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1. Improved Spin-Dependent WIMP Limits from a Bubble Chamber

Author

Behnke, E., Collar, J. I., Cooper, P. S., Crum, K., Crisler, M., Hu, M., Levine, I., Nakazawa, D., Nguyen, H., Odom, B., Ramberg, E., Rasmussen, J., Riley, N., Sonnenschein, A., Szydagis, M., and Tschirhart, R.

Subjects
Astrophysics, High Energy Physics - Experiment, Physics - Instrumentation and Detectors
Abstract

Bubble Chambers provided the dominant particle detection technology in accelerator experiments for several decades, eventually falling into disuse with the advent of other techniques. We report here on the first period of operation of an ultra-clean, room-temperature bubble chamber containing 1.5 kg of superheated CF$_{3}$I, a target maximally sensitive to spin-dependent and -independent Weakly Interacting Massive Particle (WIMP) couplings. An exposure in excess of 250 kg-days is obtained, with a live-time fraction reaching 80%. This illustrates the ability to employ bubble chambers in a new realm, the search for dark matter particles. Improved limits on the spin-dependent WIMP-proton scattering cross section are extracted from this first period. An extreme intrinsic insensitivity to the backgrounds commonly limiting these experiments (a rejection factor for photon-induced electrons of $\sim10^{-10}$) has been measured in operating conditions leading to the detection of low-energy nuclear recoils such as those expected from WIMPs., Comment: This is the author's version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science 319, 15 February 2008, doi:10.1126/science.1149999

Published
2008
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2. Development of Bubble Chambers With Enhanced Stability and Sensitivity to Low-Energy Nuclear Recoils

Author

Bolte, W. J., Collar, J. I., Crisler, M., Hall, J., Holmgren, D., Nakazawa, D., Odom, B., O'Sullivan, K., Plunkett, R., Ramberg, E., Raskin, A., Sonnenschein, A., and Vieira, J. D.

Subjects
Astrophysics, High Energy Physics - Experiment, Nuclear Experiment, Physics - Instrumentation and Detectors
Abstract

The viability of using a Bubble Chamber for rare event searches and in particular for the detection of dark matter particle candidates is considered. Techniques leading to the deactivation of inhomogeneous nucleation centers and subsequent enhanced stability in such a detector are described. Results from prototype trials indicate that sensitivity to low-energy nuclear recoils like those expected from Weakly Interacting Massive Particles can be obtained in conditions of near total insensitivity to minimum ionizing backgrounds. An understanding of the response of superheated heavy refrigerants to these recoils is demonstrated within the context of existing theoretical models. We comment on the prospects for the detection of supersymmetric dark matter particles with a large $CF_{3}I$ chamber., Comment: 4 pages, 3 figures. Submitted to Phys. Rev. Lett

Published
2005
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8. To NET or not to NET:current opinions and state of the science regarding the formation of neutrophil extracellular traps

Author

Boeltz, S., Amini, P., Anders, H.J., Andrade, F., Bilyy, R., Chatfield, S., Cichon, I., Clancy, D.M., Desai, J., Dumych, T., Dwivedi, N., Gordon, R.A., Hahn, J., Hidalgo, A., Hoffmann, M.H., Kaplan, M.J., Knight, J.S., Kolaczkowska, E., Kubes, P., Leppkes, M., Manfredi, A.A., Martin, S.J., Maueroder, C., Maugeri, N., Mitroulis, I., Munoz, L.E., Nakazawa, D., Neeli, I., Nizet, V., Pieterse, E., Radic, M.Z., Reinwald, C., Ritis, K., Rovere-Querini, P., Santocki, M., Schauer, C., Schett, G., Shlomchik, M.J., Simon, H.U., Skendros, P., Stojkov, D., Vandenabeele, P., Berghe, T.V., Vlag, J. van der, Vitkov, L., Kockritz-Blickwede, M. von, Yousefi, S., Zarbock, A., Herrmann, M., Boeltz, S., Amini, P., Anders, H.J., Andrade, F., Bilyy, R., Chatfield, S., Cichon, I., Clancy, D.M., Desai, J., Dumych, T., Dwivedi, N., Gordon, R.A., Hahn, J., Hidalgo, A., Hoffmann, M.H., Kaplan, M.J., Knight, J.S., Kolaczkowska, E., Kubes, P., Leppkes, M., Manfredi, A.A., Martin, S.J., Maueroder, C., Maugeri, N., Mitroulis, I., Munoz, L.E., Nakazawa, D., Neeli, I., Nizet, V., Pieterse, E., Radic, M.Z., Reinwald, C., Ritis, K., Rovere-Querini, P., Santocki, M., Schauer, C., Schett, G., Shlomchik, M.J., Simon, H.U., Skendros, P., Stojkov, D., Vandenabeele, P., Berghe, T.V., Vlag, J. van der, Vitkov, L., Kockritz-Blickwede, M. von, Yousefi, S., Zarbock, A., and Herrmann, M.

Abstract

Item does not contain fulltext, Since the discovery and definition of neutrophil extracellular traps (NETs) 14 years ago, numerous characteristics and physiological functions of NETs have been uncovered. Nowadays, the field continues to expand and novel mechanisms that orchestrate formation of NETs, their previously unknown properties, and novel implications in disease continue to emerge. The abundance of available data has also led to some confusion in the NET research community due to contradictory results and divergent scientific concepts, such as pro- and anti-inflammatory roles in pathologic conditions, demarcation from other forms of cell death, or the origin of the DNA that forms the NET scaffold. Here, we present prevailing concepts and state of the science in NET-related research and elaborate on open questions and areas of dispute.

Published
2019

14. COUPP, a Heavy-Liquid Bubble Chamber for WIMP Detection

Author

Bolte, J., primary, Collar, J.I., additional, Crisler, M.B., additional, Holmgren, D., additional, Nakazawa, D., additional, Odom, B., additional, O’Sullivan, K., additional, Plunkett, R., additional, Ramberg, E., additional, Raskin, A., additional, Sonnenschein, A., additional, and Vieira, J., additional

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18. Experimental pathology

Author

Yi Chun, D. X., primary, Alexandre, H., additional, Edith, B., additional, Nacera, O., additional, Julie, P., additional, Chantal, J., additional, Eric, R., additional, Zhang, X., additional, Jin, Y., additional, Miravete, M., additional, Dissard, R., additional, Klein, J., additional, Gonzalez, J., additional, Caubet, C., additional, Pecher, C., additional, Pipy, B., additional, Bascands, J.-L., additional, Mercier-Bonin, M., additional, Schanstra, J., additional, Buffin-Meyer, B., additional, Claire, R., additional, Rigothier, C., additional, Richard, D., additional, Sebastien, L., additional, Moin, S., additional, Chantal, B., additional, Christian, C., additional, Jean, R., additional, Migliori, M., additional, Cantaluppi, V., additional, Mannari, C., additional, Medica, D., additional, Giovannini, L., additional, Panichi, V., additional, Goldwich, A., additional, Alexander, S., additional, Andre, G., additional, Amann, K., additional, Migliorini, A., additional, Sagrinati, C., additional, Angelotti, M. L., additional, Mulay, S. R., additional, Ronconi, E., additional, Peired, A., additional, Romagnani, P., additional, Anders, H.-J., additional, Chiang, W. C., additional, Lai, C. F., additional, Peng, W.-H., additional, Wu, C. F., additional, Chang, F.-C., additional, Chen, Y.-T., additional, Lin, S.-L., additional, Chen, Y. M., additional, Wu, K. D., additional, Lu, K.-S., additional, Tsai, T. J., additional, Virgine, O., additional, Qing Feng, F., additional, Zhang, S.-Y., additional, Dominique, D., additional, Vincent, A., additional, Marina, C., additional, Philippe, L., additional, Georges, G., additional, Pawlak, A., additional, Sahali, D., additional, Matsumoto, S., additional, Kiyomoto, H., additional, Ichimura, A., additional, Dan, T., additional, Nakamichi, T., additional, Tsujita, T., additional, Akahori, K., additional, Ito, S., additional, Miyata, T., additional, Xie, S., additional, Zhang, B., additional, Shi, W., additional, Yang, Y., additional, Nagasu, H., additional, Satoh, M., additional, Kidokoro, K., additional, Nishi, Y., additional, Ihoriya, C., additional, Kadoya, H., additional, Sasaki, T., additional, Kashihara, N., additional, Wu, C.-F., additional, Chou, Y.-H., additional, Duffield, J., additional, Rocca, C., additional, Gregorini, M., additional, Corradetti, V., additional, Valsania, T., additional, Bedino, G., additional, Bosio, F., additional, Pattonieri, E. F., additional, Esposito, P., additional, Sepe, V., additional, Libetta, C., additional, Rampino, T., additional, Dal Canton, A., additional, Omori, H., additional, Kawada, N., additional, Inoue, K., additional, Ueda, Y., additional, Yamamoto, R., additional, Matsui, I., additional, Kaimori, J., additional, Takabatake, Y., additional, Moriyama, T., additional, Isaka, Y., additional, Rakugi, H., additional, Wasilewska, A., additional, Taranta-Janusz, K., additional, Deebek, W., additional, Kuroczycka-Saniutycz, E., additional, Lee, A. S., additional, Lee, J. E., additional, Jung, Y. J., additional, Kang, K. P., additional, Lee, S., additional, Kim, W., additional, Arfian, N., additional, Emoto, N., additional, Yagi, K., additional, Nakayama, K., additional, Hartopo, A. B., additional, Nugrahaningsih, D. A., additional, Yanagisawa, M., additional, Hirata, K.-I., additional, Munoz-Felix, J. M., additional, Lopez-Novoa, J. M., additional, Martinez-Salgado, C., additional, Oujo, B., additional, Arevalo, M., additional, Bernabeu, C., additional, Perez-Barriocanal, F., additional, Jesper, K., additional, Nathalie, V., additional, Pierre, G., additional, Yi Chun, D. X., additional, Iyoda, M., additional, Shibata, T., additional, Matsumoto, K., additional, Shindo-Hirai, Y., additional, Kuno, Y., additional, Wada, Y., additional, Akizawa, T., additional, Schwartz, I., additional, Schwartz, D., additional, Prot Bertoye, C., additional, Terryn, S., additional, Claver, J., additional, Beghdadi, W. B., additional, Monteiro, R., additional, Blank, U., additional, Devuyst, O., additional, Daugas, E., additional, Van Beneden, K., additional, Geers, C., additional, Pauwels, M., additional, Mannaerts, I., additional, Van den Branden, C., additional, Van Grunsven, L. A., additional, Seckin, I., additional, Pekpak, M., additional, Uzunalan, M., additional, Uruluer, B., additional, Kokturk, S., additional, Ozturk, Z., additional, Sonmez, H., additional, Yaprak, E., additional, Furuno, Y., additional, Tsutsui, M., additional, Morishita, T., additional, Shimokawa, H., additional, Otsuji, Y., additional, Yanagihara, N., additional, Kabashima, N., additional, Ryota, S., additional, Kanegae, K., additional, Miyamoto, T., additional, Nakamata, J., additional, Ishimatsu, N., additional, Tamura, M., additional, Nakagawa, T., additional, Ichikawa, K., additional, Miyamoto, M., additional, Takabayashi, D., additional, Yamazaki, H., additional, Kakeshita, K., additional, Koike, T., additional, Kagitani, S., additional, Tomoda, F., additional, Hamashima, T., additional, Ishii, Y., additional, Inoue, H., additional, Sasahara, M., additional, El Machhour, F., additional, Kerroch, M., additional, Mesnard, L., additional, Chatziantoniou, C., additional, Dussaule, J.-C., additional, Inui, K., additional, Sasai, F., additional, Maruta, Y., additional, Nishiwaki, H., additional, Kawashima, E., additional, Inoue, Y., additional, Yoshimura, A., additional, Musacchio, E., additional, Priante, G., additional, Valvason, C., additional, Sartori, L., additional, Baggio, B., additional, Kim, J. H., additional, Gross, O., additional, Diana, R., additional, Gry, D. H., additional, Asimal, B., additional, Johanna, T., additional, Imke, S.-E., additional, Lydia, W., additional, Gerhard-Anton, M., additional, Hassan, D., additional, Cano, J. L., additional, Griera, M., additional, Olmos, G., additional, Martin, P., additional, Cortes, M. A., additional, Lopez-Ongil, S., additional, Rodriguez-Puyol, D., additional, DE Frutos, S., additional, Gonzalez, M., additional, Luengo, A., additional, Rodriguez-Puyol, M., additional, Calleros, L., additional, Lupica, R., additional, Lacquaniti, A., additional, Donato, V., additional, Maggio, R., additional, Mastroeni, C., additional, Lucisano, S., additional, Cernaro, V., additional, Fazio, M. R., additional, Quartarone, A., additional, Buemi, M., additional, Kacik, M., additional, Goedicke, S., additional, Eggert, H., additional, Hoyer, J. D., additional, Wurm, S., additional, Steege, A., additional, Banas, M., additional, Kurtz, A., additional, Banas, B., additional, Lasagni, L., additional, Lazzeri, E., additional, Romoli, S., additional, Schaefer, I., additional, Teng, B., additional, Worthmann, K., additional, Haller, H., additional, Schiffer, M., additional, Prattichizzo, C., additional, Netti, G. S., additional, Rocchetti, M. T., additional, Cormio, L., additional, Carrieri, G., additional, Stallone, G., additional, Grandaliano, G., additional, Ranieri, E., additional, Gesualdo, L., additional, Kucher, A., additional, Smirnov, A., additional, Parastayeva, M., additional, Beresneva, O., additional, Kayukov, I., additional, Zubina, I., additional, Ivanova, G., additional, Abed, A., additional, Schlekenbach, L., additional, Foglia, B., additional, Kwak, B., additional, Chadjichristos, C., additional, Queisser, N., additional, Schupp, N., additional, Brand, S., additional, Himer, L., additional, Szebeni, B., additional, Sziksz, E., additional, Saijo, S., additional, Kis, E., additional, Prokai, A., additional, Banki, N. F., additional, Fekete, A., additional, Tulassay, T., additional, Vannay, A., additional, Hegner, B., additional, Schaub, T., additional, Lange, C., additional, Dragun, D., additional, Klinkhammer, B. M., additional, Rafael, K., additional, Monika, M., additional, Anna, M., additional, Van Roeyen, C., additional, Boor, P., additional, Eva Bettina, B., additional, Simon, O., additional, Esther, S., additional, Floege, J., additional, Kunter, U., additional, Janke, D., additional, Jankowski, J., additional, Hayashi, M., additional, Takamatsu, I., additional, Horimai, C., additional, Yoshida, T., additional, Seno DI Marco, G., additional, Koenig, M., additional, Stock, C., additional, Reiermann, S., additional, Amler, S., additional, Koehler, G., additional, Fobker, M., additional, Buck, F., additional, Pavenstaedt, H., additional, Lang, D., additional, Brand, M., additional, Plotnikov, E., additional, Morosanova, M., additional, Pevzner, I., additional, Zorova, L., additional, Pulkova, N., additional, Zorov, D., additional, Wornle, M., additional, Ribeiro, A., additional, Belling, F., additional, Merkle, M., additional, Nakazawa, D., additional, Nishio, S., additional, Shibasaki, S., additional, Tomaru, U., additional, Akihiro, I., additional, Kobayashi, I., additional, Imanishi, Y., additional, Kurajoh, M., additional, Nagata, Y., additional, Yamagata, M., additional, Emoto, M., additional, Michigami, T., additional, Ishimura, E., additional, Inaba, M., additional, Wu, C.-C., additional, Lu, K.-C., additional, Chen, J.-S., additional, Chu, P., additional, Lin, Y.-F., additional, Eller, K., additional, Schroll, A., additional, Kirsch, A., additional, Huber, J., additional, Weiss, G., additional, Theurl, I., additional, Rosenkranz, A. R., additional, Zawada, A., additional, Rogacev, K., additional, Achenbach, M., additional, Fliser, D., additional, Held, G., additional, Heine, G. H., additional, Miyamoto, Y., additional, Iwao, Y., additional, Watanabe, H., additional, Kadowaki, D., additional, Ishima, Y., additional, Chuang, V. T. G., additional, Sato, K., additional, Otagiri, M., additional, Maruyama, T., additional, Iwatani, H., additional, Honda, D., additional, Noguchi, T., additional, Tanaka, M., additional, Tanaka, H., additional, Fukagawa, M., additional, Pircher, J., additional, Koppel, S., additional, Mannell, H., additional, Krotz, F., additional, Virzi, G. M., additional, Bolin, C., additional, Cruz, D., additional, Scalzotto, E., additional, De Cal, M., additional, Vescovo, G., additional, Ronco, C., additional, Grobmayr, R., additional, Lech, M., additional, Ryu, M., additional, Aoshima, Y., additional, Mizobuchi, M., additional, Ogata, H., additional, Kumata, C., additional, Nakazawa, A., additional, Kondo, F., additional, Ono, N., additional, Koiwa, F., additional, Kinugasa, E., additional, Freisinger, W., additional, Lale, N., additional, Lampert, A., additional, Ditting, T., additional, Heinlein, S., additional, Schmieder, R. E., additional, Veelken, R., additional, Nave, H., additional, Perthel, R., additional, Suntharalingam, M., additional, Bode-Boger, S., additional, Beutel, G., additional, Kielstein, J., additional, Rodrigues-Diez, R., additional, Rayego-Mateos, S., additional, Lavoz, C., additional, Stark Aroeira, L. G., additional, Orejudo, M., additional, Alique, M., additional, Ortiz, A., additional, Egido, J., additional, Ruiz-Ortega, M., additional, Oskar, W., additional, Rusan, C., additional, Padberg, J.-S., additional, Wiesinger, A., additional, Reuter, S., additional, Grabner, A., additional, Kentrup, D., additional, Lukasz, A., additional, Oberleithner, H., additional, Pavenstadt, H., additional, Kumpers, P., additional, Eberhardt, H. U., additional, Skerka, C., additional, Chen, Q., additional, Hallstroem, T., additional, Hartmann, A., additional, Kemper, M. J., additional, Zipfel, P. F., additional, N'gome-Sendeyo, K., additional, Fan, Q.-F., additional, Toblli, J., additional, Cao, G., additional, Giani, J. F., additional, Dominici, F. P., additional, Kim, J. S., additional, Yang, J. W., additional, Kim, M. K., additional, Han, B. G., additional, and Choi, S. O., additional

Published
2012
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19. Diabetes - Experimental

Author

Kang, K. P., primary, Lee, J. E., additional, Lee, A. S., additional, Jung, Y. J., additional, Lee, S., additional, Park, S. K., additional, Kim, W., additional, Pokrywczynska, M., additional, Jundzill, A., additional, Krzyzanowska, S., additional, Flisinski, M., additional, Brymora, A., additional, Bodnar, M., additional, Deptula, A., additional, Marszalek, A., additional, Manitius, J., additional, Drewa, T., additional, Kloskowski, T., additional, Grosjean, F., additional, Esposito, V., additional, Torreggiani, M., additional, Esposito, C., additional, Zheng, F., additional, Vlassara, H., additional, Striker, G., additional, Michael, S., additional, Viswanathan, P., additional, Ganesh, R., additional, Kimachi, M., additional, Nishio, S., additional, Nakazawa, D., additional, Ishikawa, Y., additional, Toyoyama, T., additional, Satou, A., additional, Nakagaki, T., additional, Shibasaki, S., additional, Atumi, T., additional, Gattone, V., additional, Peterson, R., additional, Zimmerman, K., additional, Mega, C., additional, Reis, F., additional, Teixeira de Lemos, E., additional, Vala, H., additional, Fernandes, R., additional, Oliveira, J., additional, Teixeira, F., additional, Niculae, A., additional, Checherita, I.-A., additional, Ciocalteu, A., additional, Hamano, Y., additional, Udagawa, Y., additional, Ueda, Y., additional, Yokosuka, O., additional, Ogawa, M., additional, Satoh, M., additional, Kidokoro, K., additional, Nagasu, H., additional, Nishi, Y., additional, Ihoriya, C., additional, Kadoya, H., additional, Yada, T., additional, Channon, K. M., additional, Sasaki, T., additional, Kashihara, N., additional, Nyengaard, J. R., additional, Razga, Z., additional, Hartono, S., additional, Knudsen, B., additional, Grande, J., additional, Watanabe, M., additional, Ito, K., additional, Abe, Y., additional, Ogahara, S., additional, Nakashima, H., additional, Sato, T., additional, Saito, T., additional, Shin, Y. T., additional, Choi, D. E., additional, Na, K.-R., additional, Chang, Y. K., additional, Kim, S. S., additional, Lee, K. W., additional, Mace, C., additional, Chugh, S., additional, Clement, L., additional, Tomochika, M., additional, Seiji, H., additional, Toshio, M., additional, Tetsuya, K., additional, Takao, K., additional, Jaen, J. C., additional, Sullivan, T. J., additional, Miao, Z., additional, Zhao, N., additional, Berahovich, R., additional, Krasinski, A., additional, Powers, J. P., additional, Ertl, L., additional, Schall, T. J., additional, Han, S. Y., additional, Sun, H.-K., additional, Han, K. H., additional, Kim, H.-S., additional, Ahn, S.-H., additional, Kokeny, G., additional, Gasparics, A., additional, Fang, L., additional, Rosivall, L., additional, Sebe, A., additional, Banki, N. F., additional, Fekete, A., additional, Wagner, L., additional, Ver, A., additional, Degrell, P., additional, Prokai, A., additional, George, R., additional, Szabo, A., additional, Baylis, C., additional, Vannay, A., additional, Tulassay, T., additional, Chollet, C., additional, Hus-Citharel, A., additional, Caron, N., additional, Bouby, N., additional, Silva, K., additional, Rampaso, R., additional, Luiz, R., additional, De Angelis, K., additional, Mostarda, C. T., additional, Abreu, N., additional, Irigoyen, M. C., additional, Schor, N., additional, Montemor, J., additional, Higa, E. M. S., additional, Nakayama, Y., additional, Fukami, K., additional, Obara, N., additional, Ando, R., additional, Kaida, Y., additional, Ueda, S., additional, Yamagishi, S.-I., additional, Okuda, S., additional, Qin, Q., additional, Wang, Z., additional, Niu, J., additional, Xu, W., additional, Qiao, Z., additional, Qi, W., additional, Gu, Y., additional, Zitman-Gal, T., additional, Golan, E., additional, Green, J., additional, Pasmanik-Chor, M., additional, Oron-Karni, V., additional, Bernheim, J., additional, Benchetrit, S., additional, Tang, R.-N., additional, Wu, M., additional, Gao, M., additional, Liu, H., additional, Zhang, X.-L., additional, and Liu, B. C., additional

Published
2012
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20. Dark Matter Detection with Bubble Chambers

Author

Behnke, E., primary, Collar, J.I., additional, Cooper, P.S., additional, Crum, K., additional, Crisler, M., additional, Hu, M., additional, Levine, I., additional, Mishra, S., additional, Nakazawa, D., additional, Odom, B., additional, Ramberg, E., additional, Rasmussen, J., additional, Riley, N., additional, Sonnenschein, A., additional, Szydagis, M., additional, Tschirhart, R., additional, and Vander Werf, N., additional

Published
2011
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21. Diabetes - Basic research

Author

Lopez-Parra, V., primary, Mallavia, B., additional, Oguiza, A., additional, Recio, C., additional, Egido, J., additional, Gomez-Guerrero, C., additional, Ito, M., additional, Nishio, S., additional, Koike, T., additional, Takayanagi, K., additional, Hasegawa, H., additional, Shimizu, T., additional, Asakura, J., additional, Iwashita, T., additional, Tayama, Y., additional, Hara, H., additional, Inamura, M., additional, Kanozawa, K., additional, Kato, H., additional, Mitarai, T., additional, Sanchez-Nino, M. D., additional, Sanchez-Lopez, E., additional, Sanz, A. B., additional, Ruiz-Ortega, M., additional, Saleem, M. A., additional, Mathieson, P. W., additional, Mezzano, S., additional, Ortiz, A., additional, Liu, L., additional, Hu, X., additional, Cai, G.-Y., additional, Lv, Y., additional, Zhuo, L., additional, Gao, J.-J., additional, Cui, S.-Y., additional, Feng, Z., additional, Fu, B., additional, Chen, X.-M., additional, Zaladek Gil, F., additional, Costa, M. C., additional, Hirata, A. E., additional, Camara, N. O., additional, Chen, J.-S., additional, Chang, L.-C., additional, Shieh, Y.-S., additional, Wu, C.-C., additional, Zhang, L., additional, Gu, Y., additional, Lin, S., additional, Buraczynska, M., additional, Zukowski, P., additional, Kuczmaszewska, A., additional, Ksiazek, A., additional, Kimachi, M., additional, Sato, A., additional, Nakagaki, T., additional, Nakazawa, D., additional, Ishikawa, Y., additional, Shibasaki, S., additional, Ahn, E.-M., additional, Choi, J.-Y., additional, Shin, J.-I., additional, Ha, T.-S., additional, Mozul, S., additional, Dragan, M., additional, Lumi, Z., additional, Liu, J., additional, Xiufen, Z., additional, Jun, Q., additional, Changying, X., additional, Zitman-Gal, T., additional, Green, J., additional, Bernheim, J., additional, Benchetrit, S., additional, Watanabe, M., additional, Nakashima, H., additional, Abe, Y., additional, Ito, K., additional, Sato, T., additional, Saito, T., additional, Riera, M., additional, Marquez, E., additional, Rigol, J., additional, Roca, H., additional, Pascual, J., additional, Soler, M. J., additional, Aizawa, K., additional, Hirata, M., additional, Moriguchi, Y., additional, Iehara, N., additional, Terada, M., additional, Matsubara, T., additional, Araki, M., additional, Torikoshi, K., additional, Doi, T., additional, and Fukatsu, A., additional

Published
2011
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23. Transplantation: clinical studies

Author

Crespo, M., primary, Collado, S., additional, Mir, M., additional, Hurtado, S., additional, Cao, H., additional, Barbosa, F., additional, Serra, C., additional, Hidalgo, C., additional, Faura, A., additional, Garcia de Lomas, J., additional, Montero, M., additional, Horcajada, J. P., additional, Puig, J. M., additional, Pascual, J., additional, Ulusal Okyay, G., additional, Uludag, K., additional, Sozen, H., additional, Arman, D., additional, Dalgic, A., additional, Guz, G., additional, Fraile, P., additional, Garcia-Cosmes, P., additional, Rosado, C., additional, Gonzalez, C., additional, Tabernero, J. M., additional, Costa, C., additional, Saldan, A., additional, Astegiano, S., additional, Terlizzi, M. E., additional, Messina, M., additional, Bergallo, M., additional, Segoloni, G., additional, Cavallo, R., additional, Schwarz, A., additional, Grosshennig, A., additional, Heim, A., additional, Broecker, V., additional, Haller, H., additional, Linnenweber, S., additional, Liborio, A. B., additional, Mendoza, T. R., additional, Esmeraldo, R. M., additional, Oliveira, M. L. M. B., additional, Nogueira Paes, F. J. V., additional, Silva Junior, G. B., additional, Daher, E. F., additional, Hodgson, K., additional, Baharani, J., additional, Fenton, A., additional, Mjoen, G., additional, Hartmann, A., additional, Reisaeter, A., additional, Midtvedt, K., additional, Dahle, D. O., additional, Holdaas, H., additional, Shabir, S., additional, Lukacik, P., additional, Bevins, A., additional, Basnayake, K., additional, Bental, A., additional, Hughes, R. G., additional, Cockwell, P., additional, Burrows, R., additional, Hutchison, C. A., additional, Varma, P., additional, Kumar, A., additional, Hooda, A., additional, Badwal, S., additional, Barrios, C., additional, Crespo, M., additional, Fumado, L., additional, Frances, A., additional, Arango, O., additional, Pawlik, A., additional, Chudek, J., additional, Kolonko, A., additional, Wilk, J., additional, Jalowiecki, P., additional, Wiecek, A., additional, Teplan, V., additional, Kralova-Lesna, I., additional, Mahrova, A., additional, Racek, J., additional,  tollova, M., additional, Maggisano, V., additional, Caracciolo, V., additional, Solazzo, A., additional, Montanari, M., additional, Della Grotta, F., additional, Nakazawa, D., additional, Nishio, S., additional, Nakagaki, T., additional, Ishikawa, Y., additional, Ito, M., additional, Shibazaki, S., additional, Shimoda, N., additional, Miura, M., additional, Morita, K., additional, Nonomura, K., additional, Koike, T., additional, Locsey, L., additional, Seres, I., additional, Sztanek, F., additional, Harangi, M., additional, Padra, J., additional, Asztalos, L., additional, Paragh, G., additional, Rodriguez-Reimundes, E., additional, Soler-Pujol, G., additional, Diaz, C. H., additional, Davalos-Michel, M., additional, Vilches, A. R., additional, Laham, G., additional, Stavem, K., additional, Norby, G., additional, Tutal, E., additional, Canver, B., additional, Can, S., additional, Sezer, S., additional, Colak, T., additional, Paschoalin, R., additional, Barros, X., additional, Duran, C., additional, Torregrosa, J. V., additional, Tellez, E., additional, Marin, M., additional, Smalcelj, R., additional, Smalcelj, A., additional, Claes, K., additional, Petit, T., additional, Bammens, B., additional, Kuypers, D., additional, Naesens, M., additional, Vanrenterghem, Y., additional, Evenepoel, P., additional, Gerhart, M. K., additional, Colbus, S., additional, Seiler, S., additional, Grun, O., additional, Fliser, D., additional, Heine, G. H., additional, Vincenti, F., additional, Grinyo, J., additional, Larsen, C., additional, Medina Pestana, J., additional, Dong, Y., additional, Thomas, D., additional, Charpentier, B., additional, Luna, E., additional, Martinez, R., additional, Cerezo, I., additional, Ferreira, F., additional, Cubero, J., additional, Villa, J., additional, Martinez, C., additional, Garcia, C., additional, Rodrigo, E., additional, Santos, L., additional, Pinera, C., additional, Quintela, E., additional, Ruiz, J. C., additional, Fernandez-Fresnedo, G., additional, Palomar, R., additional, Gomez-Alamillo, C., additional, Martin de Francisco, A. L., additional, Arias, M., additional, Nainan, G., additional, del Carmen Rial, M., additional, Steinberg, S., additional, Kamar, N., additional, Durrbach, A., additional, Becker, T., additional, Florman, S., additional, Lang, P., additional, Schnitzler, M., additional, Duan, T., additional, Block, A., additional, Sawosz, M., additional, Cieciura, T., additional, Durlik, M., additional, Perkowska, A., additional, Sikora, P., additional, Beck, B., additional, De Mauri, A., additional, Brambilla, M., additional, Stratta, P., additional, Chiarinotti, D., additional, De Leo, M., additional, Attou, S., additional, Arzour, H., additional, Boudrifa, N., additional, Mekhlouf, N., additional, Gaouar, A., additional, Merazga, S., additional, Kalem, K., additional, and Haddoum, F., additional

Published
2011
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25. A bubble chamber for dark matter detection (the COUPP project status)

Author

Bolte, W J, primary, Collar, J I, additional, Crisler, M, additional, Hall, J, additional, Krider, J, additional, Crum, K, additional, Holmgren, D, additional, Lei, C M, additional, Nakazawa, D, additional, Nguyen, H, additional, Odom, B, additional, O'Sullivan, K, additional, Plunkett, R, additional, Ramberg, E, additional, Raskin, A, additional, Rasmussen, J, additional, Schmitt, R, additional, Sonnenschein, A, additional, Szydagis, M, additional, and Vieira, J D, additional

Published
2006
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26. COUPP, A HEAVY-LIQUID BUBBLE CHAMBER FOR WIMP DETECTION

Author

BOLTE, J., primary, COLLAR, J.I., additional, CRISLER, M., additional, HOLMGREN, D., additional, NAKAZAWA, D., additional, ODOM, B., additional, O'SULLIVAN, K., additional, PLUNKETT, R., additional, RAMBERG, E., additional, RASKIN, A., additional, SONNENSCHEIN, A., additional, and VIEIRA, J., additional

Published
2005
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28. Cf-252 Shuffler for Waste Assays and Safeguards Applications.

Author

Menaa, N., McElroy, R. D., Kane Smith, S., Kirkpatrick, J., Nakazawa, D., Mowry, R., M. F. Villani, D. Martancik, and Henry, M.

Subjects
RADIOACTIVE wastes, PLUTONIUM, URANIUM
Abstract

The accurate determination of uranium and plutonium content in both nuclear waste and safeguards fields is very important. The measurement field is quite wide and often quite difficult to apply alpha spectrometry, gamma ray spectrometry or mass spectroscopy. Many nondestructive assay (NDA) techniques use neutron interrogation methods because of the high penetrability and the selective sensitivity of neutrons. The Cf-252 Shuffler is able to identify small quantities of uranium or other fissile material in large and/or dense waste drums. In this paper we report on a first Cf-252 Shuffler that uses software running in Windows XP and a Programmable Logic Controller. The system was developed at Canberra and is based on the Los Alamos National Laboratory (LANL) Cf-252 Shuffler design. The shuffler contains sixty-four 10-atm He-3 tubes configured in eight banks and two 4-atm He-3 tubes used as flux monitors. The neutron interrogation is realized using a 600 μg source. The control mechanism is a Programmable Logic Controller (PLC). Both communications with the PLC and data acquisition are performed through Canberra's NDA 2000 software running on the Windows XP operating system. The shuffler data acquisition system uses the latest shift register electronics; the JSR-15, the JSB-96 and two Multiport II Multi-channel Analyzers. In this work we describe the system and algorithms utilized to convert the response of the system into fissile masses. Preliminary results using Uranium NBL-CRM-969 standards are presented. [ABSTRACT FROM AUTHOR]

Published
2010

36. Tubulointerstitial nephritis with IgM-positive plasma cells complicated by liver failure.

Author

Kudo T, Nakazawa D, Nishio S, Hattanda F, Ueda Y, Yoshikawa J, Shiratori-Aso S, Iwasaki S, Tsuji T, Nakanuma Y, Suda G, Ogawa K, Sakamoto N, and Atsumi T

Abstract

Tubulointerstitial nephritis (TIN) is characterized by inflammation of the renal interstitium with the infiltration of immune cells, mainly consisting of T cells. Recently, patients with TIN with the predominant infiltration of immunoglobulin M (IgM)-positive plasma cells were reported, coined IgMPC-TIN. Here we report the case of a 70-year-old woman diagnosed with Fanconi syndrome and renal tubular acidosis. Renal biopsy revealed IgMPC-TIN. Her renal dysfunction and clinical findings improved after corticosteroid therapy. However, the patient died of progressive liver failure and spontaneous bacterial peritonitis. In laboratory tests, viral hepatitis was excluded, and autoantibodies associated with liver diseases were negative. Generally, IgMPC-TIN is often complicated by primary biliary cholangitis (PBC), whereas her autopsy revealed the local infiltration of IgM-positive plasma cells, obliterative portal venopathy, and nodular regenerative hyperplasia in liver. This case is the first demonstration that IgMPC-TIN is also seen in liver disease with nodular regenerative hyperplasia, although IgMPC-TIN is more common in anti-M2 antibody-positive disease., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Published
2024
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37. Cathepsin C inhibition reduces neutrophil serine protease activity and improves activated neutrophil-mediated disorders.

Author

Nishibata Y, Arai S, Taniguchi M, Nakade I, Ogawa H, Kitano S, Hosoi Y, Shindo A, Nishiyama R, Masuda S, Nakazawa D, Tomaru U, Shimizu T, Sinko W, Nagakura T, Terada Y, and Ishizu A

Subjects
Animals, Humans, Rats, Male, Serine Proteases metabolism, Rats, Sprague-Dawley, Disease Models, Animal, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis drug therapy, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis immunology, Cathepsin C metabolism, Cathepsin C antagonists & inhibitors, Neutrophils immunology, Neutrophils drug effects, Extracellular Traps drug effects, Extracellular Traps immunology, Extracellular Traps metabolism, Neutrophil Activation drug effects, Leukocyte Elastase metabolism, Leukocyte Elastase antagonists & inhibitors, Peroxidase metabolism, Peroxidase antagonists & inhibitors
Abstract

Cathepsin C (CatC) is an enzyme which regulates the maturation of neutrophil serine proteases (NSPs) essential for neutrophil activation. Activated neutrophils are key players in the innate immune system, and are also implicated in the etiology of various inflammatory diseases. This study aims to demonstrate a therapeutic potential for CatC inhibitors against disorders in which activated neutrophil-derived neutrophil extracellular traps (NETs) play a significant role. We demonstrate that a CatC inhibitor, MOD06051, dose-dependently suppresses the cellular activity of NSPs, including neutrophil elastase (NE), in vitro. Neutrophils derived from MOD06051-administered rats exhibit significantly lower NE activity and NET-forming ability than controls. Furthermore, MOD06051 dose-dependently ameliorates vasculitis and significantly decreases NETs when administered to a rat model of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody-associated vasculitis (AAV). These findings suggest that CatC inhibition is a promising strategy to reduce neutrophil activation and improve activated neutrophil-mediated diseases such as MPO-AAV., (© 2024. The Author(s).)

Published
2024
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38. Transcription factor Nrf2 activation regulates NETosis, endothelial injury, and kidney disease in myeloperoxidase-positive antineutrophil cytoplasmic antibody-associated vasculitis.

Author

Ueda Y, Nakazawa D, Nishio S, Shiratori-Aso S, Kudo T, Miyoshi-Harashima A, Watanabe-Kusunoki K, Hattanda F, Iwasaki S, Tsuji T, Tomaru U, Aratani Y, Yamamoto M, Ishizu A, and Atsumi T

Subjects
Animals, Mice, Humans, Oxidative Stress immunology, Mice, Inbred C57BL, Endothelial Cells immunology, Endothelial Cells metabolism, Endothelial Cells pathology, Glomerulonephritis immunology, Glomerulonephritis pathology, Glomerulonephritis genetics, Glomerulonephritis metabolism, Glomerulonephritis etiology, Antibodies, Antineutrophil Cytoplasmic immunology, Male, Kidney pathology, Kidney immunology, Signal Transduction immunology, NF-E2-Related Factor 2 metabolism, NF-E2-Related Factor 2 genetics, Extracellular Traps immunology, Extracellular Traps metabolism, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis immunology, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis pathology, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis genetics, Neutrophils immunology, Neutrophils metabolism, Reactive Oxygen Species metabolism, Disease Models, Animal, Peroxidase metabolism, Peroxidase genetics, Mice, Knockout
Abstract

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease pathologically characterized by vascular necrosis with inflammation. During AAV development, activated neutrophils produce reactive oxygen species (ROS), leading to the aberrant formation of neutrophil extracellular traps (NETs) via NETosis and subsequent fibrinoid vascular necrosis. Nuclear factor-erythroid 2-related factor 2 (Nrf2) functions as an intracellular defense system to counteract oxidative stress by providing antioxidant properties. Herein, we explored the role of Nrf2 in the pathogenesis of AAV. The role and mechanism of Nrf2 in ANCA-stimulated neutrophils and subsequent endothelial injury were evaluated in vitro using Nrf2 genetic deletion and Nrf2 activator treatment. In corresponding in vivo studies, the role of Nrf2 in ANCA-transfer AAV and spontaneous AAV murine models was examined. Pharmacological activation of Nrf2 in vitro suppressed ANCA-induced NET formation via the inhibition of ROS. In contrast, NET formation was enhanced in Nrf2-deficient neutrophils. Furthermore, Nrf2 activation protected endothelial cells from ANC-induced NETs-mediated injury. In vivo, Nrf2 activation ameliorated glomerulonephritis in two AAV models by upregulating antioxidants and inhibiting ROS-mediated NETs. Furthermore, Nrf2 activation restrained the expansion of splenic immune cells, including T lymphocytes and limited the infiltration of Th17 cells into the kidney. In contrast, Nrf2 genetic deficiency exacerbated vasculitis in a spontaneous AAV model. Thus, the pathophysiological process in AAV may be downregulated by Nrf2 activation, potentially leading to a new therapeutic strategy by regulating NETosis., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Published
2024
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39. Survey of Japanese nephrologists' use of clinical practice guidelines for rapidly progressive glomerulonephritis.

Author

Takahashi-Kobayashi M, Sada KE, Kawashima S, Miyawaki Y, Nakazawa D, Furuichi K, Okada H, Narita I, and Usui J

Subjects
Humans, Adrenal Cortex Hormones, Antibodies, Antineutrophil Cytoplasmic, Japan, Nephrologists, Surveys and Questionnaires, Practice Guidelines as Topic, Glomerulonephritis drug therapy, Nephritis
Abstract

Background: The guidelines in Japan for the treatment of rapidly progressive glomerulonephritis (RPGN) have been revised; the latest update was released in 2020. We investigated the actual usage of the new guidelines in Japan., Methods: We distributed a survey electronically to board-certified nephrologists throughout Japan from December 15, 2021 to January 31, 2022. The survey focused on anti-neutrophil cytoplasmic antibody (ANCA)-associated RPGN and anti-glomerular basement membrane (GBM)-antibody RPGN, plus the treatment strategies and infection-prevention measures used., Results: The survey was completed by 155 certified nephrologists from medical facilities across Japan. Their responses regarding treatment procedures revealed that ANCA-associated RPGN was treated with immunosuppressants and/or biologics by 58.1% of the survey respondents, and with plasma exchange (PE) in combination with corticosteroids by 21.3%. Regarding anti-GBM-antibody RPGN, 78.1% of the respondents used corticosteroids in combination with PE (63.2%), cyclophosphamide (CY) (23.9%), or rituximab (RTX) (8.4%), suggesting a discrepancy between clinical practice and the actual use of the guidelines. Trimethoprim-sulfamethoxazole was prescribed as prophylaxis by 94.8% of the respondents, reflecting the widespread recognition of the need to prevent infectious disease in patients with RPGN., Conclusions: The survey responses revealed how Japan's new RPGN guidelines are used in actual clinical practice. Our findings will contribute to the guidelines' dissemination and implementation., (© 2023. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Published
2024
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40. Successful initiation of hemodialysis for a hemophilia A patient with factor VIII inhibitor: a case report and literature review.

Author

Komatsumoto M, Nakazawa D, Endo T, Nishio S, Kawamura T, Miyoshi-Harashima A, Takenaka S, Shiratori-Aso S, Kurotori M, Matsuoka N, and Atsumi T

Subjects
Humans, Factor VIII therapeutic use, Hemorrhage etiology, Hemorrhage prevention & control, Renal Dialysis, Fistula chemically induced, Fistula drug therapy, Hemophilia A complications, Hemophilia A drug therapy, Kidney Failure, Chronic complications, Kidney Failure, Chronic therapy
Abstract

We report the first case of hemophilia A with factor VIII (FVIII) inhibitor who received hemodialysis via an arteriovenous (AV) fistula. Hemophilia A is a congenital deficiency of blood coagulation FVIII that is characterized by prolonged bleeding. Approximately 30% of patients with hemophilia develop allogeneic antibodies of FVIII. The inhibitors decrease the hemostatic effect of replacement therapy; thus, the prophylaxis strategy should be well designed. Prophylactic treatment with invasive procedures is needed to prevent excessive bleeding in patients with hemophilia undergoing hemodialysis. On the contrary, hemodialysis requires attention to the development of intracircuit coagulation during dialysis. Peritoneal dialysis or hemodialysis with a long-term tunneled central venous catheter has mainly been selected as the dialysis modality for patients with hemophilia and end-stage renal disease requiring renal replacement therapy because hemodialysis with an arteriovenous fistula may result in bleeding from the puncture site after each hemodialysis session. In our patient, hemodialysis was safely performed without any anticoagulant agents, and replacement therapy with FVIII concentrates prevented bleeding after puncture of the AV fistula., (© 2023. The Author(s) under exclusive licence to The Japan Society of Nephrology.)

Published
2024
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41. Methylprednisolone pulse-enhanced neutrophil extracellular trap formation in mice with imiquimod-induced lupus-like disease, resulting in ischaemia of the femoral head cartilage.

Author

Ogawa H, Yokota S, Hosoi Y, Shindo A, Ogawa N, Yamamura R, Shimizu T, Nakade I, Arai S, Taniguchi M, Nishibata Y, Masuda S, Nakazawa D, Tomaru U, Iwasaki N, and Ishizu A

Subjects
Mice, Humans, Animals, Methylprednisolone therapeutic use, Methylprednisolone metabolism, Methylprednisolone pharmacology, Femur Head pathology, Imiquimod metabolism, Imiquimod pharmacology, Imiquimod therapeutic use, Proteome metabolism, Proteome pharmacology, Cartilage, Ischemia metabolism, Ischemia pathology, Extracellular Traps, Lupus Erythematosus, Systemic chemically induced, Lupus Erythematosus, Systemic drug therapy
Abstract

Objectives: Methylprednisolone (mPSL) pulse therapy is an essential option for patients with active systemic lupus erythematosus, but there is a risk of adverse events related to microcirculation disorders, including idiopathic osteonecrosis of the femoral head (ONFH). Recent studies have revealed that excessive neutrophil extracellular traps (NETs) are involved in microcirculation disorders. This study aimed to demonstrate that mPSL pulse could induce NETs in lupus mice and identify the factors contributing to this induction., Methods: Six mice with imiquimod (IMQ)-induced lupus-like disease and six normal mice were intraperitoneally injected with mPSL on days 39 to 41, and five mice with IMQ-induced lupus-like disease and six normal mice were injected with phosphate-buffered saline. Pathological examinations were conducted to evaluate the ischaemic state of the femoral head and tissue infiltration of NET-forming neutrophils. Proteome analysis was performed to extract plasma proteins specifically elevated in mPSL-administered mice with IMQ-induced lupus-like disease, and their effects on NET formation were assessed in vitro., Results: Mice with IMQ-induced lupus-like disease that received mPSL pulse demonstrated ischaemia of the femoral head cartilage with tissue infiltration of NET-forming neutrophils. Proteome analysis suggested that prenylcysteine oxidase 1 (PCYOX1) played a role in this phenomenon. The reaction of PCYOX1-containing very low-density lipoproteins (VLDL) with its substrate farnesylcysteine (FC) induced NETs in vitro. The combined addition of IMQ and mPSL synergistically enhanced VLDL-plus-FC-induced NET formation., Conclusion: PCYOX1 and related factors are worthy of attention to understand the underlying mechanisms and create novel therapeutic strategies for mPSL-mediated microcirculation disorders, including ONFH., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2023
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42. Bruton's tyrosine kinase is a possible therapeutic target in microscopic polyangiitis.

Author

Nakade I, Tamura Y, Hashimoto F, Ariza Y, Hotta S, Fujigaya H, Arai S, Taniguchi M, Ogawa H, Nishibata Y, Masuda S, Nakazawa D, Tomaru U, and Ishizu A

Subjects
Humans, Rats, Animals, Antibodies, Antineutrophil Cytoplasmic, Agammaglobulinaemia Tyrosine Kinase, Receptors, IgG, Rats, Sprague-Dawley, Autoantibodies, Rats, Inbred WKY, Peroxidase, Microscopic Polyangiitis
Abstract

Background: Bruton's tyrosine kinase (Btk) is an enzyme expressed in leukocytes other than T lymphocytes and plasma cells and involved in B-cell receptor- and Fcγ receptor (FcγR)-mediated signal transduction. Btk inhibitors potentially suppress autoantibody production due to the expected inhibitory ability of B lymphocyte differentiation into antibody-producing plasma cells and reduce FcγR-mediated neutrophil activation, including the release of neutrophil extracellular traps (NETs). Microscopic polyangiitis (MPA) is a systemic small-vessel vasculitis characterized by the pathogenic autoantibody, antineutrophil cytoplasmic antibody (ANCA) that reacts with myeloperoxidase (MPO). MPO and MPO-ANCA immune complex (IC)-induced FcγR-mediated NETs are critically involved in MPA pathogenesis. This study aimed to demonstrate the therapeutic efficacy of the Btk inhibitor tirabrutinib on MPA., Methods: Various doses of tirabrutinib or vehicle were orally administered to Sprague-Dawley rats daily. Four weeks later, the number of peripheral B lymphocytes was counted, and Btk phosphorylation in B lymphocytes was evaluated by flow cytometry. Human peripheral blood neutrophils were stimulated by MPO and anti-MPO antibody ICs (MPO and anti-MPO-ICs), and Btk and its downstream Vav phosphorylation were assessed by western blotting. The effects of tirabrutinib on MPO and anti-MPO-IC-induced NET formation were examined in vitro. Wistar Kyoto rats were immunized with human MPO to induce experimental MPA and given drug-free or tirabrutinib-containing feed (0.0037% or 0.012%) from day 0 or 28. All rats were euthanized on day 42 for serological and histological evaluation., Results: Tirabrutinib inhibited Btk phosphorylation without decreasing B lymphocytes in vivo. Neutrophil Btk and Vav were phosphorylated when stimulated with MPO and anti-MPO-ICs. Tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA in a dose-dependent manner in vivo. Although MPO-ANCA production was not affected, NET-forming neutrophils in the blood were significantly reduced by tirabrutinib., Conclusions: The Btk inhibitor tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA by reducing NET-forming neutrophils but not decreasing MPO-ANCA titer in vivo. This study suggests that Btk is a possible therapeutic target in MPA., (© 2023. The Author(s).)

Published
2023
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43. The involvement of NETs in ANCA-associated vasculitis.

Author

Shiratori-Aso S and Nakazawa D

Subjects
Humans, Aged, Antibodies, Antineutrophil Cytoplasmic, Neutrophils, Necrosis pathology, Extracellular Traps, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis drug therapy
Abstract

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a serious autoimmune disease that is characterized by vascular necrosis. The pathogenesis of AAV includes ANCA-mediated neutrophil activation, subsequent release of inflammatory cytokines and reactive oxygen species (ROS), and formation of neutrophil extracellular traps (NETs). Excessive NETs could participate not only in ANCA-mediated vascular injury but also in the production of ANCAs per se as autoantigens. Thus, a vicious cycle of NET formation and ANCA production is critical for AAV pathogenesis. Elucidating the molecular signaling pathways in aberrant neutrophil activation and NETs clearance systems will allow specific therapeutics to regulate these pathways. Currently, standard therapy with high doses of glucocorticoids and immunosuppressants has improved outcomes in patients with AAV. However, AAV frequently develops in elderly people, and adverse effects such as severe infections in the standard regimens might contribute to the mortality. Mechanistically, cytokines or complement factors activate and prime neutrophils for ANCA-binding; thus, C5a receptor blocker has garnered attention as potential replacement for glucocorticoids in clinical settings. Recent studies have demonstrated that receptor-interacting protein kinases (RIPK3) and cyclophilin D (CypD), which regulate cell necrosis, may be involved in ANCA-induced NETs formation. Meanwhile, targeting NETs clearance, including the addition of deoxyribonuclease I (DNase I) and macrophage engulfment, may improve vasculitis. In this review, we focus on the pathogenesis of NETs and discuss potential targeted therapies for AAV based on recent experimental evidence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shiratori-Aso and Nakazawa.)

Published
2023
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44. Inhibition of Toll-like receptor 4 and Interleukin-1 receptor prevent SARS-CoV-2 mediated kidney injury.

Author

Nakazawa D, Takeda Y, Kanda M, Tomaru U, Ogawa H, Kudo T, Shiratori-Aso S, Watanabe-Kusunoki K, Ueda Y, Miyoshi A, Hattanda F, Nishio S, Uozumi R, Ishizu A, and Atsumi T

Abstract

Acute kidney injury (AKI) is a common and severe complication of the coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly affects the glomerular and tubular epithelial cells to induce AKI; however, its pathophysiology remains unclear. Here, we explored the underlying mechanisms and therapeutic targets of renal involvement in COVID-19. We developed an in vitro human kidney cellular model, including immortalized tubular epithelial and endothelial cell lines, demonstrating that SARS-CoV-2 directly triggers cell death. To identify the molecular targets in the process of SARS-CoV-2-mediated cell injury, we performed transcriptional analysis using RNA sequencing. Tubular epithelial cells were more prone to dying by SARS-CoV-2 than endothelial cells; however, SARS-CoV-2 did not replicate in renal cells, distinct from VeroE6/transmembrane protease serine 2 cells. Transcriptomic analysis revealed increased inflammatory and immune-related gene expression levels in renal cells incubated with SARS-CoV-2. Toll-like receptor (TLR) 3 in renal cells recognized viral RNA and underwent cell death. Furthermore, analysis of upstream regulators identified several key transcriptional regulators. Among them, inhibition of the interleukin-1 receptor (IL-1R) and TLR4 pathways protects tubular epithelial and endothelial cells from injury via regulation of the signal transducer and activator of transcription protein-3/nuclear factor-kB pathway. Our results reveal that SARS-CoV-2 directly injures renal cells via the proinflammatory response without viral replication, and that IL-1R and TLR4 may be used as therapeutic targets for SARS-CoV-2 mediated kidney injury., (© 2023. Cell Death Differentiation Association (ADMC).)

Published
2023
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45. CD47 blockade ameliorates autoimmune vasculitis via efferocytosis of neutrophil extracellular traps.

Author

Shiratori-Aso S, Nakazawa D, Kudo T, Kanda M, Ueda Y, Watanabe-Kusunoki K, Nishio S, Iwasaki S, Tsuji T, Masuda S, Tomaru U, Ishizu A, and Atsumi T

Subjects
Humans, Mice, Animals, Antibodies, Antineutrophil Cytoplasmic metabolism, CD47 Antigen metabolism, Extracellular Traps, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis metabolism, Glomerulonephritis, Granulomatosis with Polyangiitis metabolism, Mucocutaneous Lymph Node Syndrome, Giant Cell Arteritis metabolism
Abstract

Neutrophil extracellular trap (NET) formation contributes to immune defense and is a distinct form of cell death. Excessive NET formation is found in patients with anti-neutrophil cytoplasmic antibody-associated (ANCA-associated) vasculitis (AAV), contributing to disease progression. The clearance of dead cells by macrophages, a process known as efferocytosis, is regulated by the CD47-mediated "don't eat me" signal. Hence, we hypothesized that pathogenic NETs in AAV escape from efferocytosis via the CD47 signaling pathway, resulting in the development of necrotizing vasculitis. Immunostaining for CD47 in human renal tissues revealed high CD47 expression in crescentic glomerular lesions of patients with AAV. In ex vivo studies, ANCA-induced netting neutrophils increased the expression of CD47 with the reduction of efferocytosis. After efferocytosis, macrophages displayed proinflammatory phenotypes. The blockade of CD47 in spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mice ameliorated renal disease and reduced myeloperoxidase-ANCA (MPO-ANCA) titers with a reduction in NET formation. Thus, CD47 blockade would protect against developing glomerulonephritis in AAV via restored efferocytosis of ANCA-induced NETs.

Published
2023
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46. Development of ANCA-associated vasculitis followed by SARS-CoV-2 vaccination in a patient with HLA-DRB1*09:01 allele.

Author

Kawamura T, Nakazawa D, Nishio S, Isozaki T, Komatsumoto M, and Atsumi T

Subjects
Female, Humans, Aged, COVID-19 Vaccines adverse effects, HLA-DRB1 Chains genetics, Peroxidase, SARS-CoV-2 genetics, Alleles, Antibodies, Antineutrophil Cytoplasmic, Vaccination adverse effects, COVID-19 prevention & control, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis etiology, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis genetics
Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents with severe pneumonia and fatal systemic complications. Currently, SARS-CoV-2 vaccines are effective in reducing the risk of new onset and getting worse of the disease. However, autoimmune diseases such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been reported to develop after COVID-19 vaccine administration. A 71-year-old woman presented with fever, malaise, urinary abnormalities, and renal dysfunction after receiving the COVID-19 vaccine (Pfizer-BioNTech). We clinically diagnosed AAV with her manifestations and serological test (myeloperoxidase-ANCA-positive). Her clinical findings were improved after immunosuppressive therapy. We examined her genetic susceptibility to AAV, and we found that her allele was HLA-DRB1*09:01, which is a risk allele of myeloperoxidase-AAV. Mechanistically, SARS-CoV-2 vaccines would activate immunity, including neutrophils, and trigger AAV onset in this patient with a genetic risk to develop AAV. The pathophysiology of this case would share with that of autoimmune/inflammatory syndrome induced by adjuvants in the absence of external adjuvants., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Published
2023
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47. Itaconate ameliorates autoimmunity by modulating T cell imbalance via metabolic and epigenetic reprogramming.

Author

Aso K, Kono M, Kanda M, Kudo Y, Sakiyama K, Hisada R, Karino K, Ueda Y, Nakazawa D, Fujieda Y, Kato M, Amengual O, and Atsumi T

Subjects
Animals, Epigenesis, Genetic, Succinates pharmacology, T-Lymphocytes immunology, Autoimmunity genetics, Encephalomyelitis, Autoimmune, Experimental drug therapy, Encephalomyelitis, Autoimmune, Experimental genetics
Abstract

Dysregulation of Th17 and Treg cells contributes to the pathophysiology of many autoimmune diseases. Herein, we show that itaconate, an immunomodulatory metabolite, inhibits Th17 cell differentiation and promotes Treg cell differentiation by orchestrating metabolic and epigenetic reprogramming. Mechanistically, itaconate suppresses glycolysis and oxidative phosphorylation in Th17- and Treg-polarizing T cells. Following treatment with itaconate, the S-adenosyl-L-methionine/S-adenosylhomocysteine ratio and 2-hydroxyglutarate levels are decreased by inhibiting the synthetic enzyme activities in Th17 and Treg cells, respectively. Consequently, these metabolic changes are associated with altered chromatin accessibility of essential transcription factors and key gene expression in Th17 and Treg cell differentiation, including decreased RORγt binding at the Il17a promoter. The adoptive transfer of itaconate-treated Th17-polarizing T cells ameliorates experimental autoimmune encephalomyelitis. These results indicate that itaconate is a crucial metabolic regulator for Th17/Treg cell balance and could be a potential therapeutic agent for autoimmune diseases., (© 2023. The Author(s).)

Published
2023
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48. Expert perspectives on pathological findings in vasculitis.

Author

Ishizu A, Kawakami T, Kanno H, Takahashi K, Miyazaki T, Ikeda E, Oharaseki T, Ogawa Y, Onimaru M, Kurata M, Nakazawa D, Muso E, and Harigai M

Subjects
Humans, Consensus, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis complications, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis diagnosis
Abstract

Pathological findings are important in the diagnosis of vasculitis. However, due to the rarity of the disease, standard textbooks usually devote only a few pages to this topic, and this makes it difficult for clinicians not specializing in vasculitis to fully understand the pathological findings in vasculitis. To address the paucity of information, we present representative pathological findings in vasculitis classified in the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (CHCC2012). The CHCC2012 classifies 26 vasculitides into seven categories: (1) large-vessel vasculitis, (2) medium-vessel vasculitis, (3) small-vessel vasculitis, including antineutrophil cytoplasmic antibody-associated vasculitis and immune complex small-vessel vasculitis, (4) variable-vessel vasculitis, (5) single-organ vasculitis, (6) vasculitis associated with systemic disease, and (7) vasculitis associated with probable aetiology. Moreover, representative pathological findings of vasculitis-related diseases and non-inflammatory vasculopathy not mentioned in the CHCC2012 are also presented. This will be useful for clinicians to refer to typical pathological findings of vasculitis in daily practice., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

Published
2023
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49. Use of Mixed Lymphocyte Reaction Assay to Evaluate Immune Tolerance before Kidney Transplantation with an Immunosuppression-Free Protocol following Hematopoietic Stem Cell Transplantation from the Same Donor.

Author

Nonoyama S, Hotta K, Iwahara N, Tanabe T, Hirose T, Harada S, Junichi S, Nakazawa D, Shigematsu A, Otsuka T, and Shinohara N

Subjects
Humans, Female, Adult, Lymphocyte Culture Test, Mixed, Immune Tolerance, Immunosuppressive Agents therapeutic use, Kidney Transplantation methods, Hematopoietic Stem Cell Transplantation methods, Kidney Failure, Chronic surgery
Abstract

Several cases of kidney transplantation after hematopoietic stem cell transplantation (HSCT) from the same donor for end-stage renal disease have been reported. In those cases, immunosuppressive drugs were discontinued since immune tolerance was supposed to be induced. Theoretically, the recipient's immune system recognizes the kidney allograft as its own tissue with the same human leukocyte antigen (HLA) profile, and the kidney allograft will not be rejected, even without the use of immunosuppressive agents. However, almost all recipients receive immunosuppressants in the early stages after kidney transplantation owing to concerns of acute rejection. Here, we report a successful case of post-HSCT kidney transplantation without the use of immunosuppressive drugs, in which a mixed lymphocyte reaction (MLR) assay was used to evaluate immune tolerance before kidney transplantation. The patient was a 25-year-old woman. Five years prior, she developed acute myeloid leukemia and underwent HLA-half-matched peripheral blood stem cell transplantation. Thereafter, she was in remission of the acute myeloid leukemia, but 1 year later, she developed renal graft-versus-host disease. Subsequently, the patient's renal function gradually deteriorated to end-stage renal failure, and she underwent kidney transplantation with the previous stem cell donor: her mother. HLA typing of donor and recipient showed a complete chimerism in the peripheral blood. The pretransplantation complement-dependent cytotoxic crossmatch and flow cytometric T-cell crossmatch results were both negative, and HLA antibody measurements were all negative. The MLR assay revealed no T-lymphocyte reaction to the donor; therefore, immunosuppressants were not used. Two years after transplantation, the patient's serum creatinine concentration was around 0.8 mg/dL (down from 4 mg/dL before transplantation). No abnormalities were observed in a renal biopsy performed after 3 months. Our study, along with others, indicates that immune tolerance to a donor develops in post-HSCT kidney transplantation from the same donor., (© 2023 S. Karger AG, Basel.)

Published
2023
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50. Transcriptional dynamics of granulocytes in direct response to incubation with SARS-CoV-2.

Author

Nakazawa D, Takeda Y, Kanda M, Tomaru U, Ogawa H, Kudo T, Shiratori-Aso S, Watanabe-Kusunoki K, Ueda Y, Miyoshi A, Hattanda F, Nishio S, Uozumi R, Ishizu A, and Atsumi T

Subjects
Humans, SARS-CoV-2, Granulocytes, Neutrophils, COVID-19, Extracellular Traps
Abstract

Severe coronavirus disease 2019 (COVID-19) is characterized by acute respiratory distress syndrome and multiple organ dysfunction, in which the host immune response plays a pivotal role. Excessive neutrophil activation and subsequent superfluity of neutrophil extracellular traps (NETs) can lead to tissue damage, and several studies have shown the involvement of neutrophils in severe COVID-19. However, the detailed responses of each neutrophil subset to SARS-CoV-2 infection has not been fully described. To explore this issue, we incubated normal-density granulocytes (NDGs) and low-density granulocytes (LDGs) with different viral titers of SARS-CoV-2. NDGs form NETs with chromatin fibers in response to SARS-CoV-2, whereas LDGs incubated with SARS-CoV-2 display a distinct morphology with condensed nuclei and moderate transcriptional changes. Based on these transcriptional changes, we suggest that AGO2 possibly plays a role in LDG regulation in response to SARS-CoV-2., (© 2022 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Published
2023
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