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2. Protease‐ and PAR2‐induced pain

Author

Cattaruzza, F, Amadesi, S, Carlsson, JF, Murphy, JE, Lyo, V, Kirkwood, K, Cottrell, GS, Bogyo, M, Knecht, W, and Bunnett, NW

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Pain Research, Chronic Pain, Aetiology, 2.1 Biological and endogenous factors, Animals, Azetidines, Benzylamines, Bradykinin, Cell Line, Female, Foot, Formaldehyde, Inflammation, Male, Mice, Inbred C57BL, Mice, Transgenic, Oligopeptides, Pain, Receptor, PAR-2, Serine Proteases, Serine Proteinase Inhibitors, Trypsin, Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences
Abstract

Background and purposeAlthough serine proteases and agonists of protease-activated receptor 2 (PAR2) cause inflammation and pain, the spectrum of proteases that are activated by proinflammatory and algesic stimuli and their contribution to inflammatory pain are uncertain.Experimental approachEnzymic assays and selective inhibitors were used to characterize protease activity in mice after intraplantar injections of formalin, bradykinin, PAR2 activating peptide (AP) or vehicle. The capacity of these proteases and of recombinant mouse trypsin 4 to cleave fragments of PAR2 and to activate PAR2 in cell lines was determined. Protease inhibitors and par2 (-/-) mice were used to assess the contributions of proteases and PAR2 to pain and inflammation.Key resultsIntraplantar injection of formalin, bradykinin or PAR2-AP led to the activation of proteases that were susceptible to the serine protease inhibitor melagatran but resistant to soybean trypsin inhibitor (SBTI). Melagatran inhibited mouse trypsin 4, which degraded SBTI. Proteases generated in inflamed tissues cleaved PAR2-derived peptides. These proteases and trypsin 4 increased [Ca(2+) ]i in PAR2-transfected but not in untransfected cells, and melagatran suppressed this activity. Melagatran or PAR2 deletion suppressed oedema and mechanical hypersensitivity induced by intraplantar formalin, bradykinin and PAR2-AP, but had no effect on capsaicin-induced pain.Conclusions and implicationsDiverse proinflammatory and algesic agents activate melagatran-sensitive serine proteases that cause inflammation and pain by a PAR2-mediated mechanism. By inducing self-activating proteases, PAR2 amplifies and sustains inflammation and pain. Serine protease inhibitors can attenuate the inflammatory and algesic effects of diverse stimuli, representing a useful therapeutic strategy.

Published
2014

8. New insights into the interaction of class II dihydroorotate dehydrogenases with ubiquinone in lipid bilayers as a function of lipid composition

Author

Orozco Rodriguez, J.M., Wacklin-Knecht, H.P., Clifton, L.A., Bogojevic, O., Leung, A., Fragneto, G., and Knecht, W.

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

The fourth enzymatic reaction in the de novo pyrimidine biosynthesis, the oxidation of dihydroorotate to orotate, is catalyzed by dihydroorotate dehydrogenase (DHODH). Enzymes belonging to the DHODH Class II are membrane-bound proteins that use ubiquinones as their electron acceptors. We have designed this study to understand the interaction of an N-terminally truncated human DHODH (HsΔ29DHODH) and the DHODH from Escherichia coli (EcDHODH) with ubiquinone (Q10) in supported lipid membranes using neutron reflectometry (NR). NR has allowed us to determine in situ, under solution conditions, how the enzymes bind to lipid membranes and to unambiguously resolve the location of Q10. Q10 is exclusively located at the center of all of the lipid bilayers investigated, and upon binding, both of the DHODHs penetrate into the hydrophobic region of the outer lipid leaflet towards the Q10. We therefore show that the interaction between the soluble enzymes and the membrane-embedded Q10 is mediated by enzyme penetration. We can also show that EcDHODH binds more efficiently to the surface of simple bilayers consisting of 1-palmitoyl, 2-oleoyl phosphatidylcholine, and tetraoleoyl cardiolipin than HsΔ29DHODH, but does not penetrate into the lipids to the same degree. Our results also highlight the importance of Q10, as well as lipid composition, on enzyme binding.

Published
2022

11. New Trends in Physics Teaching. Vol. 1, 1965-1966.

Author

United Nations Educational, Scientific, and Cultural Organization, Paris (France). and Knecht, W.

Abstract

This publication provides an exchange of information on modern content, approaches, curricula, and techniques introduces in the early 1960's, as well as additions or modifications made to older teaching methods during this period. The information presented consists partly of reprints from scientific journals and books and partly of reports. The contributions and extracts are reproduced in the original language, as received. The section classified by countries gives details of: (1) new approaches to physics teaching and improvement of course content; (2) curriculum reform; (3) books of special interest for the improvement of physics teaching; (4) new materials for use in classrooms, laboratories, and testing; and (5) journals devoted to the teaching of physics. This booklet is intended for use by physics teachers at universities, teacher-training institutions, and secondary schools, as well as by science editors and the staff of physics sections of teachers' associations. (Author/EB)

Published
1972

16. The late 1970s bubble in Dutch collectible postage stamps

Author

Franses, Ph.H.B.F. (Philip Hans), Knecht, W. (Wouter), Franses, Ph.H.B.F. (Philip Hans), and Knecht, W. (Wouter)

Abstract

Collectible postage stamp prices in the Netherlands witnessed a bubble in the late 1970s, while prices rapidly floored in the mid-1980s. We analyze 500 individual stamps prices (instead of a single index) to examine whether the bubble could somehow have been predicted and whether there were early warning signals. Also, we study whether the characteristics of these stamps mediated the bubble and the price landing afterward. Scarcity and initial price levels appear to have predictive value in various dimensions. Implications for recognizing bubbles in other asset prices are discussed.

Published
2016
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21. The Late 1970's Bubble in Dutch Collectible Postage Stamps

Author

Franses, Ph.H.B.F. and Knecht, W.

Subjects
jel:Z11, forecasting, positive feedback, postage stamps, price bubbles, jel:G12, jel:G11
Abstract

Collectible postage stamp prices in the Netherlands witnessed a bubble in the late 1970’s, while prices rapidly floored in the mid 1980’s. We analyze 500 individual stamps prices (instead of a single index) to examine if the bubble could somehow have been predicted and whether there were early warning signals. Also, we study whether the characteristics of these stamps mediated the bubble and the price landing afterwards. Scarcity and initial price levels seem to have predictive value in various dimensions. Implications for recognizing bubbles in other asset prices are discussed.

Published
2012

23. Creating novel F1 inhibitors through fragment based lead generation and structure aided drug design

Author

Sandmark, J., primary, Oster, L., additional, Fjellstrom, O., additional, Akkaya, S., additional, Beisel, H.G., additional, Eriksson, P.O., additional, Erixon, K., additional, Gustafsson, D., additional, Jurva, U., additional, Kang, D., additional, Karis, D., additional, Knecht, W., additional, Nerme, V., additional, Nilsson, I., additional, Olsson, T., additional, Redzic, A., additional, Roth, R., additional, and Tigerstrom, A., additional

Published
2015
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24. Identification of small molecule inhibitors selective for apo(a) kringles KIV-7, KIV-10 and KV.

Author

Sandmark, J., primary, Althage, M., additional, Andersson, G.M.K., additional, Antonsson, T., additional, Blaho, S., additional, Bodin, C., additional, Bostrom, J., additional, Chen, Y., additional, Dahlen, A., additional, Eriksson, P.O., additional, Evertsson, E., additional, Fex, T., additional, Fjellstrom, O., additional, Gustafsson, D., additional, Hallberg, C., additional, Hicks, R., additional, Jarkvist, E., additional, Johansson, C., additional, Kalies, I., additional, Kang, D., additional, Svalstedt Karlsson, B., additional, Kartberg, F., additional, Legnehed, A., additional, Lindqvist, A.M., additional, Martinsson, S.A., additional, Moberg, A., additional, Petersson, A.U., additional, Ridderstrom, M., additional, Thelin, A., additional, Tigerstrom, A., additional, Vinblad, J., additional, Xu, B., additional, and Knecht, W., additional

Published
2014
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25. The Late 1970's Bubble in Dutch Collectible Postage Stamps

Author

Franses, Ph.H.B.F. (Philip Hans), Knecht, W. (Wouter), Franses, Ph.H.B.F. (Philip Hans), and Knecht, W. (Wouter)

Abstract

Collectible postage stamp prices in the Netherlands witnessed a bubble in the late 1970’s, while prices rapidly floored in the mid 1980’s. We analyze 500 individual stamps prices (instead of a single index) to examine if the bubble could somehow have been predicted and whether there were early warning signals. Also, we study whether the characteristics of these stamps mediated the bubble and the price landing afterwards. Scarcity and initial price levels seem to have predictive value in various dimensions. Implications for recognizing bubbles in other asset prices are discussed.

Published
2012

26. Drosophila deoxyribonucleoside kinase mutants with enhanced ability to phosphorylate purine analogs

Author

Knecht, W., Rozpedowska, E., Breton, C. Le, Willer, Martin, Gojkovic, Z., Sandrini, Michael Paolo Bastner, Jørgensen, T., Hasholt, Lis Frydenreich, Munch-Petersen, B., Piskur, J., Knecht, W., Rozpedowska, E., Breton, C. Le, Willer, Martin, Gojkovic, Z., Sandrini, Michael Paolo Bastner, Jørgensen, T., Hasholt, Lis Frydenreich, Munch-Petersen, B., and Piskur, J.

Abstract

Udgivelsesdato: 2007/9

Published
2007

27. PDE10A in complex with the inhibitor AZ5

Author

Bauer, U., primary, Giordanetto, F., additional, Bauer, M., additional, OMahony, G., additional, Johansson, K.E., additional, Knecht, W., additional, Hartleib-Geschwindner, J., additional, Toppner Carlsson, E., additional, Enroth, C., additional, and Sjogren, T., additional

Published
2012
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39. Functional expression of a multisubstrate deoxyribonucleoside kinase from Drosophila melanogaster and its C-terminal deletion mutants.

Author

Munch-Petersen, B, Knecht, W, Lenz, C, Søndergaard, L, and Piskur, J

Abstract

The occurrence of a deoxyribonucleoside kinase in Drosophila melanogaster (Dm-dNK) with remarkably broad substrate specificity has recently been indicated (Munch-Petersen, B., Piskur, J., and Søndergaard, L. (1998) J. Biol. Chem. 273, 3926-3931). To prove that the capacity to phosphorylate all four deoxyribonucleosides is in fact associated to one polypeptide chain, partially sequenced cDNA clones, originating from the Berkeley Drosophila genome sequencing project, were searched for homology with human deoxyribonucleoside kinases. The total sequence of one cDNA clone and the corresponding genomic DNA was determined and expressed in Escherichia coli as a glutathione S-transferase fusion protein. The purified and thrombin cleaved recombinant protein phosphorylated the four deoxyribonucleosides with high turnover and K(m) values similar to those of the native Dm-dNK, as well as the four ribonucleosides and many therapeutical nucleoside analogs. Dm-dNK has apparently the same origin as the mammalian kinases, thymidine kinase 2, deoxycytidine kinase, deoxyguanosine kinase, and the herpes viral thymidine kinases, but it has a unique C terminus that seems to be important for catalytic activity and specificity. The C-terminal 20 amino acids were dispensable for phosphorylation of deoxyribonucleosides but necessary for full activity with purine ribonucleosides. Removal of the C-terminal 20 amino acids increased the specific activity 2-fold, but 99% of the activity was lost after removal of the C-terminal 30 amino acids.

Published
2000

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