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1. Experiments On Electron Cooling and Intense Space-charge at IOTA

Author

Banerjee, N., Stancari, G., Bossard, M. K., Brandt, J., Kim, Y-K., and Nagaitsev, S.

Subjects
Physics - Accelerator Physics
Abstract

The Integrable Optics Test Accelerator at Fermilab will explore beam dynamics in a ring with intense space-charge using 2.5 MeV proton beams with an incoherent tune shift approaching -0.5. We will use this machine to explore the interplay between electron cooling, intense space-charge, and coherent instabilities. In this contribution, we describe the machine setup including the design of the electron cooler and the lattice, list specific experiments and discuss the results of numerical simulations which include the effects of electron cooling and transverse space-charge forces., Comment: 14th International Workshop on Beam Cooling and Related Topics (COOL'23)

Published
2023

2. Thermionic Sources for Electron Cooling at IOTA

Author

Bossard, M. K., Brandt, J., Kim, Y. -K., Kladov, S., Banerjee, N., Cathey, B., Stancari, G., and Nagaitsev, S.

Subjects
Physics - Accelerator Physics
Abstract

We are designing and fabricating two new thermionic sources of magnetized electrons for use in the electron lens project in the Integrable Optics Test Accelerator (IOTA) at Fermilab. These electron sources will be used for cooling 2.5 MeV protons. One source will be used to compensate for emittance growth due to Intra Beam Scattering in experiments with weak space-charge, while the other source will be used to research the interplay between electron cooling and intense space charge. In this paper we present the progress made so far and the upcoming steps for the thermionic electron sources., Comment: 14th International Particle Accelerator Conference (IPAC'23). arXiv admin note: text overlap with arXiv:2209.02480

Published
2023

3. Commissioning of the Low Energy Electron Gun Test Stand at the University of Chicago

Author

Kladov, S., Bossard, M., Brandt, J., Kim, Y-K., Banerjee, N., Stancari, G., Cathey, B., and Nagaitsev, S.

Subjects
Physics - Accelerator Physics
Abstract

We built a test stand for evaluating the performance of the thermionic electron sources for the electron lens project at the Integrable Optics Test Accelerator (IOTA) in Fermilab. The lens will be used to study nonlinear dynamics and electron cooling of 2.5 MeV protons with strong space charge. The test stand will validate the characteristics of the thermionic sources and the main parameters of the generated beams. In this paper we present the results of the commissioning of the UChicago test stand and validation of the hollow beam source., Comment: 14th International Particle Accelerator Conference (IPAC'23)

Published
2023

4. Electron Cooling Experiment for Proton Beams with Intense Space-charge in IOTA

Author

Banerjee, N., Bossard, M. K., Brandt, J., Kim, Y-K., Cathey, B., Nagaitsev, S., and Stancari, G.

Subjects
Physics - Accelerator Physics
Abstract

Electron cooling as a method of creating intense ion beams has a practical upper limit when it comes to the peak phase space density of ion beams which can be achieved in practice. We describe a new experiment to study electron cooling of 2.5 MeV protons at the intensity limit using the Integrable Optics Test Accelerator (IOTA), which is a storage ring dedicated to beam physics research at Fermilab. This system will enable the study of magnetized electron cooling of a proton beam with transverse incoherent tune shifts approaching -0.5 due to the presence of intense space-charge forces. We present an overview of the hardware design, simulations and specific experiments planned for this project., Comment: arXiv admin note: text overlap with arXiv:2201.10363

Published
2022

5. Thermionic Sources For Electron Cooling At IOTA

Author

Bossard, M. K., Banerjee, N., Brandt, J., Kim, Y. -K., Krieg, M., Cathey, B., Nagaitsev, S., and Stancari, G.

Subjects
Physics - Accelerator Physics
Abstract

We are designing and fabricating two new thermionic sources of magnetized electrons for use in the electron lens project at the Integrable Optics Test Accelerator (IOTA) at Fermilab. These electron sources will be used for cooling of 2.5 MeV protons in the presence of intense space-charge. Furthermore, we are constructing an electron source test stand at the University of Chicago which will validate the electrical, thermal, and vacuum characteristics of thermionic sources. In this paper we present the progress made so far and the upcoming steps for the thermionic electron sources for electron cooling and the test stand.

Published
2022

6. Electron Cooling with Space-Charge Dominated Proton Beams at Iota

Author

Banerjee, N., Bossard, M. K., Brandt, J., Kim, Y-K., Cathey, B., Nagaitsev, S., and Stancari, G.

Subjects
Physics - Accelerator Physics
Abstract

We describe a new electron cooler being developed for 2.5 MeV protons at the Integrable Optics Test Accelerator (IOTA), which is a highly re-configurable storage ring at Fermilab. This system would enable the study of magnetized electron cooling in the presence of intense space-charge with transverse tune shifts approaching -0.5 as well as highly nonlinear focusing optics in the IOTA ring. We present an overview of the design, simulations and hardware to be used for this project., Comment: 13th Workshop on Beam Cooling and Related Topics

Published
2022

8. The diagnostic accuracy of experienced physicians to clinically discriminate type 1 myocardial infarction from type 2 myocardial infarction or myocardial injury

Author

Bossard, M, primary, Nestelberger, T, additional, Kaiser, C, additional, Gschwend, M, additional, Madanchi, M, additional, Reichlin, T, additional, Toggweiler, S, additional, Majcen, I, additional, Kobza, R, additional, Osswald, S, additional, Cuculi, F, additional, and Mueller, C, additional

Published
2023
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11. Thermionic Sources for Electron Cooling at IOTA

Author

Bossard, M., primary, Banerjee, Banerjee, N., additional, Kladov, Kladov, S., additional, Kim, Kim, Y.-K., additional, Nagaitsev, Nagaitsev, S., additional, Brandt, Brandt, J., additional, and Stancari, G., additional

Published
2023
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14. Direct oral anticoagulants compared to vitamin K-antagonists in patients with left ventricular thrombus

Author

Seiler, T, primary, Vasiliauskaite, E, additional, Cioffi, G M, additional, Madanchi, M, additional, Attinger, A, additional, Staempfli, S F, additional, De Boeck, B, additional, Kobza, R, additional, Toggweiler, S, additional, Moccetti, F, additional, Wolfrum, M, additional, Suter, Y, additional, Grueter, D, additional, Cuculi, F, additional, and Bossard, M, additional

Published
2022
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16. Design and synthesis of potent and selective inhibitors of the osteoclast-specific cysteine protease, cathepsin K

Author

Veber, D. F., Marquis, R. W., Ru, Y., Yamashita, D. S., Oh, H. -J., Thompson, S. K., Halbert, S. M., Carr, T. J., Gleason, J. G., Tomaszek, T. A., Levy, M. A., Jr., Bossard, M., Tew, D. G., James, I. E., Briand, J., Carr, S. A., Zymbryki, D., Lee-Rykaczewski, L., Desjarlais, R. L., Mcqueney, M. S., D’Alessio, K. J., Zhao, B., Janson, C. A., Abdel-Meguid, S. S., Smith, W. W., and Shimonishi, Yasutsugu, editor

Published
2002
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18. Utility and safety of the MANTA device for access site closure after removal of the mechanical hemodynamic support device Impella on the intensive care unit

Author

Burkart, P, primary, Bossard, M, additional, Moccetti, F, additional, Hess, S, additional, Jeyarasa, M, additional, Madanchi, M, additional, Cioffi, G, additional, Seiler, T, additional, Wolfrum, M, additional, Hakimi, M, additional, Seelos, R, additional, Toggweiler, S, additional, Attinger-Toller, A, additional, Kobza, R, additional, and Cuculi, F, additional

Published
2021
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19. Antiplatelet therapy in patients with myocardial infarction without obstructive coronary artery disease

Author

Bossard M, Gao P, Boden W, Steg G, Tanguay JF, Joyner C, Granger CB, Kastrati A, Faxon D, Budaj A, Pais P, Di Pasquale G, Valentin V, Flather M, Moccetti T, Yusuf S, and Mehta SR

Subjects
coronary artery disease, acute myocardial infarction, acute coronary syndromes
Abstract

OBJECTIVE: Approximately 10% of patients with myocardial infarction (MI) have no obstructive coronary artery disease. The prognosis and role of intensified antiplatelet therapy in those patients were evaluated. METHODS: We analysed data from the Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events-Seventh Organisation to Assess Strategies in Ischaemic Symptoms trial randomising patients with ACS referred for early intervention to receive either double-dose (600 mg, day 1; 150 mg, days 2-7; then 75 mg/day) or standard-dose (300 mg, day 1; then 75 mg/day) clopidogrel. Outcomes in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) versus those with obstructive coronary artery disease (CAD) and their relation to standard-dose versus double-dose clopidogrel were evaluated. The primary outcome was cardiovascular (CV) death, MI or stroke at 30 days. RESULTS: We included 23 783 patients with MI and 1599 (6.7%) with MINOCA. Patients with MINOCA were younger, presented more frequently with non-ST-segment elevation MI and had fewer comorbidities. All-cause mortality (0.6% vs 2.3%, p=0.005), CV mortality (0.6% vs 2.2%, p=0.006), repeat MI (0.5% vs 2.3%, p=0.001) and major bleeding (0.6% vs 2.4%, p

Published
2021

29. Effect of a Strategy of Comprehensive Vasodilation vs Usual Care on Mortality and Heart Failure Rehospitalization Among Patients With Acute Heart Failure The GALACTIC Randomized Clinical Trial

Author

Kozhuharov, N, Goudev, A, Flores, D, Maeder, MT, Walter, J, Shrestha, S, Gualandro, DM, de Oliveira, MT, Sabti, Z, Muller, B, Noveanu, M, Socrates, T, Ziller, R, Bayes-Genis, A, Sionis, A, Simon, P, Michou, E, Gujer, S, Gori, T, Wenzel, P, Pfister, O, Conen, D, Kapos, I, Kobza, R, Rickli, H, Breidthardt, T, Munzel, T, Erne, P, Mueller, C, Dimov, B, Herr, N, Isenrich, R, Mosimann, T, Twerenbold, R, Boeddinghaus, J, Nestelberger, T, Puelacher, C, Freese, M, Vogele, J, Meissner, K, Martin, J, Strebel, I, Wussler, D, Schumacher, C, Osswald, S, Vogt, F, Hilti, J, Schwarz, J, Fitze, B, Hartwiger, S, Arenja, N, Glatz, B, Rentsch, K, Bossa, A, Jallad, S, Soeiro, A, Jansen, T, Gebel, G, Bossard, M, and Christ, M

Abstract

IMPORTANCE Short-term infusions of single vasodilators, usually given in a fixed dose, have not improved outcomes in patients with acute heart failure (AHF). OBJECTIVE To evaluate the effect of a strategy that emphasized early intensive and sustained vasodilation using individualized up-titrated doses of established vasodilators in patients with AHF. DESIGN, SETTING, AND PARTICIPANTS Randomized, open-label blinded-end-point trial enrolling 788 patients hospitalized for AHF with dyspnea, increased plasma concentrations of natriuretic peptides, systolic blood pressure of at least 100mmHg, and plan for treatment in a general ward in 10 tertiary and secondary hospitals in Switzerland, Bulgaria, Germany, Brazil, and Spain. Enrollment began in December 2007 and follow-up was completed in February 2019. INTERVENTIONS Patients were randomized 1:1 to a strategy of early intensive and sustained vasodilation throughout the hospitalization (n = 386) or usual care (n = 402). Early intensive and sustained vasodilation was a comprehensive pragmatic approach of maximal and sustained vasodilation combining individualized doses of sublingual and transdermal nitrates, low-dose oral hydralazine for 48 hours, and rapid up-titration of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or sacubitril-valsartan. MAIN OUTCOMES AND MEASURES The primary end pointwas a composite of all-cause mortality or rehospitalization for AHF at 180 days. RESULTS Among 788 patients randomized, 781 (99.1%; median age, 78 years; 36.9% women) completed the trial and were eligible for primary end point analysis. Follow-up at 180 days was completed for 779 patients (99.7%). The primary end point, a composite of all-cause mortality or rehospitalization for AHF at 180 days, occurred in 117 patients (30.6%) in the intervention group (including 55 deaths [14.4%]) and in 111 patients (27.8%) in the usual care group (including 61 deaths [15.3%]) (absolute difference for the primary end point, 2.8% [95% CI, -3.7% to 9.3%]; adjusted hazard ratio, 1.07 [95% CI, 0.83-1.39]; P =.59). The most common clinically significant adverse events with early intensive and sustained vasodilation vs usual care were hypokalemia (23% vs 25%), worsening renal function (21% vs 20%), headache (26% vs 10%), dizziness (15% vs 10%), and hypotension (8% vs 2%). CONCLUSIONS AND RELEVANCE Among patients with AHF, a strategy of early intensive and sustained vasodilation, compared with usual care, did not significantly improve a composite outcome of all-cause mortality and AHF rehospitalization at 180 days.

Published
2019

30. Design and synthesis of potent and selective inhibitors of the osteoclast-specific cysteine protease, cathepsin K

Author

Veber, D. F., primary, Marquis, R. W., additional, Ru, Y., additional, Yamashita, D. S., additional, Oh, H. -J., additional, Thompson, S. K., additional, Halbert, S. M., additional, Carr, T. J., additional, Gleason, J. G., additional, Tomaszek, T. A., additional, Levy, M. A., additional, Bossard, M., additional, Tew, D. G., additional, James, I. E., additional, Briand, J., additional, Carr, S. A., additional, Zymbryki, D., additional, Lee-Rykaczewski, L., additional, Desjarlais, R. L., additional, Mcqueney, M. S., additional, D’Alessio, K. J., additional, Zhao, B., additional, Janson, C. A., additional, Abdel-Meguid, S. S., additional, and Smith, W. W., additional

Published
1999
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31. 2387Recurrent cardiovascular events and mortality in relation to antiplatelet therapy in patients with myocardial infarction without obstructive coronary artery disease (MINOCA)

Author

Bossard, M, primary, Yusuf, S, additional, Tanguay, J F, additional, Faxon, D P, additional, Boden, W E, additional, Steg, P G, additional, Granger, C, additional, Kastrati, A, additional, Budaj, A, additional, Di Pasquale, G, additional, Valentin, V, additional, Diaz, R, additional, Joyner, C, additional, Gao, P, additional, and Mehta, S, additional

Published
2019
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33. Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Author

Fang, J, Jia, J, Makowski, M, Xu, M, Wang, Z, Zhang, T, Hoskins, Jw, Choi, J, Han, Y, Zhang, M, Thomas, J, Kovacs, M, Collins, I, Dzyadyk, M, Thompson, A, O'Neill, M, Das, S, Lan, Q, Koster, R, Solomon, Rs, Kraft, P, Wolpin, Bm, Jansen, Pwtc, Olson, S, Mcglynn, Ka, Kanetsky, Pa, Chatterjee, N, Barrett, Jh, Dunning, Am, Taylor, Jc, Newton Bishop, Ja, Bishop, Dt, Andresson, T, Petersen, Gm, Amos, Ci, Iles, Mm, Nathanson, Kl, Landi, Mt, Vermeulen, M, Brown, Km, Amundadottir, Lt, Canzian, F, Kooperberg, C, Arslan, Aa, Bracci, Pm, Buring, J, Duell, Ej, Gallinger, S, Jacobs, Ej, Kamineni, A, Van Den Eeden, S, Klein, Ap, Kolonel, Ln, Li, D, Olson, Sh, Risch, Ha, Sesso, Hd, Visvanathan, K, Zheng, W, Albanes, D, Austin, Ma, Boutron Ruault, Mc, Bueno de Mesquita, Hb, Cotterchio, M, Gaziano, Jm, Giovannucci, El, Goggins, M, Gross, M, Hassan, M, Helzlsouer, Kj, Holly, Ea, Hunter, Dj, Jenab, M, Kaaks, R, Key, Tj, Khaw, Kt, Krogh, V, Kurtz, Rc, Lacroix, A, Le Marchand, L, Mannisto, S, Patel, Av, Peeters, Phm, Riboli, E, Shu, Xo, Sund, M, Thornquist, M, Tjønneland, A, Tobias, Gs, Trichopoulos, D, Wactawski Wende, J, Yu, H, Yu, K, Zeleniuch Jacquotte, A, Hoover, R, Hartge, P, Fuchs, C, Chanock, Sj, Stevens, V, Caporaso, Ne, Brennan, P, Mckay, J, Wu, X, Hung, Rj, Mclaughlin, Jr, Bickeboller, H, Risch, A, Wichmann, E, Houlston, R, Mann, G, Hopper, J, Aitken, J, Armstrong, B, Giles, G, Holland, E, Kefford, R, Cust, A, Jenkins, M, Schmid, H, Puig, S, Aguilera, P, Badenas, C, Barreiro, A, Carrera, C, Gabriel, D, Xavier, Pg, Iglesias Garcia, P, Malvehy, J, Mila, M, Pigem, R, Potrony, M, Batille, Ja, Marti, Gt, Hayward, N, Martin, N, Montgomery, G, Duffy, D, Whiteman, D, Gregor, Sm, Calista, D, Landi, G, Minghetti, P, Arcangeli, F, Bertazzi, Pa, Ghiorzo, Paola, Bianchi, Giovanna, Pastorino, Lorenza, Bruno, William, Andreotti, Virginia, Queirolo, P, Spagnolo, Francesco, Mackie, R, Lang, J, Gruis, N, van Nieuwpoort, Fa, Out, C, Bergman, W, Kukutsch, N, Bavinck, Jnb, Bakker, B, van der Stoep, N, Ter Huurne, J, van der Rhee, H, Bekkenk, M, Snels, D, van Praag, M, Brochez, L, Gerritsen, R, Crijns, M, Vasen, H, Janssen, B, Ingvar, C, Olsson, H, Jonsson, G, Borg, A, Harbst, K, Nielsen, K, Zander, As, Molvern, A, Helsing, P, Andresen, Pa, Rootwelt, H, Akslen, La, Bressac de Paillerets, B, Demenais, F, Avril, Mf, Chaudru, V, Jeannin, P, Lesueur, F, Maubec, E, Mohamdi, H, Bossard, M, Vaysse, A, Boitier, F, Caron, O, Caux, F, Dalle, S, Dereure, O, Leroux, D, Martin, L, Mateus, C, Robert, C, Stoppa Lyonnet, D, Thomas, L, Wierzbicka, E, Elder, D, Ming, M, Mitra, N, Debniak, T, Lubinski, J, Hocevar, M, Novakovic, S, Peric, B, Skerl, P, Hansson, J, Hoiom, V, Freidman, E, Azizi, E, Baron Epel, O, Scope, A, Pavlotsky, F, Cohen Manheim, I, Laitman, Y, Harland, M, Randerson Moor, J, Laye, J, Davies, J, Nsengimana, J, O'Shea, S, Chan, M, Gascoyne, J, Tucker, Ma, Goldstein, Am, and Yang, X. r.

Subjects
0301 basic medicine, Male, Lung Neoplasms, Skin Neoplasms, General Physics and Astronomy, Genome-wide association study, VARIANTS, Histones, Skin cancer, RNA, Small Interfering, Melanoma, Telomerase, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Pancreas cancer, Regulation of gene expression, Genetics, Zinc finger, Gene knockdown, Multidisciplinary, Proteomics and Chromatin Biology, TRICL Consortium, Chromosome Mapping, GenoMEL Consortium, PANCREATIC-CANCER, Multidisciplinary Sciences, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Science & Technology - Other Topics, Chromosomes, Human, Pair 5, Female, Lung cancer, Signal Transduction, SUSCEPTIBILITY LOCI, Science, Locus (genetics), Single-nucleotide polymorphism, PROMOTES GROWTH, Biology, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, LUNG-CANCER, Testicular Neoplasms, Cell Line, Tumor, MD Multidisciplinary, Humans, Genetic Predisposition to Disease, QUANTITATIVE PROTEOMICS, GENOME-WIDE ASSOCIATION, Gene, PanScan Consortium, Càncer de pell, Càncer de pàncrees, Alleles, Science & Technology, Kirurgi, HUMAN-CELLS, Telomere Homeostasis, Correction, General Chemistry, Molecular biology, TERT-CLPTM1L LOCUS, Telomere, Pancreatic Neoplasms, 030104 developmental biology, Genetic Loci, TELOMERE LENGTH, Càncer de pulmó, Surgery, Genètica, Genome-Wide Association Study, Transcription Factors
Abstract

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele., Genetic variants at multiple loci of chr5p15.33 have been associated with susceptibility to numerous cancers. Here the authors show that the association of one of these loci may be explained by a variant, rs36115365, influencing telomerase reverse transcriptase (TERT) expression via ZNF148.

Published
2017

36. Nano-patterned Fluorinated Diamond-Like Carbon (DLC) thin films used as UV-NanoImprint Lithography templates

Author

Bossard, M., Le Drogoff, B., Zelsmann, M., DELPRAT, Sebastien, Chaker, M., Boussey, J., Laboratoire des technologies de la microélectronique (LTM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Énergie Matériaux Télécommunications - INRS (EMT-INRS), Institut National de la Recherche Scientifique [Québec] (INRS)-Université du Québec à Montréal = University of Québec in Montréal (UQAM), Clot, Marielle, and Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)

Published
2011

42. BAX 855, a PEGylated rFVIII product with prolonged half-life

Author

Bossard, M. J., primary, Graninger, M., primary, Gritsch, H., primary, Höllriegl, W., primary, Kaliwoda, M., primary, Matthiessen, P., primary, Mitterer, A., primary, Muchitsch, E.-M., primary, Purtscher, M., primary, Rottensteiner, H., primary, Schiviz, A., primary, Schrenk, G., primary, Siekmann, J., primary, Varadi, K., primary, Riley, T., primary, Ehrlich, H. J., primary, Schwarz, H. P., primary, Scheiflinger, F., primary, and Turecek, P. L., additional

Published
2012
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47. BAX 855, a PEGylated rFVIII product with prolonged half-life

Author

Turecek, P. L., Bossard, M. J., Graninger, M., Gritsch, H., Höllriegl, W., Kaliwoda, M., Matthiessen, P., Mitterer, A., Muchitsch, E.-M., Purtscher, M., Rottensteiner, H., Schiviz, A., Schrenk, G., Siekmann, J., Varadi, K., Riley, T., Ehrlich, H. J., Schwarz, H. P., and Scheiflinger, F.

Published
2012
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48. Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification.

Author

Bossard, M J, Tomaszek, T A, Thompson, S K, Amegadzie, B Y, Hanning, C R, Jones, C, Kurdyla, J T, McNulty, D E, Drake, F H, Gowen, M, and Levy, M A

Abstract

Human cathepsin K is a recently identified protein with high primary sequence homology to members of the papain cysteine protease superfamily including cathepsins S, L, and B and is selectively expressed in osteoclasts (Drake, F.H., Dodds, R., James I., Connor J., Debouck, C., Richardson, S., Lee, E., Rieman, D., Barthlow, R., Hastings, G., and Gowen, M. (1996) J. Biol., Chem. 271, 12511-12516). To characterize its catalytic properties, cathepsin K has been expressed in baculovirus-infected SF21 cells and the soluble recombinant protein isolated from growth media was purified. Purified protein includes an inhibitory pro-leader sequence common to this family of protease. Conditions for enzyme activation upon removal of the pro-sequence have been identified. Fluorogenic peptides have been identified as substrates for mature cathepsin K. In addition, two protein components of bone matrix, collagen and osteonectin, have been shown to be substrates of the activated protease. Cathepsin K is inhibited by E-64 and leupeptin, but not for by pepstatin, EDTA, phenylmethylsulfonyl fluoride, or phenanthroline, consistent with its classification within the cysteine protease class. Leupeptin has been characterized as a slow binding inhibitor of cathepsin K (kobs/[I] = 273,000 m(-1).s(-1)). Cathepsin K may represent the elusive protease implicated in degradation of protein matrix during bone resorption and represents a novel molecular target in treatment of disease states associated with excessive bone loss such as osteoporosis.

Published
1996

49. Mechanism-based inhibition of dopamine beta-monooxygenase by aldehydes and amides.

Author

Bossard, M J and Klinman, J P

Abstract

A mechanism for beta-chlorophenethylamine inhibition of dopamine beta-monooxygenase has been postulated in which enzyme-bound alpha-aminoacetophenone is generated, followed by an intramolecular redox reaction to yield a ketone-derived radical cation as the enzyme inhibitory species (Mangold, J. B., and Klinman, J. P. (1984) J. Biol. Chem. 259, 7772-7779). If correct, additional compounds capable of producing enzyme-bound (formula; see text) reductant should inhibit dopamine beta-monooxygenase. Phenylacetaldehyde was chosen to test this model, since beta-hydroxyphenylacetaldehyde is expected to function as a reductant in a manner analogous to alpha-aminoacetophenone. Phenylacetaldehyde exhibits the properties of a mechanism-based inhibitor. Kinetic parameters are comparable to beta-chlorophenethylamine under both initial velocity and inactivation conditions. Since phenylacetaldehyde bears little resemblance to beta-chlorophenethylamine, its analogous inhibitory action provides support for an intramolecular redox reaction (via beta-hydroxyphenylacetaldehyde oxidation to a radical cation) in dopamine beta-monooxygenase inactivation. beta-Hydroxyphenylacetaldehyde was identified as the enzymatic product of phenylacetaldehyde turnover. As predicted, this product behaves both as a time-dependent inhibitor of dopamine beta-monooxygenase and as an electron donor in enzyme-catalyzed hydroxylation of tyramine to octopamine. Phenylacetamide and p-hydroxyphenylacetamide are also found to be mechanism-based inhibitors of dopamine beta-monooxygenase. In this case the product of hydroxylation (beta-hydroxyphenylacetamide) is redox inactive and, therefore, is unable to function as either a reductant or an inhibitor. Thus, mechanism-based inhibitors are divided into two types: type I, which undergoes hydroxylation prior to inactivation, and type II, which only requires hydrogen atom abstraction. A general mechanism for dopamine beta-monooxygenase inactivation is described, in which a common mechanistic radical intermediate is formed from both pathways.

Published
1986
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