwindt, G. M., Freilinger, T., Ran, C., Gordon, S. D., Borck, G., Adams, H. H. H., Lehtimäki, T., Wedenoja, J., Buring, J. E., Schürks, M., Hrafnsdottir, M., Hottenga, J.-J., Penninx, B., Artto, V., Kaunisto, M., Vepsäläinen, S., Martin, N. G., Montgomery, G. W., Kurki, M. I., Hämäläinen, E., Huang, H., Huang, J., Sandor, C., Webber, C., Muller-Myhsok, B., Schreiber, S., Salomaa, V., Loehrer, E., Göbel, H., Macaya, A., Pozo-Rosich, P., Hansen, T., Werge, T., Kaprio, J., Metspalu, A., Kubisch, C., Ferrari, M. D., Belin, A. C., van den Maagdenberg, A. M. J. M., Zwart, J.-A., Boomsma, D., Eriksson, N., Olesen, J., Chasman, D. I., Nyholt, D. R., Avbersek, A., Baum, L., Berkovic, S., Bradfield, J., Buono, R., Catarino, C. B., Cossette, P., De Jonghe, P., Depondt, C., Dlugos, D., Ferraro, T. N., French, J., Hjalgrim, H., Jamnadas-Khoda, J., Kälviäinen, R., Kunz, W. S., Lerche, H., Leu, C., Lindhout, D., Lo, W., Lowenstein, D., McCormack, M., Moller, R. S., Molloy, A., Ng, P.-W., Oliver, K., Privitera, M., Radtke, R., Ruppert, A.-K., Sander, T., Schachter, S., Schankin, C., Scheffer, I., Schoch, S., Sisodiya, S. M., Smith, P., Sperling, M., Striano, P., Surges, R., Thomas, G. N., Visscher, F., Whelan, C. D., Zara, F., Heinzen, E. L., Marson, A., Becker, F., Stroink, H., Zimprich, F., Gasser, T., Gibbs, R., Heutink, P., Martinez, M., Morris, H. R., Sharma, M., Ryten, M., Mok, K. Y., Pulit, S., Bevan, S., Holliday, E., Attia, J., Battey, T., Boncoraglio, G., Thijs, V., Chen, W.-M., Mitchell, B., Rothwell, P., Sharma, P., Sudlow, C., Vicente, A., Markus, H., Kourkoulis, C., Pera, J., Raffeld, M., Silliman, S., Boraska Perica, V., Thornton, L. M., Huckins, L. M., William Rayner, N., Lewis, C. M., Gratacos, M., Rybakowski, F., Keski-Rahkonen, A., Raevuori, A., Hudson, J. I., Reichborn-Kjennerud, T., Monteleone, P., Karwautz, A., Mannik, K., Baker, J. H., OToole, J. K., Trace, S. E., Davis, O. S. P., Helder, S. G., Ehrlich, S., Herpertz-Dahlmann, B., Danner, U. N., van Elburg, A. A., Clementi, M., Forzan, M., Docampo, E., Lissowska, J., Hauser, J., Tortorella, A., Maj, M., Gonidakis, F., Tziouvas, K., Papezova, H., Yilmaz, Z., Wagner, G., Cohen-Woods, S., Herms, S., Julia, A., Rabionet, R., Dick, D. M., Ripatti, S., Andreassen, O. A., Espeseth, T., Lundervold, A. J., Steen, V. M., Pinto, D., Scherer, S. W., Aschauer, H., Schosser, A., Alfredsson, L., Padyukov, L., Halmi, K. A., Mitchell, J., Strober, M., Bergen, A. W., Kaye, W., Szatkiewicz, J. P., Cormand, B., Ramos-Quiroga, J. A., Sanchez-Mora, C., Ribases, M., Casas, M., Hervas, A., Arranz, M. J., Haavik, J., Zayats, T., Johansson, S., Williams, N., Dempfle, A., Rothenberger, A., Kuntsi, J., Oades, R. D., Banaschewski, T., Franke, B., Buitelaar, J. K., Arias Vasquez, A., Doyle, A. E., Reif, A., Lesch, K.-P., Freitag, C., Rivero, O., Palmason, H., Romanos, M., Langley, K., Rietschel, M., Witt, S. H., Dalsgaard, S., Borglum, A. D., Waldman, I., Wilmot, B., Molly, N., Bau, C. H. D., Crosbie, J., Schachar, R., Loo, S. K., McGough, J. J., Grevet, E. H., Medland, S. E., Robinson, E., Weiss, L. A., Bacchelli, E., Bailey, A., Bal, V., Battaglia, A., Betancur, C., Bolton, P., Cantor, R., Celestino-Soper, P., Dawson, G., De Rubeis, S., Duque, F., Green, A., Klauck, S. M., Leboyer, M., Levitt, P., Maestrini, E., Mane, S., De-Luca, D. M.-, Parr, J., Regan, R., Reichenberg, A., Sandin, S., Vorstman, J., Wassink, T., Wijsman, E., Cook, E., Santangelo, S., Delorme, R., Roge, B., Magalhaes, T., Arking, D., Schulze, T. G., Thompson, R. C., Strohmaier, J., Matthews, K., Melle, I., Morris, D., Blackwood, D., McIntosh, A., Bergen, S. E., Schalling, M., Jamain, S., Maaser, A., Fischer, S. B., Reinbold, C. S., Fullerton, J. M., Guzman-Parra, J., Mayoral, F., Schofield, P. R., Cichon, S., Mühleisen, T. W., Degenhardt, F., Schumacher, J., Bauer, M., Mitchell, P. B., Gershon, E. S., Rice, J., Potash, J. B., Zandi, P. P., Craddock, N., Ferrier, I. N., Alda, M., Rouleau, G. A., Turecki, G., Ophoff, R., Pato, C., Anjorin, A., Stahl, E., Leber, M., Czerski, P. M., Cruceanu, C., Jones, I. R., Posthuma, D., Andlauer, T. F. M., Forstner, A. J., Streit, F., Baune, B. T., Air, T., Sinnamon, G., Wray, N. R., Mac; Intyre, D. J., Porteous, D., Homuth, G., Rivera, M., Grove, J., Middeldorp, C. M., Hickie, I., Pergadia, M., Mehta, D., Smit, J. H., Jansen, R., de Geus, E., Dunn, E., Li, Q. S., Nauck, M., Schoevers, R. A., Beekman, A. T., Knowles, J. A., Viktorin, A., Arnold, P., Barr, C. L., Bedoya-Berrio, G., Bienvenu, O. J., Brentani, H., Burton, C., Camarena, B., Cappi, C., Cath, D., Cavallini, M., Cusi, D., Darrow, S., Denys, D., Derks, E. M., Dietrich, A., Fernandez, T., Figee, M., Freimer, N., Gerber, G., Grados, M., Greenberg, E., Hanna, G. L., Hartmann, A., Hirschtritt, M. E., Hoekstra, P. J., Huang, A., Huyser, C., Illmann, C., Jenike, M., Kuperman, S., Leventhal, B., Lochner, C., Lyon, G. J., Macciardi, F., Madruga-Garrido, M., Malaty, I. A., Maras, A., McGrath, L., Miguel, E. C., Mir, P., Nestadt, G., Nicolini, H., Okun, M. S., Pakstis, A., Paschou, P., Piacentini, J., Pittenger, C., Plessen, K., Ramensky, V., Ramos, E. M., Reus, V., Richter, M. A., Riddle, M. A., Robertson, M. M., Roessner, V., Rosario, M., Samuels, J. F., Sandor, P., Stein, D. J., Tsetsos, F., Van Nieuwerburgh, F., Weatherall, S., Wendland, J. R., Wolanczyk, T., Worbe, Y., Zai, G., Goes, F. S., McLaughlin, N., Nestadt, P. S., Grabe, H.-J., Depienne, C., Konkashbaev, A., Lanzagorta, N., Valencia-Duarte, A., Bramon, E., Buccola, N., Cahn, W., Cairns, M., Chong, S. A., Cohen, D., Crespo-Facorro, B., Crowley, J., Davidson, M., De; Lisi, L., Dinan, T., Donohoe, G., Drapeau, E., Duan, J., Haan, L., Hougaard, D., Karachanak-Yankova, S., Khrunin, A., Klovins, J., Kucinskas, V., Lee Chee Keong, J., Limborska, S., Loughland, C., Lönnqvist, J., Maher, B., Mattheisen, M., McDonald, C., Murphy, K. C., Nenadic, I., van Os, J., Pantelis, C., Pato, M., Petryshen, T., Quested, D., Roussos, P., Sanders, A. R., Schall, U., Schwab, S. G., Sim, K., So, H.-C., Stögmann, E., Subramaniam, M., Toncheva, D., Waddington, J., Walters, J., Weiser, M., Cheng, W., Cloninger, R., Curtis, D., Gejman, P. V., Henskens, F., Mattingsdal, M., Oh, S.-Y., Scott, R., Webb, B., Breen, G., Churchhouse, C., Bulik, C. M., Daly, M., Dichgans, M., Faraone, S. V., Guerreiro, R., Holmans, P., Kendler, K. S., Koeleman, B., Mathews, C. A., Price, A., Scharf, J., Sklar, P., Williams, J., Wood, N. W., Cotsapas, C., Palotie, A., Smoller, J. W., Sullivan, P., Rosand, J., Corvin, A., Neale, B. M.
    American Association for the Advancement of Science (AAAS)
    Published 2018
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    Publication Date:
    2018-06-22
    Publisher:
    American Association for the Advancement of Science (AAAS)
    Print ISSN:
    0036-8075
    Electronic ISSN:
    1095-9203
    Topics:
    Biology
    Chemistry and Pharmacology
    Geosciences
    Computer Science
    Medicine
    Natural Sciences in General
    Physics
    Keywords:
    Genetics, Medicine, Diseases, Online Only
    Published by:
    http://www.aaas.org/

    Latest Papers from Table of Contents or Articles in Press
  2. 2
    L. G. Thompson ; E. Mosley-Thompson ; M. E. Davis ; V. S. Zagorodnov ; I. M. Howat ; V. N. Mikhalenko ; P. N. Lin
    American Association for the Advancement of Science (AAAS)
    Published 2013
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    Publication Date:
    2013-04-06
    Publisher:
    American Association for the Advancement of Science (AAAS)
    Print ISSN:
    0036-8075
    Electronic ISSN:
    1095-9203
    Topics:
    Biology
    Chemistry and Pharmacology
    Computer Science
    Medicine
    Natural Sciences in General
    Physics
    Keywords:
    *Climate Change ; *Ice Cover ; Nitrates/analysis ; Oxygen Isotopes/analysis ; Peru ; Plants ; Quaternary Ammonium Compounds/analysis ; *Tropical Climate ; Wetlands
    Published by:
    http://www.aaas.org/

    Latest Papers from Table of Contents or Articles in Press
  3. 3
    Staff View
    Publication Date:
    2015-07-15
    Publisher:
    American Association for the Advancement of Science (AAAS)
    Print ISSN:
    0036-8075
    Electronic ISSN:
    1095-9203
    Topics:
    Biology
    Chemistry and Pharmacology
    Computer Science
    Medicine
    Natural Sciences in General
    Physics
    Published by:
    http://www.aaas.org/

    Latest Papers from Table of Contents or Articles in Press
  4. 4
    P. Abbot ; J. Abe ; J. Alcock ; S. Alizon ; J. A. Alpedrinha ; M. Andersson ; J. B. Andre ; M. van Baalen ; F. Balloux ; S. Balshine ; N. Barton ; L. W. Beukeboom ; J. M. Biernaskie ; T. Bilde ; G. Borgia ; M. Breed ; S. Brown ; R. Bshary ; A. Buckling ; N. T. Burley ; M. N. Burton-Chellew ; M. A. Cant ; M. Chapuisat ; E. L. Charnov ; T. Clutton-Brock ; A. Cockburn ; B. J. Cole ; N. Colegrave ; L. Cosmides ; I. D. Couzin ; J. A. Coyne ; S. Creel ; B. Crespi ; R. L. Curry ; S. R. Dall ; T. Day ; J. L. Dickinson ; L. A. Dugatkin ; C. El Mouden ; S. T. Emlen ; J. Evans ; R. Ferriere ; J. Field ; S. Foitzik ; K. Foster ; W. A. Foster ; C. W. Fox ; J. Gadau ; S. Gandon ; A. Gardner ; M. G. Gardner ; T. Getty ; M. A. Goodisman ; A. Grafen ; R. Grosberg ; C. M. Grozinger ; P. H. Gouyon ; D. Gwynne ; P. H. Harvey ; B. J. Hatchwell ; J. Heinze ; H. Helantera ; K. R. Helms ; K. Hill ; N. Jiricny ; R. A. Johnstone ; A. Kacelnik ; E. T. Kiers ; H. Kokko ; J. Komdeur ; J. Korb ; D. Kronauer ; R. Kummerli ; L. Lehmann ; T. A. Linksvayer ; S. Lion ; B. Lyon ; J. A. Marshall ; R. McElreath ; Y. Michalakis ; R. E. Michod ; D. Mock ; T. Monnin ; R. Montgomerie ; A. J. Moore ; U. G. Mueller ; R. Noe ; S. Okasha ; P. Pamilo ; G. A. Parker ; J. S. Pedersen ; I. Pen ; D. Pfennig ; D. C. Queller ; D. J. Rankin ; S. E. Reece ; H. K. Reeve ; M. Reuter ; G. Roberts ; S. K. Robson ; D. Roze ; F. Rousset ; O. Rueppell ; J. L. Sachs ; L. Santorelli ; P. Schmid-Hempel ; M. P. Schwarz ; T. Scott-Phillips ; J. Shellmann-Sherman ; P. W. Sherman ; D. M. Shuker ; J. Smith ; J. C. Spagna ; B. Strassmann ; A. V. Suarez ; L. Sundstrom ; M. Taborsky ; P. Taylor ; G. Thompson ; J. Tooby ; N. D. Tsutsui ; K. Tsuji ; S. Turillazzi ; F. Ubeda ; E. L. Vargo ; B. Voelkl ; T. Wenseleers ; S. A. West ; M. J. West-Eberhard ; D. F. Westneat ; D. C. Wiernasz ; G. Wild ; R. Wrangham ; A. J. Young ; D. W. Zeh ; J. A. Zeh ; A. Zink
    Nature Publishing Group (NPG)
    Published 2011
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    Publication Date:
    2011-03-25
    Publisher:
    Nature Publishing Group (NPG)
    Print ISSN:
    0028-0836
    Electronic ISSN:
    1476-4687
    Topics:
    Biology
    Chemistry and Pharmacology
    Medicine
    Natural Sciences in General
    Physics
    Keywords:
    *Altruism ; Animals ; *Biological Evolution ; Cooperative Behavior ; Female ; Game Theory ; *Genetic Fitness ; Genetics, Population ; Heredity ; Humans ; Male ; *Models, Biological ; Phenotype ; Reproducibility of Results ; *Selection, Genetic ; Sex Ratio
    Published by:
    http://www.nature.com/

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  5. 5
    X. Cai ; J. Wang ; M. J. Strain ; B. Johnson-Morris ; J. Zhu ; M. Sorel ; J. L. O'Brien ; M. G. Thompson ; S. Yu
    American Association for the Advancement of Science (AAAS)
    Published 2012
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    Publication Date:
    2012-10-23
    Publisher:
    American Association for the Advancement of Science (AAAS)
    Print ISSN:
    0036-8075
    Electronic ISSN:
    1095-9203
    Topics:
    Biology
    Chemistry and Pharmacology
    Computer Science
    Medicine
    Natural Sciences in General
    Physics
    Published by:
    http://www.aaas.org/

    Latest Papers from Table of Contents or Articles in Press
  6. 6
    Staff View
    Publication Date:
    2018-05-11
    Publisher:
    BMJ Publishing Group
    Print ISSN:
    0143-005X
    Electronic ISSN:
    1470-2738
    Topics:
    Medicine
    Published by:
    http://www.bmj.com/

    Latest Papers from Table of Contents or Articles in Press
  7. 7
    C. Kinnard ; C. M. Zdanowicz ; D. A. Fisher ; E. Isaksson ; A. de Vernal ; L. G. Thompson
    Nature Publishing Group (NPG)
    Published 2011
    Staff View
    Publication Date:
    2011-11-25
    Publisher:
    Nature Publishing Group (NPG)
    Print ISSN:
    0028-0836
    Electronic ISSN:
    1476-4687
    Topics:
    Biology
    Chemistry and Pharmacology
    Medicine
    Natural Sciences in General
    Physics
    Keywords:
    Arctic Regions ; Atmosphere ; Geologic Sediments/chemistry ; Global Warming/*statistics & numerical data ; History, 15th Century ; History, 16th Century ; History, 17th Century ; History, 18th Century ; History, 19th Century ; History, 20th Century ; History, 21st Century ; History, Ancient ; History, Medieval ; Human Activities ; *Ice Cover ; Reproducibility of Results ; Seasons ; Seawater
    Published by:
    http://www.nature.com/

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  8. 8
    J. C. Matthews ; M. G. Thompson
    Nature Publishing Group (NPG)
    Published 2012
    Staff View
    Publication Date:
    2012-03-23
    Publisher:
    Nature Publishing Group (NPG)
    Print ISSN:
    0028-0836
    Electronic ISSN:
    1476-4687
    Topics:
    Biology
    Chemistry and Pharmacology
    Medicine
    Natural Sciences in General
    Physics
    Keywords:
    Animals ; Humans ; Models, Theoretical ; *Motion ; *Optics and Photonics ; *Photons ; *Quantum Theory ; Walking
    Published by:
    http://www.nature.com/

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  9. 9
    A. J. Heymsfield ; G. Thompson ; H. Morrison ; A. Bansemer ; R. M. Rasmussen ; P. Minnis ; Z. Wang ; D. Zhang
    American Association for the Advancement of Science (AAAS)
    Published 2011
    Staff View
    Publication Date:
    2011-07-02
    Publisher:
    American Association for the Advancement of Science (AAAS)
    Print ISSN:
    0036-8075
    Electronic ISSN:
    1095-9203
    Topics:
    Biology
    Chemistry and Pharmacology
    Computer Science
    Medicine
    Natural Sciences in General
    Physics
    Published by:
    http://www.aaas.org/

    Latest Papers from Table of Contents or Articles in Press
  10. 10
    Staff View
    ISSN:
    1573-4943
    Keywords:
    Insulin analogues ; A14 position of insulin ; structure-activity relationships ; biological activity of insulin ; receptor binding potency of insulin
    Source:
    Springer Online Journal Archives 1860-2000
    Topics:
    Chemistry and Pharmacology
    Notes:
    Abstract As part of our aim to investigate the contribution of the tyrosine residue found in the 14 position of the A-chain to the biological activity of insulin, we have synthesized six insulin analogues in which the A14 Tyr has been substituted by a variety of amino acid residues. We have selected three hydrophilic and charged residues—glutamic acid, histidine, and lysine—as well as three hydrophobic residues—cycloleucine, cyclohexylalanine, and naphthyl-(1)-alanine—to replace the A14 Tyr. All six analogues exhibit full agonist activity, reaching the same maximum stimulation of lipogenesis as is achieved with procine insulin. The potency for five of the six analogues, [A14 Glu]-, [A14 His]-, [A14 Lys]-, [A14 cycloleucine]-, and [A14 naphthyl-(1)-alanine]-insulins in receptor binding assays ranges from 40–71% and in stimulation of lipogenesis ranges from 35-120% relative to porcine insulin. In contrast, the potency of the sixth analogue, [A14 cyclohexylalanine]insulin, in both types of assays is less than 1% of the natural hormone. The retention time on reversed-phase high-performance liquid chromatography for the first five analogues is similar to that of bovine insulin, whereas for the sixth analogue, [A14 cyclohexylalanine]insulin, it is approximately 11 min longer than that of the natural hormone. This suggests a profound change in conformation of the latter analogue. Apparently, the A14 position of insulin can tolerate a wide latitude of structural alterations without substantial decrease in potency. This suggests that the A14 position does not participate directly in insulin receptor interaction. Only when a substitution which has the potential to disrupt the conformation of the molecule is made at this position, is the affinity for the receptor, and hence the biological potency, greatly reduced.
    Type of Medium:
    Electronic Resource
    URL:
    http://dx.doi.org/10.1007/BF01025035

    Articles: DFG German National Licenses
  11. 11
    Staff View
    ISSN:
    1573-4943
    Keywords:
    insulin analog ; synthesis ; structure-activity studies
    Source:
    Springer Online Journal Archives 1860-2000
    Topics:
    Chemistry and Pharmacology
    Notes:
    Abstract Two analogs of sheep insulin, both differing from the native material by a single amino acid in the A chain, have been synthesized and isolated in highly purified form by procedures developed in this laboratory. In one case, the glutamine residue in position A5 was replaced by leucine ([Leu5-A]); in the other, the tyrosine residue in position A19 was replaced by phenylalanine ([Phe19-A]). The biological behavior of these analogs was compared with natural bovine insulin inin vitro tests and in receptor-binding assays, as well as in radioimmunoassay. In the stimulation of glucose oxidation by rat adipocytes, the analogs gave relative potencies of 30% and 7.8% for [Leu5-A] and [Phe19-A], respectively. Receptor-binding assays in rat liver plasma membranes showed similar behavior for both analogs. In radioimmunoassay, [Leu5-A] displayed a relative potency of 27.9%, while [Phe19-A] showed a relative potency of 19–27%, compared with bovine insulin. At high concentration, both analogs displayed the same maximal activity as bovine insulin, and the dose-response curves are essentially parallel. It is speculated that the interaction between the glutamine residue in position 5 and the tyrosine residue in position 19 of the A chain of insulin are important in maintaining a three-dimensional structure commensurate with high biological activity. The full intrinsic activity of both analogs at high concentrations and the similarity of the potency figures in receptor-binding and glucose-oxidation assays permit the further conclusion that the reduced potency in the latter assay can be ascribed wholly to the reduced binding affinity toward insulin receptors caused by the substitutions made in the analogs. The receptor-analog complexes are fully capable of triggering the next event in the chain leading to the biological response.
    Type of Medium:
    Electronic Resource
    URL:
    http://dx.doi.org/10.1007/BF01025378

    Articles: DFG German National Licenses
  12. 12
    Staff View
    ISSN:
    1573-4943
    Keywords:
    Synthetic analogues ; structure-activity ; B-chain ; peptide synthesis
    Source:
    Springer Online Journal Archives 1860-2000
    Topics:
    Chemistry and Pharmacology
    Notes:
    Abstract We report the synthesis and biological evaluation of five insulin analogues in which one or both of the B-chain tyrosine residues have been substituted. [B16 Phe]insulin and [B16 Trp]insulin display a very modest reduction in potency (c. 65%) relative to porcine insulin; [B26 Phe]insulin is less active (30–50%), and the doubly substituted [B16 Phe, B26 Phe]insulin displays still lower potency (c. 35%). The further substitution of Asp for B10 His in [B16 Phe, B26 Phe]insulin raises its activity to approximately twofold greater than natural insulin, an increase of approximately fivefold over the parent compound. We conclude that the bulk and/or aromaticity of the amino acid residue at position B16, but not its hydrogen-bonding capacity, contributes to the biological activity of the hormone. We further conclude that hydrogen-bonding capacity or special side-chain packing characteristics are required at the B26 position for insulin to display high biological activity.
    Type of Medium:
    Electronic Resource
    URL:
    http://dx.doi.org/10.1007/BF01024932

    Articles: DFG German National Licenses
  13. 13
    Staff View
    ISSN:
    1573-4943
    Keywords:
    Insulin analogue ; insulin-like-growth factor ; peptide synthesis ; receptor binding assay ; lipogenesis
    Source:
    Springer Online Journal Archives 1860-2000
    Topics:
    Chemistry and Pharmacology
    Notes:
    Abstract We report the synthesis and biological evaluation of a two-chain, disulfide-linked, insulin-like compound consisting of the B-chain of bovine insulin and an A-chain corresponding to the A- and D- domains of human insulin-like growth factor-I (IGF-I) in which the A-domain amino-acid residues -Phe49-Arg50-Ser51- found in IGF-I have been replaced by -Ala-Gly-Val-, the homologous region of sheep insulin. The compound is indistinguishable from a previously reported compound whose A-chain corresponds to the A- and D-domains of IGF-I without the substitution, in assays for insulin-like activity as well as in assays for growth-promoting activity. We conclude that these A-domain residues do not contribute significantly to the interaction of IGF-I with either insulin or IGF-I receptors.
    Type of Medium:
    Electronic Resource
    URL:
    http://dx.doi.org/10.1007/BF01025314

    Articles: DFG German National Licenses
  14. 14
    Staff View
    ISSN:
    1573-4943
    Keywords:
    insulin analogues ; insulin-like growth factor ; peptide synthesis
    Source:
    Springer Online Journal Archives 1860-2000
    Topics:
    Chemistry and Pharmacology
    Notes:
    Abstract A modified insulin, in which the A chain moiety has been extended at the C-terminus with the “D region” of the insulin-like growth factor II, has been synthesized essentially by the procedures employed in this laboratory for the synthesis of insulin and analogues. This hybrid molecule displayed reduced insulin-like activities, 34.5% receptor binding, and 40.4% stimulation of lipogenesis relative to natural insulin. These findings suggest that the extension sequence (“D region”) attached at the C-terminus of the A chain may partially cover the putative receptor binding region of insulin, in support of speculations based on computer-generated models. These same models indicate that the extension peptide may interfere with one of the two regions implicated in insulin antibody recognition. In this regard, radioimmunoassay of the hybrid revealed potency even more reduced than biological activity: 18% relative to insulin. Growth factor assays of the hybrid (this laboratory, unpublished data) suggest that the “D region” of insulin-like growth factor II is not in itself the determinant of growth-promoting activity.
    Type of Medium:
    Electronic Resource
    URL:
    http://dx.doi.org/10.1007/BF01025170

    Articles: DFG German National Licenses
  15. 15
    Staff View
    ISSN:
    1573-4943
    Keywords:
    insulin analog ; synthesis ; structure-activity
    Source:
    Springer Online Journal Archives 1860-2000
    Topics:
    Chemistry and Pharmacology
    Notes:
    Abstract An analog of human insulin, which differs from the parent molecule in that the histidine residue at position 10 of the B chain (B10) is replaced by lysine, has been synthesized and isolated in purified form. This analog, [10-lysine-B] insulin ([Lys10-B] insulin), in stimulating lipogenesis and in radioimmunoassays, exhibited potencies of 14.2% and 14.7%, respectively, as compared to the natural hormone. In insulin receptor binding in rat liver membranes, [Lys10-B] insulin was found to possess a potency of ∼17% compared to insulin. We have shown previously that substitution of the B10 polar residue histidine with the nonpolar leucine results in an analog exhibiting inin vivo assays ∼50% of the activity of the parent molecule. It is speculated that in insulin the relative size of the amino acid residue at B10, rather than its polarity, is the most important factor in maintaining a structure commensurate with high biological activity.
    Type of Medium:
    Electronic Resource
    URL:
    http://dx.doi.org/10.1007/BF01024998

    Articles: DFG German National Licenses
  16. 16
    Staff View
    ISSN:
    1573-4943
    Keywords:
    Insulin analogues ; β-turn modification ; peptide synthesis ; biological evaluation
    Source:
    Springer Online Journal Archives 1860-2000
    Topics:
    Chemistry and Pharmacology
    Notes:
    Abstract The β-turn formed by the amino acid residues 20–23 of the B-chain of insulin has been implicated as an important structural feature of the molecule. In other biologically active peptides, stabilization of β-turns has resulted in increases in activity. We have synthesized three insulin analogues containing modifications which would be expected to increase the stability of the β-turn. In two analogues, we have substituted α-aminoisobutyric acid (Aib) for the Glu residue normally present in position B21 or for the Arg residue normally present in position B22; in a third compound, we have replaced the Glu residue with its D-isomer. Biological evaluation of these compounds showed that [B21 Aib]insulin displays a potencyca. one-fourth that of natural insulin, while [B22 Aib]insulin is less than 10% as potent. In contrast, [B21 D-Glu]insulin is equipotent with natural insulin. We conclude that the β-turn region of the insulin molecule normally possesses considerable flexibility, which may be necessary for it to assume a conformation commensurate with high biological activity. If this is the case, [B21 D-Glu]insulin may exhibit a stabilized geometry similar to that of natural insulin when bound to the insulin receptor.
    Type of Medium:
    Electronic Resource
    URL:
    http://dx.doi.org/10.1007/BF01025630

    Articles: DFG German National Licenses
  17. 17
    Staff View
    ISSN:
    1573-4943
    Keywords:
    5-Hydroxytryptophan ; tryptophan ; insulin analogs ; fluorescence
    Source:
    Springer Online Journal Archives 1860-2000
    Topics:
    Chemistry and Pharmacology
    Notes:
    Abstract Use of insulin's intrinsic tyrosine absorption and fluorescence to monitor its interaction with the insulin receptor is limited because the spectral properties of the receptor tryptophan residues mask the spectral properties of the hormone tyrosine residues. We describe the synthesis of an insulin analog where A14 tyrosine is replaced by a tryptophan analog, 5-hydroxytryptophan. This insulin is spectrally enhanced since 5-hydroxytryptophan has an absorption band above 300 nm which is at lower energies than the absorption of tryptophan. Steady-state and time-resolved fluorescence parameters indicate that 5-hydroxytryptophan reports the same information about the environment of the A14 side chain as does the corresponding tryptophan-containing insulin. The synthetic hormone is a full agonist compared to porcine insulin, but has slightly reduced specific activity. Consequently, this spectrally enhanced insulin analog will be useful for hormone-receptor interaction studies since it can be observed by both absorption and fluorescence even in the presence of the tryptophan-containing receptor.
    Type of Medium:
    Electronic Resource
    URL:
    http://dx.doi.org/10.1007/BF01886763

    Articles: DFG German National Licenses
  18. 18
    Staff View
    ISSN:
    1573-4943
    Keywords:
    insulin analogue ; insulin-like growth factor ; metabolic assay ; mitogenic assay ; synthesis
    Source:
    Springer Online Journal Archives 1860-2000
    Topics:
    Chemistry and Pharmacology
    Notes:
    Abstract An analogue of insulin in which the naturally occurring tyrosine residue in position B16 is replaced by a glutamine residue has been synthesized. Glutamine appears in the corresponding position in the B-domain of the insulin-like growth factors. This analogue displays 9% of the potency of insulin in binding to the insulin receptor from rat liver plasma membranes, 17% in stimulating the conversion of [3-3H] glucose into lipids in rat adipocytes, and 23% in insulin radioimmunoassay, but 40% of the potency of insulin in stimulating DNA synthesis in cultured chick fibroblasts. The analogue is a more potent mitogen than is a hybrid molecule which contains the A-chain of insulin and the entire B-domain sequence of IGF-I.
    Type of Medium:
    Electronic Resource
    URL:
    http://dx.doi.org/10.1007/BF01025264

    Articles: DFG German National Licenses
  19. 19
    Staff View
    ISSN:
    1573-4943
    Keywords:
    insulin analogue ; peptide synthesis ; receptor binding assay ; radioimmunoassay ; lipogenesis assay
    Source:
    Springer Online Journal Archives 1860-2000
    Topics:
    Chemistry and Pharmacology
    Notes:
    Abstract As part of our aim to study the conformation of insulin in solution by time-resolved fluorescence spectroscopy, we have synthesized the analogue [19-Tryptophan-A]insulin. In this compound, the tyrosine residue at position 19 of the A-chain of insulin, one of the most strongly conserved residues in insulins from various species, is substituted with the strongly fluorescent tryptophan residue. [19-Tryptophan-A]insulin displays 4.1±1.9% of the potency of natural insulin in binding to the insulin receptor from rat liver plasma membranes, 5.0±2.3% in stimulating lipogenesis in rat adipocytes, and 75.7±4% of the potency of insulin in radioimmunoassay. In connection with our previous work, these data indicate that an aromatic side chain at position A19 of insulin seems necessary but not sufficient for high biological activity. We further conclude that in regard to the immunogenic determinants of insulin, tryptophan in position A19 is an essentially neutral substitution for tyrosine in that position, in sharp contrast to the situation with regard to biological activity.
    Type of Medium:
    Electronic Resource
    URL:
    http://dx.doi.org/10.1007/BF01025414

    Articles: DFG German National Licenses
  20. 20
    Staff View
    ISSN:
    1573-4943
    Keywords:
    IGF-I/insulin hybrid ; growth-promoting activity ; insulin activity ; structure-function relationships
    Source:
    Springer Online Journal Archives 1860-2000
    Topics:
    Chemistry and Pharmacology
    Notes:
    Abstract We have synthesized an insulin-like compound, consisting of the B-chain of bovine insulin and an A-chain corresponding to the A-domain of human insulin-like growth factor-I (IGF-I), in which the isoleucine residue normally present in position 2 of the A-domain of IGF-I has been replaced with glycine. Biological evaluation of the compound indicated that its insulin-like activity (insulin receptor-binding and stimulation of lipogenesis) was 0.2%, and its growth-factor activity (stimulation of thymidine incorporation) was less than 1%, both relative to natural insulin. We conclude that interactions between IleA2 and TyrA19, which are crucial to high biological activity in insulin, are also present in IGF-I, and are equally critical for its biological activity.
    Type of Medium:
    Electronic Resource
    URL:
    http://dx.doi.org/10.1007/BF01024614

    Articles: DFG German National Licenses