340 results on '"K. Yonezawa"'
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2. Empagliflozin in the treatment of heart failure with reduced ejection fraction in addition to background therapies and therapeutic combinations (EMPEROR-Reduced): a post-hoc analysis of a randomised, double-blind trial
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Subodh Verma, Nitish K Dhingra, Javed Butler, Stefan D Anker, Joao Pedro Ferreira, Gerasimos Filippatos, James L Januzzi, Carolyn S P Lam, Naveed Sattar, Barbara Peil, Matias Nordaby, Martina Brueckmann, Stuart J Pocock, Faiez Zannad, Milton Packer, M Packer, S Anker, J Butler, G Filippatos, S Pocock, F Zannad, JP Ferreira, M Brueckmann, J George, W Jamal, FK Welty, M Palmer, T Clayton, KG Parhofer, TR Pedersen, B Greenberg, MA Konstam, KR Lees, P Carson, W Doehner, A Miller, M Haas, S Pehrson, M Komajda, I Anand, J Teerlink, A Rabinstein, T Steiner, H Kamel, G Tsivgoulis, J Lewis, J Freston, N Kaplowitz, J Mann, J Petrie, S Perrone, S Nicholls, S Janssens, E Bocchi, N Giannetti, S Verma, J Zhang, J Spinar, M-F Seronde, M Boehm, B Merkely, V Chopra, M Senni, S Taddi, H Tsutsui, D-J Choi, E Chuquiure, HPB La Rocca, P Ponikowski, JRG Juanatey, I Squire, J Januzzi, I Pina, R Bernstein, A Cheung, J Green, S Kaul, C Lam, G Lip, N Marx, P McCullough, C Mehta, J Rosenstock, N Sattar, B Scirica, S Shah, C Wanner, D Aizenberg, L Cartasegna, F Colombo Berra, H Colombo, M Fernandez Moutin, J Glenny, C Alvarez Lorio, D Anauch, R Campos, A Facta, A Fernandez, R Ahuad Guerrero, L Lobo Márquez, RA Leon de la Fuente, M Mansilla, M Hominal, E Hasbani, M Najenson, G Moises Azize, H Luquez, L Guzman, H Sessa, M Amuchástegui, O Salomone, E Perna, D Piskorz, M Sicer, D Perez de Arenaza, C Zaidman, S Nani, C Poy, J Resk, R Villarreal, C Majul, T Smith Casabella, S Sassone, A Liberman, G Carnero, A Caccavo, M Berli, N Budassi, J Bono, A Alvarisqueta, J Amerena, K Kostner, A Hamilton, A Begg, J Beltrame, D Colquhoun, G Gordon, A Sverdlov, G Vaddadi, J Wong, J Coller, D Prior, A Friart, A Leone, G Vervoort, P Timmermans, P Troisfontaines, C Franssen, T Sarens, H Vandekerckhove, P Van De Borne, F Chenot, J De Sutter, E De Vuyst, P Debonnaire, M Dupont, O Pereira Dutra, LH Canani, MdC Vieira Moreira, W de Souza, LM Backes, L Maia, B De Souza Paolino, ER Manenti, W Saporito, F Villaça Guimarães Filho, T Franco Hirakawa, LA Saliba, FC Neuenschwander, CA de Freitas Zerbini, G Gonçalves, Y Gonçalves Mello, J Ascenção de Souza, L Beck da Silva Neto, EA Bocchi, J Da Silveira, JB de Moura Xavier Moraes Junior, JD de Souza Neto, M Hernandes, HC Finimundi, CR Sampaio, E Vasconcellos, FJ Neves Mancuso, MM Noya Rabelo, M Rodrigues Bacci, F Santos, M Vidotti, MV Simões, FL Gomes, C Vieira Nascimento, D Precoma, FA Helfenstein Fonseca, JA Ribas Fortes, PE Leães, D Campos de Albuquerque, JF Kerr Saraiva, S Rassi, FA Alves da Costa, G Reis, S Zieroth, D Dion, D Savard, R Bourgeois, C Constance, K Anderson, M-H Leblanc, D Yung, E Swiggum, L Pliamm, Y Pesant, B Tyrrell, T Huynh, J Spiegelman, J-P Lavoie, M Hartleib, R Bhargava, L Straatman, S Virani, A Costa-Vitali, L Hill, M Heffernan, Y Khaykin, J Ricci, M Senaratne, A Zhai, B Lubelsky, M Toma, L Yao, R McKelvie, L Noronha, M Babapulle, A Pandey, G Curnew, A Lavoie, J Berlingieri, S Kouz, E Lonn, R Chehayeb, Y Zheng, Y Sun, H Cui, Z Fan, X Han, X Jiang, Q Tang, J Zhou, Z Zheng, X Zhang, N Zhang, Y Zhang, A Shen, J Yu, J Ye, Y Yao, J Yan, X Xu, Z Wang, J Ma, Y Li, S Li, S Lu, X Kong, Y Song, G Yang, Z Yao, Y Pan, X Guo, Z Sun, Y Dong, J Zhu, D Peng, Z Yuan, J Lin, Y Yin, O Jerabek, H Burianova, T Fiala, J Hubac, O Ludka, Z Monhart, P Vodnansky, K Zeman, D Foldyna, J Krupicka, I Podpera, L Busak, M Radvan, Z Vomacka, R Prosecky, R Cifkova, V Durdil, J Vesely, J Vaclavik, P Cervinka, A Linhart, T Brabec, R Miklik, H Bourhaial, H-G Olbrich, S Genth-Zotz, E Kemala, B Lemke, M Böhm, S Schellong, W Rieker, T Heitzer, H Ince, M Faghih, A Birkenfeld, A Begemann, A Ghanem, A Ujeyl, S von Haehling, T Dorsel, J Bauersachs, M Prull, F Weidemann, H Darius, G Nickenig, A Wilke, J Sauter, U Rauch-Kroehnert, N Frey, CP Schulze, W König, L Maier, F Menzel, N Proskynitopoulos, H-H Ebert, H-E Sarnighausen, H-D Düngen, M Licka, C Stellbrink, B Winkelmann, N Menck, JL López-Sendón, L de la Fuente Galán, JF Delgado Jiménez, N Manito Lorite, M Pérez de Juan Romero, E Galve Basilio, F Cereto Castro, JR González Juanatey, JJ Gómez, M Sanmartín Fernández, X Garcia-Moll Marimon, D Pascual Figal, R Bover Freire, E Bonnefoy Cudraz, A Jobbe Duval, D Tomasevic, G Habib, R Isnard, F Picard, P Khanoyan, J-L Dubois-Rande, M Galinier, F Roubille, J Alexandre, D Babuty, N Delarche, J-B Berneau, N Girerd, M Saxena, G Rosano, Z Yousef, C Clifford, C Arden, A Bakhai, C Boos, G Jenkins, C Travill, D Price, L Koenyves, F Lakatos, A Matoltsy, E Noori, Z Zilahi, P Andrassy, S Kancz, G Simon, T Sydo, A Vorobcsuk, RG Kiss, K Toth, I Szakal, L Nagy, T Barany, A Nagy, E Szolnoki, VK Chopra, S Mandal, V Rastogi, B Shah, A Mullasari, J Shankar, V Mehta, A Oomman, U Kaul, S Komarlu, D Kahali, A Bhagwat, V Vijan, NK Ghaisas, A Mehta, J Kashyap, Y Kothari, S TaddeI, M Scherillo, V Zacà, S Genovese, A Salvioni, A Fucili, F Fedele, F Cosmi, M Volpe, C Mazzone, G Esposito, M Doi, H Yamamoto, S Sakagami, S Oishi, Y Yasaka, H Tsuboi, Y Fujino, S Matsuoka, Y Watanabe, T Himi, T Ide, M Ichikawa, Y Kijima, T Koga, S Yuda, K Fukui, T Kubota, M Manita, H Fujinaga, T Matsumura, Y Fukumoto, R Kato, Y Kawai, G Hiasa, Y Kazatani, M Mori, A Ogimoto, M Inoko, M Oguri, M Kinoshita, K Okuhara, N Watanabe, Y Ono, K Otomo, Y Sato, T Matsunaga, A Takaishi, N Miyagi, H Uehara, H Takaishi, H Urata, T Kataoka, H Matsubara, T Matsumoto, T Suzuki, N Takahashi, M Imamaki, T Yoshitama, T Saito, H Sekino, Y Furutani, M Koda, T Shinozaki, K Hirabayashi, R Tsunoda, K Yonezawa, H Hori, M Yagi, M Arikawa, T Hashizume, R Ishiki, T Koizumi, K Nakayama, S Taguchi, M Nanasato, Y Yoshida, S Tsujiyama, T Nakamura, K Oku, M Shimizu, M Suwa, Y Momiyama, H Sugiyama, K Kobayashi, S Inoue, T Kadokami, K Maeno, K Kawamitsu, Y Maruyama, A Nakata, T Shibata, A Wada, H-J Cho, JO Na, B-S Yoo, J-O Choi, SK Hong, J-H Shin, M-C Cho, SH Han, J-O Jeong, J-J Kim, SM Kang, D-S Kim, MH Kim, G Llamas Esperon, J Illescas Díaz, P Fajardo Campos, J Almeida Alvarado, A Bazzoni Ruiz, J Echeverri Rico, I Lopez Alcocer, L Valle Molina, C Hernandez Herrera, C Calvo Vargas, FG Padilla Padilla, I Rodriguez Briones, EJJR Chuquiure Valenzuela, ME Aguilera Real, J Carrillo Calvillo, M Alpizar Salazar, JL Cervantes Escárcega, R Velasco Sanchez, N Al - Windy, L van Heerebeek, L Bellersen, H-P Brunner-La Rocca, J Post, GCM Linssen, M van de Wetering, R Peters, R van Stralen, R Groutars, P Smits, A Yilmaz, WEM Kok, P Van der Meer, P Dijkmans, R Troquay, AP van Alem, R Van de Wal, L Handoko, ICD Westendorp, PFMM van Bergen, BJWM Rensing, P Hoogslag, B Kietselaer, JA Kragten, FR den Hartog, A Alings, L Danilowicz-Szymanowicz, G Raczak, W Piesiewicz, W Zmuda, W Kus, P Podolec, W Musial, G Drelich, G Kania, P Miekus, S Mazur, A Janik, J Spyra, J Peruga, P Balsam, B Krakowiak, J Szachniewicz, M Ginel, J Grzybowski, W Chrustowski, P Wojewoda, A Kalinka, A Zurakowski, R Koc, M Debinski, W Fil, M Kujawiak, J Forys, M Kasprzak, M Krol, P Michalski, E Mirek-Bryniarska, K Radwan, G Skonieczny, K Stania, G Skoczylas, A Madej, J Jurowiecki, B Firek, B Wozakowska-Kaplon, K Cymerman, J Neutel, K Adams, P Balfour, A Deswal, A Djamson, P Duncan, M Hong, C Murray, D Rinde-Hoffman, S Woodhouse, R MacNevin, B Rama, C Broome-Webster, S Kindsvater, D Abramov, M Barettella, S Pinney, J Herre, A Cohen, K Vora, K Challappa, S West, S Baum, J Cox, S Jani, A Karim, A Akhtar, O Quintana, L Paukman, R Goldberg, Z Bhatti, M Budoff, E Bush, A Potler, R Delgado, B Ellis, J Dy, J Fialkow, R Sangrigoli, K Ferdinand, C East, S Falkowski, S Donahoe, R Ebrahimi, G Kline, B Harris, R Khouzam, N Jaffrani, N Jarmukli, N Kazemi, M Koren, K Friedman, W Herzog, J Silva Enciso, D Cheung, M Grover-McKay, P Hauptman, D Mikhalkova, V Hegde, J Hodsden, S Khouri, F McGrew, R Littlefield, P Bradley, B McLaurin, S Lupovitch, I Labin, V Rao, M Leithe, M Lesko, N Lewis, D Lombardo, S Mahal, V Malhotra, I Dauber, A Banerjee, J Needell, G Miller, L Paladino, K Munuswamy, M Nanna, E McMillan, M Mumma, M Napoli, W Nelson, T O'Brien, A Adlakha, A Onwuanyi, H Serota, J Schmedtje, A Paraschos, R Potu, C Sai-Sudhakar, M Saltzberg, A Sauer, P Shah, H Skopicki, H Bui, K Carr, G Stevens, N Tahirkheli, J Tallaj, K Yousuf, B Trichon, J Welker, P Tolerico, A Vest, R Vivo, X Wang, R Abadier, S Dunlap, N Weintraub, A Malik, P Kotha, V Zaha, G Kim, N Uriel, T Greene, A Salacata, R Arora, R Gazmuri, J Kobayashi, B Iteld, R Vijayakrishnan, R Dab, Z Mirza, V Marques, M Nallasivan, D Bensimhon, B Peart, H Saint-Jacques, K Barringhaus, J Contreras, A Gupta, S Koneru, V Nguyen, Verma, S, Dhingra, N, Butler, J, Anker, S, Ferreira, J, Filippatos, G, Januzzi, J, Lam, C, Sattar, N, Peil, B, Nordaby, M, Brueckmann, M, Pocock, S, Zannad, F, Packer, M, George, J, Jamal, W, Welty, F, Palmer, M, Clayton, T, Parhofer, K, Pedersen, T, Greenberg, B, Konstam, M, Lees, K, Carson, P, Doehner, W, Miller, A, Haas, M, Pehrson, S, Komajda, M, Anand, I, Teerlink, J, Rabinstein, A, Steiner, T, Kamel, H, Tsivgoulis, G, Lewis, J, Freston, J, Kaplowitz, N, Mann, J, Petrie, J, Perrone, S, Nicholls, S, Janssens, S, Bocchi, E, Giannetti, N, Zhang, J, Spinar, J, Seronde, M, Boehm, M, Merkely, B, Chopra, V, Senni, M, Taddi, S, Tsutsui, H, Choi, D, Chuquiure, E, La Rocca, H, Ponikowski, P, Juanatey, J, Squire, I, Pina, I, Bernstein, R, Cheung, A, Green, J, Kaul, S, Lip, G, Marx, N, Mccullough, P, Mehta, C, Rosenstock, J, Scirica, B, Shah, S, Wanner, C, Aizenberg, D, Cartasegna, L, Colombo Berra, F, Colombo, H, Fernandez Moutin, M, Glenny, J, Alvarez Lorio, C, Anauch, D, Campos, R, Facta, A, Fernandez, A, Ahuad Guerrero, R, Lobo Marquez, L, Leon de la Fuente, R, Mansilla, M, Hominal, M, Hasbani, E, Najenson, M, Moises Azize, G, Luquez, H, Guzman, L, Sessa, H, Amuchastegui, M, Salomone, O, Perna, E, Piskorz, D, Sicer, M, Perez de Arenaza, D, Zaidman, C, Nani, S, Poy, C, Resk, J, Villarreal, R, Majul, C, Smith Casabella, T, Sassone, S, Liberman, A, Carnero, G, Caccavo, A, Berli, M, Budassi, N, Bono, J, Alvarisqueta, A, Amerena, J, Kostner, K, Hamilton, A, Begg, A, Beltrame, J, Colquhoun, D, Gordon, G, Sverdlov, A, Vaddadi, G, Wong, J, Coller, J, Prior, D, Friart, A, Leone, A, Vervoort, G, Timmermans, P, Troisfontaines, P, Franssen, C, Sarens, T, Vandekerckhove, H, Van De Borne, P, Chenot, F, De Sutter, J, De Vuyst, E, Debonnaire, P, Dupont, M, Pereira Dutra, O, Canani, L, Vieira Moreira, M, de Souza, W, Backes, L, Maia, L, De Souza Paolino, B, Manenti, E, Saporito, W, Villaca Guimaraes Filho, F, Franco Hirakawa, T, Saliba, L, Neuenschwander, F, de Freitas Zerbini, C, Goncalves, G, Goncalves Mello, Y, Ascencao de Souza, J, Beck da Silva Neto, L, Da Silveira, J, de Moura Xavier Moraes Junior, J, de Souza Neto, J, Hernandes, M, Finimundi, H, Sampaio, C, Vasconcellos, E, Neves Mancuso, F, Noya Rabelo, M, Rodrigues Bacci, M, Santos, F, Vidotti, M, Simoes, M, Gomes, F, Vieira Nascimento, C, Precoma, D, Helfenstein Fonseca, F, Ribas Fortes, J, Leaes, P, Campos de Albuquerque, D, Kerr Saraiva, J, Rassi, S, Alves da Costa, F, Reis, G, Zieroth, S, Dion, D, Savard, D, Bourgeois, R, Constance, C, Anderson, K, Leblanc, M, Yung, D, Swiggum, E, Pliamm, L, Pesant, Y, Tyrrell, B, Huynh, T, Spiegelman, J, Lavoie, J, Hartleib, M, Bhargava, R, Straatman, L, Virani, S, Costa-Vitali, A, Hill, L, Heffernan, M, Khaykin, Y, Ricci, J, Senaratne, M, Zhai, A, Lubelsky, B, Toma, M, Yao, L, Mckelvie, R, Noronha, L, Babapulle, M, Pandey, A, Curnew, G, Lavoie, A, Berlingieri, J, Kouz, S, Lonn, E, Chehayeb, R, Zheng, Y, Sun, Y, Cui, H, Fan, Z, Han, X, Jiang, X, Tang, Q, Zhou, J, Zheng, Z, Zhang, X, Zhang, N, Zhang, Y, Shen, A, Yu, J, Ye, J, Yao, Y, Yan, J, Xu, X, Wang, Z, Ma, J, Li, Y, Li, S, Lu, S, Kong, X, Song, Y, Yang, G, Yao, Z, Pan, Y, Guo, X, Sun, Z, Dong, Y, Zhu, J, Peng, D, Yuan, Z, Lin, J, Yin, Y, Jerabek, O, Burianova, H, Fiala, T, Hubac, J, Ludka, O, Monhart, Z, Vodnansky, P, Zeman, K, Foldyna, D, Krupicka, J, Podpera, I, Busak, L, Radvan, M, Vomacka, Z, Prosecky, R, Cifkova, R, Durdil, V, Vesely, J, Vaclavik, J, Cervinka, P, Linhart, A, Brabec, T, Miklik, R, Bourhaial, H, Olbrich, H, Genth-Zotz, S, Kemala, E, Lemke, B, Bohm, M, Schellong, S, Rieker, W, Heitzer, T, Ince, H, Faghih, M, Birkenfeld, A, Begemann, A, Ghanem, A, Ujeyl, A, von Haehling, S, Dorsel, T, Bauersachs, J, Prull, M, Weidemann, F, Darius, H, Nickenig, G, Wilke, A, Sauter, J, Rauch-Kroehnert, U, Frey, N, Schulze, C, Konig, W, Maier, L, Menzel, F, Proskynitopoulos, N, Ebert, H, Sarnighausen, H, Dungen, H, Licka, M, Stellbrink, C, Winkelmann, B, Menck, N, Lopez-Sendon, J, de la Fuente Galan, L, Delgado Jimenez, J, Manito Lorite, N, Perez de Juan Romero, M, Galve Basilio, E, Cereto Castro, F, Gonzalez Juanatey, J, Gomez, J, Sanmartin Fernandez, M, Garcia-Moll Marimon, X, Pascual Figal, D, Bover Freire, R, Bonnefoy Cudraz, E, Jobbe Duval, A, Tomasevic, D, Habib, G, Isnard, R, Picard, F, Khanoyan, P, Dubois-Rande, J, Galinier, M, Roubille, F, Alexandre, J, Babuty, D, Delarche, N, Berneau, J, Girerd, N, Saxena, M, Rosano, G, Yousef, Z, Clifford, C, Arden, C, Bakhai, A, Boos, C, Jenkins, G, Travill, C, Price, D, Koenyves, L, Lakatos, F, Matoltsy, A, Noori, E, Zilahi, Z, Andrassy, P, Kancz, S, Simon, G, Sydo, T, Vorobcsuk, A, Kiss, R, Toth, K, Szakal, I, Nagy, L, Barany, T, Nagy, A, Szolnoki, E, Mandal, S, Rastogi, V, Shah, B, Mullasari, A, Shankar, J, Mehta, V, Oomman, A, Kaul, U, Komarlu, S, Kahali, D, Bhagwat, A, Vijan, V, Ghaisas, N, Mehta, A, Kashyap, J, Kothari, Y, Taddei, S, Scherillo, M, Zaca, V, Genovese, S, Salvioni, A, Fucili, A, Fedele, F, Cosmi, F, Volpe, M, Mazzone, C, Esposito, G, Doi, M, Yamamoto, H, Sakagami, S, Oishi, S, Yasaka, Y, Tsuboi, H, Fujino, Y, Matsuoka, S, Watanabe, Y, Himi, T, Ide, T, Ichikawa, M, Kijima, Y, Koga, T, Yuda, S, Fukui, K, Kubota, T, Manita, M, Fujinaga, H, Matsumura, T, Fukumoto, Y, Kato, R, Kawai, Y, Hiasa, G, Kazatani, Y, Mori, M, Ogimoto, A, Inoko, M, Oguri, M, Kinoshita, M, Okuhara, K, Watanabe, N, Ono, Y, Otomo, K, Sato, Y, Matsunaga, T, Takaishi, A, Miyagi, N, Uehara, H, Takaishi, H, Urata, H, Kataoka, T, Matsubara, H, Matsumoto, T, Suzuki, T, Takahashi, N, Imamaki, M, Yoshitama, T, Saito, T, Sekino, H, Furutani, Y, Koda, M, Shinozaki, T, Hirabayashi, K, Tsunoda, R, Yonezawa, K, Hori, H, Yagi, M, Arikawa, M, Hashizume, T, Ishiki, R, Koizumi, T, Nakayama, K, Taguchi, S, Nanasato, M, Yoshida, Y, Tsujiyama, S, Nakamura, T, Oku, K, Shimizu, M, Suwa, M, Momiyama, Y, Sugiyama, H, Kobayashi, K, Inoue, S, Kadokami, T, Maeno, K, Kawamitsu, K, Maruyama, Y, Nakata, A, Shibata, T, Wada, A, Cho, H, Na, J, Yoo, B, Choi, J, Hong, S, Shin, J, Cho, M, Han, S, Jeong, J, Kim, J, Kang, S, Kim, D, Kim, M, Llamas Esperon, G, Illescas Diaz, J, Fajardo Campos, P, Almeida Alvarado, J, Bazzoni Ruiz, A, Echeverri Rico, J, Lopez Alcocer, I, Valle Molina, L, Hernandez Herrera, C, Calvo Vargas, C, Padilla Padilla, F, Rodriguez Briones, I, Chuquiure Valenzuela, E, Aguilera Real, M, Carrillo Calvillo, J, Alpizar Salazar, M, Cervantes Escarcega, J, Velasco Sanchez, R, Al - Windy, N, van Heerebeek, L, Bellersen, L, Brunner-La Rocca, H, Post, J, Linssen, G, van de Wetering, M, Peters, R, van Stralen, R, Groutars, R, Smits, P, Yilmaz, A, Kok, W, Van der Meer, P, Dijkmans, P, Troquay, R, van Alem, A, Van de Wal, R, Handoko, L, Westendorp, I, van Bergen, P, Rensing, B, Hoogslag, P, Kietselaer, B, Kragten, J, den Hartog, F, Alings, A, Danilowicz-Szymanowicz, L, Raczak, G, Piesiewicz, W, Zmuda, W, Kus, W, Podolec, P, Musial, W, Drelich, G, Kania, G, Miekus, P, Mazur, S, Janik, A, Spyra, J, Peruga, J, Balsam, P, Krakowiak, B, Szachniewicz, J, Ginel, M, Grzybowski, J, Chrustowski, W, Wojewoda, P, Kalinka, A, Zurakowski, A, Koc, R, Debinski, M, Fil, W, Kujawiak, M, Forys, J, Kasprzak, M, Krol, M, Michalski, P, Mirek-Bryniarska, E, Radwan, K, Skonieczny, G, Stania, K, Skoczylas, G, Madej, A, Jurowiecki, J, Firek, B, Wozakowska-Kaplon, B, Cymerman, K, Neutel, J, Adams, K, Balfour, P, Deswal, A, Djamson, A, Duncan, P, Hong, M, Murray, C, Rinde-Hoffman, D, Woodhouse, S, Macnevin, R, Rama, B, Broome-Webster, C, Kindsvater, S, Abramov, D, Barettella, M, Pinney, S, Herre, J, Cohen, A, Vora, K, Challappa, K, West, S, Baum, S, Cox, J, Jani, S, Karim, A, Akhtar, A, Quintana, O, Paukman, L, Goldberg, R, Bhatti, Z, Budoff, M, Bush, E, Potler, A, Delgado, R, Ellis, B, Dy, J, Fialkow, J, Sangrigoli, R, Ferdinand, K, East, C, Falkowski, S, Donahoe, S, Ebrahimi, R, Kline, G, Harris, B, Khouzam, R, Jaffrani, N, Jarmukli, N, Kazemi, N, Koren, M, Friedman, K, Herzog, W, Silva Enciso, J, Cheung, D, Grover-McKay, M, Hauptman, P, Mikhalkova, D, Hegde, V, Hodsden, J, Khouri, S, Mcgrew, F, Littlefield, R, Bradley, P, Mclaurin, B, Lupovitch, S, Labin, I, Rao, V, Leithe, M, Lesko, M, Lewis, N, Lombardo, D, Mahal, S, Malhotra, V, Dauber, I, Banerjee, A, Needell, J, Miller, G, Paladino, L, Munuswamy, K, Nanna, M, Mcmillan, E, Mumma, M, Napoli, M, Nelson, W, O'Brien, T, Adlakha, A, Onwuanyi, A, Serota, H, Schmedtje, J, Paraschos, A, Potu, R, Sai-Sudhakar, C, Saltzberg, M, Sauer, A, Shah, P, Skopicki, H, Bui, H, Carr, K, Stevens, G, Tahirkheli, N, Tallaj, J, Yousuf, K, Trichon, B, Welker, J, Tolerico, P, Vest, A, Vivo, R, Wang, X, Abadier, R, Dunlap, S, Weintraub, N, Malik, A, Kotha, P, Zaha, V, Kim, G, Uriel, N, Greene, T, Salacata, A, Arora, R, Gazmuri, R, Kobayashi, J, Iteld, B, Vijayakrishnan, R, Dab, R, Mirza, Z, Marques, V, Nallasivan, M, Bensimhon, D, Peart, B, Saint-Jacques, H, Barringhaus, K, Contreras, J, Gupta, A, Koneru, S, Nguyen, V, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
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Male ,medicine.medical_specialty ,Angiotensin receptor ,Glucoside ,Endocrinology, Diabetes and Metabolism ,[SDV]Life Sciences [q-bio] ,Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,Adrenergic beta-Antagonists ,Angiotensin-Converting Enzyme Inhibitors ,030204 cardiovascular system & hematology ,Placebo ,03 medical and health sciences ,Angiotensin Receptor Antagonists ,0302 clinical medicine ,Endocrinology ,Mineralocorticoid receptor ,Glucosides ,Double-Blind Method ,Internal medicine ,Post-hoc analysis ,Internal Medicine ,medicine ,Empagliflozin ,Humans ,030212 general & internal medicine ,Benzhydryl Compounds ,ComputingMilieux_MISCELLANEOUS ,Aged ,Benzhydryl Compound ,Heart Failure ,Ejection fraction ,business.industry ,Angiotensin Receptor Antagonist ,Adrenergic beta-Antagonist ,Angiotensin-Converting Enzyme Inhibitor ,Stroke Volume ,medicine.disease ,3. Good health ,Heart failure ,ACE inhibitor ,Female ,Hypotension ,business ,medicine.drug ,Human - Abstract
Contains fulltext : 249977.pdf (Publisher’s version ) (Closed access) BACKGROUND: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies. METHODS: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II-IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as β blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977. FINDINGS: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65-0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69-1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52-0·88]; p(interaction)=0·18). A similar result was seen for β blockers at doses of less than 50% of the target dose (HR 0·66 [0·54-0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66-1·00]; p(interaction)=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus β blocker plus MRA (given combination HR 0·73 [0·61-0·88]; not given combination HR 0·76 [0·62-0·94]; p(interaction)=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups. INTERPRETATION: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy. FUNDING: Boehringer Ingelheim and Eli Lilly and Company.
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- 2022
3. PI 3-kinase: structural and functional analysis of intersubunit interactions
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Hara Kenta, George Panayotou, Michael J. Fry, Mike Waterfield, K. Yonezawa, Ritu Dhand, M. Kasuga, Benjamin D. Bax, Ivan Gout, and Ian Hiles
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animal structures ,Protein subunit ,Molecular Sequence Data ,Restriction Mapping ,macromolecular substances ,Biology ,Moths ,SH2 domain ,Transfection ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Mice ,Phosphatidylinositol 3-Kinases ,Structure-Activity Relationship ,Protein structure ,L Cells ,Animals ,Amino Acid Sequence ,Binding site ,Molecular Biology ,Peptide sequence ,G alpha subunit ,Glutathione Transferase ,chemistry.chemical_classification ,Binding Sites ,General Immunology and Microbiology ,General Neuroscience ,musculoskeletal system ,Fusion protein ,Amino acid ,enzymes and coenzymes (carbohydrates) ,Phosphotransferases (Alcohol Group Acceptor) ,chemistry ,Biochemistry ,Mutation ,Cattle ,Electrophoresis, Polyacrylamide Gel ,hormones, hormone substitutes, and hormone antagonists ,Research Article - Abstract
Phosphatidylinositol (PI) 3-kinase has an 85 kDa subunit (p85 alpha) which mediates its association with activated protein tyrosine kinase receptors through SH2 domains, and an 110 kDa subunit (p110) which has intrinsic catalytic activity. Here p85 alpha and a related protein p85 beta are shown to form stable complexes with recombinant p110 in vivo and in vitro. Using a panel of glutathione S-transferase (GST) fusion proteins of the inter-SH2 region of p85, 104 amino acids were found to bind directly the p110 protein, while deletion mutants within this region further defined the binding site to a sequence of 35 amino acids. Transient expression of the mutant p85 alpha protein in mouse L cells showed it was unable to bind PI 3-kinase activity in vivo. Mapping of the complementary site of interaction on the p110 protein defined 88 amino acids in the N-terminal region of p110 which mediate the binding of this subunit to either the p85 alpha or the p85 beta proteins. The inter-SH2 region of p85 is predicted to be an independently folded module of a coiled-coil of two long anti-parallel alpha-helices. The predicted structure of p85 suggests a basis for the intersubunit interaction and the relevance of this interaction with respect to the regulation of the PI 3-kinase complex is discussed.
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- 1994
4. A prospective pilot study of the effect of neutrophil elastase on the pulmonary vascular permeability in patients with pneumonia
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Mariko Omura, H Hirama, Hiroyuki Yokota, Tomohiko Masuno, Shigeki Kushimoto, K Yonezawa, Takashi Tagami, Yasuhiro Yamamoto, G Akiyama, and Ryoichi Tosa
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medicine.medical_specialty ,Pathology ,ARDS ,biology ,business.industry ,Vascular permeability ,Lung injury ,Critical Care and Intensive Care Medicine ,medicine.disease ,Gastroenterology ,respiratory tract diseases ,Hypoxemia ,Pulmonary vascular permeability ,Pneumonia ,Internal medicine ,Neutrophil elastase ,Poster Presentation ,medicine ,biology.protein ,In patient ,medicine.symptom ,business - Abstract
Some cases of pneumonia may lead to hypoxemia with acute respiratory failure, acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), which may require intensive management. Neutrophil elastase is thought to be one of the causes of ALI/ARDS, because it raises the pulmonary capillary permeability, lyses of pulmonary connective tissue proteins, and produces leukocyte chemotactic factors. However, a causal relationship between the plasma neutrophil elastase level and changes in the pulmonary capillary permeability has not been established in patients with pneumonia, one of the most serious diseases underlying ALI/ARDS. Therefore, the objective of this study was to determine whether an increase in plasma neutrophil elastase is related to elevation of the pulmonary capillary permeability in patients with pneumonia.
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- 2010
5. Factors associated with breastfeeding rates at 1 month of age: Focusing on newborn feeding behaviours in a Japanese maternity hospital.
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Tomita A, Tahara-Sasagawa E, Yonezawa K, Usui Y, and Haruna M
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Aim: This study investigated the relationship between newborn feeding behaviour and feeding type among month-old babies and explored maternal and neonatal factors associated with breastfeeding rates at 1 month of age., Methods: This observational study was conducted in Japan with healthy mothers and full-term newborns. Newborn feeding behaviours were assessed using the Japanese Infant Breastfeeding Assessment Tool (IBFAT) within approximately 1 day of birth. Obstetric and newborn characteristics, including newborn feeding behaviours, were investigated in relation feeding type (breast milk or mixed milk) at 1 month of age., Results: This study included 176 mother-newborn pairs. IBFAT scores were significantly higher in the breast-milk group (Median (M) = 10.5, Interquartile Ranges (IQR): 9.0-11.0) than in the mixed-milk group (M = 10.0, IQR: 7.5-11.0) (P = 0.046). Additionally, the sucking pattern of breastfeeding was showing a greater distribution of higher scores in the breast-milk group (M = 2.0, IQR: 2.0-2.5) than in the mixed-milk group (M = 2.0, IQR: 1.5-2.5) (P = 0.015). Compared to mothers who received epidural analgesia or synthetic oxytocin, primiparas who did not receive them were more likely to breastfeed (epidural analgesia: (33.3% vs. 65.8%, P = 0.004); synthetic oxytocin: (42.0% vs. 78.6%, P = 0.018)). For multiparas, Apgar and IBFAT scores were associated with feeding type at 1 month of age., Conclusions: This study found that newborns' effective and sustained sucking within 1 day of birth is an important factor for breastfeeding at 1 month of age. When assessing feeding type, maternal factors such as epidural analgesia should be the focus for primiparas, while neonatal factors such as feeding behaviour should be prioritised for multiparas., (© 2024 The Author(s). Journal of Paediatrics and Child Health published by John Wiley & Sons Australia, Ltd on behalf of Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)
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- 2024
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6. Using qPCR and ddPCR to study biodistribution of cell therapy products: a multi-site evaluation.
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Fujita E, Yamamoto S, Hanada T, Jogasaki S, Koga Y, Yatsuda Y, Kakizaki Y, Jo Y, Asano Y, Yonezawa K, Moriya Y, Nakayama M, Arimura Y, Okawa Y, Komatsu H, Ito M, Suzuki S, Kuroda T, Yasuda S, Kamiyama Y, and Sato Y
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Backgroud Aims: Regenerative therapies employing cell therapy products (CTPs) have attracted considerable attention. Biodistribution (BD) evaluation of CTPs is mainly performed to clarify the cell survival time, engraftment, and distribution site. This evaluation is crucial for predicting the efficacy and safety profiles of clinical studies based on non-clinical BD study outcomes. However, no internationally unified method has been established for assessing cell BD after administration. Here, we aimed to standardize the BD assay method used for CTPs, conducting the following evaluations using the same protocol across multiple study facilities: (1) in vitro validation of quantitative polymerase chain reaction (qPCR) and droplet digital PCR (ddPCR) analyses using the primate-specific Alu gene, and (2) in vivo BD studies after the intravenous administration of human mesenchymal stem cells (hMSCs) to immunodeficient mice, commonly used in non-clinical tumorigenicity studies., Methods: Quality control samples were prepared and analyzed by adding a fixed number of human-derived cells to several mouse tissues. The respective quantitative performances of the qPCR and ddPCR methods were compared for accuracy and precision. hMSCs were intravenously administered to immunodeficient mice, and tissues were collected at 1, 4, and 24 h after administration., Results: Both methods demonstrated an accuracy (relative error) generally within ±50% and a precision (coefficient of variation) generally less than 50%. While differences in calibration curve ranges were observed between qPCR and ddPCR, no significant differences in quantification were found among the assay facilities. The BD of hMSCs in mice was evaluated at seven facilities (qPCR at three facilities; ddPCR at four facilities), revealing similar tissue distribution profiles in all facilities, with the lungs showing the highest cell distribution among the tissues tested., Conclusions: Quantitative evaluation of qPCR and ddPCR using Alu sequences was conducted, demonstrating that the test method can be adapted for BD evaluation., Competing Interests: Declarations of competing interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article except for YY, who is an employee of Bio-Rad Laboratories., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)
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- 2024
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7. Factors associated with non-intervention of antifibrotic agents in IPF patients.
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Asami-Noyama M, Hamada K, Asai Y, Abe T, Yonezawa K, Watanabe M, Hisamoto Y, Murakawa K, Fukatsu A, Matsuda K, Ohata S, Suetake R, Murata Y, Yamaji Y, Oishi K, Edakuni N, Hirano T, Kakugawa T, and Matsunaga K
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Background: The efficacy of antifibrotic agents in idiopathic pulmonary fibrosis (IPF) has been demonstrated and early introduction is recommended, especially in patients with preserved performance status (PS). We aimed to determine the proportion of untreated IPF cases using real-world data and to assess the factors associated with non-intervention., Methods: A prospective observational study using questionnaires was performed on 518 patients with interstitial lung disease (ILD) and their attending physicians who visited a clinic, general hospital, or tertiary respiratory center between December 2019 and October 2020. Patients responded with subjective symptoms and PS, whereas physicians responded with diagnosis, treatment, and reasons for their treatment choices. Principal component analysis (PCA) was performed using age, sex, BMI, medical facility, specialized tests, and symptom severity., Results: We included 207 patients with IPF. Among them, 168 has a good PS (≤2), which could be indicative of treatment; 130 (77.4%) were not treated with antifibrotic agents. The PCA revealed a trend consistent with that of antifibrotic agent therapy and the distribution of medical facilities, with a treatment intervention rate of 16% in general hospitals and 62% in tertiary respiratory centers. In general hospitals, low symptom severity (PS, mMRC, and no use of long-term oxygen therapy) was a relevant factor for non-intervention with antifibrotic agents (p < 0.001)., Conclusion: Antifibrotic treatment interventions varied by facility in cases with good PS. Patients with milder symptoms are not being treated early in general hospitals and more collaboration between general hospitals and specialized facilities is necessary., Competing Interests: Declaration of competing interest M.A. (Maki Asami-Noyama) received subsidies from Nippon Boehringer Ingelheim Co., Ltd. The other authors have no conflicts of interests., (Copyright © 2024 The Author. Published by Elsevier B.V. All rights reserved.)
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- 2024
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8. Relationship Between Cytokines and Face Skin Symptoms in Newborns in Two Japanese Cities.
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Yonezawa K, Higuchi S, Shimizu S, Minematsu T, and Haruna M
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- Female, Humans, Infant, Newborn, Male, Cross-Sectional Studies, East Asian People, Face, Facial Dermatoses epidemiology, Japan epidemiology, Cytokines, Skin pathology, Skin Diseases epidemiology
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Aim: Several skin disorder symptoms may appear in infants, each resulting from a different inflammatory response. In this study, we investigated the relationship between skin cytokine levels and skin symptoms in newborns., Methods: This cross-sectional study was conducted in Tokyo and Oita, two Japanese cities. The participants were healthy, 1-month-old infants and their parents. Symptoms including erythema, papules, dryness, and exudate/yellow scaling on infant faces were evaluated as outcomes. Cytokine levels (interleukin [IL]-4, IL-6, IL-8, and IL-17) were measured by skin blotting. A multilevel analysis using a mixed-effects model was conducted to account for regional differences., Results: A total of 231 infants (119 from Tokyo and 112 from Oita) participated in this study. Erythema, papules, dryness, and exudate/yellow scaling were present in 59 (25.5%), 133 (57.6%), 37 (16.0%), and 16 (6.9%) of the infants, respectively. In terms of the associations between symptoms and cytokines, there was a significant association between papules and IL-8 positivity (adjusted odds ratio [AOR]: 1.94, 95% confidence interval [CI] 1.09-3.47) even after adjustment for differences in barrier function, area, and skin care., Conclusions: This study demonstrated that cytokines were linked to skin conditions, even after accounting for regional differences and genetic factors. This suggests that different symptoms point to the involvement of various cytokines in skin conditions in neonates, with mechanisms varying based on the symptoms. These findings could aid in developing specific preventive strategies in the future., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)
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- 2024
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9. Development of the Japanese version of the Challenging Experience Questionnaire.
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Tani H, Yonezawa K, Kusudo K, Barrett FS, Nakajima S, and Uchida H
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- Humans, Japan, Surveys and Questionnaires standards, Translations, Reproducibility of Results, Adult, Female, Male, Patient Reported Outcome Measures, East Asian People, Hallucinogens therapeutic use, Hallucinogens pharmacology
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Introduction: The therapeutic potential of psychedelics for various mental disorders has gained significant interest. Previous studies have highlighted that psychedelics induce psychoactive effects, including challenging aspects of experiences. These experiences are assessed using the Challenging Experience Questionnaire (CEQ), yet its Japanese version has been unavailable. This study aimed to create a Japanese version of the CEQ., Methods: We followed the "Principles of Good Practice for the Translation and Cultural Adaptation Process for Patient-Reported Outcomes (PRO) Measures: Report of the ISPOR Task Force for Translation and Cultural Adaptation." Initially, two Japanese psychiatrists independently conducted the forward translations. These were then reconciled into a single version, which was back-translated into English. The original authors reviewed this back-translation for accuracy, leading to revisions through continuous dialogue until the original authors approved the final version., Results: The final, approved back-translated version of the CEQ is presented in the figure., Conclusions: This study developed a Japanese version of the CEQ, enabling the assessment of challenging experiences during psychedelic-assisted therapy for Japanese speakers. Further studies are needed to assess the reliability and validity of this newly translated version., (© 2024 The Author(s). Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)
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- 2024
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10. Efficacy and safety of intravenous ketamine treatment in Japanese patients with treatment-resistant depression: A double-blind, randomized, placebo-controlled trial.
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Ohtani Y, Tani H, Nomoto-Takahashi K, Yatomi T, Yonezawa K, Tomiyama S, Nagai N, Kusudo K, Honda S, Moriyama S, Nakajima S, Yamada T, Morisaki H, Iwabuchi Y, Jinzaki M, Yoshimura K, Eiro T, Tsugawa S, Ichijo S, Fujimoto Y, Miyazaki T, Takahashi T, and Uchida H
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Aim: Although the antidepressant effect of ketamine on treatment-resistant depression (TRD) has been frequently reported in North American and European countries, evidence is scarce among the Asian population. We aimed to evaluate the efficacy and safety of intravenous ketamine in Japanese patients with TRD., Methods: In this double-blind randomized placebo-controlled trial, 34 Japanese patients with TRD were randomized to receive either intravenous ketamine (0.5 mg/kg) or placebo, administered over 40 min, twice a week, for 2 weeks. The primary outcome was the change in the Montgomery Åsberg Depression Rating Scale (MADRS) total score from baseline to post-treatment. Secondary outcomes included changes in other depressive symptomatology scores and remission, response, and partial response rates. We also examined the association between baseline clinical demographic characteristics and changes in the MADRS total score., Results: Intention-to-treat analysis indicated no significant difference in the decrease in MADRS total score between the groups (-8.1 ± 10.0 vs -2.5 ± 5.2, t[32] = 2.02, P = 0.052), whereas per-protocol analysis showed a significant reduction in the ketamine group compared to the placebo group (-9.1 ± 10.2 vs -2.7 ± 5.3, t[29] = 2.22, P = 0.034). No significant group differences were observed in other outcomes. Adverse events were more frequent in the ketamine group than in the placebo group, and no serious adverse events were reported. A higher baseline MADRS total score and body mass index were associated with a greater reduction in the MADRS total score., Conclusion: Intravenous ketamine outperformed placebo in Japanese patients with TRD who completed the study, suggesting that ketamine could alleviate depressive symptoms of TRD across diverse ethnic populations., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences © 2024 Japanese Society of Psychiatry and Neurology.)
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- 2024
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11. Relief of Airflow Limitation and Airway Inflammation by Endoscopic Sinus Surgery in a Patient with Severe Asthma with Eosinophilic Chronic Rhinosinusitis.
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Matsumori K, Hamada K, Oishi K, Okimura M, Yonezawa K, Watanabe M, Hisamoto Y, Murakawa K, Fukatsu-Chikumoto A, Matsuda K, Ohata S, Suetake R, Utsunomiya T, Murata Y, Yamaji Y, Asami-Noyama M, Edakuni N, Kakugawa T, Hirano T, and Matsunaga K
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- Humans, Chronic Disease, Eosinophilia surgery, Eosinophilia complications, Male, Severity of Illness Index, Middle Aged, Treatment Outcome, Female, Rhinosinusitis, Sinusitis surgery, Sinusitis complications, Asthma surgery, Asthma complications, Asthma physiopathology, Rhinitis surgery, Rhinitis complications, Endoscopy methods
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Although endoscopic sinus surgery (ESS) is beneficial in improving asthma symptoms, its impact on the lung function in patients with asthma and chronic rhinosinusitis remains unclear. We herein report a case of severe asthma with eosinophilic chronic rhinosinusitis, in which ESS substantially improved airflow limitation and concomitantly reduced fractional exhaled nitric oxide and blood eosinophil counts. ESS likely relieved airflow limitation by suppressing type 2 inflammatory pathways. This case highlights ESS as a promising strategy for achieving clinical remission in patients with severe asthma and chronic rhinosinusitis.
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- 2024
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12. The Sri Lanka Mother and Newborn Growth (S-MaNGro) Cohort: Protocol of a Nationwide Prospective Study.
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Pathirathna ML, Haruna M, Sasaki S, Yonezawa K, Usui Y, and Hagiwara Y
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Perinatal cohort studies with a prospective longitudinal design are critical for determining the effects of early-life exposures on offspring's health outcomes. The Sri Lanka Mother and Newborn Growth cohort study aims to investigate the impact of maternal nutritional and psychosocial factors on newborns' birth weight in the Sri Lankan context. This paper presents the methodology of participant recruitment, follow-ups, an overview of measurements, and planned data analyses. This study included a nationally representative sample of Sri Lankan pregnant women recruited in their first trimester of pregnancy. Follow-up assessments were conducted once during the second and third trimesters of pregnancy and after the baby's birth, prospectively tracking the women's dietary intake, mental health, hemoglobin concentrations, and gestational weight gain data. Once the participants delivered their babies, the data on gestational age, sex of the newborn, birth weight, length and occipitofrontal circumference at birth, and mode of delivery were collected. Between August 2022 and August 2023, we recruited 2000 first-trimester pregnant women to the cohort and continued to follow up with them until the baby's birth. The response rates were 90.4%, 81.4%, and 75.2% in the first, second, and third follow-ups. We plan to analyze the data in July 2024. We expect this study to provide valuable insights into various early-life exposures affecting neonatal birth weight. The study's findings will serve as a valuable information resource for a broader scientific community, enabling the development of effective policies to prevent low-birth-weight deliveries in low-resource settings.
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- 2024
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13. Complete Response to Pembrolizumab in a Patient with Castration-Resistant Prostate Cancer with Both BRCA Positivity and a High Frequency of Microsatellite Instability: A Case Report.
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Hirano T, Yonezawa K, Kawahara T, Mizuno N, Hayashi H, Karibe Y, Asano J, Fusayasu S, Makiyama K, Uemura H, Ohta J, and Moriyama M
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Introduction: There have been few reports of patients for whom a cancer gene panel test for solid tumors revealed the simultaneous presence of BRCA mutation and microsatellite instability (MSI)-high status. BRCA mutations have been reported in 13% of castration-resistant prostate cancer (CRPC) patients, and 3.1% of prostate cancer cases are MSI-high/mismatch repair deficient., Case Presentation: A 71-year-old man with a history of urinary retention was referred to our department for clinically suspected prostate cancer and a high prostate-specific antigen (PSA) level (141 ng/mL). MRI revealed features of prostate cancer invading the bladder, seminal vesicles, and rectum. A histopathological examination of a transperineal needle biopsy specimen obtained from the prostate revealed adenocarcinoma. Bone scintigraphy revealed multiple metastases. The patient was treated with abiraterone acetate combined with androgen deprivation therapy followed by local radiation. Rectal wall thickening and lymph node metastasis were also observed, and docetaxel was administered. A cancer gene panel test was positive results for BRCA2 mutation with a MSI-high. After six courses of docetaxel, lymph node enlargement was observed and olaparib was initiated. Two months later, the metastatic lesions showed enlargement and the PSA level increased. Subsequently, pembrolizumab was administered. At 2 to the patient months after the initiation of pembrolizumab administration, PSA levels decreased to <0.025 ng/mL and the rectal lesions and lymph node metastases disappeared. The patient was continuing to receive pembrolizumab without any apparent adverse events or exacerbations, 9 months after initiation., Conclusion: We herein report a case in which pembrolizumab treatment resulted in a complete response in a CRPC patient with both a BRCA2 mutation and an MSI-high status., Competing Interests: The authors declare no conflicts of interest in association with the present study., (© 2024 The Author(s). Published by S. Karger AG, Basel.)
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- 2024
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14. Effects of automatic heel lancet on invasiveness in neonates: A systematic review and meta-analysis.
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Shiroshita Y, Yonezawa K, Ota E, and Ozawa M
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- Humans, Infant, Newborn, Blood Specimen Collection methods, Blood Specimen Collection instrumentation, Heel
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Aim: We conducted a meta-analysis comparing the invasiveness of automatic lancet devices, which can collect adequate amount of blood at shallow puncture depths, with conventional manual lance devices (lancet or needle) to statistically identify less invasive instruments for neonatal heel lance., Methods: We searched PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, and Ichushi databases for studies comparing the invasiveness between automatic lancet and manual lancet or needle in term and preterm neonates in neonatal intensive care unit., Results: This review included 9 out of 449 searched articles, with 673 neonates. Automatic lancet had significantly lower pain scores (standardised mean difference: -2.0, 95% confidence interval: -3.3 to -0.7), heart rate (mean difference: -8.0, 95% confidence interval: -13.8 to -2.1), cry duration (mean difference: -21.5, 95% confidence interval: -32.5 to -10.4), number of punctures (mean difference: -0.6, 95% confidence interval: -1.1 to -0.2), and duration of procedures (mean difference: -37.7, 95% confidence interval: -75.2 to -0.2) than manual lancet or needle. Furthermore, peripheral oxygen saturation was significantly higher in automatic lancet than in manual lancet or needle (mean difference: 4.5, 95% confidence interval: 0.5-8.5)., Conclusion: Automatic heel lancet devices were less invasive than manual heel lance devices (lancet or needle)., (© 2024 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)
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- 2024
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15. Detection of dynamic lung hyperinflation using cardiopulmonary exercise testing and respiratory function in patients with stable cardiac disease: a multicenter, cross-sectional study.
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Kominami K, Noda K, Minagawa N, Yonezawa K, Ueda M, Kobayashi Y, Murata M, and Akino M
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Background: Many patients with heart disease potentially have comorbid chronic obstructive pulmonary disease (COPD); however, there are not enough opportunities for screening, and the qualitative differentiation of shortness of breath (SOB) has not been well established. We investigated the detection rate of SOB based on a visual and qualitative dynamic lung hyperinflation (DLH) detection index during cardiopulmonary exercise testing (CPET) and assessed potential differences in respiratory function between groups., Methods: We recruited 534 patients with heart disease or patients who underwent simultaneous CPET and spirometry (369 males, 67.0 ± 12.9 years) to scrutinize physical functions. The difference between inspiratory and expiratory tidal volume was calculated (TV E-I) from the breath-by-breath data. Patients were grouped into convex (decreased TV E-I) and non-convex (unchanged or increased TV E-I) groups based on their TV E-I values after the start of exercise., Results: Among the recruited patients, 129 (24.2%) were categorized in the convex group. There was no difference in clinical characteristics between the two groups. The Borg scale scores at the end of the CPET showed no difference. VE/VCO
2 slope, its Y-intercept, and minimum VE/VCO2 showed no significant difference between the groups. In the convex group, FEV1.0/FVC was significantly lower compared to that in the non-convex group (69.4 ± 13.1 vs. 75.0 ± 9.0%). Moreover, significant correlations were observed between FEV1.0/FVC and Y-intercept (r=-0.343), as well as between the difference between minimum VE/VCO2 and VE/VCO2 slope (r=-0.478)., Conclusions: The convex group showed decreased respiratory function, suggesting a potential airway obstruction during exercise. A combined assessment of the TV E-I and Y-intercept of the VE/VCO2 slope or the difference between the minimum VE/VCO2 and VE/VCO2 slopes could potentially detect COPD or airway obstruction., (© 2024. The Author(s).)- Published
- 2024
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16. Understanding the effects of ethanol on the liposome bilayer structure using microfluidic-based time-resolved small-angle X-ray scattering and molecular dynamics simulations.
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Maeki M, Kimura N, Okada Y, Shimizu K, Shibata K, Miyazaki Y, Ishida A, Yonezawa K, Shimizu N, Shinoda W, and Tokeshi M
- Abstract
Lipid nanoparticles (LNPs) are essential carrier particles in drug delivery systems, particularly in ribonucleic acid delivery. In preparing lipid-based nanoparticles, microfluidic-based ethanol injection may produce precisely size-controlled nanoparticles. Ethanol is critical in LNP formation and post-treatment processes and affects liposome size, structure, lamellarity, and drug-loading efficiency. However, the effects of time-dependent changes in the ethanol concentration on the structural dynamics of liposomes are not clearly understood. Herein, we investigated ethanol-induced lipid bilayer changes in liposomes on a time scale from microseconds to tens of seconds using a microfluidic-based small-angle X-ray scattering (SAXS) measurement system coupled with molecular dynamics (MD) simulations. The time-resolved SAXS measurement system revealed that single unilamellar liposomes were converted to multilamellar liposomes within 0.8 s of contact with ethanol, and the d -spacing was decreased from 6.1 (w/o ethanol) to 4.4 nm (80% ethanol) with increasing ethanol concentration. We conducted 1 μs MD simulations to understand the molecular-level structural changes in the liposomes. The MD simulations revealed that the changes in the lamellar structure caused by ethanol at the molecular level could explain the structural changes in the liposomes observed via time-resolved SAXS. Therefore, the post-treatment process to remove residual ethanol is critical in liposome formation., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)
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- 2024
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17. Structure of full-length ERGIC-53 in complex with MCFD2 for cargo transport.
- Author
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Watanabe S, Kise Y, Yonezawa K, Inoue M, Shimizu N, Nureki O, and Inaba K
- Subjects
- Protein Binding, Binding Sites, Golgi Apparatus metabolism, Mannose-Binding Lectins metabolism, Vesicular Transport Proteins metabolism, Membrane Proteins metabolism
- Abstract
ERGIC-53 transports certain subsets of newly synthesized secretory proteins and membrane proteins from the endoplasmic reticulum to the Golgi apparatus. Despite numerous structural and functional studies since its identification, the overall architecture and mechanism of action of ERGIC-53 remain unclear. Here we present cryo-EM structures of full-length ERGIC-53 in complex with its functional partner MCFD2. These structures reveal that ERGIC-53 exists as a homotetramer, not a homohexamer as previously suggested, and comprises a four-leaf clover-like head and a long stalk composed of three sets of four-helix coiled-coil followed by a transmembrane domain. 3D variability analysis visualizes the flexible motion of the long stalk and local plasticity of the head region. Notably, MCFD2 is shown to possess a Zn
2+ -binding site in its N-terminal lid, which appears to modulate cargo binding. Altogether, distinct mechanisms of cargo capture and release by ERGIC- 53 via the stalk bending and metal binding are proposed., (© 2024. The Author(s).)- Published
- 2024
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18. Development of the Japanese version of the 30-item Mystical Experience Questionnaire.
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Yonezawa K, Tani H, Nakajima S, and Uchida H
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- Humans, Reproducibility of Results, Japan, Surveys and Questionnaires, Hallucinogens pharmacology, Mental Disorders
- Abstract
Introduction: Psychedelics have garnered increased attention as potential therapeutic options for various mental illnesses. Previous studies reported that psychedelics cause psychoactive effects through mystical experiences induced by these substances, including an altered state of consciousness. While this phenomenon is commonly assessed by the Mystical Experiences Questionnaire (MEQ30), a Japanese version of the MEQ30 has not been available. The aim of this study was to develop the Japanese version of the MEQ30., Methods: We adhered to the "Principles of Good Practice for the Translation and Cultural Adaptation Process for Patient-Reported Outcomes (PRO) Measures: Report of the ISPOR Task Force for Translation and Cultural Adaptation" in our translation process. Two Japanese psychiatrists independently performed forward translations, from which a unified version was derived through reconciliation. This version was subsequently back-translated into English and reviewed by the original authors for equivalency. The iterative revision process was carried out through ongoing discussions with the original authors until they approved the final back-translated version., Results: The final, approved back-translated version of the MEQ30 is presented in the accompanying figure. Additionally, the authorized Japanese version of the MEQ30 is included in the Appendix A., Conclusions: In this study, we successfully developed a Japanese version of the MEQ30. This scale will facilitate the assessment of mystical experiences associated with psychedelic-assisted therapy among Japanese speakers. Further research is warranted to evaluate the reliability and validity of this newly translated scale., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)
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- 2024
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19. Development of the Japanese version of the Ego-Dissolution Inventory (EDI).
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Kusudo K, Tani H, Yonezawa K, Nakajima S, Nour MM, Carhart-Harris R, and Uchida H
- Subjects
- Humans, Reproducibility of Results, Japan, Ego, Hallucinogens, Mental Disorders
- Abstract
Aim: Psychedelics have recently gained attention as potential therapeutic agents for various psychiatric disorders. Previous research has highlighted that a diminished sense of self, commonly termed "ego-dissolution" is a pivotal feature of the psychedelic-induced state. While the Ego-Dissolution Inventory (EDI) is a widely acknowledged instrument for measuring this phenomenon, no Japanese version has been available. This study aimed to develop a Japanese version of the EDI., Methods: We adhered to the "Guidelines for Best Practices in the Translation and Cultural Modification Process for Patient-Reported Outcomes Instruments: Document from the ISPOR Committee on Translation and Cultural Modification" during our translation approach. Two Japanese psychiatrists independently conducted initial translations, and a consolidated version was achieved via mutual agreement. This version was then back-translated to English and assessed by the original authors for consistency. The repetitive modification process was conducted in continuous dialogues with the original authors until they accepted the concluding back-translated version., Results: The finalized, approved back-translated version of the EDI is presented in the accompanying figure. In addition, the authorized Japanese version of the EDI is included in the Appendix., Conclusions: In this study, we successfully developed the Japanese version of the EDI. This instrument will assist in assessing ego-dissolution experiences associated with psychedelic-assisted therapy among Japanese speakers. Additional studies are necessary to evaluate the reliability and validity of this newly translated instrument., (© 2024 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)
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- 2024
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20. The association between fear of childbirth and social support through the Internet and Social Networking Services in pregnant women: A cross-sectional study.
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Seto N, Tahara-Sasagawa E, Yonezawa K, Hikita N, Usui Y, and Haruna M
- Subjects
- Pregnancy, Female, Humans, Cross-Sectional Studies, Fear psychology, Social Support, Surveys and Questionnaires, Delivery, Obstetric psychology, Pregnant Women psychology, Parturition psychology
- Abstract
Social support is an important factor in reducing fear of childbirth (FOC). Recently, the Internet and Social Networking Services (SNS) have become new forms of social support. However, it is unclear whether such support can reduce pregnant women's fear. This study aimed to investigate the association between FOC and social support through the Internet and SNS in pregnant women. A cross-sectional study using a web-based questionnaire including questions about FOC, social support, the Internet and SNS usage, psychological variables, and sociodemographic variables was conducted. Data from 111 participants were analyzed. A greater number of social support from people who are often seen during pregnancy, and becoming relieved by interaction with others through the Internet and SNS were negatively associated with FOC. This study showed that face-to-face social support was associated with lower FOC, while social support through the Internet and SNS was not. Further research is needed on how to use Internet and SNS to reduce FOC in pregnant women., (© 2024 The Authors. Nursing & Health Sciences published by John Wiley & Sons Australia, Ltd.)
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- 2024
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21. Lipid cubic phase with an organic-inorganic hybrid structure formed by organoalkoxysilane lipid.
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Kariya M, Omoto K, Nomura K, Yonezawa K, Kamikubo H, Nishino T, Inoie T, Rapenne G, and Yasuhara K
- Abstract
A lipid cubic phase encompassing a cross-linked siloxane structure was formed by the self-assembly of a synthetic organoalkoxysilane lipid in water. The spontaneous sol-gel reaction of the alkoxysilane moiety on the lipid head group produced an organic-inorganic hybrid material with a double gyroid Ia 3 d cubic structure.
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- 2024
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22. Factors Associated with Anemia and Iron Deficiency during Pregnancy: A Prospective Observational Study in Japan.
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Habe S, Haruna M, Yonezawa K, Usui Y, Sasaki S, Nagamatsu T, Fujita M, Suetsugu Y, Ohori R, Tanaka M, and Aoyama S
- Subjects
- Female, Humans, Infant, Newborn, Male, Pregnancy, Dietary Supplements, Japan epidemiology, Prospective Studies, Anemia epidemiology, Anemia, Iron-Deficiency epidemiology, Iron Deficiencies, Premature Birth epidemiology
- Abstract
Gestational anemia (GA) is a global health concern with a remarkably high prevalence in Japan, which is associated with various maternal and neonatal outcomes. This study aimed to explore whether GA and non-anemic iron deficiency (NAID) during the third trimester is associated with maternal characteristics, nutrient intake, low birth weight (LBW), and preterm birth. Participants were categorized into GA, NAID, and normal groups, based on serum ferritin and hemoglobin levels. Nutrient intake was assessed using the Brief Diet History Questionnaire. Data from 317 pregnant women were analyzed, including 110 (34.7%), 151 (47.6%), and 56 (17.6%) women in the GA, NAID, and normal groups, respectively. Factors associated with GA included being multipara ( p < 0.001) and not taking any type of iron supplements in the third trimester ( p = 0.043). The normal group had a significantly higher proportion of preterm birth and LBW than the GA and NAID groups. The GA group had a significantly higher energy intake than the normal group ( p = 0.044). Overall, energy and micronutrient intake were significantly below the estimated average requirement in the dietary reference intakes for Japanese. Health care professionals need to consider nutritional advice that can prevent GA by focusing on overall micronutrients, not just energy intake.
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- 2024
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23. A global survey on national standard care for newborn bathing.
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Kido M, Yonezawa K, Haruna M, Tahara-Sasagawa E, and Usui Y
- Subjects
- Pregnancy, Child, Infant, Newborn, Humans, Female, Body Temperature, Surveys and Questionnaires, Water, Infant Care, Midwifery
- Abstract
Aim: To describe national standard care for newborn bathing and its influential factors., Methods: A global survey was conducted using a web-based questionnaire. The targeted countries were 166 member countries of either the International Confederation of Midwives (ICM) or the International Council of Nurses (ICN). An eligible person included someone well informed of midwifery education/training or neonatal care, including newborn bathing, in their country. To examine the factors associated with the standard care for newborn bathing, information on mean annual temperature, precipitation, gross domestic product per capita, and basic water coverage was collected as external factors. Student's t tests and Chi-square tests were used for analysis., Results: Care standards were identified in 46 countries: seven from Africa, eight from the Americas, 15 from Asia, 14 from Europe, and two from Oceania. In most countries, newborns were bathed with warm water in a tub within 10 min. Bathing frequency, moisturization, and use of soap or cleanser varied by country. There were significant associations between bathing frequency and temperature and between moisturization and precipitation., Conclusion: The national standard care for newborn bathing in each country was unique. Standard bathing care was associated with the climate. More consideration should be given to the differences in standard care for newborn bathing between countries when interpreting existing studies and conducting future studies on neonatal skin care., (© 2023 The Authors. Japan Journal of Nursing Science published by John Wiley & Sons Australia, Ltd on behalf of Japan Academy of Nursing Science.)
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- 2024
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24. Factors Associated with Antidepressant Effects of Ketamine: A Reanalysis of Double-Blind Randomized Placebo-Controlled Trial of Intravenous Ketamine for Treatment-Resistant Depression.
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Yonezawa K, Uchida H, Yatomi T, Ohtani Y, Nomoto-Takahashi K, Nakajima S, Mimura M, and Tani H
- Subjects
- Adult, Humans, Female, Middle Aged, Infant, Newborn, Depression drug therapy, Antidepressive Agents therapeutic use, Double-Blind Method, Treatment Outcome, Infusions, Intravenous, Ketamine therapeutic use, Depressive Disorder, Treatment-Resistant drug therapy
- Abstract
Introduction: Predictors of treatment response to intravenous ketamine remain unclear in patients with treatment-resistant depression (TRD); therefore, this study aimed to clarify these predictors using the US National Institutes of Health database of clinical trials., Methods: Data from a placebo-controlled, double-blind, randomized controlled trial were used to assess the efficacy of intravenous ketamine in adult patients with TRD (NCT01920555). For the analysis, data were used from the participants who had received therapeutic doses of intravenous ketamine (i. e., 0.5 and 1.0 mg/kg). Logistic and multivariable regression analyses were conducted to explore the demographic and clinical factors associated with response to treatment or changes in the Hamilton Depression Rating Scale 6 items (HAM-D-6) total score., Results: This study included 31 patients with TRD (13 women; mean±standard deviation age, 48.4±10.9 years). Logistic regression analysis showed that the age of onset was positively correlated with treatment response after three days of ketamine administration (β=0.08, p=0.037); however, no association was observed between treatment response and age, sex, baseline HAM-D-6 total score, or dissociative score assessed with the Clinician-Administered Dissociative States Scale 40 min after ketamine infusion. Multiple regression analysis showed that no factors were correlated significantly with the percentage change in the HAM-D-6 total score three days after ketamine administration., Discussion: Later disease onset correlates with a better treatment response three days after ketamine infusion in patients with TRD. Glutamatergic signal transmission may be impaired in patients with an earlier onset of depression, resulting in decreased neuroplasticity, which diminishes ketamine response., Competing Interests: Dr. Yonezawa has received manuscript fees from Sumitomo Pharma and Wiley Japan within the past three years. Dr. Uchida has received grants from Daiichi Sankyo, Eisai, Mochida, Otsuka, and Sumitomo Pharma; speaker’s fees from Eisai, Janssen, Lundbeck, Meiji Seika Pharma, Otsuka, and Sumitomo Pharma; and advisory board fees from Lundbeck, Sumitomo Pharma, Takeda Pharmaceutical Company, and Boehringer Ingelheim Japan. Dr. Yatomi has received grants from the Japan Society for the Promotion of Science (21K07508), and The Keio University Doctorate Student Grant-in-Aid Program from Ushioda Memorial Fund (Graduate school recommendation) within the past three years. Dr. Ohtani has received manuscript fees or speaker’s honoraria from Dainippon Sumitomo Pharma within the past three years. Dr. Nomoto-Takahashi declare no conflict of interest. Dr. Nakajima has received grants from the Japan Society for the Promotion of Science (18H02755, 22H03002), Japan Agency for Medical Research and Development (AMED), Japan Research Foundation for Clinical Pharmacology, Naito Foundation, Takeda Science Foundation, and Uehara Memorial Foundation within the past three years. Dr. Nakajima has also received research support, manuscript fees or speaker’s honoraria from Dainippon Sumitomo Pharma, Meiji-Seika Pharma, Otsuka Pharmaceutical, Shionogi, and Yoshitomi Yakuhin within the past three years. Dr. Mimura has received speaker’s honoraria from Biogen Japan, Byer Pharmaceutical, Daiichi Sankyo, Dainippon-Sumitomo Pharma, Demant Japan, Eisai, Eli Lilly, Fuji Film RI Pharma, Hisamitsu Pharmaceutical, H.U. Frontier, Janssen Pharmaceutical, Mochida Pharmaceutical, MSD, Mylan EPD, Nippon Chemipher, Novartis Pharma, Ono Yakuhin, Otsuka Pharmaceutical, Pfizer, Shionogi, Takeda Yakuhin, Teijin Pharma, and Viatris within the past three years. Also, he received grants from Daiichi Sankyo, Eisai, Fronteo, Shionogi, Takeda, Tanabe Mitsubishi and Tsumura within the past three years outside the submitted work. Dr. Tani has received manuscript or speaker fees from Sumitomo Pharma, Janssen Pharmaceutical, Otsuka Pharmaceutical, Takeda, Wiley Japan, and Yoshitomi Yakuhin within the past three years., (Thieme. All rights reserved.)
- Published
- 2024
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25. Association of serum docosahexaenoic acid and eicosapentaenoic acid levels with dietary intakes and supplement use during pregnancy: a prospective observational study.
- Author
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Wakabayashi N, Haruna M, Yonezawa K, Sasagawa E, Usui Y, Ohori R, Aoyama S, Sasaki S, and Nagamatsu T
- Subjects
- Animals, Female, Humans, Pregnancy, Biomarkers, Dietary Supplements, Eating, Prospective Studies, Docosahexaenoic Acids, Eicosapentaenoic Acid
- Abstract
This study aimed to determine the association of serum docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) levels with dietary intakes and supplement use during pregnancy. This prospective observational study was conducted at a university hospital in Tokyo, Japan. Participants in their second and third trimesters were given a self-administered questionnaire assessing the frequency of DHA and EPA supplement use in the past month and a brief-type self-administered diet history questionnaire. Non-fasting serum DHA and EPA levels were analysed using gas chromatography. Differences in biomarkers by frequency of supplement use were determined using multiple comparison analyses, and Spearman's correlation coefficient was used to determine biomarkers and DHA and EPA intakes by food group. Of the 116 participants, 11 (9⋅5 %) in the second trimester and 18 (15⋅5 %) in the third trimester regularly used supplements (≥5 times per week). Regular users had higher serum DHA and EPA levels than never users in the second and third trimesters. Dietary DHA and EPA intake from fish and shellfish was positively correlated with serum DHA and EPA in the second and third trimesters. Supplement use ≥5 times per week and fish and shellfish intake were associated with high serum DHA and EPA levels., (© The Author(s) 2023.)
- Published
- 2023
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26. SAXS/WAXS data of conformationally flexible ribose binding protein.
- Author
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Choudhury J, Yonezawa K, Anu A, Shimizu N, and Chaudhuri B
- Abstract
Modern artificial intelligence-based protein structure prediction methods, such as Alphafold2, can predict structures of folded proteins with reasonable accuracy. However, Alphafold2 provides a static view of a protein, which does not show the conformational variability of the protein, domain movement in a multi-domain protein, or ligand-induced conformational changes it might undergo in solution. Small-angle X-ay scattering (SAXS) and wide-angle X-ray scattering (WAXS) are solution techniques that can aid in integrative modeling of conformationally flexible proteins, or in validating their predicted ensemble structures. While SAXS is sensitive to global structural features, WAXS can expand the scope of structural modeling by including information about local structural changes. We present SAXS and WAXS datasets obtained from conformationally flexible d-ribose binding protein (RBP) from Escherichia coli in the ribose bound and unbound forms. SAXS/WAXS datasets of RBP provided here may aid in method development efforts for more accurate prediction of structural ensembles of conformationally flexible proteins, and their conformational changes., (© 2023 The Authors. Published by Elsevier Inc.)
- Published
- 2023
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27. Psychological factors of pregnant women associated with inadequate maternal weight gain in Japan.
- Author
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Maejima M, Yonezawa K, Sasagawa E, Hikita N, Usui Y, and Haruna M
- Subjects
- Female, Pregnancy, Humans, Pregnant Women, Japan epidemiology, Body Mass Index, Parturition, Weight Loss, Pregnancy Outcome, Gestational Weight Gain, Hyperemesis Gravidarum
- Abstract
Objectives: Inadequate gestational weight gain (GWG) has been associated with low birth weight (LBW). However, factors associated with inadequate GWG in Japan remain unclear. Here, we aimed to determine the factors associated with inadequate GWG and the characteristics of inadequate GWG based on the pre-pregnancy body mass index (BMI) among pregnant women in Japan., Methods: This observational study included pregnant women at ≥16 weeks of gestation. The study was conducted at two general hospitals in Tokyo, Japan. The participants were requested to complete a questionnaire during the antenatal checkup visit and a mail survey after childbirth. Data were also collected from medical records. The GWG level and associated factors were assessed using the chi-square test or t -test., Results: In total, 252 pregnant women were recruited and completed the questionnaires. Data from 128 pregnant women were analyzed. Overall, 23 (18.0%) women were classified as having inadequate GWG. The factors associated with inadequate GWG were as follows: pre-pregnancy underweight, hospital admission owing to hyperemesis, low body esteem, high Edinburgh Postnatal Depression Scale score, low target GWG, more significant weight loss during pregnancy when compared with that pre-pregnancy, high maximum weight loss during pregnancy, delay in return to pre-pregnancy weight, lower birth weight, and inadequate GWG perception. Pregnant women with inadequate weight gain did not receive any medical advice to avoid being overweight but were rather advised to gain additional weight., Conclusion: Target GWG and low body esteem were associated with inadequate GWG and other factors that could be modified. Medical staff should focus on achieving the target GWG and improving the body appreciation level among pregnant women.
- Published
- 2023
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28. Conformation state-specific monobodies regulate the functions of flexible proteins through conformation trapping.
- Author
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Nakamura I, Amesaka H, Hara M, Yonezawa K, Okamoto K, Kamikubo H, Tanaka SI, and Matsuo T
- Subjects
- Binding Sites, Crystallography, X-Ray, Protein Binding, Protein Conformation, Scattering, Small Angle, X-Ray Diffraction, Chromatography, Carrier Proteins
- Abstract
Synthetic binding proteins have emerged as modulators of protein functions through protein-protein interactions (PPIs). Because PPIs are influenced by the structural dynamics of targeted proteins, investigating whether the synthetic-binders-based strategy is applicable for proteins with large conformational changes is important. This study demonstrates the applicability of monobodies (fibronectin type-III domain-based synthetic binding proteins) in regulating the functions of proteins that undergo tens-of-angstroms-scale conformational changes, using an example of the A55C/C77S/V169C triple mutant (Adk
tm ; a phosphoryl transfer-catalyzing enzyme with a conformational change between OPEN/CLOSED forms). Phage display successfully developed monobodies that recognize the OPEN form (substrate-unbound form), but not the CLOSED form of Adktm . Two OPEN form-specific clones (OP-2 and OP-4) inhibited Adktm kinase activity. Epitope mapping with a yeast-surface display/flow cytometry indicated that OP-2 binds to the substrate-entry side of Adktm , whereas OP-4 binding occurs at another site. Small angle X-ray scattering coupled with size-exclusion chromatography (SEC-SAXS) indicated that OP-4 binds to the hinge side opposite to the substrate-binding site of Adktm , retaining the whole OPEN-form structure of Adktm . Titration of the OP-4-Adktm complex with Ap5 A, a transition-state analog of Adktm , showed that the conformational shift to the CLOSED form was suppressed although Adktm retained the OPEN-form (i.e., substrate-binding ready form). These results show that OP-4 captures and stabilizes the OPEN-form state, thereby affecting the hinge motion. These experimental results indicate that monobody-based modulators can regulate the functions of proteins that show tens-of-angstroms-scale conformational changes, by trapping specific conformational states generated during large conformational change process that is essential for function exertion., (© 2023 The Protein Society.)- Published
- 2023
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29. Association of Eicosapentaenoic and Docosahexaenoic Acid Intake with Low Birth Weight in the Second Trimester: The Japan Pregnancy Eating and Activity Cohort Study.
- Author
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Yoshimura M, Fujita M, Shibata A, Ohori R, Aoyama S, Yonezawa K, Sato Y, Sasaki S, Matsuzaki M, Suetsugu Y, and Haruna M
- Subjects
- Infant, Newborn, Humans, Female, Pregnancy, Cohort Studies, Pregnancy Trimester, Second, Japan epidemiology, Infant, Low Birth Weight, Docosahexaenoic Acids, Eicosapentaenoic Acid
- Abstract
This study examined the association of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake during the second trimester with low birth weight (LBW) in pregnant Japanese women and was conducted in conjunction with the Japan Pregnancy Eating and Activity Cohort (J-PEACH) study. The study included 504 pregnant women from four Japanese sites. During the second trimester (14-27 weeks), the participants filled out a self-administered questionnaire assessing the frequency of DHA and EPA supplement intake in the past month, as well as a brief-type self-administered diet history questionnaire (BDHQ). The analysis involved data from two time points: responses to the BDHQ and infant data at birth. In total, 471 and 33 participants were classified into the normal birth weight and LBW groups, respectively. The participants were divided into high-, medium-, and low-intake groups based on their total dietary and EPA and DHA supplementary intakes. The Cochran-Armitage trend test was used to analyze the data; the prevalence of LBW was higher in the low-intake group ( p = 0.04). There was no significant sex-based trend ( p = 0.27 and p = 0.35). In Japanese women, low dietary and supplementary EPA and DHA intake until the second trimester were risk factors for LBW.
- Published
- 2023
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30. The two-step cargo recognition mechanism of heterotrimeric kinesin.
- Author
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Jiang X, Ogawa T, Yonezawa K, Shimizu N, Ichinose S, Uchihashi T, Nagaike W, Moriya T, Adachi N, Kawasaki M, Dohmae N, Senda T, and Hirokawa N
- Subjects
- Biological Transport, Microtubules metabolism, Kinesins metabolism, Cell Communication
- Abstract
Kinesin-driven intracellular transport is essential for various cell biological events and thus plays a crucial role in many pathological processes. However, little is known about the molecular basis of the specific and dynamic cargo-binding mechanism of kinesins. Here, an integrated structural analysis of the KIF3/KAP3 and KIF3/KAP3-APC complexes unveils the mechanism by which KIF3/KAP3 can dynamically grasp APC in a two-step manner, which suggests kinesin-cargo recognition dynamics composed of cargo loading, locking, and release. Our finding is the first demonstration of the two-step cargo recognition and stabilization mechanism of kinesins, which provides novel insights into the intracellular trafficking machinery., (© 2023 The Authors.)
- Published
- 2023
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31. Relationship Between Degree of Neonatal Physiologic Desquamation and Skin Barrier Function.
- Author
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Yonezawa K and Haruna M
- Subjects
- Humans, Infant, Newborn, Cross-Sectional Studies, Water, Gestational Age, Skin Physiological Phenomena, Epidermis
- Abstract
Background/objectives: This study examined the relationship between degree of neonatal physiologic desquamation and skin barrier functionality. In addition, we identified factors associated with neonatal desquamation., Methods: This cross-sectional study assessed 4-day-old newborns. The desquamation level was evaluated and placed in one of the following categories based on the severity of the desquamation: no desquamation, a small amount, and severe (including cracked or bleeding). Skin barrier function was assessed by evaluating transepidermal water loss, stratum corneum hydration, skin pH, and sebum secretion., Results: Among study participants, 67 (39.9%) showed no desquamation, 82 (48.8%) displayed a small amount, and 19 (11.3%) had severe desquamation. The group with severe desquamation had significantly elevated facial transepidermal water loss levels and reduced levels of stratum corneum hydration throughout the body, indicating skin barrier dysfunction, than other groups. In addition, the group with severe desquamation had a significantly longer gestational age, lower temperature and humidity level, smaller vernix caseosa, and tended to be born during winter., Conclusions: To our knowledge, this is the first report indicating that infants with severe desquamation had worsened skin barrier function versus those with moderate and no desquamation. Future research should consider what kind of care should be provided to newborns with severe desquamation., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2023
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32. Dietary Intake and Its Association with Birth Outcomes in Women with Nausea and Vomiting during the Second Trimester of Pregnancy: A Prospective Cohort Study in Japan.
- Author
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Nishihara N, Haruna M, Usui Y, Yonezawa K, Hikita N, Sasagawa E, Nakano K, Tanaka M, Ohori R, Aoyama S, Sasaki S, Fujita M, Matsuzaki M, Suetsugu Y, and Sato Y
- Subjects
- Pregnancy, Humans, Infant, Newborn, Female, Pregnancy Trimester, Second, Prospective Studies, Japan, Nausea etiology, Vomiting, Eating, Premature Birth, Pregnancy Complications
- Abstract
Nausea and vomiting in pregnancy (NVP) is a common symptom. Although the influence of NVP during the first trimester on dietary intake and birth outcomes has been revealed, no study has focused on NVP during the second trimester. This study aimed to reveal whether NVP severity during the second trimester is associated with dietary intake, gestational weight gain (GWG), birth weight, and delivery week. Participants completed a questionnaire at 18-27 gestational weeks. NVP severity was assessed using the modified Pregnancy-Unique Quantification of Emesis and Nausea scale in the questionnaire. Dietary habits were assessed using a brief-type diet history questionnaire. In total, 825 responses were analyzed: 202 (24.5%), 135 (16.4%), and 8 (1.0%) women reported mild, moderate, and severe NVP, respectively; 480 (58.2%) women did not have NVP during the second trimester. No significant association was observed between energy and nutrient intake and no/mild and moderate/severe NVP. Women with moderate/severe NVP had lower total GWG than those with no/mild NVP ( p = 0.007). There was no significant difference in low birth weight and preterm birth rates ( p = 0.246 and p = 0.604). This is the first study to investigate whether NVP severity during the second trimester is associated with dietary intake and birth outcomes.
- Published
- 2023
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33. Targeting transglutaminase 2 mediated exostosin glycosyltransferase 1 signaling in liver cancer stem cells with acyclic retinoid.
- Author
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Qin XY, Furutani Y, Yonezawa K, Shimizu N, Kato-Murayama M, Shirouzu M, Xu Y, Yamano Y, Wada A, Gailhouste L, Shrestha R, Takahashi M, Keillor JW, Su T, Yu W, Fujii S, Kagechika H, Dohmae N, Shirakami Y, Shimizu M, Masaki T, Matsuura T, Suzuki H, and Kojima S
- Subjects
- Humans, Protein Glutamine gamma Glutamyltransferase 2, Neoplastic Stem Cells, Glycosyltransferases, Carcinoma, Hepatocellular, Liver Neoplasms
- Abstract
Transglutaminase 2 (TG2) is a multifunctional protein that promotes or suppresses tumorigenesis, depending on intracellular location and conformational structure. Acyclic retinoid (ACR) is an orally administered vitamin A derivative that prevents hepatocellular carcinoma (HCC) recurrence by targeting liver cancer stem cells (CSCs). In this study, we examined the subcellular location-dependent effects of ACR on TG2 activity at a structural level and characterized the functional role of TG2 and its downstream molecular mechanism in the selective depletion of liver CSCs. A binding assay with high-performance magnetic nanobeads and structural dynamic analysis with native gel electrophoresis and size-exclusion chromatography-coupled multi-angle light scattering or small-angle X-ray scattering showed that ACR binds directly to TG2, induces oligomer formation of TG2, and inhibits the transamidase activity of cytoplasmic TG2 in HCC cells. The loss-of-function of TG2 suppressed the expression of stemness-related genes, spheroid proliferation and selectively induced cell death in an EpCAM+ liver CSC subpopulation in HCC cells. Proteome analysis revealed that TG2 inhibition suppressed the gene and protein expression of exostosin glycosyltransferase 1 (EXT1) and heparan sulfate biosynthesis in HCC cells. In contrast, high levels of ACR increased intracellular Ca
2+ concentrations along with an increase in apoptotic cells, which probably contributed to the enhanced transamidase activity of nuclear TG2. This study demonstrates that ACR could act as a novel TG2 inhibitor; TG2-mediated EXT1 signaling is a promising therapeutic target in the prevention of HCC by disrupting liver CSCs., (© 2023. The Author(s).)- Published
- 2023
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34. Reliability and validity of the Japanese version of the Infant Breastfeeding Assessment Tool.
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Tomita A, Tahara-Sasagawa E, Yonezawa K, Usui Y, and Haruna M
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- Female, Humans, Infant, Newborn, Pregnancy, Feeding Behavior, Mothers, Reproducibility of Results, Japan, Breast Feeding
- Abstract
Objective: To translate the Infant Breastfeeding Assessment Tool (IBFAT) into Japanese and confirm the reliability and validity of the Japanese version of IBFAT., Design: The methodological study examining the reliability and validity of the Japanese version of the IBFAT., Setting: A maternity hospital in Tokyo., Participants: Ten mother-newborn pairs were recruited for the reliability analysis. 101 mother-newborn pairs were recruited for the validity analysis., Measurements and Findings: Reliability was verified by video recording and direct observation. The observers are one researcher, and 11 evaluators consisting of midwives and nurses. Amongst the 11 evaluators, six evaluators directly observed breastfeeding behaviours and five evaluators observed breastfeeding behaviours through video viewing. Regarding the inter-rater agreement, the intraclass correlation (ICC) between the researcher and six direct evaluators was 0.985 (95% confidence interval [CI]: 0.941-0.996) and that amongst five video viewing evaluators was 0.827 (95% CI: 0.647-0.945). In the intra-rater agreement, the lowest ICC amongst all those investigating IBFAT scores was 0.810 (95% CI: 0.433-0.948). In concurrent validity, the correlation coefficients between the IBFAT and Breastfeeding behaviour Assessment (BBA) scores on the first day after birth and the fourth or fifth day after birth (at discharge) were 0.66 (p < 0.001) and 0.40 (p < 0.001), respectively. In predictive validity, the medians and interquartile ranges (IQRs) of IBFAT scores at discharge were 11.0 (IQR: 11.0-12.0) and 11.0 (IQR: 11.0-12.0) for the breast and mixed milk groups at one-month check-up, respectively. While both median values were the same, the Mann-Whitney U test showed a significant difference., Key Conclusions: The Japanese version of the IBFAT is valid and reliable for measuring feeding behaviour amongst newborns in the first week of life., Implications for Practice: The Japanese version of the IBFAT can be available both in a clinical setting and in research to help support breastfeeding., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023. Published by Elsevier Ltd.)
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- 2023
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35. Value of apparent diffusion coefficient on MRI for prediction of histopathological type in anal fistula cancer.
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Yamamoto S, Yonezawa K, Fukata N, Takeshita K, Kodama M, Yamana T, Kiryu S, and Okada Y
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- Male, Humans, Middle Aged, Aged, Female, Retrospective Studies, Magnetic Resonance Imaging, Diffusion Magnetic Resonance Imaging methods, Anus Neoplasms diagnostic imaging, Adenocarcinoma pathology, Adenocarcinoma, Mucinous diagnostic imaging, Rectal Fistula diagnostic imaging
- Abstract
The main histopathological types of anal fistula cancers are mucinous adenocarcinoma and tubular adenocarcinoma. The purpose of this study was to investigate the utility of the apparent diffusion coefficient (ADC) value in magnetic resonance imaging (MRI) to determine the histopathological type of an anal fistula cancer, and to investigate the relationship between ADC values and histopathological type (mucinous type or tubular carcinoma), clinical information, and surgical findings. We retrospectively identified 69 patients diagnosed with anal fistula cancer at our hospital from January 2013 to December 2021. Among them, we selected the patients diagnosed using the same 1.5-T MRI machine, underwent surgery, and a pathological sample was obtained during the operation. Finally, these 25 patients were selected for the analysis since they underwent the imaging scan using the same MRI machine. The ADC value was compared between mucinous and tubular adenocarcinomas, and between tumors at the Tis-T1-T2 and T3-T4 stages. Finally, 25 patients were selected. The mean age of the 25 patients included in the analysis was 60.8 ± 13.3 years and all were males. The median ADC of anal fistula cancers was 1.97 × 10-3 mm2/s for mucinous adenocarcinomas and 1.36 × 10-3 mm2/s for tubular adenocarcinomas; this difference was statistically significant (P < .01). Furthermore, the median ADC was 1.62 × 10-3 mm2/s for tumors in Tis-T1-T2 stages and 2.01 × 10-3 mm2/s for T3-T4 tumors (P = .02). The ADC value in MR images may predict the histopathological type and depth of anal fistula cancers. Also, the different ADC values between Tis-T1-T2 and T3-T4 tumors could help predict the classification of progression., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2023
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36. Relationship between facial skin problems with a focus on inflammatory cytokines and the presence of Malassezia in 1-month-old infants.
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Shimizu S, Yonezawa K, Haruna M, Tahara-Sasagawa E, Usui Y, Minematsu T, and Higuchi S
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- Humans, Infant, Cytokines, Cross-Sectional Studies, Skin microbiology, Interleukin-8, Malassezia
- Abstract
Infantile skin problems not only cause temporary pain and discomfort, but also have a long-term impact on health. Hence, the purpose of this cross-sectional study was to clarify the relationship between inflammatory cytokines and Malassezia fungal facial skin problems in infants. Ninety-six 1-month-old infants were examined. Facial skin problems and the presence of inflammatory cytokines in the forehead skin were assessed using the infant facial skin visual assessment tool (IFSAT) and the skin blotting method, respectively. Malassezia, a fungal commensal, was detected using forehead skin swabs, and its percentage in the total fungal population was analyzed. Infants with positive interleukin-8 signals were more likely to have severe facial skin problems (p = 0.006) and forehead papules (p = 0.043). No significant association between IFSAT scores and Malassezia was found, but infants with forehead dryness had a lower percentage of M. arunalokei in the total fungal population (p = 0.006). No significant association was observed between inflammatory cytokines and Malassezia in the study participants. Longitudinal studies on the development of facial skin problems in infants are warranted to investigate the involvement of interleukin-8 and devise preventive strategies in the future., (© 2023. The Author(s).)
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- 2023
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37. The concept of detection of dynamic lung hyperinflation using cardiopulmonary exercise testing.
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Kominami K, Noda K, Minagawa N, Yonezawa K, and Akino M
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- Humans, Male, Forced Expiratory Volume, Dyspnea etiology, Lung, Exercise Tolerance, Exercise Test methods, Pulmonary Disease, Chronic Obstructive
- Abstract
Dynamic lung hyperinflation (DLH) caused by air trapping, which increases residual air volume, is a common cause of shortness of breath on exertion in chronic obstructive pulmonary disease (COPD). DLH is commonly evaluated by measuring the decrease in maximal inspiratory volume during exercise, or using the hyperventilation method. However, only few facilities perform these methods, and testing opportunities are limited. Therefore, we investigated the possibility of visually and qualitatively detecting DLH using data from a cardiopulmonary exercise test (CPET). Four men who underwent symptom-limiting CPET were included in this study, including a male patient in his 60s with confirmed COPD, a 50s male long-term smoker, and 2 healthy men in their 20s and 70s, respectively. We calculated the difference between the inspiratory tidal volume (TV I) and expiratory tidal volume (TV E) per breath (TV E-I) from the breath-by-breath data of each CPET and plotted it against the time axis. No decrease in TV E-I was observed in either of the healthy men. However, in the patient with COPD and long-term smoker, TV E-I began to decrease immediately after the initiation of exercise. These results indicate that DLH can be visually detected using CPET data. However, this study was a validation of a limited number of cases, and a comparison with existing evaluation methods and verification of disease specificity are required., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2023
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38. Detection of impaired gas exchange using the 1-minute sit-to-stand test in patients with interstitial lung disease.
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Oishi K, Asami-Noyama M, Yamamoto T, Matsumori K, Yonezawa K, Watanabe M, Hisamoto Y, Fukatsu A, Matsuda K, Hamada K, Suetake R, Ohata S, Murata Y, Yamaji Y, Sakamoto K, Ito K, Osoreda H, Edakuni N, Kakugawa T, Hirano T, and Matsunaga K
- Subjects
- Humans, Retrospective Studies, Lung, Respiratory Function Tests, Pulmonary Diffusing Capacity, Lung Diseases, Interstitial diagnosis
- Abstract
Background: Although pulmonary function tests (PFTs) are important in patients with interstitial lung disease (ILD), they cannot be easily performed in a primary healthcare setting. This study aimed to examine the usefulness of the difference between pulse oxygen saturation (SpO2) at rest and the lowest SpO2 during the 1-min sit-to-stand test (delta SpO2-1STST) for predicting pulmonary function impairment., Methods: We retrospectively reviewed 116 patients with ILD who underwent 1STST and PFTs., Results: The delta SpO2-1STST and diffusing capacity for carbon monoxide (DLco) strongly correlated (ρ = 0.70). The delta SpO2-1STST was effective in predicting impaired gas exchange (cut-off value, -4%; AUC, 0.86; sensitivity, 74%; specificity, 87%)., Conclusions: The Delta SpO2-1STST may be a reasonable tool for predicting abnormalities in PFTs., Competing Interests: Conflict of Interest K.O. reports the receipt of personal fees (honoraria) from Nippon Boehringer Ingelheim Co., Ltd. outside the submitted work. T.K. reports the receipt of personal fees (honoraria) from Nippon Boehringer Ingelheim Co., Ltd. outside the submitted work. K.M. (Kazuto Matsunaga) reports the receipt of personal fees (honoraria) from AstraZeneca K.K., GlaxoSmithKline K.K., Kyorin Pharmaceutical Co., Ltd., Novartis Pharma K.K., Nippon Boehringer Ingelheim Co., Ltd., and Sanofi K.K., outside the submitted work. The other authors have no conflicts of interest to declare., (Copyright © 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)
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- 2023
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39. Stiff left atrial syndrome? Don't overlook underlying disease.
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Chiba Y, Iwano H, Imagawa S, and Yonezawa K
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- Humans, Heart Atria diagnostic imaging, Syndrome, Atrial Fibrillation, Atrial Appendage
- Abstract
Competing Interests: Conflict of interest: None declared.
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- 2023
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40. Integrated Evaluation of the Aeroacoustics and Psychoacoustics of a Single Propeller.
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Sun J, Yonezawa K, Shima E, and Liu H
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- Psychoacoustics, Acoustics, Benchmarking, Noise, Sound
- Abstract
Aeroacoustic noise in multiple rotor drones has been increasingly recognized as a crucial issue, while noise reduction is normally associated with a trade-off between aerodynamic performance and sound suppression as well as sound quality improvement. Here, we propose an integrated methodology to evaluate both aeroacoustics and psychoacoustics of a single propeller. For a loop-type propeller, an experimental investigation was conducted in association with its aerodynamic and acoustic characteristics via a hover stand test in an anechoic chamber; the psychoacoustic performance was then examined with psychoacoustic annoyance models to evaluate five psychoacoustic metrics comprising loudness, fluctuation strength, roughness, sharpness, and tonality. A comparison of the figure of merit (FM), the overall sound pressure level (OASPL) and psychoacoustic metrics was undertaken among a two-blade propeller, a four-blade propeller, the loop-type propeller, a wide chord loop-type propeller, and a DJI Phantom III propeller, indicating that the loop-type propeller enables a remarkable reduction in OASPL and a noticeable improvement in sound quality while achieving comparable aerodynamic performance. Furthermore, the psychoacoustic analysis demonstrates that the loop-type propeller can improve the psychological response to various noises in terms of the higher-level broadband and lower-level tonal noise components. It is thus verified that the integrated evaluation methodology of aeroacoustics and psychoacoustics can be a useful tool in the design of low-noise propellers in association with multirotor drones.
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- 2023
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41. MOLASS: Software for automatic processing of matrix data obtained from small-angle X-ray scattering and UV-visible spectroscopy combined with size-exclusion chromatography.
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Yonezawa K, Takahashi M, Yatabe K, Nagatani Y, and Shimizu N
- Abstract
Recent small-angle X-ray scattering (SAXS) for biological macromolecules (BioSAXS) is generally combined with size-exclusion chromatography (SEC-SAXS) at synchrotron facilities worldwide. For SEC-SAXS analysis, the final scattering profile for the target molecule is calculated from a large volume of continuously collected data. It would be ideal to automate this process; however, several complex problems exist regarding data measurement and analysis that have prevented automation. Here, we developed the analytical software MOLASS (Matrix Optimization with Low-rank factorization for Automated analysis of SEC-SAXS) to automatically calculate the final scattering profiles for solution structure analysis of target molecules. In this paper, the strategies for automatic analysis of SEC-SAXS data are described, including correction of baseline-drift using a low percentile method, optimization of peak decompositions composed of multiple scattering components using modified Gaussian fitting against the chromatogram, and rank determination for extrapolation to infinite dilution. In order to easily calculate each scattering component, the Moore-Penrose pseudo-inverse matrix is adopted as a basic calculation. Furthermore, this analysis method, in combination with UV-visible spectroscopy, led to better results in terms of accuracy in peak decomposition. Therefore, MOLASS will be able to smoothly suggest to users an accurate scattering profile for the subsequent structural analysis., Competing Interests: All authors declare that they have no conflict of interest., (2023 THE BIOPHYSICAL SOCIETY OF JAPAN.)
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- 2023
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42. Skin care interventions in infants for preventing eczema and food allergy.
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Kelleher MM, Phillips R, Brown SJ, Cro S, Cornelius V, Carlsen KCL, Skjerven HO, Rehbinder EM, Lowe AJ, Dissanayake E, Shimojo N, Yonezawa K, Ohya Y, Yamamoto-Hanada K, Morita K, Axon E, Cork M, Cooke A, Van Vogt E, Schmitt J, Weidinger S, McClanahan D, Simpson E, Duley L, Askie LM, Williams HC, and Boyle RJ
- Subjects
- Female, Animals, Cattle, Emollients therapeutic use, Allergens therapeutic use, Eczema prevention & control, Eczema drug therapy, Food Hypersensitivity prevention & control, Milk Hypersensitivity
- Abstract
Background: Eczema and food allergy are common health conditions that usually begin in early childhood and often occur in the same people. They can be associated with an impaired skin barrier in early infancy. It is unclear whether trying to prevent or reverse an impaired skin barrier soon after birth is effective for preventing eczema or food allergy., Objectives: Primary objective To assess the effects of skin care interventions such as emollients for primary prevention of eczema and food allergy in infants. Secondary objective To identify features of study populations such as age, hereditary risk, and adherence to interventions that are associated with the greatest treatment benefit or harm for both eczema and food allergy., Search Methods: We performed an updated search of the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase in September 2021. We searched two trials registers in July 2021. We checked the reference lists of included studies and relevant systematic reviews, and scanned conference proceedings to identify further references to relevant randomised controlled trials (RCTs). SELECTION CRITERIA: We included RCTs of skin care interventions that could potentially enhance skin barrier function, reduce dryness, or reduce subclinical inflammation in healthy term (> 37 weeks) infants (≤ 12 months) without pre-existing eczema, food allergy, or other skin condition. Eligible comparisons were standard care in the locality or no treatment. Types of skin care interventions could include moisturisers/emollients; bathing products; advice regarding reducing soap exposure and bathing frequency; and use of water softeners. No minimum follow-up was required., Data Collection and Analysis: This is a prospective individual participant data (IPD) meta-analysis. We used standard Cochrane methodological procedures, and primary analyses used the IPD dataset. Primary outcomes were cumulative incidence of eczema and cumulative incidence of immunoglobulin (Ig)E-mediated food allergy by one to three years, both measured at the closest available time point to two years. Secondary outcomes included adverse events during the intervention period; eczema severity (clinician-assessed); parent report of eczema severity; time to onset of eczema; parent report of immediate food allergy; and allergic sensitisation to food or inhalant allergen., Main Results: We identified 33 RCTs comprising 25,827 participants. Of these, 17 studies randomising 5823 participants reported information on one or more outcomes specified in this review. We included 11 studies, randomising 5217 participants, in one or more meta-analyses (range 2 to 9 studies per individual meta-analysis), with 10 of these studies providing IPD; the remaining 6 studies were included in the narrative results only. Most studies were conducted at children's hospitals. Twenty-five studies, including all those contributing data to meta-analyses, randomised newborns up to age three weeks to receive a skin care intervention or standard infant skin care. Eight of the 11 studies contributing to meta-analyses recruited infants at high risk of developing eczema or food allergy, although the definition of high risk varied between studies. Durations of intervention and follow-up ranged from 24 hours to three years. All interventions were compared against no skin care intervention or local standard care. Of the 17 studies that reported information on our prespecified outcomes, 13 assessed emollients. We assessed most of the evidence in the review as low certainty and had some concerns about risk of bias. A rating of some concerns was most often due to lack of blinding of outcome assessors or significant missing data, which could have impacted outcome measurement but was judged unlikely to have done so. We assessed the evidence for the primary food allergy outcome as high risk of bias due to the inclusion of only one trial, where findings varied based on different assumptions about missing data. Skin care interventions during infancy probably do not change the risk of eczema by one to three years of age (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.81 to 1.31; risk difference 5 more cases per 1000 infants, 95% CI 28 less to 47 more; moderate-certainty evidence; 3075 participants, 7 trials) or time to onset of eczema (hazard ratio 0.86, 95% CI 0.65 to 1.14; moderate-certainty evidence; 3349 participants, 9 trials). Skin care interventions during infancy may increase the risk of IgE-mediated food allergy by one to three years of age (RR 2.53, 95% CI 0.99 to 6.49; low-certainty evidence; 976 participants, 1 trial) but may not change risk of allergic sensitisation to a food allergen by age one to three years (RR 1.05, 95% CI 0.64 to 1.71; low-certainty evidence; 1794 participants, 3 trials). Skin care interventions during infancy may slightly increase risk of parent report of immediate reaction to a common food allergen at two years (RR 1.27, 95% CI 1.00 to 1.61; low-certainty evidence; 1171 participants, 1 trial); however, this was only seen for cow's milk, and may be unreliable due to over-reporting of milk allergy in infants. Skin care interventions during infancy probably increase risk of skin infection over the intervention period (RR 1.33, 95% CI 1.01 to 1.75; risk difference 17 more cases per 1000 infants, 95% CI one more to 38 more; moderate-certainty evidence; 2728 participants, 6 trials) and may increase the risk of infant slippage over the intervention period (RR 1.42, 95% CI 0.67 to 2.99; low-certainty evidence; 2538 participants, 4 trials) and stinging/allergic reactions to moisturisers (RR 2.24, 95% 0.67 to 7.43; low-certainty evidence; 343 participants, 4 trials), although CIs for slippages and stinging/allergic reactions were wide and include the possibility of no effect or reduced risk. Preplanned subgroup analyses showed that the effects of interventions were not influenced by age, duration of intervention, hereditary risk, filaggrin (FLG) mutation, chromosome 11 intergenic variant rs2212434, or classification of intervention type for risk of developing eczema. We could not evaluate these effects on risk of food allergy. Evidence was insufficient to show whether adherence to interventions influenced the relationship between skin care interventions and eczema or food allergy development., Authors' Conclusions: Based on low- to moderate-certainty evidence, skin care interventions such as emollients during the first year of life in healthy infants are probably not effective for preventing eczema; may increase risk of food allergy; and probably increase risk of skin infection. Further study is needed to understand whether different approaches to infant skin care might prevent eczema or food allergy., (Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)
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- 2022
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43. A Unique Surgical Case of Ancient Calcified Intravascular Papillary Endothelial Hyperplasia in the Tibia with Knee Joint Osteoarthritis.
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Kitajima H, Shioya A, Kadoguchi R, Han J, Sawano H, Yonezawa K, Shimizu Y, Hiromura K, Yokoyama M, Nojima T, and Yamada S
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- Male, Humans, Aged, Hyperplasia pathology, Endothelial Cells, Knee Joint pathology, Tibia pathology, Osteoarthritis, Knee pathology
- Abstract
Background: Intravascular papillary endothelial hyperplasia (IPEH) is a reactive lesion histopathologically characterized by papillary growth of vascular endothelial cells. IPEH is most commonly found in the skin and subcutaneous tissues of the head, neck, and extremities. Furthermore, it has been reported to occur in oral surgery, but its occurrence in bone is extremely rare., Case Presentation: We present the case of a 77-year-old man with a chief complaint of left knee arthralgia. The knee joint X-ray showed Kellgren-Lawrence grade 4 osteoarthritis and a mass lesion with decreased permeability within the bone in the medial part of the proximal tibia. Computerized tomography (CT) scan of the left knee showed a localized mass in the left proximal tibia with clear margins and granular internal calcification. The preoperative diagnosis was left knee osteoarthritis and a benign tumor of the left proximal tibia (enchondroma or hemangioma). The patient requested surgical treatment, so left total knee arthroplasty (TKA) and resection of the tumor were performed. The pathology revealed a rare intraosseous IPEH with marked calcification., Conclusions: Since intraosseous IPEH could not be considered from the clinical findings, the pathological diagnosis was the decisive factor. This report showed the world's first case of intraosseous IPEH with marked calcification. Similar to the calcification of intraosseous hemangiomas, we considered the possibility that, in IPEH, the thrombus may fibrosis and organize in concentric circles, causing necrosis at the center and resulting in calcification. TKA was performed on the degenerative knee joint with IPEH, and a good patient outcome was obtained., (© 2022 The Authors. Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.)
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- 2022
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44. Development and validation of an infant facial skin assessment tool: a prospective observational study.
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Matsubara M, Haruna M, Yonezawa K, Yokoyama M, Tahara-Sasagawa E, Hikita N, Nakamura Y, Mizuno Y, Sanada H, Tamai N, Abe M, and Kashiwabara K
- Subjects
- Infant, Humans, Reproducibility of Results, Prospective Studies, Caregivers
- Abstract
Background: Severe infant eczema on the face should be treated early because it may lead to allergic diseases in the future. However, caregivers find it difficult to assess. A visual tool for caregivers is needed to easily determine infants' facial skin condition severity based on the tool's scores. We developed an infant facial skin assessment tool (IFSAT) and evaluated its reliability and validity., Methods: The IFSAT draft was developed based on results of a previous literature review and qualitative sketch. Panels including medical professionals and a caregiver checked the draft's content and face validity, and the IFSAT was finalized. To test the IFSAT's reliability and validity, caregivers and one-month-old infants were recruited. Two scoring methods were additionally created based on the relation between the items and cure period. The relationships between scores and cure period, and the ability to predict whether the infant needed medical treatment were examined by each scoring method. For the predictive validity, scores for infants requiring medical treatment and those for infants who did not were also compared. For the intra-examiner reliability analysis, two pediatricians rated the scores separately twice using photographs. Inter-rater reliabilities were analyzed among pediatricians, nurses, and caregivers., Results: Altogether, 113 infant-caregiver pairs participated in the testing phase. Of the two scoring methods created (versions 1 and 2), pediatricians' and caregivers' scores using versions 1 and 2 were related to the cure period. These scores predict whether the infant needed medical treatment. We then selected version 2 based on the medical professionals' opinions. The scores of caregivers of infants requiring medical treatment were higher than those of caregivers of infants not requiring treatment (p < 0.001). The intraclass correlation coefficient (ICC) of intra-examiner reliability was 0.87. The ICC of inter-rater reliabilities between pediatricians' and caregivers' scores and between nurses' and caregivers' scores were 0.66, and 0.66, respectively., Conclusions: The proposed IFSAT may be used to assess whether infants need medical treatment and whether to extend the cure period. The tool's reliability and validity were confirmed., (© 2022. The Author(s).)
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- 2022
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45. The factors related to recovery time of diaper dermatitis in infants: A prospective observational study.
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Yokoyama M, Yonezawa K, Matsubara M, Hikita N, Sasagawa E, and Haruna M
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- Child, Erythema complications, Humans, Infant, Infant Care, Prospective Studies, Skin, Diaper Rash epidemiology, Diaper Rash etiology
- Abstract
Aim: Prolonged diaper dermatitis may increase the risk of atopic dermatitis or infections. This prospective observational study aimed to investigate the prevalence, symptoms, areas, and recovery time of diaper dermatitis in infants aged 1 month and identify the factors related to recovery time., Methods: Diaper dermatitis was defined as the presence of erythema, papules, dryness, erosion, or ulceration in the diapered area. Recovery time was days between infant's 1-month medical check-up and disappearance of symptoms. Survival analysis was performed using the Kaplan-Meier method, and the log-rank test was used to identify the factors related to recovery time., Results: Among 113 infants, 66 (58.4%) had diaper dermatitis, with erythema at the perianal area being the most common symptom. The median recovery time was 10 days. Four infants (6.1%) had diaper dermatitis for >5 weeks. Severity was not related to recovery time., Conclusions: A frequency of diaper changing of ≤10 times per day was a risk factor for recovery time. Our data showed recovery in approximately 10 days, regardless of severity at study enrollment. Health care professionals could inform parents of recovery time and recommended diaper changing frequency., (© 2022 Japan Academy of Nursing Science.)
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- 2022
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46. A case of laparoscopic distal gastrectomy and median arcuate ligament release for a gastric cancer patient with median arcuate ligament syndrome.
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Ueda S, Maeda M, Nishitani K, Seiichiro T, Kawamorita K, Takayanagi T, Kobayashi T, Hashimoto Y, and Yonezawa K
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Background: The median arcuate ligament syndrome (MALS) is a disease in which the celiac artery is compressed by the arcuate ligament and causes stenosis. If abdominal pain or an aneurysm is observed in the head of the pancreas, it is necessary to release the arcuate ligament, and recently laparoscopic surgery has been reported. However, the indication for treatment in asymptomatic cases is unknown. The treatment for asymptomatic MALS in patients with gastric cancer who are indicated for surgery is also novel., Case Presentation: A 70-year-old female was found with early gastric cancer in the middle body of the stomach. An enhanced CT scan showed no metastasis, but a gallstone and stenosis of the celiac artery due to the MALS were found. The patient underwent releasing median arcuate ligament after lymph node dissection. A median arcuate ligament was located on the ventral side of the left gastric artery stump, and the celiac artery was exposed when cutting it off. The operation time was 4 h and 59 min, and the bleeding was 6 ml. It took about 5 min to dissect the medial arcuate ligament. The postoperative course was satisfactory, and the patient was discharged 7 days after the operation. CT scan and 3-D CT angiography were performed about 2 months after the operation, and the findings revealed that the celiac artery's stenosis resolved., Conclusion: The patient underwent laparoscopic gastrectomy and simultaneously the median arcuate ligament release under an excellent visual field. Therefore, median arcuate ligament release may be considered if MALS is found in a gastrectomy case., (© 2022. The Author(s).)
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- 2022
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47. Diagnostic performance of nutritional indicators in patients with heart failure.
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Kinugasa Y, Sota T, Kamitani H, Nakayama N, Nakamura K, Hirai M, Yanagihara K, Kato M, Ono T, Takahashi M, Matsuo H, Matsukawa R, Yoshida I, Kakinoki S, Yonezawa K, Himura Y, Yokota T, Yamamoto K, Tsuchihashi-Makaya M, and Kinugawa S
- Subjects
- Aged, Geriatric Assessment methods, Humans, Nutrition Assessment, Heart Failure diagnosis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Malnutrition
- Abstract
Aims: The aim of this study was to compare the diagnostic performance of the nutritional indicators, the mini nutritional assessment-short form (MNA-SF), the geriatric nutritional risk index (GNRI), and the controlling nutritional status (CONUT), in heart failure (HF) patients., Methods and Results: Nutritional status was prospectively assessed by the aforementioned three nutritional indicators in 150 outpatients with HF who were then followed for 1 year. The prevalence of patients with the nutritional risk as assessed by the MNA-SF, GNRI, and CONUT scores was 50.0%, 13.3%, and 54.0%, respectively. There was slight agreement of nutritional risk assessment between the MNA-SF and GNRI scores (κ coefficient = 0.16), as well as the GNRI and CONUT scores (κ = 0.11), but poor agreement between the MNA-SF and CONUT scores (κ = -0.09). The CONUT score had the lowest area under the curve (AUC) for the identification of low body weight, low muscle mass, and low physical function among the three indicators (all P < 0.05). Compared with the MNA-SF score, both the GNRI and CONUT scores had lower AUCs for the identification of reduced dietary intake and weight loss (all P < 0.05). There was no significant difference in predicting all-cause mortality or HF rehospitalization among the three indicators. The prescription of statins reduced the diagnostic performance of the CONUT score, as the CONUT score includes cholesterol level assessment., Conclusions: Of the three indicators, the diagnostic ability of the MNA-SF score was the highest, and that of the CONUT score was the lowest, for the assessment of HF patient nutritional status. The CONUT score may misrepresent nutritional status, particularly in patients receiving statins., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)
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- 2022
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48. Revision balloon kyphoplasty and vertebra-pediculoplasty using cannulated screws for osteoporotic vertebral fractures with cement dislodgement following conventional balloon kyphoplasty.
- Author
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Yonezawa Y, Yonezawa N, Kanazawa Y, Yonezawa T, Yonezawa K, and Demura S
- Subjects
- Bone Cements, Humans, Spine, Treatment Outcome, Fractures, Compression surgery, Kyphoplasty, Osteoporotic Fractures diagnostic imaging, Osteoporotic Fractures surgery, Spinal Fractures diagnostic imaging, Spinal Fractures surgery
- Abstract
We report the usefulness of revision balloon kyphoplasty (re-BKP) and vertebra-pediculoplasty using cannulated screws (VPCS) for osteoporotic vertebral fractures (OVF) following cement dislodgement of conventional BKP. Between 2015 and 2020, three patients with OVF developed symptomatic cement dislodgement following BKP and underwent re-BKP. All three patients showed a loose cemented mass and spinal instability. Balloon inflation was performed in the gap between the loosened cemented mass and the remaining cortical bone rim, and this extended gap was filled with cement. To prevent re-dislodgement of the cement mass, a cannulated screw was inserted into the cemented mass through the pedicle. All patients achieved early pain relief, and improved vertebral stability of the fractured vertebra and all related symptoms, with no perioperative complications. Re-BKP and VPCS are innovative concepts and could be an effective minimally invasive treatment for OVF following cement dislodgement of conventional BKP treatment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2022
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49. Novel Antidepressants in the Pipeline (Phase II and III): A Systematic Review of the US Clinical Trials Registry.
- Author
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Sakurai H, Yonezawa K, Tani H, Mimura M, Bauer M, and Uchida H
- Subjects
- Antidepressive Agents therapeutic use, Clinical Trials, Phase II as Topic, Humans, Registries, Depressive Disorder, Major drug therapy, Depressive Disorder, Treatment-Resistant drug therapy
- Abstract
Introduction: There is an imminent need for faster-acting and more effective antidepressants beyond the monoaminergic hypothesis., Methods: We systematically searched the US Clinical Trials registry for antidepressant compounds with completed phase II and III trials. Compounds that demonstrated significant superiority over placebo in the primary outcome measure in the latest phase of phase II and III trials were identified. The collateral information was gathered via a PubMed search and press releases., Results: Nine compounds were identified. AXS-05 (a combination of dextromethorphan and bupropion) and ansofaxine hydrochloride showed a positive result over placebo in a phase III study for major depressive disorder or treatment-resistant depression. MIJ821, nitrous oxide, psilocybin, ayahuasca, facial injection of botulinum toxin A, prasterone, and casopitant demonstrated at least one positive result in phase II trials. Ayahuasca showed a greater response rate than placebo at week one, indicating the rapid antidepressant effect., Discussion: These new compounds with novel mechanisms of action are expected to provide a greater variety of treatment options for depression if preliminary positive results are confirmed., Competing Interests: Dr. Sakurai reports grants from the Uehara Memorial Foundation and manuscript fees or speaker’s honoraria from Eisai, Meiji Seika Pharma, Shionogi Pharma, Sumitomo Dainippon Pharma, Takeda Pharma, and Yoshitomi Yakuhin. Dr. Yonezawa has nothing to declare. Dr. Tani received a fellowship from the Japanese Society of Clinical Neuropsychopharmacology and the Canadian Institutes of Health Research, a research grant from Eli Lilly, and manuscript fees from Dainippon Sumitomo Pharma, Otsuka Pharmaceutical, Wiley Japan, and Yoshitomi Yakuhin. Dr. Mimura has received speaker’s honoraria from Byer Pharmaceutical, Daiichi Sankyo, Dainippon-Sumitomo Pharma, Eisai, Eli Lilly, Fuji Film RI Pharma, Hisamitsu Pharmaceutical, Janssen Pharmaceutical, Kyowa Pharmaceutical, Mochida Pharmaceutical, MSD, Mylan EPD, Nihon Medi-physics, Nippon Chemipher, Novartis Pharma, Ono Yakuhin, Otsuka Pharmaceutical, Pfizer, Santen Pharmaceutical, Shire Japan, Takeda Yakuhin, Tsumura, and Yoshitomi Yakuhin within the past three years. Also, he received grants from Daiichi Sankyo, Eisai, Pfizer, Shionogi, Takeda, Tanabe Mitsubishi, and Tsumura within the past three years outside the submitted work. Dr. Bauer has received institutional funding/grant support from Deutsche Forschungsgemeinschaft (DFG), Bundesministeriums für Bildung und Forschung (BMBF), and the European Commission. He has received speaker honoraria and/or travel compensation from Aristo, Hexal AG, Janssen Pharmaceutica NV, Janssen-Cilag, and Sunovion. He has served on advisory boards or honoraria for consultancy from GH Research, Janssen-Cilag, Neuraxpharm, Novartis, Sandoz, Shire International GmbH, Sumitomo Dainippon, Sunovion, and Takeda. Dr. Uchida has received grants from Eisai, Otsuka Pharmaceutical, Dainippon-Sumitomo Pharma, Daiichi Sankyo Company, Mochida Pharmaceutical, and Meiji-Seika Pharma; speaker’s honoraria from Otsuka Pharmaceutical, Dainippon-Sumitomo Pharma, Eisai, and Meiji-Seika Pharma, and advisory panel payments from Dainippon-Sumitomo Pharma within the past 3 years., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)
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- 2022
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50. Ca 2+ -induced structural changes and intramolecular interactions in N-terminal region of diacylglycerol kinase alpha.
- Author
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Takahashi D, Yonezawa K, Okizaki Y, Caaveiro JMM, Ueda T, Shimada A, Sakane F, and Shimizu N
- Subjects
- Endopeptidases, Scattering, Small Angle, X-Ray Diffraction, Diacylglycerol Kinase genetics, Diglycerides
- Abstract
Diacylglycerol kinases (DGKs) are multi-domain lipid kinases that modulate the levels of lipid messengers, diacylglycerol, and phosphatidic acid. Recently, increasing attention has been paid to its α isozyme (DGKα) as a potential target for cancer immunotherapy. However, little progress has been made on the structural biology of DGKs, and a detailed understanding of the Ca
2+ -triggered activation of DGKα, for which the N-terminal domains likely play a critical role, remains unclear. We have recently shown that Ca2+ binding to DGKα-EF induces conformational changes from a protease-susceptible "open" conformation in the apo state to a well-folded one in its holo state. Here, we further studied the structural properties of DGKα N-terminal (RVH and EF) domains using a series of biophysical techniques. We first revealed that the N-terminal RVH domain is a novel Ca2+ -binding domain, but the Ca2+ -induced conformational changes mainly occur in the EF domain. This was corroborated by NMR experiments showing that the EF domain adopts a molten-globule like structure in the apo state. Further analyses using SEC-SAXS and NMR indicate that the partially unfolded EF domain interacts with RVH domain, likely via hydrophobic interactions in the absence of Ca2+ , and this interaction is modified in the presence of Ca2+ . Taken together, these results present novel insights into the structural rearrangement of DGKα N-terminal domains upon binding to Ca2+ , which is essential for the activation of the enzyme., (© 2022 The Protein Society.)- Published
- 2022
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