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  • 1.
    Abbas, Alaa
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Palladium-Catalysed Carbonylative Synthesis of Acylamidines2014Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
  • 2.
    Abdurakhmanov, Eldar
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Discovery and evaluation of direct acting antivirals against hepatitis C virus2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Until recently, the standard therapy for hepatitis C treatment has been interferon and ribavirin. Such treatment has only 50% efficacy and is not well tolerated. The emergence of new drugs has increased the treatment efficacy to 90%. Despite such an achievement, the success is limited since the virus mutates rapidly, causing the emergence of drug resistant forms. In addition, most new drugs were developed to treat genotype 1 infections. Thus, development of new potent antivirals is needed and drug discovery against hepatitis C is continued.

    In this thesis, a FRET-based protease assay was used to evaluate new pyrazinone based NS3 protease inhibitors that are structurally different to the newly approved and currently developing drugs. Several compounds in this series showed good potencies in the nanomolar range against NS3 proteases from genotype 1, 3, and the drug resistance variant R155K. We assume that these compounds can be further developed into drug candidates that possess activity against above mentioned enzyme variants.

    By using SPR technology, we analyzed interaction mechanisms and characteristics of allosteric inhibitors targeting NS5B polymerases from genotypes 1 and 3. The compounds exhibited different binding mechanisms and displayed a low affinity against NS5B from genotype 3.

    In order to evaluate the activity and inhibitors of the NS5B polymerase, we established an SPR based assay, which enables the monitoring of polymerization and its inhibition in real time. This assay can readily be implemented for the discovery of inhibitors targeting HCV.

    An SPR based fragment screening approach has also been established. A screen of a fragment library has been performed in order to identify novel scaffolds that can be used as a starting point for development of new allosteric inhibitors against NS5B polymerase. Selected fragments will be further elaborated to generate a new potent allosteric drug candidate.

    Alternative approaches have successfully been developed and implemented to the discovery of potential lead compounds targeting two important HCV drug targets.

  • 3.
    Abdurakhmanov, Eldar
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Solbak, Sara
    Danielson, Helena
    Characterization of allosteric inhibitors of hepatitis C virus polymerase – a genotype comparative studyManuscript (preprint) (Other academic)
  • 4.
    Abdurakhmanov, Eldar
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Solbak, Sara Oie
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase2017In: Viruses, ISSN 1999-4915, E-ISSN 1999-4915, Vol. 9, no 6, article id 151Article in journal (Refereed)
    Abstract [en]

    Allosteric inhibitors of hepatitis C virus (HCV) non-structural protein 5B (NS5B) polymerase are effective for treatment of genotype 1, although their mode of action and potential to inhibit other isolates and genotypes are not well established. We have used biophysical techniques and a novel biosensor-based real-time polymerase assay to investigate the mode-of-action and selectivity of four inhibitors against enzyme from genotypes 1b (BK and Con1) and 3a. Two thumb inhibitors (lomibuvir and filibuvir) interacted with all three NS5B variants, although the affinities for the 3a enzyme were low. Of the two tested palm inhibitors (dasabuvir and nesbuvir), only dasabuvir interacted with the 1b variant, and nesbuvir interacted with NS5B 3a. Lomibuvir, filibuvir and dasabuvir stabilized the structure of the two 1b variants, but not the 3a enzyme. The thumb compounds interfered with the interaction between the enzyme and RNA and blocked the transition from initiation to elongation. The two allosteric inhibitor types have different inhibition mechanisms. Sequence and structure analysis revealed differences in the binding sites for 1b and 3a variants, explaining the poor effect against genotype 3a NS5B. The indirect mode-of-action needs to be considered when designing allosteric compounds. The current approach provides an efficient strategy for identifying and optimizing allosteric inhibitors targeting HCV genotype 3a.

  • 5.
    Ablikim, M.
    et al.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Achasov, M. N.
    GI Budker Inst Nucl Phys SB RAS BINP, Novosibirsk 630090, Russia..
    Ahmed, S.
    Helmholtz Inst Mainz, D-55099 Mainz, Germany..
    Ai, X. C.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Albayrak, O.
    Carnegie Mellon Univ, Pittsburgh, PA 15213 USA..
    Albrecht, M.
    Ruhr Univ Bochum, D-44780 Bochum, Germany..
    Ambrose, D. J.
    Univ Rochester, Rochester, NY 14627 USA..
    Amoroso, A.
    GI Budker Inst Nucl Phys SB RAS BINP, Novosibirsk 630090, Russia.;Helmholtz Inst Mainz, D-55099 Mainz, Germany.;Johannes Gutenberg Univ Mainz, D-55099 Mainz, Germany.;Chinese Acad Sci, Beijing 100049, Peoples R China.;Univ Hawaii, Honolulu, HI 96822 USA.;Univ Punjab, Lahore 54590, Pakistan.;Univ Turin, I-10125 Turin, Italy.;INFN, I-10125 Turin, Italy..
    An, F. F.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    An, Q.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Bai, J. Z.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Ferroli, R. Baldini
    INFN Lab Nazl Frascati, I-00044 I- Frascati, Italy..
    Ban, Y.
    Peking Univ, Beijing 100871, Peoples R China..
    Bennett, D. W.
    Indiana Univ, Bloomington, IN 47405 USA..
    Bennett, J. V.
    Carnegie Mellon Univ, Pittsburgh, PA 15213 USA..
    Berger, N. B.
    Johannes Gutenberg Univ Mainz, D-55099 Mainz, Germany..
    Bertani, M.
    INFN Lab Nazl Frascati, I-00044 I- Frascati, Italy..
    Bettoni, D.
    INFN, Sez Ferrara, I-44122 Ferrara, Italy..
    Bian, J. M.
    Univ Minnesota, Minneapolis, MN 55455 USA..
    Bianchi, F.
    Univ Turin, I-10125 Turin, Italy.;INFN, I-10125 Turin, Italy..
    Boger, E.
    Joint Inst Nucl Res, Dubna 141980, Moscow Region, Russia..
    Boyko, I.
    Joint Inst Nucl Res, Dubna 141980, Moscow Region, Russia..
    Briere, R. A.
    Carnegie Mellon Univ, Pittsburgh, PA 15213 USA..
    Cai, H.
    Wuhan Univ, Wuhan 430072, Peoples R China..
    Cai, X.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Cakir, O.
    Ankara Univ, TR-06100 Ankara, Turkey..
    Calcaterra, A.
    INFN Lab Nazl Frascati, I-00044 I- Frascati, Italy.;Johannes Gutenberg Univ Mainz, D-55099 Mainz, Germany.;Chinese Acad Sci, Beijing 100049, Peoples R China.;Univ Turin, I-10125 Turin, Italy.;INFN, I-10125 Turin, Italy..
    Cao, G. F.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Cetin, S. A.
    Istanbul Bilgi Univ, TR-34060 Istanbul, Turkey..
    Chang, J. F.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Chelkov, G.
    Joint Inst Nucl Res, Dubna 141980, Moscow Region, Russia..
    Chen, G.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Chen, H. S.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Chen, H. Y.
    Beihang Univ, Beijing 100191, Peoples R China..
    Chen, J. C.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Chen, M. L.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Chen, S.
    Chinese Acad Sci, Beijing 100049, Peoples R China..
    Chen, S. J.
    Nanjing Univ, Nanjing 210093, Peoples R China..
    Chen, X.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Chen, X. R.
    Lanzhou Univ, Lanzhou 730000, Peoples R China..
    Chen, Y. B.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Cheng, H. P.
    Huangshan Coll, Huangshan 245000, Peoples R China..
    Chu, X. K.
    Peking Univ, Beijing 100871, Peoples R China..
    Cibinetto, G.
    INFN, Sez Ferrara, I-44122 Ferrara, Italy..
    Dai, H. L.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Dai, J. P.
    Shanghai Jiao Tong Univ, Shanghai 200240, Peoples R China..
    Dbeyssi, A.
    Helmholtz Inst Mainz, D-55099 Mainz, Germany..
    Dedovich, D.
    Joint Inst Nucl Res, Dubna 141980, Moscow Region, Russia..
    Deng, Z. Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Denig, A.
    Johannes Gutenberg Univ Mainz, D-55099 Mainz, Germany..
    Denysenko, I.
    Joint Inst Nucl Res, Dubna 141980, Moscow Region, Russia..
    Destefanis, M.
    Univ Turin, I-10125 Turin, Italy.;INFN, I-10125 Turin, Italy..
    De Mori, F.
    Liaoning Univ, Shenyang 110036, Peoples R China..
    Ding, Y.
    Liaoning Univ, Shenyang 110036, Peoples R China..
    Dong, C.
    Nankai Univ, Tianjin 300071, Peoples R China..
    Dong, J.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Dong, L. Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Dong, M. Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Dou, Z. L.
    Nanjing Univ, Nanjing 210093, Peoples R China..
    Du, S. X.
    Zhengzhou Univ, Zhengzhou 450001, Peoples R China..
    Duan, P. F.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Fan, J. Z.
    Tsinghua Univ, Beijing 100084, Peoples R China..
    Fang, J.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Fang, S. S.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Fang, X.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Fang, Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Farinelli, R.
    INFN, Sez Ferrara, I-44122 Ferrara, Italy.;Univ Ferrara, I-44122 Ferrara, Italy..
    Fava, L.
    Univ Piemonte Orientale, I-15121 Alessandria, Italy.;INFN, I-10125 Turin, Italy..
    Fedorov, O.
    Joint Inst Nucl Res, Dubna 141980, Moscow Region, Russia..
    Feldbauer, F.
    Johannes Gutenberg Univ Mainz, D-55099 Mainz, Germany..
    Felici, G.
    INFN Lab Nazl Frascati, I-00044 I- Frascati, Italy..
    Feng, C. Q.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Fioravanti, E.
    INFN, Sez Ferrara, I-44122 Ferrara, Italy..
    Fritsch, M.
    Helmholtz Inst Mainz, D-55099 Mainz, Germany.;Johannes Gutenberg Univ Mainz, D-55099 Mainz, Germany..
    Fu, C. D.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Gao, Q.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Gao, X. L.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Gao, X. Y.
    Beihang Univ, Beijing 100191, Peoples R China..
    Gao, Y.
    Tsinghua Univ, Beijing 100084, Peoples R China..
    Gao, Z.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Garzia, I.
    INFN, Sez Ferrara, I-44122 Ferrara, Italy..
    Goetzen, K.
    GSI Helmholtzcentre Heavy Ion Res GmbH, D-64291 Darmstadt, Germany..
    Gong, L.
    Nankai Univ, Tianjin 300071, Peoples R China..
    Gong, W. X.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Gradl, W.
    Johannes Gutenberg Univ Mainz, D-55099 Mainz, Germany..
    Greco, M.
    Univ Turin, I-10125 Turin, Italy.;INFN, I-10125 Turin, Italy..
    Gu, M. H.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Gu, Y. T.
    Guangxi Univ, Nanning 530004, Peoples R China..
    Guan, Y. H.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Guo, A. Q.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Guo, L. B.
    Nanjing Normal Univ, Nanjing 210023, Peoples R China..
    Guo, R. P.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Guo, Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Guo, Y. P.
    Johannes Gutenberg Univ Mainz, D-55099 Mainz, Germany..
    Haddadi, Z.
    Univ Groningen, KVI CART, NL-9747 AA Groningen, Netherlands..
    Hafner, A.
    Johannes Gutenberg Univ Mainz, D-55099 Mainz, Germany..
    Han, S.
    Wuhan Univ, Wuhan 430072, Peoples R China..
    Hao, X. Q.
    Henan Normal Univ, Xinxiang 453007, Peoples R China..
    Harris, F. A.
    Univ Hawaii, Honolulu, HI 96822 USA..
    He, K. L.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Heinsius, F. H.
    Ruhr Univ Bochum, D-44780 Bochum, Germany..
    Held, T.
    Ruhr Univ Bochum, D-44780 Bochum, Germany..
    Heng, Y. K.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Holtmann, T.
    Ruhr Univ Bochum, D-44780 Bochum, Germany..
    Hou, Z. L.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Hu, C.
    Nanjing Normal Univ, Nanjing 210023, Peoples R China..
    Hu, H. M.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Hu, J. F.
    Univ Turin, I-10125 Turin, Italy.;INFN, I-10125 Turin, Italy..
    Hu, T.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Hu, Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Huang, G. S.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Huang, J. S.
    Henan Normal Univ, Xinxiang 453007, Peoples R China..
    Huang, X. T.
    Shandong Univ, Jinan 250100, Peoples R China..
    Huang, X. Z.
    Nanjing Univ, Nanjing 210093, Peoples R China..
    Huang, Y.
    Nanjing Univ, Nanjing 210093, Peoples R China..
    Huang, Z. L.
    Liaoning Univ, Shenyang 110036, Peoples R China..
    Hussain, T.
    Univ Punjab, Lahore 54590, Pakistan..
    Ji, Q.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Ji, Q. P.
    Nankai Univ, Tianjin 300071, Peoples R China..
    Ji, X. B.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Ji, X. L.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Jiang, L. W.
    Wuhan Univ, Wuhan 430072, Peoples R China..
    Jiang, X. S.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Jiang, X. Y.
    Nankai Univ, Tianjin 300071, Peoples R China..
    Jiao, J. B.
    Shandong Univ, Jinan 250100, Peoples R China..
    Jiao, Z.
    Huangshan Coll, Huangshan 245000, Peoples R China..
    Jin, D. P.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Jin, S.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Johansson, T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Julin, A.
    Univ Minnesota, Minneapolis, MN 55455 USA..
    Kalantar-Nayestanaki, N.
    Univ Groningen, KVI CART, NL-9747 AA Groningen, Netherlands..
    Kang, X. L.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Kang, X. S.
    Nankai Univ, Tianjin 300071, Peoples R China..
    Kavatsyuk, M.
    Univ Groningen, KVI CART, NL-9747 AA Groningen, Netherlands..
    Ke, B. C.
    Carnegie Mellon Univ, Pittsburgh, PA 15213 USA..
    Kiese, P.
    Johannes Gutenberg Univ Mainz, D-55099 Mainz, Germany..
    Kliemt, R.
    Helmholtz Inst Mainz, D-55099 Mainz, Germany..
    Kloss, B.
    Johannes Gutenberg Univ Mainz, D-55099 Mainz, Germany..
    Kolcu, O. B.
    Istanbul Bilgi Univ, TR-34060 Istanbul, Turkey..
    Kopf, B.
    Ruhr Univ Bochum, D-44780 Bochum, Germany..
    Kornicer, M.
    Univ Hawaii, Honolulu, HI 96822 USA..
    Kupsc, Andrzej
    Uppsala University, The Svedberg Laboratory. Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Khn, W.
    Justus Liebig Univ Giessen, Phys Inst 2, D-35392 Giessen, Germany..
    Lange, J. S.
    Justus Liebig Univ Giessen, Phys Inst 2, D-35392 Giessen, Germany..
    Lara, M.
    Indiana Univ, Bloomington, IN 47405 USA..
    Larin, P.
    Helmholtz Inst Mainz, D-55099 Mainz, Germany..
    Leithoff, H.
    Johannes Gutenberg Univ Mainz, D-55099 Mainz, Germany..
    Leng, C.
    INFN, I-10125 Turin, Italy..
    Li, Cui
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Li, Cheng
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Li, D. M.
    Zhengzhou Univ, Zhengzhou 450001, Peoples R China..
    Li, F.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Li, F. Y.
    Peking Univ, Beijing 100871, Peoples R China..
    Li, G.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Li, H. B.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Li, H. J.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Li, J. C.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Li, Jin
    Seoul Natl Univ, Seoul 151747, South Korea..
    Li, K.
    Hangzhou Normal Univ, Hangzhou 310036, Peoples R China.;Shandong Univ, Jinan 250100, Peoples R China..
    Li, Lei
    Beijing Inst Petrochem Technol, Beijing 102617, Peoples R China..
    Li, P. R.
    Chinese Acad Sci, Beijing 100049, Peoples R China..
    Li, Q. Y.
    Shandong Univ, Jinan 250100, Peoples R China..
    Li, T.
    Shandong Univ, Jinan 250100, Peoples R China..
    Li, W. D.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Li, W. G.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Li, X. L.
    Shandong Univ, Jinan 250100, Peoples R China..
    Li, X. M.
    Guangxi Univ, Nanning 530004, Peoples R China..
    Li, X. N.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Li, X. Q.
    Nankai Univ, Tianjin 300071, Peoples R China..
    Li, Y. B.
    Beihang Univ, Beijing 100191, Peoples R China..
    Li, Z. B.
    Sun Yat Sen Univ, Guangzhou 510275, Guangdong, Peoples R China..
    Liang, H.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Liang, J. J.
    Guangxi Univ, Nanning 530004, Peoples R China..
    Liang, Y. F.
    Sichuan Univ, Chengdu 610064, Peoples R China..
    Liang, Y. T.
    Justus Liebig Univ Giessen, Phys Inst 2, D-35392 Giessen, Germany..
    Liao, G. R.
    Guangxi Normal Univ, Guilin 541004, Peoples R China..
    Lin, D. X.
    Helmholtz Inst Mainz, D-55099 Mainz, Germany..
    Liu, B.
    Shanghai Jiao Tong Univ, Shanghai 200240, Peoples R China..
    Liu, B. J.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Liu, C. X.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Liu, D.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Liu, F. H.
    Shanxi Univ, Taiyuan 030006, Peoples R China..
    Liu, Fang
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Liu, Feng
    Cent China Normal Univ, Wuhan 430079, Peoples R China..
    Liu, H. B.
    Guangxi Univ, Nanning 530004, Peoples R China..
    Liu, H. H.
    Inst High Energy Phys, Beijing 100049, Peoples R China.;Henan Univ Sci & Technol, Luoyang 471003, Peoples R China..
    Liu, H. M.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Liu, J.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Liu, J. B.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Liu, J. P.
    Wuhan Univ, Wuhan 430072, Peoples R China..
    Liu, J. Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Liu, K.
    Tsinghua Univ, Beijing 100084, Peoples R China..
    Liu, K. Y.
    Liaoning Univ, Shenyang 110036, Peoples R China..
    Liu, L. D.
    Peking Univ, Beijing 100871, Peoples R China..
    Liu, P. L.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Liu, Q.
    Chinese Acad Sci, Beijing 100049, Peoples R China..
    Liu, S. B.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Liu, X.
    Lanzhou Univ, Lanzhou 730000, Peoples R China..
    Liu, Y. B.
    Nankai Univ, Tianjin 300071, Peoples R China..
    Liu, Y. Y.
    Nankai Univ, Tianjin 300071, Peoples R China..
    Liu, Z. A.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Liu, Zhiqing
    Johannes Gutenberg Univ Mainz, D-55099 Mainz, Germany..
    Loehner, H.
    Univ Groningen, KVI CART, NL-9747 AA Groningen, Netherlands..
    Lou, X. C.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Lu, H. J.
    Huangshan Coll, Huangshan 245000, Peoples R China..
    Lu, J. G.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Lu, Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Lu, Y. P.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Luo, C. L.
    Nanjing Normal Univ, Nanjing 210023, Peoples R China..
    Luo, M. X.
    Zhejiang Univ, Hangzhou 310027, Zhejiang, Peoples R China..
    Luo, T.
    Univ Hawaii, Honolulu, HI 96822 USA..
    Luo, X. L.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Lyu, X. R.
    Chinese Acad Sci, Beijing 100049, Peoples R China..
    Ma, F. C.
    Liaoning Univ, Shenyang 110036, Peoples R China..
    Ma, H. L.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Ma, L. L.
    Shandong Univ, Jinan 250100, Peoples R China..
    Ma, M. M.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Ma, Q. M.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Ma, T.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Ma, X. N.
    Nankai Univ, Tianjin 300071, Peoples R China..
    Ma, X. Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Ma, Y. M.
    Shandong Univ, Jinan 250100, Peoples R China..
    Maas, F. E.
    Helmholtz Inst Mainz, D-55099 Mainz, Germany..
    Maggiora, M.
    Univ Turin, I-10125 Turin, Italy.;INFN, I-10125 Turin, Italy..
    Malik, Q. A.
    Univ Punjab, Lahore 54590, Pakistan..
    Mao, Y. J.
    Peking Univ, Beijing 100871, Peoples R China..
    Mao, Z. P.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Marcello, S.
    Univ Turin, I-10125 Turin, Italy.;INFN, I-10125 Turin, Italy..
    Messchendorp, J. G.
    Univ Groningen, KVI CART, NL-9747 AA Groningen, Netherlands..
    Mezzadri, G.
    Univ Ferrara, I-44122 Ferrara, Italy..
    Min, J.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Mitchell, R. E.
    Indiana Univ, Bloomington, IN 47405 USA..
    Mo, X. H.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Mo, Y. J.
    Cent China Normal Univ, Wuhan 430079, Peoples R China..
    Morales, C. Morales
    Helmholtz Inst Mainz, D-55099 Mainz, Germany..
    Muchnoi, N. Yu.
    GI Budker Inst Nucl Phys SB RAS BINP, Novosibirsk 630090, Russia..
    Muramatsu, H.
    Univ Minnesota, Minneapolis, MN 55455 USA..
    Musiol, P.
    Ruhr Univ Bochum, D-44780 Bochum, Germany..
    Nefedov, Y.
    Joint Inst Nucl Res, Dubna 141980, Moscow Region, Russia..
    Nerling, F.
    Helmholtz Inst Mainz, D-55099 Mainz, Germany..
    Nikolaev, I. B.
    GI Budker Inst Nucl Phys SB RAS BINP, Novosibirsk 630090, Russia..
    Ning, Z.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Nisar, S.
    COMSATS Inst Informat Technol, Lahore 54000, Pakistan..
    Niu, S. L.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Niu, X. Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Olsen, S. L.
    Seoul Natl Univ, Seoul 151747, South Korea..
    Ouyang, Q.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Pacetti, S.
    INFN, I-06100 Perugia, Italy.;Univ Perugia, I-06100 Perugia, Italy..
    Pan, Y.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Patteri, P.
    INFN Lab Nazl Frascati, I-00044 I- Frascati, Italy..
    Pelizaeus, M.
    Ruhr Univ Bochum, D-44780 Bochum, Germany..
    Peng, H. P.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Peters, K.
    GSI Helmholtzcentre Heavy Ion Res GmbH, D-64291 Darmstadt, Germany..
    Pettersson, Jean
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Ping, J. L.
    Nanjing Normal Univ, Nanjing 210023, Peoples R China..
    Ping, R. G.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Poling, R.
    Univ Minnesota, Minneapolis, MN 55455 USA..
    Prasad, V.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Qi, H. R.
    Beihang Univ, Beijing 100191, Peoples R China..
    Qi, M.
    Nanjing Univ, Nanjing 210093, Peoples R China..
    Qian, S.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Qiao, C. F.
    Chinese Acad Sci, Beijing 100049, Peoples R China..
    Qin, L. Q.
    Shandong Univ, Jinan 250100, Peoples R China..
    Qin, N.
    Wuhan Univ, Wuhan 430072, Peoples R China..
    Qin, X. S.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Qin, Z. H.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Qiu, J. F.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Rashid, K. H.
    Univ Punjab, Lahore 54590, Pakistan..
    Redmer, C. F.
    Johannes Gutenberg Univ Mainz, D-55099 Mainz, Germany..
    Ripka, M.
    Johannes Gutenberg Univ Mainz, D-55099 Mainz, Germany..
    Rong, G.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Rosner, Ch.
    Helmholtz Inst Mainz, D-55099 Mainz, Germany..
    Ruan, X. D.
    Guangxi Univ, Nanning 530004, Peoples R China..
    Sarantsev, A.
    Joint Inst Nucl Res, Dubna 141980, Moscow Region, Russia..
    Savrie, M.
    Univ Ferrara, I-44122 Ferrara, Italy..
    Schnier, C.
    Ruhr Univ Bochum, D-44780 Bochum, Germany..
    Schönning, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics. Uppsala University, The Svedberg Laboratory.
    Schumann, S.
    Johannes Gutenberg Univ Mainz, D-55099 Mainz, Germany..
    Shan, W.
    Peking Univ, Beijing 100871, Peoples R China..
    Shao, M.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Shen, C. P.
    Beihang Univ, Beijing 100191, Peoples R China..
    Shen, P. X.
    Nankai Univ, Tianjin 300071, Peoples R China..
    Shen, X. Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Sheng, H. Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Shi, M.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Song, W. M.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Song, X. Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Sosio, S.
    Univ Turin, I-10125 Turin, Italy.;INFN, I-10125 Turin, Italy..
    Spataro, S.
    Univ Turin, I-10125 Turin, Italy.;INFN, I-10125 Turin, Italy..
    Sun, G. X.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Sun, J. F.
    Henan Normal Univ, Xinxiang 453007, Peoples R China..
    Sun, S. S.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Sun, X. H.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Sun, Y. J.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Sun, Y. Z.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Sun, Z. J.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Sun, Z. T.
    Indiana Univ, Bloomington, IN 47405 USA..
    Tang, C. J.
    Sichuan Univ, Chengdu 610064, Peoples R China..
    Tang, X.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Tapan, I.
    Uludag Univ, TR-16059 Bursa, Turkey..
    Thorndike, E. H.
    Univ Rochester, Rochester, NY 14627 USA..
    Tiemens, M.
    Univ Groningen, KVI CART, NL-9747 AA Groningen, Netherlands..
    Uman, I.
    Near East Univ, Nicosia 10, Turkey..
    Varner, G. S.
    Univ Hawaii, Honolulu, HI 96822 USA..
    Wang, B.
    Nankai Univ, Tianjin 300071, Peoples R China..
    Wang, B. L.
    Chinese Acad Sci, Beijing 100049, Peoples R China..
    Wang, D.
    Peking Univ, Beijing 100871, Peoples R China..
    Wang, D. Y.
    Peking Univ, Beijing 100871, Peoples R China..
    Wang, K.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Wang, L. L.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Wang, L. S.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Wang, M.
    Shandong Univ, Jinan 250100, Peoples R China..
    Wang, P.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Wang, P. L.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Wang, S. G.
    Peking Univ, Beijing 100871, Peoples R China..
    Wang, W.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Wang, W. P.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Wang, X. F.
    Tsinghua Univ, Beijing 100084, Peoples R China..
    Wang, Y.
    Soochow Univ, Suzhou 215006, Peoples R China..
    Wang, Y. D.
    Helmholtz Inst Mainz, D-55099 Mainz, Germany..
    Wang, Y. F.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Wang, Y. Q.
    Johannes Gutenberg Univ Mainz, D-55099 Mainz, Germany..
    Wang, Z.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Wang, Z. G.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Wang, Z. H.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Wang, Z. Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Weber, T.
    Johannes Gutenberg Univ Mainz, D-55099 Mainz, Germany..
    Wei, D. H.
    Guangxi Normal Univ, Guilin 541004, Peoples R China..
    Wei, J. B.
    Peking Univ, Beijing 100871, Peoples R China..
    Weidenkaff, P.
    Johannes Gutenberg Univ Mainz, D-55099 Mainz, Germany..
    Wen, S. P.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Wiedner, U.
    Ruhr Univ Bochum, D-44780 Bochum, Germany..
    Wolke, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Wu, L. H.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Wu, L. J.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Wu, Z.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Xia, L.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Xia, L. G.
    Tsinghua Univ, Beijing 100084, Peoples R China..
    Xia, Y.
    Hunan Univ, Changsha 410082, Peoples R China..
    Xiao, D.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Xiao, H.
    Univ South China, Hengyang 421001, Peoples R China..
    Xiao, Z. J.
    Nanjing Normal Univ, Nanjing 210023, Peoples R China..
    Xie, Y. G.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Xiu, Q. L.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Xu, G. F.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Xu, J. J.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Xu, L.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Xu, Q. J.
    Hangzhou Normal Univ, Hangzhou 310036, Peoples R China..
    Xu, Q. N.
    Chinese Acad Sci, Beijing 100049, Peoples R China..
    Xu, X. P.
    Soochow Univ, Suzhou 215006, Peoples R China..
    Yan, L.
    Univ Turin, I-10125 Turin, Italy.;INFN, I-10125 Turin, Italy..
    Yan, W. B.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Yan, W. C.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Yan, Y. H.
    Hunan Univ, Changsha 410082, Peoples R China..
    Yang, H. J.
    Shanghai Jiao Tong Univ, Shanghai 200240, Peoples R China..
    Yang, H. X.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Yang, L.
    Wuhan Univ, Wuhan 430072, Peoples R China..
    Yang, Y. X.
    Guangxi Normal Univ, Guilin 541004, Peoples R China..
    Ye, M.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Ye, M. H.
    China Ctr Adv Sci & Technol, Beijing 100190, Peoples R China..
    Yin, J. H.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Yu, B. X.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Yu, C. X.
    Nankai Univ, Tianjin 300071, Peoples R China..
    Yu, J. S.
    Lanzhou Univ, Lanzhou 730000, Peoples R China..
    Yuan, C. Z.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Yuan, W. L.
    Nanjing Univ, Nanjing 210093, Peoples R China..
    Yuan, Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Yuncu, A.
    Istanbul Bilgi Univ, TR-34060 Istanbul, Turkey..
    Zafar, A. A.
    Univ Punjab, Lahore 54590, Pakistan..
    Zallo, A.
    INFN Lab Nazl Frascati, I-00044 I- Frascati, Italy..
    Zeng, Y.
    Hunan Univ, Changsha 410082, Peoples R China..
    Zeng, Z.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Zhang, B. X.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhang, B. Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhang, C.
    Nanjing Univ, Nanjing 210093, Peoples R China..
    Zhang, C. C.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhang, D. H.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhang, H. H.
    Sun Yat Sen Univ, Guangzhou 510275, Guangdong, Peoples R China..
    Zhang, H. Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhang, J.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhang, J. J.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhang, J. L.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhang, J. Q.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhang, J. W.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhang, J. Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhang, J. Z.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhang, K.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhang, L.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhang, S. Q.
    Nankai Univ, Tianjin 300071, Peoples R China..
    Zhang, X. Y.
    Shandong Univ, Jinan 250100, Peoples R China..
    Zhang, Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhang, Y. H.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhang, Y. N.
    Chinese Acad Sci, Beijing 100049, Peoples R China..
    Zhang, Y. T.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Zhang, Yu
    Chinese Acad Sci, Beijing 100049, Peoples R China..
    Zhang, Z. H.
    Cent China Normal Univ, Wuhan 430079, Peoples R China..
    Zhang, Z. P.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Zhang, Z. Y.
    Wuhan Univ, Wuhan 430072, Peoples R China..
    Zhao, G.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhao, J. W.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhao, J. Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhao, J. Z.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhao, Lei
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Zhao, Ling
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhao, M. G.
    Nankai Univ, Tianjin 300071, Peoples R China..
    Zhao, Q.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhao, Q. W.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhao, S. J.
    Zhengzhou Univ, Zhengzhou 450001, Peoples R China..
    Zhao, T. C.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhao, Y. B.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhao, Z. G.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Zhemchugov, A.
    Joint Inst Nucl Res, Dubna 141980, Moscow Region, Russia..
    Zheng, B.
    Univ South China, Hengyang 421001, Peoples R China..
    Zheng, J. P.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zheng, W. J.
    Shandong Univ, Jinan 250100, Peoples R China..
    Zheng, Y. H.
    Chinese Acad Sci, Beijing 100049, Peoples R China..
    Zhong, B.
    Nanjing Normal Univ, Nanjing 210023, Peoples R China..
    Zhou, L.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhou, X.
    Wuhan Univ, Wuhan 430072, Peoples R China..
    Zhou, X. K.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Zhou, X. R.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Zhou, X. Y.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhu, K.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhu, K. J.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhu, S.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhu, S. H.
    Univ Sci & Technol Liaoning, Anshan 114051, Peoples R China..
    Zhu, X. L.
    Tsinghua Univ, Beijing 100084, Peoples R China..
    Zhu, Y. C.
    Univ Sci & Technol China, Hefei 230026, Peoples R China..
    Zhu, Y. S.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhu, Z. A.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zhuang, J.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zotti, L.
    Univ Turin, I-10125 Turin, Italy.;INFN, I-10125 Turin, Italy..
    Zou, B. S.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Zou, J. H.
    Inst High Energy Phys, Beijing 100049, Peoples R China..
    Amplitude analysis of D0 -> K -π+π+π-2017In: Physical Review D: covering particles, fields, gravitation, and cosmology, ISSN 2470-0010, E-ISSN 2470-0029, Vol. 95, no 7, article id 072010Article in journal (Refereed)
    Abstract [en]

    We present an amplitude analysis of the decay D-0 -> K- pi(+)pi(+)pi(-) based on a data sample of 2.93 fb(-1) acquired by the BESIII detector at the psi(3770) resonance. With a nearly background free sample of about 16000 events, we investigate the substructure of the decay and determine the relative fractions and the phases among the different intermediate processes. Our amplitude model includes the two-body decays D-0 -> (K) over bar*(0)rho(0), D-0 -> K- a(1)(+) (1260) and D-0 -> K-1(-)(1270)pi(+), the three-body decays D-0 -> K-1(-)*(0)pi(+)pi(-) and D-0 -> K- pi(+)rho(0), as well as the four-body nonresonant decay D-0 -> K- pi(+)pi(+)pi(-). The dominant intermediate process is D-0 -> K(-)a(1)(+)(1260)accounting for a fit fraction of 54.6%.

  • 6.
    Abramsson, Mia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Production and characterization of Acetylcholine Binding Protein2018Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 7.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Musunuri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Proteomic differences between focal and diffuse traumatic brain injury in human brain tissue2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 6807Article in journal (Refereed)
    Abstract [en]

    The early molecular response to severe traumatic brain injury (TBI) was evaluated using biopsies of structurally normal-appearing cortex, obtained at location for intracranial pressure (ICP) monitoring, from 16 severe TBI patients. Mass spectrometry (MS; label free and stable isotope dimethyl labeling) quantitation proteomics showed a strikingly different molecular pattern in TBI in comparison to cortical biopsies from 11 idiopathic normal pressure hydrocephalus patients. Diffuse TBI showed increased expression of peptides related to neurodegeneration (Tau and Fascin, p < 0.05), reduced expression related to antioxidant defense (Glutathione S-transferase Mu 3, Peroxiredoxin-6, Thioredoxin-dependent peroxide reductase; p < 0.05) and increased expression of potential biomarkers (e.g. Neurogranin, Fatty acid-binding protein, heart p < 0.05) compared to focal TBI. Proteomics of human brain biopsies displayed considerable molecular heterogeneity among the different TBI subtypes with consequences for the pathophysiology and development of targeted treatments for TBI.

  • 8.
    Afifi, Hala
    et al.
    Institute of Pharmaceutical Science, King’s College London, UK.
    Karlsson, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Heenan, Richard K.
    ISIS-CCLRC, Rutherford Appleton Laboratory, Chilton, UK.
    Dreiss, Cécile A.
    Institute of Pharmaceutical Science, King’s College London, UK.
    Structural transitions in cholesterol-based wormlike micelles induced by encapsulating alkyl ester oils with varying architecture2012In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 378, no 1, p. 125-134Article in journal (Refereed)
    Abstract [en]

    The effect of encapsulating oils on the phase behaviour and the microstructure of wormlike micelles formed by polyoxyethylene cholesteryl ether (ChEO10) and triethylene glycol monododecyl ether co-surfactant (C12EO3) was investigated using rheology, Cryo-TEM and small-angle neutron scattering measurements. Six alkyl ester oils bearing small, systematic variations in their molecular structure were encapsulated: ethyl butyrate (EB24), ethyl caproate (ECO26), ethyl caprylate (EC28), methyl enanthate (ME17), methyl caprylate (MC18) and butyl butyrate (BB44), where the subscripts refer to the length of the alkyl chain and fatty acid chain, respectively, on either sides of the ester link. The addition of alkyl ester oils to ChEO10/C12EO3 solutions promotes the longitudinal growth of the surfactant aggregates into wormlike micelles possessing an elliptical cross-section, with rminor 31&#xa0;±&#xa0;2&#xa0;Å and rmajor varying from 45 to 70&#xa0;Å. At fixed alkyl chain length, oils with longer fatty acid chains were found to be more efficient in inducing wormlike micelle formation or their elongation, following the order: EC28&#xa0;&gt;&#xa0;ECO26&#xa0;&gt;&#xa0;EB24. Instead, at fixed fatty acid chain length, increasing the alkyl chain has a negative effect on the longitudinal micellar growth (MC18&#xa0;&gt;&#xa0;EC28 and EB24&#xa0;&gt;&#xa0;BB44). At high co-surfactant concentrations and in the presence of EB24, an unusual phase of ring-like micelles was detected. Overall, the orientation of the oil molecules within the micelles enables them to act as co-surfactants with a small head-group, decreasing the average cross-section area and promoting longitudinal growth of the micelles into worms.

  • 9.
    Agalo, Faith
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Synthesis of Insulin-Regulated Aminopeptidase (IRAP) inhibitors2015Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The need for alternative cognitive enhancers has risen due to the fact that clinical trial results of the drugs currently approved for treating these disorders have not been satisfactory.

    IRAP has become a possible drug target for treating cognitive impairment brought about by Alzheimer’s disease, head trauma or cerebral ischemia, among others. This came after the revelation that Angiotensin IV enhances memory and learning. Angiotensin IV, the endogenous ligand of IRAP has been structurally modified with the aim of producing potent IRAP inhibitors. However, the peptidic nature of these inhibitors restricts their use; they are not likely to cross the blood brain barrier.

    Other strategies for generating IRAP inhibitors have been through structure-based design and receptor based virtual screening. These drug-like molecules have exhibited positive results in animal studies.

    IRAP inhibitors have been identified via a HTS of 10500 low-molecular weight compounds to give the hit based on a spirooxindole dihydroquinazolinone scaffold, with an IC50 value of 1.5 µM. In this project, some analogues to this hit compound have successfully been synthesized using a known method, whereas others have been synthesized after additional method development.

    The application of the developed method was found to be limited, because poor yield was obtained when a compound with an electron withdrawing substituent on the aniline was synthesized. As a result of this, modification of this method may be required or new methods may have to be developed to synthesize these types of analogues.

    Inhibition capability of 5 new spirooxindole dihydroquinazolinones was tested through a biochemical assay. Compound 6e emerged as the most potent inhibitor in the series, with an IC50 value of 0.2 µM. This compound will now serve as a lead compound and should be used as a starting point for future optimization in order to generate more potent IRAP inhibitors.

     

  • 10.
    Agmo Hernández, Víctor
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Eriksson, Emma K.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Edwards, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Ubiquinone-10 alters mechanical properties and increases stability of phospholipid membranes2015In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1848, no 10, p. 2233-2243Article in journal (Refereed)
    Abstract [en]

    Abstract Ubiquinone-10 is mostly known for its role as an electron and proton carrier in aerobic cellular respiration and its function as a powerful antioxidant. Accumulating evidence suggest, however, that this well studied membrane component could have several other important functions in living cells. The current study reports on a previously undocumented ability of ubiquinone-10 to modulate the mechanical strength and permeability of lipid membranes. Investigations of DPH fluorescence anisotropy, spontaneous and surfactant induced leakage of carboxyfluorescein, and interactions with hydrophobic and hydrophilic surfaces were used to probe the effects caused by inclusion of ubiquinone-10 in the membrane of phospholipid liposomes. The results show that ubiquinone in concentrations as low as 2&#xa0;mol.% increases the lipid packing order and condenses the membrane. The altered physicochemical properties result in a slower rate of release of hydrophilic components, and render the membrane more resistant towards rupture. As judged from comparative experiments using the polyisoprenoid alcohol solanesol, the quinone moiety is essential for the membrane stabilizing effects to occur. Our findings imply that the influence of ubiquinone-10 on the permeability and mechanical properties of phospholipid membranes is similar to that of cholesterol. The reported data indicate, however, that the molecular mechanisms are different in the two cases.

  • 11.
    Agmo Hernández, Víctor
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Lendeckel, Uwe
    Institut für Medizinische Biochemie und Molekularbiologie, Universitätsmedizin Greifswald, Germany.
    Scholz, Fritz
    Institut für Biochemie, Universität Greifswald, Germany.
    Electrochemistry of Adhesion and Spreading of Lipid Vesicles on Electrodes2013In: Applications of Electrochemistry in Medicine / [ed] Schlesinger, Mordechay, Springer US , 2013, Vol. 56, p. 189-247Chapter in book (Other academic)
    Abstract [en]

    Biological membranes have developed to separate different compartments of organisms and cells. There is a large number of rather different functions which membranes have to fulfil: (1) they control the material and energy fluxes of metabolic processes, (2) they provide a wrapping protecting the compartments from chemical and physical attacks of the environment, (3) they provide interfaces at which specific biochemical machineries can operate (e.g., membrane bound enzymes), (4) they are equipped for signal transduction, (5) they possess the necessary stability and flexibility to allow cell division, and endo- and exocytosis as well as migration, (6) they present anchoring structures that enable cell-to-cell and cell-to-matrix physical interactions and intercellular communication. These are certainly not all functions of membranes as new functionalities are continuously reported. Since the biological membranes separate essentially aqueous solutions, such separating borders—if they should possess a reasonable stability and also flexibility combined with selective permeability—have to be built up of hydrophobic molecules exposing to both sides a similar interface. It was one of the most crucial and most lucky circumstances for the development and existence of life that certain amphiphilic molecules are able to assemble in bilayer structures (membranes), which—on one side—possess a rather high physical and chemical stability, and—on the other side—are able to incorporate foreign molecules for modifying both the physical properties as well as the permeability of the membranes for defined chemical species. The importance of the chemical function of membranes and all its constituents, e.g., ion channels, pore peptides, transport peptides, etc., is generally accepted. The fluid-mosaic model proposed by Singer and Nicolson [1] is still the basis to understand the biological, chemical, and physical properties of biological membranes. The importance of the purely mechanical properties of membranes came much later into the focus of research. The reasons are probably the dominance of biochemical thinking and biochemical models among biologists and medical researchers, as well as a certain lack of appropriate methods to probe mechanical properties of membranes. The last decades have changed that situation due to the development of techniques like the Atomic Force Microscopy, Fluorescence Microscopy, Micropipette Aspiration, Raman Microspectroscopy, advanced Calorimetry, etc. This chapter is aimed at elucidating how the properties of membranes can be investigated by studying the interaction of vesicles with a very hydrophobic surface, i.e., with the surface of a mercury electrode. This interaction is unique as it results in a complete disintegration of the bilayer membrane of the vesicles and the formation of an island of adsorbed lipid molecules, i.e., a monolayer island. This process can be followed by current-time measurements (chronoamperometry), which allow studying the complete disintegration process in all its details: the different steps of that disintegration can be resolved on the time scale and the activation parameters can be determined. Most interestingly, the kinetics of vesicle disintegration on mercury share important features with the process of vesicle fusion and, thus, sheds light also on mechanisms of endocytosis and exocytosis. Most importantly, not only artificial vesicles (liposomes) can be studied with this approach, but also reconstituted plasma membrane vesicles and even intact mitochondria. Hence, one can expect that the method may provide in future studies also information on the membrane properties of various other vesicles, including exosomes, and may allow investigating various aspects of drug action in relation to membrane properties (transmembrane transport, tissue targeting, bioavailability, etc.), and also the impact of pathophysiological conditions (e.g., oxidative modification) on membrane properties, on a hitherto not or only hardly accessible level.

  • 12.
    Agmo Hernández, Víctor
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Reijmar, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Edwards, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Label-Free Characterization of Peptide-Lipid Interactions Using Immobilized Lipodisks2013In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 85, no 15, p. 7377-7384Article in journal (Refereed)
    Abstract [en]

    Lipodisks, planar lipid bilayer structures stabilized by PEG-ylated lipids, were in the present study covalently bound and immobilized onto sensors for quartz crystal microbalance with dissipation monitoring (QCM-D) studies. It is shown that the modified sensors can be used to characterize the interaction of lipodisks with α-helical amphiphilic peptides with an accuracy similar to that obtained with well established fluorimetric approximations. The method presented has the great advantage that it can be used with peptides in their native form even if no fluorescent residues are present. The potential of the method is illustrated by determining the parameters describing the association of melittin, mastoparan X, and mastoparan with immobilized lipodisks. Both thermodynamic and kinetic analyses are possible. The presented method constitutes a useful tool for fundamental studies of peptide–membrane interactions and can also be applied to optimize the design of lipodisks, for example, for sustained release of antimicrobial peptides in therapeutic applications.

  • 13.
    Agmo Hernández, Víctor
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Samuelsson, Jörgen
    Department of Engineering and Chemical Sciences, Karlstad University, SE-651 88 Karlstad, Sweden.
    Forssén, Patrik
    Department of Engineering and Chemical Sciences, Karlstad University, SE-651 88 Karlstad, Sweden.
    Fornstedt, Torgny
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Department of Engineering and Chemical Sciences, Karlstad University, SE-651 88 Karlstad, Sweden.
    Enhanced interpretation of adsorption data generated by liquid chromatography and by modern biosensors2013In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1317, no SI, p. 22-31Article in journal (Refereed)
    Abstract [en]

    In this study we demonstrate the importance of proper data processing in adsorption isotherm estimations. This was done by investigating and reprocessing data from five cases on two closely related platforms: liquid chromatography (LC) and biosensors. The previously acquired adsorption data were reevaluated and reprocessed using a three-step numerical procedure: (i) preprocessing of adsorption data, (ii) adsorption data analysis and (iii) final rival model fit. For each case, we will discuss what we really measure and what additional information can be obtained by numerical processing of the data. These cases clearly demonstrate that numerical processing of LC and biosensor data can be used to gain deeper understanding of molecular interactions with adsorption media. This is important because adsorption data, especially from biosensors, is often processed using old and simplified methods.

  • 14.
    Agmo Hernández, Víctor
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    The theory of metal electronucleation applied to the study of fundamental properties of liposomes2013In: Journal of Solid State Electrochemistry, ISSN 1432-8488, E-ISSN 1433-0768, Vol. 17, no 2 (SI), p. 299-305Article, review/survey (Refereed)
    Abstract [en]

    This short review describes how the theory of electrochemical metal nucleation considering non-stationary effects due to the activation of latent nucleation sites has been successfully translated and applied to describe phenomena observed on lipid membranes. This rather unexpected connection is merely formal, but has resulted in a completely new approach in liposome research. It has been proposed that hydrophobic active sites spontaneously and constantly appear and disappear on lipid membranes. These sites control the affinity of liposomes for hydrophobic surfaces and determine the permeability of the lipid membrane to small hydrophilic molecules. Thus, the kinetic models for liposome adhesion on hydrophobic substrates and for the spontaneous leakage of liposomal content are identical to that of non-stationary nucleation mentioned above. Therefore, the broad scope of the available work on metal nucleation has facilitated the interpretation of the data obtained in liposome research. Future applications of the nucleation model in the realm of liposomes are also discussed.

  • 15.
    Ahlgren, Sara
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Fondell, Amelie
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Gedda, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Swedish Radiat Safety Author, Res Unit, Solna Strandvag 96, SE-17116 Stockholm, Sweden.
    Edwards, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    EGF-targeting lipodisks for specific delivery of poorly water-soluble anticancer agents to tumour cells2017In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 7, no 36, p. 22178-22186Article in journal (Refereed)
    Abstract [en]

    Concerns regarding poor aqueous solubility, high toxicity and lack of specificity impede the translation of many hydrophobic anticancer agents into safe and effective anticancer drugs. The application of colloidal drug delivery systems, and in particular the use of lipid-based nanocarriers, has been identified as a promising means to overcome these issues. PEG-stabilized lipid nanodisks (lipodisks) have lately emerged as a novel type of biocompatible, nontoxic and adaptable drug nanocarrier. In this study we have explored the potential of lipodisks as a platform for formulation and tumour targeted delivery of hydrophobic anticancer agents. Using curcumin as a model compound, we show that lipodisks can be loaded with substantial amounts of hydrophobic drugs (curcumin/lipid molar ratio 0.15). We demonstrate moreover that by deliberate choice of preparation protocols the lipodisks can be provided with relevant amounts of targeting proteins, such as epidermal growth factor (EGF). Data from in vitro cell studies verify that such EGF-decorated curcumin-loaded lipodisks are capable of EGF-receptor specific targeting of human A-431 tumour cells, and strongly suggest that the interaction between the lipodisks and the tumour cells results in receptor-mediated internalization of the disks and their cargo.

  • 16. Ahlgren, Sara
    et al.
    Reijmar, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Edwards, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    EGF-targeting lipodisks for specific delivery of cationic amphiphilic peptides to tumour cellsManuscript (preprint) (Other academic)
  • 17.
    Ahlgren, Sara
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Reijmar, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Edwards, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Targeting lipodisks enable selective delivery of anticancer peptides to tumor cells2017In: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 13, no 7, p. 2325-2328Article in journal (Refereed)
    Abstract [en]

    Issues concerning non-specificity, degradation and hemolysis severely hamper the development of membranolytic amphiphilic peptides into safe and efficient anticancer agents. To increase the therapeutic potential, we have previously developed a strategy based on formulation of the peptides in biocompatible nanosized lipodisks. Studies using melittin as model peptide show that the proteolytic degradation and hemolytic effect of the peptide are substantially reduced upon loading in lipodisks. Here, we explored the possibilities to increase the specificity and boost the cytotoxicity of melittin to tumor cells by use of targeting lipodisk. We demonstrate that small (~20 nm) EGF-targeted lipodisks can be produced and loaded with substantial amounts of peptide (lipid/peptide molar ratio >7) by means of a simple and straightforward preparation protocol. In vitro cell studies confirm specific binding of the peptide-loaded disks to tumor cells and suggest that cellular internalization of the disks results in a significantly improved cell-killing effect.

  • 18.
    Ahmad, Shabbir
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Hysteretic Behavior, Regioselectivity, and Role of Salt Bridging Residues at the Domain Interface of Potato Epoxide Hydrolase StEH1, Site-Directed Mutagenesis and Kinetic Study2009Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
  • 19.
    Aksoy, N. H.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Aksaray Univ, Dept Biochem, Aksaray, Turkey..
    Mannervik, B.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Inhibitory effects of ethacrynic acid on glutathione S-transferase A1-1 from Callithrix jacchus2015In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 282, p. 348-348Article in journal (Other academic)
  • 20.
    Ali Ahmed, Said
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Investigation of epoxide hydrolase activity in Saccharomyces cerevisiae ORF YNR064c protein2013Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 21. Ali, M. A. E.
    et al.
    Abdel-Fatah, O. M.
    Janson, Jan-Christer
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Elshafei, A. M.
    Antimicrobial potential of Saccharomyces boulardii extracts and fractions2012In: Journal of Applied Sciences Research, ISSN 1816-157X, E-ISSN 1819-544X, Vol. 8, no 8, p. 4537-4543Article in journal (Refereed)
    Abstract [en]

    Different extracts of viable therapeutic Saccharomyces boulardii cells were evaluated for their antimicrobial activities against Escherichia coli and Candida albicans. Water, methanol, isopropanol, n-butanol and ethanol were used as solvents for extraction. Ethanol-extract exhibited the highest antimicrobial activity towards both strains, followed by water-extract. No antimicrobial activity could be detected on testing methanol-extract towards both strains. Ethanol- and water-extracts, cells remaining after water and ethanol extraction and broth were also tested for their antimicrobial activities against Gram-positive, Gram-negative, non-filamentous and filamentous fungi and showed considerable amounts of antimicrobial activities. Ethanol extracts exhibited the highest antimicrobial activity against all the tested strains, was then fractionated on a Sephadex G-100 column and the obtained fractions were examined using the agar-well diffusion method against Staphylococcus aureus, E.coli, C. albicans and Aspergillus niger. Results obtained indicate the presence of different scattered active fractions with different potencies against the four tested microorganisms. A large scale fermentation process was conducted using a BioFlo benchtop-15L Fermentor/ Bioreactor and the products were evaluated for their antimicrobial activities.

  • 22.
    Almandoz-Gil, Leire
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Welander, Hedvig
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ihse, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Khoonsari, Payam Emami
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Musunuri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Lendel, Christofer
    KTH Royal Inst Technol, Dept Chem, Stockholm, Sweden.
    Sigvardson, Jessica
    BioArctic AB, Stockholm, Sweden.
    Karlsson, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Corrigendum to “Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways” [Free Rad. Biol. Med. (2017) 421–431]2018In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 117, p. 258-258Article in journal (Other academic)
  • 23.
    Almandoz-Gil, Leire
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Welander, Hedvig
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ihse, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Khoonsari, Payam Emami
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Musunuri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Lendel, Christofer
    KTH, Royal Institute of Technology, Sweden.
    Sigvardson, Jessica
    BioArctic AB, Sweden.
    Karlsson, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways2017In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 110, p. 421-431Article in journal (Refereed)
    Abstract [en]

    Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal inclusions found in brains with Parkinson's disease and dementia with Lewy bodies. A body of evidence implicates oxidative stress in the pathogenesis of these diseases. For example, a large excess (30:1, aldehyde:protein) of the lipid peroxidation end products 4-oxo-2-nonenal (ONE) or 4-hydroxy-2-nonenal (HNE) can induce alpha-synuclein oligomer formation. The objective of the study was to investigate the effect of these reactive aldehydes on alpha-synuclein at a lower molar excess (3:1) at both physiological (7.4) and acidic (5.4) pH. As observed by size-exclusion chromatography, ONE rapidly induced the formation of alpha-synuclein oligomers at both pH values, but the effect was less pronounced under the acidic condition. In contrast, only a small proportion of alpha-synuclein oligomers were formed with low excess HNE-treatment at physiological pH and no oligomers at all under the acidic condition. With prolonged incubation times (up to 96 h), more alpha-synuclein was oligomerized at physiological pH for both ONE and HNE. As determined by Western blot, ONE-oligomers were more SDS-stable and to a higher-degree cross-linked as compared to the HNE-induced oligomers. However, as shown by their greater sensitivity to proteinase K treatment, ONE-oligomers, exhibited a less compact structure than HNE-oligomers. As indicated by mass spectrometry, ONE modified most Lys residues, whereas HNE primarily modified the His50 residue and fewer Lys residues, albeit to a higher degree than ONE. Taken together, our data show that the aldehydes ONE and HNE can modify alpha-synuclein and induce oligomerization, even at low molar excess, but to a higher degree at physiological pH and seemingly through different pathways.

  • 24.
    Almaqwashi, Ali A.
    et al.
    Northeastern Univ, Dept Phys, Boston, MA 02115 USA..
    Andersson, Johanna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Chalmers, Dept Chem & Chem Engn, S-41296 Gothenburg, Sweden..
    Lincoln, Per
    Chalmers, Dept Chem & Chem Engn, S-41296 Gothenburg, Sweden..
    Rouzina, Ioulia
    Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA..
    Westerlund, Fredrik
    Chalmers, Dept Biol & Biol Engn, S-41296 Gothenburg, Sweden..
    Williams, Mark C.
    Northeastern Univ, Dept Phys, Boston, MA 02115 USA..
    Dissecting the Dynamic Pathways of Stereoselective DNA Threading Intercalation2016In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 110, no 6, p. 1255-1263Article in journal (Refereed)
    Abstract [en]

    DNA intercalators that have high affinity and slow kinetics are developed for potential DNA-targeted therapeutics. Although many natural intercalators contain multiple chiral subunits, only intercalators with a single chiral unit have been quantitatively probed. Dumbbell-shaped DNA threading intercalators represent the next order of structural complexity relative to simple intercalators, and can provide significant insights into the stereoselectivity of DNA-ligand intercalation. We investigated DNA threading intercalation by binuclear ruthenium complex [mu-dppzip(phen)(4)Ru-2](4+) (Piz). Four Piz stereoisomers are defined by the chirality of the intercalating subunit (Ru(phen)(2)dppz) and the distal subunit (Ru(phen)(2)ip), respectively, each of which can be either right-handed (Delta) or left-handed (Lambda). We used optical tweezers to measure single DNA molecule elongation due to threading intercalation, revealing force-dependent DNA intercalation rates and equilibrium dissociation constants. The force spectroscopy analysis provided the zero-force DNA binding affinity, the equilibrium DNA-ligand elongation Delta x(eq), and the dynamic DNA structural deformations during ligand association x(on) and dissociation x(off). We found that Piz stereoisomers exhibit over 20-fold differences in DNA binding affinity, from a K-d of 27 +/- 3 nM for (Delta,Lambda)-Piz to a K-d of 622 +/- 55 nM for (Lambda,Delta)-Piz. The striking affinity decrease is correlated with increasing Delta x(eq) from 0.30 +/- 0.02 to 0.48 +/- 0.02 nm and x(on) from 0.25 +/- 0.01 to 0.46 +/- 0.02 nm, but limited x(off) changes. Notably, the affinity and threading kinetics is 10-fold enhanced for right-handed intercalating subunits, and 2- to 5-fold enhanced for left-handed distal subunits. These findings demonstrate sterically dispersed transition pathways and robust DNA structural recognition of chiral intercalators, which are critical for optimizing DNA binding affinity and kinetics.

  • 25.
    Almaqwashi, Ali A.
    et al.
    Northeastern Univ, Dept Phys, Boston, MA 02115 USA.;King Abdulaziz Univ, Dept Phys, Rabigh 21911, Saudi Arabia..
    Andersson, Johanna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Chalmers, Dept Chem & Chem Engn, SE-41296 Gothenburg, Sweden..
    Lincoln, Per
    Chalmers, Dept Chem & Chem Engn, SE-41296 Gothenburg, Sweden..
    Rouzina, Ioulia
    Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA..
    Westerlund, Fredrik
    Chalmers, Dept Biol & Biol Engn, SE-41296 Gothenburg, Sweden..
    Williams, Mark C.
    Northeastern Univ, Dept Phys, Boston, MA 02115 USA..
    DNA intercalation optimized by two-step molecular lock mechanism2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 37993Article in journal (Refereed)
    Abstract [en]

    The diverse properties of DNA intercalators, varying in affinity and kinetics over several orders of magnitude, provide a wide range of applications for DNA-ligand assemblies. Unconventional intercalation mechanisms may exhibit high affinity and slow kinetics, properties desired for potential therapeutics. We used single-molecule force spectroscopy to probe the free energy landscape for an unconventional intercalator that binds DNA through a novel two-step mechanism in which the intermediate and final states bind DNA through the same mono-intercalating moiety. During this process, DNA undergoes significant structural rearrangements, first lengthening before relaxing to a shorter DNA-ligand complex in the intermediate state to form a molecular lock. To reach the final bound state, the molecular length must increase again as the ligand threads between disrupted DNA base pairs. This unusual binding mechanism results in an unprecedented optimized combination of high DNA binding affinity and slow kinetics, suggesting a new paradigm for rational design of DNA intercalators.

  • 26.
    Almaqwashi, Ali A.
    et al.
    Northeastern Univ, Dept Phys, Boston, MA 02115 USA..
    Andersson, Johanna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Chalmers, Dept Chem & Biol Engn, S-41296 Gothenburg, Sweden..
    Lincoln, Per
    Chalmers, Dept Chem & Biol Engn, S-41296 Gothenburg, Sweden..
    Rouzina, Ioulia
    Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN USA..
    Westerlund, Fredrik
    Chalmers, Dept Chem & Biol Engn, S-41296 Gothenburg, Sweden..
    Williams, Mark C.
    Northeastern Univ, Dept Phys, Boston, MA 02115 USA..
    Resolving the DNA Binding Mode of a Rotationally Flexible Binuclear Ruthenium Complex2015In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 108, no 2, p. 396A-396AArticle in journal (Other academic)
  • 27.
    Almokhtar, Mokhtar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wikvall, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ubhayasekera, S. J. Kumari A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Norlin, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Motor neuron-like NSC-34 cells as a new model for the study of vitamin D metabolism in the brain.2016In: Journal of Steroid Biochemistry and Molecular Biology, ISSN 0960-0760, E-ISSN 1879-1220, Vol. 158, p. 178-188Article in journal (Refereed)
    Abstract [en]

    Vitamin D-3 is a pro-hormone, which is sequentially activated by 25- and 1 alpha-hydroxylation to form 25-hydroxyvitamin D-3 [25(OH)D-3] and 1 alpha,25-dihydroxyvitamin D-3 [1 alpha,25(OH)2D(3)], respectively. Subsequent inactivation is performed by 24-hydroxylation. These reactions are carried out by a series of CYP450 enzymes. The 25-hydroxylation involves mainly CYP2R1 and CYP27A1, whereas 1 alpha-hydroxylation and 24-hydroxylation are catalyzed by CYP27B1 and CYP24A1, respectively, and are tightly regulated to maintain adequate levels of the active vitamin D hormone, 1 alpha,25(OH)(2)D-3. Altered circulating vitamin D levels, in particular 25(OH)D-3, have been linked to several disorders of the nervous system, e.g., schizophrenia and Parkinson disease. However, little is known about the mechanisms of vitamin D actions in the neurons. In this study, we examined vitamin D metabolism and its regulation in a murine motor neuron-like hybrid cell line, NSC-34. We found that these cells express mRNAs for the four major CYP450 enzymes involved in vitamin D activation and inactivation, and vitamin D receptor (VDR) that mediates vitamin D actions. We also found high levels of CYP24A1-dependent 24,25-dihydroxyvitamin D-3 [24,25(OH)(2)D-3] production, that was inhibited by the well-known CYP enzyme inhibitor ketoconazole and by several inhibitors that are more specific for CYP24A1. Furthermore, CYP24A1 mRNA levels in NSC-34 cells were up-regulated by 1 alpha,25(OH)(2)D-3 and its synthetic analogs, EB1089 and tacalcitol. Our results suggest that NSC-34 cells could be a novel model for the studies of neuronal vitamin D metabolism and its mechanism of actions.

  • 28.
    al-smadi, Derar
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Enugala, Thilak Reddy
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Norberg, Thomas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Kessler, Vadim
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Widersten, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    A Comparison of Synthetic Approaches to Derivatives of 1,4-Substituted 2,3 DihydroxybutanonesManuscript (preprint) (Other academic)
  • 29.
    Al-Smadi, Derar
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Enugala, Thilak Reddy
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Norberg, Thomas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Widersten, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Synthesis of substrates for aldolase-catalyzed reactions: A comparison of methods for the synthesis of substituted phenylacetaldehydes2018In: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, Vol. 29, no 9, p. 1187-1190Article in journal (Refereed)
    Abstract [en]

    Methods for the synthesis of phenylacetaldehydes (oxidation, one-carbon chain extension) were compared by using the synthesis of 4-methoxyphenylacetaldehyde as a model example. Oxidations of 4-methoxyphenylethanol with activated DMSO (Swern oxidation) or manganese dioxide gave unsatisfactory results; whereas oxidation with 2-iodoxybenzoic add (IBX) produced 4-methoxyphenylacetaldehyde in reasonable (75%) yield. However, Wittig-type one-carbon chain extension with methoxymethylene-triphenylphosphine followed by hydrolysis gave an excellent (81% overall) yield of 4-methoxyphenylacetaldehyde from 4-methoxybenzaldehyde (a cheap starting material). This approach was subsequently used to synthesise a set of 10 substituted phenylacetaldehydes in good to excellent yields.

  • 30.
    Alvi, Muhammad Rouf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Low-coordinate Organosilicon Chemistry: Fundamentals, Excursions Outside the Field, and Potential Applications2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis reports on unsaturated silicon compounds, as well as excursions from these into germanium chemistry, single molecule electronics, and silyl protective group chemistry. Both experimental and computational investigations were performed.

    Potassium germenolates were synthesized through reactions of tris(timethylsilyl) substituted acyl- and carbamylgermanes with potassium tert-butoxide. The potassium germenolates calculated by density functional theory have pyramidal structures at the Ge atoms, similar to the Si in the corresponding potassium silenolates, indicating negative charge on germanium rather than on oxygen. Germenolates also display germyl anion-like reactivity instead of germene-like reactivity as they are alkylated at Ge and initiate anionic polymerization of dienes rather than form [4+2] cycloadducts. The NMR chemical shifts reveal more negative charge at Ge in germenolates than at Si in analogous silenolates.

    Computations indicate that silabenzenes and silapyridines are reachable via [1,3]-silyl shifts from cyclic conjugated acylsilanes. Differently sized substituents were considered to prevent dimerizations, and 1-triisopropylsilyl-2-triisopropylsiloxy-6-tert-butylsilabenzene is a good synthetic target. Computations also show that silaphenolates are species with negative charge primarily localized at oxygen atom. Their planar structures, bond lengths, and NICS values reveal significant influence of aromaticity. Electrostatic repulsion should increase their stability, however, steric bulk is also important.

    Furthermore, it was found computationally that [1,3]-silyl shift from an acylsilane to a silene can function as a molecular switch reaction. Conductance calculations support this proposition.  

    Finally, tris(trimethylsilyl)silylmethaneamide (hypersilylamide) together with catalytic amounts of triflic acid were found to be efficient for protection of a range of alkyl and aryl alcohols and thiols in good to excellent yields. The protocol can be used to protect the less hindered OH group of a diol and has a broad functional group tolerance. A catalytic cycle is proposed. Hypersilyl protected alcohols and thiols are deprotected efficiently under photolytic conditions.

  • 31.
    Alvi, Muhammad Rouf
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Anas, Saithalavi
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Emanuelsson, Rikard
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Lozinski, Kaitlin
    Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC) and Department of Chemistry, University of Richmond, UR 1099, 28 Westhampton Way, VA 23173, USA.
    Ottosson, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Scope and Limitations of an Acid Catalyzed Protocol for Hypersilyl Protection of Alcohols Manuscript (preprint) (Other academic)
    Abstract [en]

    A highly efficient and convenient triflic acid (TfOH) catalyzed protocol for the protection of various functionalized alcohols in CH2Cl2 at ambient temperature using tris(trimethylsilyl)silyl-N,N-dimethyl-methaneamide (hypersilylamide) 1 as the protecting reagent is developed. Herein, results on the scope and limitations of this protocol for a number of functionalized alcohols are presented. This method was found to be effective for the selective protection of less hindered OH groups in different classes of diols containing both pri/tert, sec/tert, or aromatic/aliphatic hydroxyl groups. In general, our protocol exhibited excellent functional group tolerance in the protection of alcohols containing alkoxy, keto, amino, as well as halo substituents in good to excellent yields.

  • 32.
    Alvi, Muhammad Rouf
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Burkhard O., Jahn
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Ottosson, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Computational Investigation of Brook-Type Silabenzenes and Their Possible Formation through [1,3]-Si -> O Silyl Shifts2013In: Organometallics, ISSN 0276-7333, E-ISSN 1520-6041, Vol. 32, no 1, p. 16-28Article in journal (Refereed)
    Abstract [en]

    Quantum chemical calculations with the M062X hybrid meta density functional theory method were performed in order to examine formation of Brook-type silabenzenes 4a 4l, silapyridines 6a 6d, and five-membered ring silaheteroaromatics 8a8d through [1,3]-trimethylsilyl (TMS) and [1,3]-tri(isopropyl)silyl (TIPS) shifts from a tetrahedral silicon atom to an adjacent carbonyl oxygen of cyclic conjugated acylsilane precursors. All Brook-type silabenzenes and silapyridines, having a 2-trialkylsiloxy substituent, are at lower relative energies than their precursors, whereas silaheteroaromatics 8a 8d are found at slightly higher energies. The free energies of activation for the thermal [1,3]-TMS shifts range from 29 to 44 kcal/mol, with the lowest for a Brook-type silapyridine and the highest for a silafuran. The geometries of the Brook-type silabenzenes, silapyridines, silafuran and silathiophene indicate aromatic character, but the silapyrroles are nonaromatic. At M062X/6-311+G(d)//M062X/6-31G(d) level all Brook-type silabenzene dimers studied herein are more stable than two silabenzenes, also for a silabenzene with bulky TIPS, OTIPS and tert-butyl substituents (4l). Yet, comparisons of the B3LYP/6-31G(d) dimerization energies of 4l with that of the isolable 1-Tbt-silabenzene (Tbt = 2,4,6-tris[bis(trimethylsilyl)methyl]phenyl) of Tokitoh [J. Chin. Chem. Soc. 2008, 55, 487] indicate that 4l will also be a monomeric silabenzene, and thus, a suitable synthetic target.

  • 33.
    Alvi, Muhammad Rouf
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Jahn, Burkhard O.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Tibbelin, Julius
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Baumgartner, Judith
    Institut für Anorganische Chemie, Technische Universität Graz, Stremayrgasse 9, A-8010 Graz, Austria.
    Gómez, Cesar Pay
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Structural Chemistry.
    Ottosson, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Highly Efficient and Convenient Acid Catalyzed Hypersilyl Protection of Alcohols and Thiols by Tris(trimethylsilyl)silyl-N,N-dimethylmethaneamide2012Article in journal (Other academic)
    Abstract [en]

    Tris(trimethylsilyl)silyl-N,N-dimethylmethaneamide, herein named hypersilylamide, is a convenient and efficient source of the hypersilyl group in the first widely applicable acid catalyzed protocol for silyl group protection of primary, secondary, tertiary alkyl as well as aryl alcohols and thiols in high yields. The sole by-product is N,N-dimethylformamide (DMF) and a range of solvents can be used, including DMF. A high selectivity in the protection of diols can be achieved, also for diols with very small differences in the steric demands at the two hydroxyl groups. Moreover, in the protection of equivalent alcohol and thiol sites the protection of the alcohol is faster, allowing for selective protection in high yields. Quantum chemical calculations at the M062X hybrid meta density functional theory level give insights on the mechanism for the catalytic process. Finally, the hypersilyl group is easily removed from all protected alcohols and thiols examined herein by irradiation at 254 nm.

  • 34. Amorati, Riccardo
    et al.
    Valgimigli, Luca
    Dinér, Peter
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Bakhtiari, Khadijeh
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Saeedi, Mina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Engman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Multi-faceted reactivity of alkyltellurophenols towards peroxyl radicals: Catalytic antioxidant versus thiol-depletion effect2013In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 23, p. 7510-7522Article in journal (Refereed)
    Abstract [en]

    Hydroxyaryl alkyl tellurides are effective antioxidants both in organic solution and aqueous biphasic systems. They react by an unconventional mechanism with ROO. radicals with rate constants as high as 107M1s1 at 303K, outperforming common phenols. The reactions proceed by oxygen atom transfer to tellurium followed by hydrogen atom transfer to the resulting RO. radical from the phenolic OH. The reaction rates do not reflect the electronic properties of the ring substituents and, because the reactions occur in a solvent cage, quenching is more efficient when the OH and TeR groups have an ortho arrangement. In the presence of thiols, hydroxyaryl alkyl tellurides act as catalytic antioxidants towards both hydroperoxides (mimicking the glutathione peroxidases) and peroxyl radicals. The high efficiency of the quenching of the peroxyl radicals and hydroperoxides could be advantageous under normal cellular conditions, but pro-oxidative (thiol depletion) when thiol concentrations are low.

  • 35.
    Amrein, Beat A.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bauer, Paul
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Duarte, Fernanda
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Janfalk Carlsson, Åsa
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Naworyta, Agata
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mowbray, Sherry L.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Widersten, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Kamerlin, Shina C. L.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Expanding the catalytic triad in epoxide hydrolases and related enzymes2015In: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 5, no 10, p. 5702-5713Article in journal (Refereed)
    Abstract [en]

    Potato epoxide hydrolase 1 exhibits rich enantio- and regioselectivity in the hydrolysis of a broadrange of substrates. The enzyme can be engineered to increase the yield of optically pureproducts, as a result of changes in both enantio- and regioselectivity. It is thus highly attractive inbiocatalysis, particularly for the generation of enantiopure fine chemicals and pharmaceuticals.The present work aims to establish the principles underlying the activity and selectivity of theenzyme through a combined computational, structural, and kinetic study, using the substratetrans-stilbene oxide as a model system. Extensive empirical valence bond simulations have beenperformed on the wild-type enzyme together with several experimentally characterized mutants.We are able to computationally reproduce the differences in activities between differentstereoisomers of the substrate, and the effects of mutations in several active-site residues. Inaddition, our results indicate the involvement of a previously neglected residue, H104, which iselectrostatically linked to the general base, H300. We find that this residue, which is highlyconserved in epoxide hydrolases and related hydrolytic enzymes, needs to be in its protonatedform in order to provide charge balance in an otherwise negatively-charged active site. Our datashow that unless the active-site charge balance is correctly treated in simulations, it is notpossible to generate a physically meaningful model for the enzyme that can accurately reproduceactivity and selectivity trends. We also expand our understanding of other catalytic residues,demonstrating in particular the role of a non-canonical residue, E35, as a “backup-base” in theabsence of H300. Our results provide a detailed view of the main factors driving catalysis andregioselectivity in this enzyme, and identify targets for subsequent enzyme design efforts.

  • 36.
    Andersson, Christoffer R.
    et al.
    Orebro Univ, Dept Neurol, Fac Med & Hlth, Orebro, Sweden..
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Theodorsson, Elvar
    Linkoping Univ, Dept Clin Chem, Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Strom, Jakob O.
    Orebro Univ, Dept Neurol, Fac Med & Hlth, Orebro, Sweden.;Linkoping Univ, Dept Clin Chem, Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Comparisons between commercial salivary testosterone enzyme-linked immunosorbent assay kits2017In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 77, no 8, p. 582-586Article in journal (Refereed)
    Abstract [en]

    Introduction: Measuring testosterone concentrations is of interest both in clinical situations and for research, the latter expanding rapidly during recent years. An increased demand for convenient methods has prompted a number of companies to develop enzyme-linked immunosorbent assay (ELISA) kits to measure testosterone concentrations in saliva. However, the inter-comparability of kits from different manufacturers have yet to be determined. Aim of study: The aim of this study was to compare commercially available ELISA kits from four different manufacturers (Salimetrics, IBL, DRG and Demeditec). Methods: Saliva was collected from 50 participants (25 men and 25 women). Each sample was analysed by the four ELISA kits. Results: The correlations between the ELISA kits from Demeditec, DRG and Salimetrics were moderate to high with r-values >.77; however, proportional errors between the methods calls for caution. The ELISA kit from IBL malfunctioned and no results from this kit was obtained. Conclusions: Results from studies using the ELISA kits from Demeditec, DRG and Salimetrics are generally comparable; however, translation using the formulae presented in the current study could increase the accuracy of these comparisons.

  • 37.
    Andersson, Claes-Henrik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Nyholm, Leif
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Grennberg, Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Synthesis and characterization of a ferrocene-linked bis-fullerene[60] dumbbell2012In: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, Vol. 41, no 8, p. 2374-2381Article in journal (Refereed)
    Abstract [en]

    A new [60]fullerene dumbbell consisting of two fulleropyrrolidines connected to a central ferrocene unit by amide linkages has been prepared and fully characterized by elemental analysis, 1H NMR, UV/Vis, fluorescence and mass spectrometry. The electrochemical properties as determined by cyclic voltammetry show ground state electronic communication between the ferrocene and the fullerene units. In addition, the preparaton of a ferrocene building block for an alternative linking approach is presented.

  • 38.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Carlsson, Anna-Carin C.
    University of Gothenburg, Gothenburg, Sweden.
    Nekoueishahraki, Bijan
    University of Gothenburg, Gothenburg, Sweden.
    Brath, Ulrika
    University of Gothenburg, Gothenburg, Sweden.
    Erdélyi, Máté
    University of Gothenburg, Gothenburg, Sweden.
    Chapter Two - Solvent Effects on Nitrogen Chemical Shifts2015In: Annual Reports on NMR Spectroscopy, Academic Press , 2015, Vol. 86, p. 73-210Chapter in book (Other academic)
    Abstract [en]

    Due to significant developments in cryogenic probe technology and the easy access to inverse detection pulse programmes (HSQC, HMBC), the sensitivity of nitrogen NMR has lately vastly improved. As a consequence, nitrogen NMR has turned into a useful and commonly available tool for solution studies of molecular structure and properties for small organic compounds likewise biopolymers. The high sensitivity of the nitrogen lone pair to changes in the molecular environment, alterations in intra- and intermolecular interactions, and in molecular conformation along with its wide, up to 1200ppm chemical shift dispersion make nitrogen NMR to an exceptionally sensitive reporter tool. The nitrogen chemical shift has been applied in various fields of chemistry, including for instance the studies of transition metal complexes, chemical reactions such as N-alkylation and N-oxidation, tautomerization, protonation–deprotonation equilibria, hydrogen and halogen bonding, and elucidation of molecular conformation and configuration. The 15N NMR data observed in the investigation of these molecular properties and processes is influenced by the medium it is acquired in. This influence may be due to direct coordination of solvent molecules to transition metal complexes, alteration of tautomerization equilibria, and solvent polarity induced electron density changes of conjugated systems, for example. Thus, the solvent may significantly alter the observed nitrogen NMR shifts. This review aims to provide an overview of solvent effects of practical importance, and discusses selected experimental reports from various subfields of chemistry.

  • 39.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. University of Gothenburg, SE-412 96 Gothenburg, Sweden.
    Gräfenstein, Jürgen
    National Sun Yat-Sen University, Kaohsiung, Taiwan.
    Isobe, Minoru
    National Sun Yat-Sen University, Kaohsiung, Taiwan.
    Erdélyi, Máté
    University of Gothenburg, SE-412 96 Gothenburg, Sweden; The Swedish NMR Centre, SE-413 96 Gothenburg, Sweden.
    Sydnes, Magne O
    University of Stavanger, NO-4036 Stavanger, Norway.
    Photochemically Induced Aryl Azide Rearrangement: Solution NMR Spectroscopic Identification of the Rearrangement Product2017In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 82, no 3, p. 1812-1816Article in journal (Refereed)
    Abstract [en]

    Photolysis of ethyl 3-azido-4,6-difluorobenzoate at room temperature in the presence of oxygen results in the regioselective formation of ethyl 5,7-difluoro-4-azaspiro[2.4]hepta-1,4,6-triene-1-carboxylate, presumably via the corresponding ketenimine intermediate which undergoes a photochemical four-electron electrocyclization followed by a rearrangement. The photorearrangement product was identified by multinuclear solution NMR spectroscopic techniques supported by DFT calculations.

  • 40.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Discovery of inhibitors of insulin-regulated aminopeptidase as cognitive enhancers2012In: International Journal of Hypertension, ISSN 2090-0384, Vol. 2012, p. 789671-Article, review/survey (Refereed)
    Abstract [en]

    The hexapeptide angiotensin IV (Ang IV) is a metabolite of angiotensin II (Ang II) and plays a central role in the brain. It was reported more than two decades ago that intracerebroventricular injection of Ang IV improved memory and learning in the rat. Several hypotheses have been put forward to explain the positive effects of Ang IV and related analogues on cognition. It has been proposed that the insulin-regulated aminopeptidase (IRAP) is the main target of Ang IV. This paper discusses progress in the discovery of inhibitors of IRAP as potential enhancers of cognitive functions. Very potent inhibitors of the protease have been synthesised, but pharmacokinetic issues (including problems associated with crossing the blood-brain barrier) remain to be solved. The paper also briefly presents an overview of the status in the discovery of inhibitors of ACE and renin, and of AT1R antagonists and AT2R agonists, in order to enable other discovery processes within the RAS system to be compared. The paper focuses on the relationship between binding affinities/inhibition capacity and the structures of the ligands that interact with the target proteins.

  • 41.
    Andersson, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Characterisation of Chromatography Media Aimed for Purification of Biomolecules2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Chromatography media (resins) are very important for and widely used by the biopharma industry in large scale production of biopharmaceuticals, e.g. monoclonal antibodies. Today there are several hundred biopharmaceuticals released globally on the healthcare market. This thesis discusses various strategies and methods for the characterisation of chemical and functional stability of chromatography media. In addition, various analytical techniques used in these areas were evaluated and applied. Further, more specific physical and chemical characterisation methods were evaluated and applied to explore different properties of various chromatography media.

    In Papers I-III, established methodologies for performing chemical and functional stability studies were used. Mainly agarose-based chromatography media were investigated. For fast screening of the chemical stability, the total organic carbon analysis technique was evaluated and applied. This technique that measures the carbon leakage from the chromatography media at different conditions, proved to be very suitable and robust. For detection and/or identification of leakage compounds responsible for or for part of the measured carbon leakage, different methods such as (high performance) liquid chromatography and gas chromatography mass spectrometry were used.

    In Papers IV-VII, different properties (i.e. functional performance, ligand content and surface chemistry) were evaluated for different agarose-based chromatography media. Standard chromatographic methods (ion exchange chromatography) and spectroscopic methods (e.g. Fourier transform infrared spectroscopy and time-of-flight secondary ion mass spectrometry) were evaluated and applied. Chemometric methods were used for efficient evaluation of data.

    Information of chemical, functional and leakage data of chromatography media are valuable and important for the biopharmaceutical companies to be able to fulfil the regulatory requirements of biopharmaceuticals. In addition, information of various chemical, functional and physical properties of chromatography media is likewise important during development and set up of new biopharmaceutical processes.

  • 42.
    Andersson, Sandra
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sundberg, Mårten
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Pristovsek, Nusa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Clausson, Carl-Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Zieba, Agata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ramström, Margareta
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Söderbert, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Estrogen receptor beta profiling in human tissues following extensive antibody validationManuscript (preprint) (Other academic)
  • 43.
    Andersson, Sandra
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sundberg, Mårten
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Pristovsek, Nusa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ibrahim, Ahmed
    KTH Royal Inst Technol, Sch Biotechnol, Div Prote & Nanotechnol, Sci Life Lab, S-17121 Solna, Sweden.;Natl Res Ctr, Div Pharmaceut Ind, Dokki 12622, Egypt..
    Jonsson, Philip
    Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA.;Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, Human Oncol & Pathogenesis Program, New York, NY 10065 USA..
    Katona, Borbala
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Clausson, Carl-Magnus
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Zieba, Agata
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ramström, Margareta
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Williams, Cecilia
    KTH Royal Inst Technol, Sch Biotechnol, Div Prote & Nanotechnol, Sci Life Lab, S-17121 Solna, Sweden.;Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA.;Karolinska Inst, Dept Biosci & Nutr, S-14183 Stockholm, Sweden..
    Asplund, Anna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Insufficient antibody validation challenges oestrogen receptor beta research2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 15840Article in journal (Refereed)
    Abstract [en]

    The discovery of oestrogen receptor beta (ER beta/ESR2) was a landmark discovery. Its reported expression and homology with breast cancer pharmacological target ER alpha (ESR1) raised hopes for improved endocrine therapies. After 20 years of intense research, this has not materialized. We here perform a rigorous validation of 13 anti-ER beta antibodies, using well-characterized controls and a panel of validation methods. We conclude that only one antibody, the rarely used monoclonal PPZ0506, specifically targets ER beta in immunohistochemistry. Applying this antibody for protein expression profiling in 44 normal and 21 malignant human tissues, we detect ER beta protein in testis, ovary, lymphoid cells, granulosa cell tumours, and a subset of malignant melanoma and thyroid cancers. We do not find evidence of expression in normal or cancerous human breast. This expression pattern aligns well with RNA-seq data, but contradicts a multitude of studies. Our study highlights how inadequately validated antibodies can lead an exciting field astray.

  • 44.
    Andersson, Simon
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Metodutveckling och analys av skumdämpare, ett additiv i vattenburna färgsystem, med vätskekromatografi och masspektrometri2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Paints mostly consist of three major components which are binder, pigment/filler andsolvent. Many other components are added in smaller amount and these are calledadditives. One of these additives is defoamers which are added to the paint todecrease foam which can cause defects in the dried paint for example as pores. Thisstudy was about investigating if the defoamers can be identified and quantified withhigh performance liquid chromatography coupled to mass spectrometry. This includessample preparation, chromatographic separation and detector settings. Calibrationcurves where constructed for paints containing different concentrations of defoamerand for a paint with 0% defoamer where different concentration of defoamer whereadded. Standard addition was done for a paint. Matrix effects were investigated bycomparing signal from defoamer in MeOH compared in paint. This study showed thatthe sample preparation of paints should involve dilution in MeOH or water followedby adding of formic acid and centrifugation and filtration to avoid problems in theinstrument. It is possible to identify if a defoamer is present in paint. Quantificationhas not been achieved, due to possible matrix effects and different response whendefoamer is added to the paint before analysis compared to when the defoamer isadded in the manufacturing process.

  • 45.
    Andersson, Sofia E. M.
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Eneljung, Tove
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Tengvall, Sara
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Jirholt, Pernilla
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Stern, Anna
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Henningsson, Louise
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Liang, Bibo
    Karolinska Inst, Dept Med Biochem & Biophys, Med Inflammat Res, Solna, Sweden.;Southern Med Univ, Guangzhou, Guangdong, Peoples R China..
    Thorarinsdottir, Katrin
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Holmdahl, Rikard
    Karolinska Inst, Dept Med Biochem & Biophys, Med Inflammat Res, Solna, Sweden.;Southern Med Univ, Guangzhou, Guangdong, Peoples R China..
    Martensson, Inga-Lill
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Gustafsson, Kenth
    UCL, Inst Child Hlth, Mol Immunol Unit, London, England..
    Gjertsson, Inger
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Collagen epitope expression on B cells is sufficient to confer tolerance to collagen-induced arthritis2016In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, article id 140Article in journal (Refereed)
    Abstract [en]

    Background: The mechanisms underlying tolerance induction and maintenance in autoimmune arthritis remain elusive. In a mouse model of rheumatoid arthritis, collagen type II (CII)-induced arthritis, we explore the contribution of B cells to antigen-specific tolerance. Methods: To generate expression of the CII-peptide specifically on B-cell major histocompatibility complex type II, lentiviral-based gene therapy including a B-cell-specific Igk promoter was used. Results: Presentation of the CII-peptide on B cells significantly reduced the frequency and severity of arthritis as well as the serum levels of CII -specific IgG antibodies. Further, both frequency and suppressive function of regulatory T cells were increased in tolerized mice. Adoptive transfer of regulatory T cells from tolerized mice to naive mice ameliorated the development of CII-induced arthritis. Conclusion: Our data suggest that endogenous presentation of the CII-peptide on B cells is one of the key contributors to arthritis tolerance induction and maintenance.

  • 46.
    Andersson, Vincent
    et al.
    AstraZeneca R&D, CVMD iMed, SE-43183 Molndal, Sweden..
    Bergström, Fredrik
    AstraZeneca R&D, CVMD iMed DMPK, SE-43183 Molndal, Sweden..
    Branalt, Jonas
    AstraZeneca R&D, CVMD iMed, SE-43183 Molndal, Sweden..
    Grönberg, Gunnar
    AstraZeneca R&D, RIA iMed, SE-43183 Molndal, Sweden..
    Gustafsson, David
    AstraZeneca, AZ Bioventure Hub, Emeriti Pharma AB, S-43183 Molndal, Sweden..
    Karlsson, Staffan
    AstraZeneca R&D, CVMD iMed, SE-43183 Molndal, Sweden..
    Polla, Magnus
    AstraZeneca R&D, CVMD iMed, SE-43183 Molndal, Sweden..
    Bergman, Joakim
    AstraZeneca R&D, CVMD iMed, SE-43183 Molndal, Sweden..
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Macrocyclic Prodrugs of a Selective Nonpeptidic Direct Thrombin Inhibitor Display High Permeability, Efficient Bioconversion but Low Bioavailability2016In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 14, p. 6658-6670Article in journal (Refereed)
    Abstract [en]

    The only oral direct thrombin inhibitors that have reached the market, ximelagatran and dabigatran etexilat, are double prodrugs with low bioavailability in humans. We have evaluated an alternative strategy: the preparation of a nonpeptidic, polar direct thrombin inhibitor as a single, macrocyclic esterase-cleavable (acyloxy)alkoxy prodrug. Two homologous prodrugs were synthesized and displayed high solubilities and Caco-2 cell permeabilities, suggesting high absorption from the intestine. In addition, they were rapidly and completely converted to the active zwitterionic thrombin inhibitor in human hepatocytes. Unexpectedly, the most promising prodrug displayed only moderately higher oral bioavailability in rat than the polar direct thrombin inhibitor, most likely due to rapid metabolism in the intestine or the intestinal wall. To the best of our knowledge, this is the first in vivo ADME study of macrocyclic (acyloxy)alkoxy prodrugs, and it remains to be established if the modest increase in bioavailability is a general feature of this category of prodrugs or not.

  • 47.
    Andres, Julien
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Borbas, K. Eszter
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Expanding the Versatility of Dipicolinate-Based Luminescent Lanthanide Complexes: A Fast Method for Antenna Testing2015In: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 54, no 17, p. 8174-8176Article in journal (Refereed)
    Abstract [en]

    A dipicolinate (dpa)-based platform for the rapid testing of potential lanthanide-sensitizing antennae was developed; 4-methyl-7-O-alkylcoumarin-appended dpa could sensitize four lanthanides. The platform could be used to estimate the photophysical properties of a more difficult-to-prepare 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid based structure carrying the same antenna.

  • 48.
    Ankner, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Norberg, Thomas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Mild Oxidative Cleavage of 9-BBN-Protected Amino Acid Derivatives2015In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 17, p. 3767-3770Article in journal (Refereed)
    Abstract [en]

    Protection of the amino acid moiety using 9-BBN is an effective method to enable side chain manipulations in synthesis of complex amino acids. We investigated the standard, mild method for deprotection of the 9-BBN group in methanolic chloroform, and found that it relies on a slow oxidation mediated by molecular oxygen. Building on this insight, we have developed a method that allows for a fast and selective deprotection using simple peroxy acid reagents. After Fmoc protection, products were isolated in >90% yield for a series of amino acid derivatives, including a galactosylated derivative of hydroxylysine.

  • 49.
    Anscombe, Elizabeth
    et al.
    Univ Oxford, Dept Biochem, Oxford OX1 3QU, England..
    Meschini, Elisa
    Newcastle Univ, Sch Chem, Northern Inst Canc Res, Newcastle Canc Ctr, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England..
    Mora-Vidal, Regina
    Newcastle Univ, Newcastle Canc Ctr, Northern Inst Canc Res, Sch Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England..
    Martin, Mathew P.
    Newcastle Univ, Newcastle Canc Ctr, Northern Inst Canc Res, Sch Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England..
    Staunton, David
    Univ Oxford, Dept Biochem, Oxford OX1 3QU, England..
    Geitmann, Matthis
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Stanley, Will A.
    Newcastle Univ, Newcastle Canc Ctr, Northern Inst Canc Res, Sch Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England..
    Wang, Lan Z.
    Newcastle Univ, Newcastle Canc Ctr, Northern Inst Canc Res, Sch Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England..
    Reuillon, Tristan
    Newcastle Univ, Sch Chem, Northern Inst Canc Res, Newcastle Canc Ctr, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England..
    Golding, Bernard T.
    Newcastle Univ, Sch Chem, Northern Inst Canc Res, Newcastle Canc Ctr, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England..
    Cano, Celine
    Newcastle Univ, Sch Chem, Northern Inst Canc Res, Newcastle Canc Ctr, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England..
    Newell, David R.
    Newcastle Univ, Newcastle Canc Ctr, Northern Inst Canc Res, Sch Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England..
    Noble, Martin E. M.
    Univ Oxford, Dept Biochem, Oxford OX1 3QU, England..
    Wedge, Stephen R.
    Newcastle Univ, Newcastle Canc Ctr, Northern Inst Canc Res, Sch Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England..
    Endicott, Jane A.
    Univ Oxford, Dept Biochem, Oxford OX1 3QU, England..
    Griffin, Roger J.
    Newcastle Univ, Sch Chem, Northern Inst Canc Res, Newcastle Canc Ctr, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England..
    Identification and Characterization of an Irreversible Inhibitor of CDK22015In: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 22, no 9, p. 1159-1164Article in journal (Refereed)
    Abstract [en]

    Irreversible inhibitors that modify cysteine or lysine residues within a protein kinase ATP binding site offer, through their distinctive mode of action, an alternative to ATP-competitive agents. 4-((6-(Cyclo-hexylmethoxy)-9H-purin-2-yl) amino) benzenesulfonamide (NU6102) is a potent and selective ATP-competitive inhibitor of CDK2 in which the sulfonamide moiety is positioned close to a pair of lysine residues. Guided by the CDK2/NU6102 structure, we designed 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl) phenyl)-9H- purin-2-amine (NU6300), which binds covalently to CDK2 as shown by a co-complex crystal structure. Acute incubation with NU6300 produced a durable inhibition of Rb phosphorylation in SKUT-1B cells, consistent with it acting as an irreversible CDK2 inhibitor. NU6300 is the first covalent CDK2 inhibitor to be described, and illustrates the potential of vinyl sulfones for the design of more potent and selective compounds.

  • 50.
    Appel, Lieuwe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Bergström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lassen, Jorgen Buus
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Tesofensine, a novel triple monoamine re-uptake inhibitor with anti-obesity effects: Dopamine transporter occupancy as measured by PET2014In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 24, no 2, p. 251-261Article in journal (Refereed)
    Abstract [en]

    Tesofensine (TE) is a novel triple monoannine re-uptake inhibitor inducing a potent inhibition of the re-uptake process in the synaptic cleft of the neurotransmitters dopamine, norepinephrine, and serotonin. In recent preclinical and clinical evaluations TE showed a robust anti-obesity effect, but the specific mechanism of this triple monoamine re-uptake inhibitor still needs to be further elucidated. This positron emission tomography (PET) study, using [C-11]beta CIT-FE, aimed to assess the degree of the dopamine transporter (DAT) occupancy, at constant TE plasma levels, following different oral, multiple doses of TE during totally 8-12 days. In addition, the relationships between DAT occupancy and TE plasma concentrations, or doses, were investigated to enable assessment of DAT occupancies in subsequent clinical trials. The results demonstrated that TE induced a dose-dependent blockade of DAT following multiple doses of 0.125-1 mg TE at anticipated steady-state conditions. The mean striatal DAT occupancy varied dose-dependently between 18% and 77%. A signnoid E-max model well described the relationship between striatal DAT occupancy and TE plasma concentrations or doses. It was estimated that the maximum achievable DAT occupancy was about 80% and that half of this effect was accomplished by approximately 0.25 mg TE and a plasma drug concentration of 4 ng/ml. The results indicated an important mechanism of action of TE on DAT. Further, these results suggest that the previously reported dose-dependent weight loss, in TE treated subjects, was in part mediated by an up-regulation of dopaminergic pathways due to enhanced amounts of synaptic dopamine after blockade of DAT.

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