1,829 results on '"A Manabe"'
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2. Molecular recognition of sialoglycans by streptococcal Siglec-like adhesins: toward the shape of specific inhibitors
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Cristina Di Carluccio, Alba Silipo, Yoshiyuki Manabe, Roberta Marchetti, Marco Fragai, Elio Pizzo, Rosa Ester Forgione, Barbara A. Bensing, Koichi Fukase, Antonio Molinaro, Andrea Bosso, Shinji Yokoyama, Di Carluccio, C., Forgione, R. E., Bosso, A., Yokoyama, S., Manabe, Y., Pizzo, E., Molinaro, A., Fukase, K., Fragai, M., Bensing, B. A., Marchetti, R., and Silipo, A.
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0303 health sciences ,Glycan ,biology ,Streptococcus gordonii ,SIGLEC ,010402 general chemistry ,biology.organism_classification ,Oral cavity ,01 natural sciences ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Biochemistry ,0104 chemical sciences ,3. Good health ,Microbiology ,Bacterial adhesin ,Chemistry ,03 medical and health sciences ,Strain specificity ,Streptococcus sanguinis ,Molecular recognition ,Chemistry (miscellaneous) ,biology.protein ,Molecular Biology ,030304 developmental biology - Abstract
Streptococcus gordonii and Streptococcus sanguinis, commensal bacteria present in the oral cavity of healthy individuals, upon entry into the bloodstream can become pathogenic, causing infective endocarditis (IE). Sialic acid-binding serine-rich repeat adhesins on the microbial surface represent an important factor of successful infection to cause IE. They contain Siglec-like binding regions (SLBRs) that variously recognize different repertoires of O-glycans, with some strains displaying high selectivity and others broader specificity. We here dissect at an atomic level the mechanism of interaction of SLBR-B and SLBR-H from S. gordonii with a multivarious approach that combines NMR spectroscopy and computational and biophysical studies. The binding pockets of both SLBRs are broad enough to accommodate extensive interactions with sialoglycans although with key differences related to strain specificity. Furthermore, and significantly, the pattern of interactions established by the SLBRs are mechanistically very different from those reported for mammalian Siglecs despite them having a similar fold. Thus, our detailed description of the binding modes of streptococcal Siglec-like adhesins sparks the development of tailored synthetic inhibitors and therapeutics specific for Streptococcal adhesins to counteract IE, without impairing the interplay between Siglecs and glycans., We here present a detailed molecular description of sialoglycans recognition by Siglec-like adhesins from S. gordonii opening the venue for the design of specific inhibitors to influence the propensity of streptococci to cause infective endocarditis.
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- 2021
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3. Diagnosis of histological gastritis based on the Kyoto classification of gastritis in Japanese subjects – including evaluation of aging and sex difference of histological gastritis
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Yoshiyuki Yamanaka, Akiko Shiotani, Sohachi Fujimoto, Toshihiro Takao, Tomoari Kamada, Takashi Akiyama, Naoki Sumi, Mitsuhiko Suehiro, Ken Haruma, and Noriaki Manabe
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Adult ,Male ,medicine.medical_specialty ,Younger age ,Gastroenterology ,Helicobacter Infections ,Young Adult ,Sex Factors ,Atrophy ,Japan ,Internal medicine ,medicine ,Humans ,Antrum ,Aged ,Metaplasia ,Helicobacter pylori ,medicine.diagnostic_test ,biology ,business.industry ,Age Factors ,Intestinal metaplasia ,Histology ,Middle Aged ,medicine.disease ,biology.organism_classification ,Endoscopy ,Gastric Mucosa ,Gastritis ,Female ,medicine.symptom ,business - Abstract
Objectives The Kyoto classification of gastritis was established for diagnosing Helicobacter pylori (H. pylori) infection via endoscopic findings. We investigated the role of the Kyoto classification of gastritis in the diagnosis of H. pylori infection and histological gastritis in Japanese individuals. Moreover, the histological findings of gastritis in H. pylori infection were examined based on age and sex differences. Methods We selected 561 patients aged 20-79 years who underwent gastroduodenal endoscopy at our hospital between 2010 and 2018. Endoscopic biopsy specimens from the antrum and corpus were used to investigate H. pylori infection and histology. Endoscopic findings were based on the Kyoto classification of gastritis, and histological findings were based on the updated Sydney System. Results Endoscopic findings based on the Kyoto classification of gastritis (H. pylori positive, 303 patients; H. pylori negative, 258 patients, based on endoscopic findings) had 98.7% sensitivity and 98.4% specificity for histological gastritis. In addition, endoscopic findings in the three age groups (20-39, 40-59, and 60-79 years) had high sensitivity and specificity. Atrophy and intestinal metaplasia were found only in the H. pylori-positive group and progressed with age. Histological inflammation of pyloric mucosa in the younger age group of H. pylori-positive patients was significantly higher than that in the elderly group. Significant inflammation was observed in young women. Conclusions The Kyoto classification of gastritis can not only diagnose H. pylori infection but also detect histological gastritis. Histological gastritis has varying characteristics of inflammation, atrophy, and intestinal metaplasia, depending on age and sex.
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- 2021
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4. Assessment of direct binding interaction between CD36 and its potential lipid ligands using a peptide mimic of the receptor labeled with a fluorophore
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Yuki Manabe, Tsutomu Sasaki, Yusaku Kimoto, Tatsuya Sugawara, Masayuki Yamasaki, Kazuo Inoue, and Satoshi Tsuzuki
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CD36 Antigens ,chemistry.chemical_classification ,biology ,Ligand ,CD36 ,Cell Differentiation ,Peptide ,General Medicine ,Ligands ,General Biochemistry, Genetics and Molecular Biology ,Amino acid ,chemistry.chemical_compound ,A-site ,chemistry ,Biochemistry ,Phosphatidylcholine ,biology.protein ,Peptides ,Receptor ,Fluorescein isothiocyanate ,Protein Binding - Abstract
Cluster of differentiation 36 (CD36) is a cell-surface receptor that recognizes diverse substances. We have presented indirect evidence that a short segment of the receptor comprising amino acids 149-168 contains a site for binding of its lipid ligands (e.g., distinct fatty acids and aldehydes). However, experimental support for their direct interactions is yet to be achieved. For this, we devised a fluorescence intensity assay, where a synthetic peptide consisting of CD36 amino acids 149-168 labeled with fluorescein isothiocyanate (FITC-CD36149-168) and its variant peptides were used as positive and negative probes, respectively. First, we obtained results indicating that 1-palmitoyl-2-(5-keto-6-octenedioyl)phosphatidylcholine (an established CD36 ligand) but not 1-palmitoyl-2-arachidonyl-phosphatidylcholine (a non-ligand of the receptor) bound in a saturable and specific manner to FITC-CD36149-168. Strikingly, the assay allowed us to provide the first evidence supporting direct and specific binding between the CD36 segment and fatty aldehydes (e.g., Z-11-hexadecenal). However, this method failed to illustrate specific interactions of the segment with fatty acids, such as oleic acid. Nonetheless, our findings offer further insight into the biologically relevant ligands and the role of CD36. In addition, we suggest that this fluorescence-based technique provides a convenient means to evaluate protein (peptide)-lipid interactions.
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- 2021
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5. Metatarsals of a large caenagnathid cf. Anzu wyliei (Theropoda: Oviraptorosauria) from the Hell Creek Formation in South Dakota, USA1
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Makoto Manabe, Takanobu Tsuihiji, Kousuke Tsujimura, and Yumiko Chiba
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010506 paleontology ,0303 health sciences ,biology ,Anzu ,biology.organism_classification ,Theropoda ,01 natural sciences ,Archaeology ,03 medical and health sciences ,General Earth and Planetary Sciences ,Caenagnathidae ,Geology ,Hell Creek Formation ,Oviraptorosauria ,030304 developmental biology ,0105 earth and related environmental sciences - Abstract
Isolated metatarsals III and IV of a caenagnathid theropod likely referable to Anzu wyliei are described from a locality of the Hell Creek Formation in northwestern South Dakota, USA. These bones are missing from the holotype and only partial shafts have been described for a specimen referable to this species. Accordingly, the present description adds further anatomical information on this already well-known species of Caenagnathidae. The present finding also demonstrates the significance of isolated or fragmentary specimens found in multitaxic bone beds.
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- 2021
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6. Mapping the human genetic architecture of COVID-19
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Niemi, MEK, Karjalainen, J, Liao, RG, Neale, BM, Daly, M, Ganna, A, Pathak, GA, Andrews, SJ, Kanai, M, Veerapen, K, Fernandez-Cadenas, I, Schulte, EC, Striano, P, Marttila, M, Minica, C, Marouli, E, Karim, MA, Wendt, FR, Savage, J, Sloofman, L, Butler-Laporte, G, Kim, H-N, Kanoni, S, Okada, Y, Byun, J, Han, Y, Uddin, MJ, Smith, GD, Willer, CJ, Buxbaum, JD, Mehtonen, J, Finucane, H, Cordioli, M, Martin, AR, Zhou, W, Pasaniuc, B, Julienne, H, Aschard, H, Shi, H, Yengo, L, Polimanti, R, Ghoussaini, M, Schwartzentruber, J, Dunham, I, Chwialkowska, K, Francescatto, M, Trankiem, A, Balaconis, MK, Davis, L, Lee, S, Priest, J, Renieri, A, Sankaran, VG, van Heel, D, Deelen, P, Richards, JB, Nakanishi, T, Biesecker, L, Kerchberger, VE, Kenneth, J, Mari, F, Bernasconi, A, Ceri, S, Canakoglu, A, Wolford, B, Faucon, A, Dutta, AK, Schurmann, C, Harry, E, Birney, E, Nguyen, H, Nasir, J, Kaunisto, M, Solomonson, M, Dueker, N, Vadgama, N, Limou, S, Rahmouni, S, Mbarek, H, Darwish, D, Uddin, MM, Albertos, R, Perez-Tur, J, Li, R, Folkersen, L, Moltke, I, Koelling, N, Teumer, A, Kousathanas, A, Utrilla, A, Verdugo, RA, Zarate, R, Medina-Gomez, C, Gomez-Cabrero, D, Carnero-Montoro, E, Cadilla, CL, Moreno-Estrada, A, Garmendia, A, Moya, L, Sedaghati-Khayat, B, Boua, PR, Fave, M-J, Francioli, L, Lemacon, A, Migeotte, I, Patel, S, Varnai, R, Szentpeteri, JL, Sipeky, C, Colombo, F, von Hohenstaufen, K, Lio, P, Vallerga, C, Wang, Q, Tanigawa, Y, Im, H, Han, C, Song, H, Lim, J, Lee, Y, Kim, S, Im, S, Atanasovska, B, Ahmad, HF, Boer, C, Jansen, P, Franke, L, Kaja, E, Pasko, D, Kennis-Szilagyi, I, Kornilov, SA, Prijatelj, V, Prokic, I, Sivanadhan, I, Perumal, S, Esmaeeli, S, Pearson, NM, Auton, A, Shelton, JF, Shastri, AJ, Filshtein-Sonmez, T, Coker, D, Symons, A, Esparza-Gordillo, J, Aslibekyan, S, O'Connell, J, Ye, C, Weldon, CH, Perera, M, O'Leary, K, Tuck, M, O'Brien, T, Meltzer, D, O'Donnell, P, Nutescu, E, Yang, G, Alarcon, C, Herrmann, S, Mazurek, S, Banagan, J, Hamidi, Z, Barbour, A, Raffat, N, Moreno, D, Friedman, P, Ferwerda, B, van de Beek, D, Brouwer, MC, Vlaar, APJ, Wiersinga, WJ, Posthuma, D, Tissink, E, Zwinderman, AHK, Uffelmann, E, van Agtmael, M, Algera, AG, van Baarle, F, Bax, D, Beudel, M, Bogaard, HJ, Bomers, M, Bonta, PI, Bos, L, Botta, M, de Brabander, J, de Bree, G, de Bruin, S, Bugiani, M, Bulle, E, Chouchane, O, Cloherty, A, Dongelmans, D, Elbers, P, Fleuren, L, Geerlings, S, Geerts, B, Geijtenbeek, T, Girbes, A, Goorhuis, B, Grobusch, MP, Hafkamp, F, Hagens, L, Hamann, J, Harris, V, Hemke, R, Hermans, SM, Heunks, L, Hollmann, M, Horn, J, Hovius, JW, de Jong, MD, Koning, R, van Mourik, N, Nellen, J, Nossent, EJ, Paulus, F, Peters, E, van der Poll, T, Preckel, B, Prins, JM, Raasveld, J, Reijnders, T, Schinkel, M, Schultz, MJ, Schuurman, A, Sigaloff, K, Smit, M, Stijnis, CS, Stilma, W, Teunissen, C, Thoral, P, Tsonas, A, van der Valk, M, Veelo, D, de Vries, H, van Vugt, M, Wouters, D, Minnaar, RP, Kromhout, A, van Uffelen, KWJ, Wolterman, RA, Roberts, G, Park, D, Ball, CA, Coignet, M, McCurdy, S, Knight, S, Partha, R, Rhead, B, Zhang, M, Berkowitz, N, Gaddis, M, Noto, K, Ruiz, L, Pavlovic, M, Hong, EL, Rand, K, Girshick, A, Guturu, H, Baltzell, AH, Guntz, J, Beguin, Y, Pigazzini, S, Nkambule, L, Bouysran, Y, Busson, A, Peyrassol, X, Wilkin, F, Pichon, B, Smits, G, Vandernoot, I, Goffard, J-C, Georges, M, Moutschen, M, Misset, B, Darcis, G, Guiot, J, Jadot, L, Azarzar, S, Dellot, P, Gofflot, S, Claassen, S, Bertrand, A, Parzibut, G, Clarinval, M, Moermans, C, Malaise, O, El Kandoussi, K, Thonon, R, Huynen, P, Mesdagh, A, Melo, S, Jacques, N, Di Valentin, E, Giroule, F, Collignon, A, Radermecker, C, Lebrun, M, Peree, H, Latour, S, Barada, O, Sanchez, J, Josse, C, Boujemla, B, Meunier, M, Mariavelle, E, Anania, S, Gazon, H, Juszczak, D, Fadeur, M, Camby, S, Meuris, C, Thys, M, Jacques, J, Henket, M, Leonard, P, Frippiat, F, Giot, J-B, Sauvage, A-S, Von Frenckell, C, Mni, M, Wery, M, Staderoli, A, Belhaj, Y, Lambermont, B, Morrison, DR, Mooser, V, Forgetta, V, Ghosh, B, Laurent, L, Belisle, A, Henry, D, Abdullah, T, Adeleye, O, Mamlouk, N, Kimchi, N, Afrasiabi, Z, Rezk, N, Vulesevic, B, Bouab, M, Guzman, C, Petitjean, L, Tselios, C, Xue, X, Afilalo, J, Afilalo, M, Oliveira, M, Brenner, B, Brassard, N, Durand, M, Schurr, E, Lepage, P, Ragoussis, J, Auld, D, Chasse, M, Kaufmann, DE, Lathrop, GM, Adra, D, Davis, LK, Cox, NJ, Below, JE, Sealock, JM, Faucon, AB, Shuey, MM, Polikowsky, HG, Petty, LE, Shaw, DM, Chen, H-H, Zhu, W, Ludwig, KU, Schroeder, J, Maj, C, Rolker, S, Noethen, MM, Fazaal, J, Keitel, V, Jensen, B-EO, Feldt, T, Kurth, I, Marx, N, Dreher, M, Pink, I, Cornberg, M, Illig, T, Lehmann, C, Schommers, P, Augustin, M, Rybniker, J, Knopp, L, Eggermann, T, Volland, S, Altmueller, J, Berger, MM, Brenner, T, Hinney, A, Witzke, O, Bals, R, Herr, C, Ludwig, N, Walter, J, Fuchsberger, C, Pattaro, C, De Grandi, A, Pramstaller, P, Emmert, D, Melotti, R, Foco, L, Mascalzoni, D, Gogele, M, Domingues, F, Hicks, A, Gignoux, CR, Wicks, SJ, Crooks, K, Barnes, KC, Daya, M, Shortt, J, Rafaels, N, Chavan, S, Goldstein, DB, Kiryluk, K, Sengupta, S, Chung, W, Reilly, MP, Khan, A, Wang, C, Povysil, G, Bhardwaj, N, Gharavi, AG, Ionita-Laza, I, Shang, N, O'Byrne, SM, Nandakumar, R, Menon, A, So, YS, Hod, E, Pendrick, D, Park, S-K, Kim, H-L, Kang, CK, Lee, H-J, Song, K-H, Yoon, KJ, Paik, N-J, Seok, W, Yoon, H, Joo, E-J, Chang, Y, Ryu, S, Park, WB, Park, JS, Park, KU, Ham, SY, Jung, J, Kim, ES, Kim, HB, Ellinghaus, D, Degenhardt, F, Caceres, M, Juzenas, S, Lenz, TL, Albillos, A, Julia, A, Heidecker, B, Garcia, F, Kurth, F, Tran, F, Hanses, F, Zoller, H, Holter, JC, Fernandez, J, Sander, LE, Rosenstiel, P, Koehler, P, de Cid, R, Asselta, R, Schreiber, S, Hehr, U, Prati, D, Baselli, G, Valenti, L, Bujanda, L, Banales, JM, Duga, S, D'Amato, M, Romero-Gomez, M, Buti, M, Invernizzi, P, Franke, A, Hov, JR, Karlsen, TH, Folseraas, T, Maya-Miles, D, Teles, A, Azuure, C, Wacker, EM, Uellendahl-Werth, F, Elabd, H, Arora, J, Lerga-Jaso, J, Wienbrandt, L, Ruehlemann, MC, Wendorff, M, Vadla, MS, Lenning, OB, Oezer, O, Myhre, R, Raychaudhuri, S, Tanck, A, Gassner, C, Hemmrich-Stanisak, G, Kaessens, J, Basso, MEF, Schulzky, M, Wittig, M, Braun, N, Wesse, T, Albrecht, W, Yi, X, Ortiz, AB, Garrido Chercoles, A, Ruiz, A, Mantovani, A, Holten, AR, Mayer, A, Cherubini, A, Protti, A, Aghemo, A, Gerussi, A, Ramirez, A, Braun, A, Barreira, A, Lleo, A, Kildal, AB, Glueck, A, Carreras Nolla, A, Latiano, A, Dyrhol-Riise, AM, Muscatello, A, Voza, A, Rando-Segura, A, Solier, A, Karina, B, Cortes, B, Mateos, B, Nafria-Jimenez, B, Schaefer, B, Bellinghausen, C, Ferrando, C, Quereda, C, Skurk, C, Thibeault, C, Spinner, CD, Lange, C, Hu, C, Cappadona, C, Bianco, C, Sancho, C, Hoff, DAL, Galimberti, D, Jimenez, D, Pestana, D, Toapanta, D, Azzolini, E, Scarpini, E, Helbig, ET, Urrechaga, E, Paraboschi, EM, Pontali, E, Reverter, E, Navas, E, Arana, E, Garcia Sanchez, F, Ceriotti, F, Malvestiti, F, Mesonero, F, Pezzoli, G, Lamorte, G, Neb, H, My, I, Hernandez, I, de Rojas, I, Galvan-Femenia, I, Heyckendorf, J, Badia, JR, Schneider, J, Goikoetxea, J, Kraft, J, Mueller, KE, Gaede, KI, Garcia-Etxebarria, K, Tonby, K, Heggelund, L, Izquierdo-Sanchez, L, Sumoy, L, Lippert, LJ, Terranova, L, Garbarino, L, Tellez, L, Roade, L, Ostadreza, M, Intxausti, M, Kogevinas, M, Gutierrez-Stampa, MA, Vehreschild, MJGT, Marquie, M, Castoldi, M, Cecconi, M, Boada, M, Seilmaier, MJ, Mazzocco, M, Rodriguez-Gandia, M, Imaz Ayo, N, Blay, N, Martinez, N, Cornely, OA, Palmieri, O, Tentorio, P, Rodrigues, PM, Espana, PP, Hoffmann, P, Bacher, P, Suwalski, P, de Pablo, R, Nieto, R, Badalamenti, S, Ciesek, S, Bombace, S, Wilfling, S, Brunak, S, Heilmann-Heimbach, S, Ripke, S, Bahmer, T, Landmesser, U, Protzer, U, Rimoldi, V, Skogen, V, Andrade, V, Moreno, V, Poller, W, Farre, X, Wang, X, Khodamoradi, Y, Karadeniz, Z, de Salazar, A, Palom, A, Garcia-Fernandez, A-E, Blanco-Grau, A, Zanella, A, Bandera, A, Nebel, A, Biondi, A, Caba Llero-Garralda, A, Gori, A, Lind, A, Fracanzani, AL, Peschuck, A, Pesenti, A, De la Horra, C, Milani, C, Paccapelo, C, Angelini, C, Cea, C, Muniz-Diaz, E, Sandoval, E, Calderon, EJ, Solligard, E, Aziz, F, Martinelli-Boneschi, F, Peyvandi, F, Blasi, F, Medrano, FJ, Rodriguez-Frias, F, Mueller, F, Grasselli, G, Costantino, G, Cardamone, G, Foti, G, Matullo, G, Kurihara, H, Afset, JE, Damas, JK, Ampuero, J, Martin, J, Erdmann, J, Bergan, J, Goerg, S, Ferrusquia-Acosta, J, Hernandez Quero, J, Delgado, J, Guerrero, JM, Risnes, K, Bettini, LR, Moreira, L, Gustad, LT, Santoro, L, Scudeller, L, Riveiro-Barciela, M, Schaefer, M, Carrabba, M, Valsecchi, MG, Hernandez-Tejero, M, Acosta-Herrera, M, D'Angio, M, Baldini, M, Cazzaniga, M, Ciccarelli, M, Bocciolone, M, Miozzo, M, Chueca, N, Montano, N, Faverio, P, Preatoni, P, Bonfanti, P, Omodei, P, Castro, P, Ferrer, R, Gualtierotti, R, Gallego-Duran, R, Morilla, R, Haider, S, Marsal, S, Aneli, S, Pelusi, S, Bosari, S, Aliberti, S, Dudman, S, Zheng, T, Pumarola, T, Gonzalez Cejudo, T, Monzani, V, Friaza, V, Peter, W, Dopazo, X, May, S, Grimsrud, MM, Gudbjartsson, DF, Stefansson, K, Sulem, P, Sveinbjornsson, G, Melsted, P, Norddahl, G, Moore, KHS, Thorsteinsdottir, U, Holm, H, Alarcon-Riquelme, ME, Bernardo, D, Martinez-Bueno, M, Rojo Rello, S, Magi, R, Milani, L, Metspalu, A, Laisk, T, Lall, K, Lepamets, M, Esko, T, Reimann, E, Naaber, P, Laane, E, Pesukova, J, Peterson, P, Kisand, K, Tabri, J, Allos, R, Hensen, K, Starkopf, J, Ringmets, I, Tamm, A, Kallaste, A, Alavere, H, Metsalu, K, Puusepp, M, Kristiansson, K, Koskelainen, S, Perola, M, Donner, K, Kivinen, K, Palotie, A, Rivolta, C, Bochud, P-Y, Bibert, S, Boillat, N, Nussle, SG, Albrich, W, Quinodoz, M, Kamdar, D, Suh, N, Neofytos, D, Erard, V, Voide, C, Bochud, PY, Friolet, R, Vollenweider, P, Pagani, JL, Oddo, M, zu Bentrup, FM, Conen, A, Clerc, O, Marchetti, O, Guillet, A, Guyat-Jacques, C, Foucras, S, Rime, M, Chassot, J, Jaquet, M, Viollet, RM, Lannepoudenx, Y, Portopena, L, Desgranges, F, Filippidis, P, Guery, B, Haefliger, D, Kampouri, EE, Manuel, O, Munting, A, Iou-Olivgeris, MP, Regina, J, Rochat-Stettler, L, Suttels, V, Tadini, E, Tschopp, J, Van Singer, M, Viala, B, Boillat-Blanco, N, Brahier, T, Hugli, O, Meuwly, JY, Pantet, O, Bochud, M, D'Acremont, V, Younes, SE, Albrich, WC, Cerny, A, O'Mahony, L, von Mering, C, Frischknecht, M, Kleger, G-R, Filipovic, M, Kahlert, CR, Wozniak, H, Negro, TR, Pugin, J, Bouras, K, Knapp, C, Egger, T, Perret, A, Montillier, P, di Bartolomeo, C, Barda, B, Carreras, A, Mercader, JM, Guindo-Martinez, M, Torrents, D, Garcia-Aymerich, J, Castano-Vinyals, G, Dobano, C, Gori, M, Mondelli, MU, Castelli, F, Vaghi, M, Rusconi, S, Montagnani, F, Bargagli, E, Franchi, F, Mazzei, MA, Cantarini, L, Tacconi, D, Feri, M, Scala, R, Spargi, G, Nencioni, C, Bandini, M, Caldarelli, GP, Spagnesi, M, Canaccini, A, Ognibene, A, Monforte, AD, Girardis, M, Antinori, A, Francisci, D, Schiaroli, E, Scotton, PG, Panese, S, Scaggiante, R, Della Monica, M, Capasso, M, Fiorentino, G, Castori, M, Aucella, F, Di Biagio, A, Masucci, L, Valente, S, Mandala, M, Zucchi, P, Giannattasio, F, Coviello, DA, Mussini, C, Bosio, G, Tavecchia, L, Crotti, L, Rizzi, M, La Rovere, MT, Sarzi-Braga, S, Bussotti, M, Ravaglia, S, Artuso, R, Perrella, A, Romani, D, Bergomi, P, Catena, E, Vincenti, A, Ferri, C, Grassi, D, Pessina, G, Tumbarello, M, Di Pietro, M, Sabrina, R, Luchi, S, Barbieri, C, Acquilini, D, Andreucci, E, Paciosi, F, Segala, FV, Tiseo, G, Falcone, M, Lista, M, Poscente, M, De Vivo, O, Petrocelli, P, Guarnaccia, A, Baroni, S, Perticaroli, V, Furini, S, Dei, S, Benetti, E, Picchiotti, N, Sanarico, M, Pinoli, P, Raimondi, F, Biscarini, F, Stella, A, Bergomi, M, Zguro, K, Capitani, K, Tanfoni, M, Fallerini, C, Daga, S, Baldassarri, M, Fava, F, Frullanti, E, Valentino, F, Doddato, G, Giliberti, A, Tita, R, Amitrano, S, Bruttini, M, Croci, S, Meloni, I, Mencarelli, MA, Lo Rizzo, C, Pinto, AM, Beligni, G, Tommasi, A, Di Sarno, L, Palmieri, M, Carriero, ML, Alaverdian, D, Iuso, N, Inchingolo, G, Busani, S, Bruno, R, Vecchia, M, Belli, MA, Mantovani, S, Ludovisi, S, Quiros-Roldan, E, Antoni, MD, Zanella, I, Siano, M, Emiliozzi, A, Fabbiani, M, Rossetti, B, Zanelli, G, Bergantini, L, D'Alessandro, M, Cameli, P, Bennet, D, Anedda, F, Marcantonio, S, Scolletta, S, Guerrini, S, Conticini, E, Frediani, B, Spertilli, C, Donati, A, Guidelli, L, Corridi, M, Croci, L, Piacentini, P, Desanctis, E, Cappelli, S, Verzuri, A, Anemoli, V, Pancrazi, A, Lorubbio, M, Merlini, E, Miraglia, FG, Venturelli, S, Cossarizza, A, Vergori, A, Gabrieli, A, Riva, A, Andretta, F, Gatti, F, Parisi, SG, Baratti, S, Piscopo, C, Russo, R, Andolfo, I, Iolascon, A, Carella, M, Merla, G, Squeo, GM, Raggi, P, Marciano, C, Perna, R, Bassetti, M, Sanguinetti, M, Giorli, A, Salerni, L, Parravicini, P, Menatti, E, Trotta, T, Coiro, G, Lena, F, Martinelli, E, Mancarella, S, Gabbi, C, Maggiolo, F, Ripamonti, D, 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Eunsoon, Jang, Hye Yoon, Kim, Sunmie, Kym, Sungmin, Kim, Yeon-Sook, Jeong, Hyeongseok, Kwon, Ki Tae, Kim, Shin-Woo, Kim, Jin Yong, Jang, Young Rock, Kim, Hyun ah, Lee, Ji Yeon, Lee, Jeong Eun, Lee, Shinwon, Choe, Kang-Won, Kang, Yu Min, Jee, Sun Ha, Jung, Keum Ji, Parikh, Victoria, Ashley, Euan, Wheeler, Matthew, Rivas, Manuel, Bustamante, Carlo, Pinksy, Benjamin, Febbo, Phillip, Farh, Kyle, Schroth, Gary P., Desouza, Franci, Dalton, Karen, Christle, Jeff, Deboever, Christopher, Szalma, Sándor, Rubinacci, Simone, Delaneau, Olivier, Gorzynski, John, de Jong, Hannah, Sutton, Shirley, Youlton, Nathan, Joshi, Ruchi, Jimenez-Morales, David, Hughes, Christopher, Amar, David, Ioannidis, Alex, Hershman, Steve, Kirillova, Anna, Seo, Kinya, Huang, Yong, Shoura, Massa, Hammond, Nathan, Watson, Nathaniel, Raja, Archana, Huang, Chunhong, Sahoo, Malaya, Wang, Hannah, Zhen, Jimmy, Rakitko, Alexander, Ilinsky, Valery, Yermakovich, Danat, Popov, Iaroslav, Chernitsov, Alexander, Kovalenko, Elena, Krasnenko, Anna, Plotnikov, Nikolay, Stetsenko, Ivan, Kim, Anna, Cirulli, Elizabeth T., Schiabor Barrett, Kelly M., Bolze, Alexandre, White, Simon, Washington, Nicole L., Lu, James T., Riffle, Stephen, Tanudjaja, Francisco, Wang, Xueqing, Ramirez, Jimmy M., Leonetti, Nicole, Sandoval, Efren, Neveux, Iva, Dabe, Shaun, Grzymski, Joseph J., Esteban Miñano, Juan Ignacio, Aguirre, Luis A., López-Collazo, Eduardo, de la Mata Pazos, Manuel, Cerrato, Luciano, Lozano-Rodríguez, Roberto, Avendaño-Ortiz, José, Arcos, Verónica Terrón, Montalbán-Hernández, Karla Marina, Quiroga, Jaime Valentín, Pascual-Iglesias, Alejandro, Maroun-Eid, Charbel, Martín-Quirós, Alejandro, Namkoong, Ho, Imoto, Seiya, Katayama, Kazuhiko, Fukunaga, Koichi, Kitagawa, Yuko, Sato, Toshiro, Hasegawa, Naoki, Kumanogoh, Atsushi, Kimura, Akinori, Ai, Masumi, Tokunaga, Katsushi, Kanai, Takanori, Miyano, Satoru, Ogawa, Seishi, Edahiro, Ryuya, Sonehara, Kyuto, Shirai, Yuya, Ishii, Makoto, Kabata, Hiroki, Masaki, Katsunori, Kamata, Hirofumi, Ikemura, Shinnosuke, Chubachi, Shotaro, Okamori, Satoshi, Terai, Hideki, Tanaka, Hiromu, Morita, Atsuho, Lee, Ho, Asakura, Takanori, Sasaki, Junichi, Morisaki, Hiroshi, Uwamino, Yoshifumi, Nanki, Kosaku, Mikami, Yohei, Tomono, Kazunori, Kato, Kazuto, Matsuda, Fumihiko, Takahashi, Meiko, Hizawa, Nobuyuki, Takeda, Yoshito, Hirata, Haruhiko, Shiroyama, Takayuki, Miyawaki, Satoru, Suzuki, Ken, Maeda, Yuichi, Nii, Takuro, Noda, Yoshimi, Niitsu, Takayuki, Adachi, Yuichi, Enomoto, Takatoshi, Amiya, Saori, Hara, Reina, Takahashi, Kunihiko, Anzai, Tatsuhiko, Hasegawa, Takanori, Ito, Satoshi, Koike, Ryuji, Endo, Akifumi, Uchimura, Yuji, Miyazaki, Yasunari, Honda, Takayuki, Tateishi, Tomoya, Tohda, Shuji, Ichimura, Naoya, Sonobe, Kazunari, Sassa, Chihiro, Nakajima, Jun, Nannya, Yasuhito, Omae, Yosuke, Takahashi, Kazuhisa, Harada, Norihiro, Hiki, Makoto, Takagi, Haruhi, Nakamura, Ai, Tagaya, Etsuko, Kawana, Masatoshi, Arimura, Ken, Ishiguro, Takashi, Takayanagi, Noboru, Isono, Taisuke, Takaku, Yotaro, Takano, Kenji, Anan, Ryusuke, Nakajima, Yukiko, Nakano, Yasushi, Nishio, Kazumi, Ueda, Soichiro, Hayashi, Reina, Tateno, Hiroki, Hase, Isano, Yoshida, Shuichi, Suzuki, Shoji, Mitamura, Keiko, Saito, Fumitake, Ueda, Tetsuya, Azuma, Masanori, Nagasaki, Tadao, Yasui, Yoshinori, Hasegawa, Yoshinori, Mutoh, Yoshikazu, Yoshiyama, Takashi, Shoko, Tomohisa, Kojima, Mitsuaki, Adachi, Tomohiro, Ishikawa, Motonao, Takahashi, Kenichiro, Watanabe, Kazuyoshi, Manabe, Tadashi, Ito, Fumimaro, Fukui, Takahiro, Funatsu, Yohei, Koh, Hidefumi, Hirai, Yoshihiro, Kawashima, Hidetoshi, Narita, Atsuya, Niwa, Kazuki, Sekikawa, Yoshiyuki, Saito, Fukuki, Yoshiya, Kazuhisa, Yoshihara, Tomoyuki, Suzuki, Yusuke, Nakayama, Sohei, Masuzawa, Keita, Nishi, Koichi, Nishitsuji, Masaru, Tani, Maiko, Inoue, Takashi, Hirano, Toshiyuki, Kobayashi, Keigo, Miyazawa, Naoki, Kimura, Yasuhiro, Sado, Reiko, Ogura, Takashi, Kitamura, Hideya, Murohashi, Kota, Nakachi, Ichiro, Baba, Rie, Arai, Daisuke, Fuke, Satoshi, Saito, Hiroshi, Kuwahara, Naota, Fujiwara, Akiko, Okada, Takenori, Baba, Tomoya, Noda, Junya, Mashimo, Shuko, Yagi, Kazuma, Shiomi, Tetsuya, Hashiguchi, Mizuha, Odani, Toshio, Mochimaru, Takao, Oyamada, Yoshitaka, Mori, Nobuaki, Izumi, Namiki, Nagata, Kaoru, Taki, Reiko, Murakami, Koji, Yamada, Mitsuhiro, Sugiura, Hisatoshi, Hayashi, Kentaro, Shimizu, Tetsuo, Gon, Yasuhiro, Fujitani, Shigeki, Tsuchida, Tomoya, Yoshida, Toru, Kagaya, Takashi, Kita, Toshiyuki, Sakagami, Satoru, Kimizuka, Yoshifumi, Kawana, Akihiko, Nakamura, Yoshihiko, Ishikura, Hiroyasu, Takata, Tohru, Kikuchi, Takahide, Taniyama, Daisuke, Nakamura, Morio, Kodama, Nobuhiro, Kaneyama, Yasunari, Maeda, Shunsuke, Nagasaki, Yoji, Okamoto, Masaki, Ishihara, Sayoko, Ito, Akihiro, Chihara, Yusuke, Takeuchi, Mayumi, Onoi, Keisuke, Hashimoto, Naozumi, Wakahara, Keiko, Ando, Akira, Masuda, Makoto, Wakabayashi, Aya, Watanabe, Hiroki, Sageshima, Hisako, Nakada, Taka-Aki, Abe, Ryuzo, Shimada, Tadanaga, Kawamura, Kodai, Ichikado, Kazuya, Nishiyama, Kenta, Yamasaki, Masaki, Hashimoto, Satoru, Kusaka, Yu, Ohba, Takehiko, Isogai, Susumu, Takada, Minoru, Kanda, Hidenori, Komase, Yuko, Sano, Fumiaki, Asano, Koichiro, Oguma, Tsuyoshi, Harada, Masahiro, Takahashi, Takeshi, Shibusawa, Takayuki, Abe, Shinji, Kono, Yuta, Togashi, Yuki, Izumo, Takehiro, Inomata, Minoru, Awano, Nobuyasu, Ogawa, Shinichi, Ogata, Tomouki, Ishihara, Shoichiro, Kanehiro, Arihiko, Ozaki, Shinji, Fuchimoto, Yasuko, Kitagawa, Yuichiro, Yoshida, Shozo, Ogura, Shinji, Nishiyama, Kei, Yoshida, Kousuke, Beppu, Satoru, Fukuyama, Satoru, Eriguchi, Yoshihiro, Yonekawa, Akiko, Inoue, Yoshiaki, Yamagata, Kunihiro, Chiba, Shigeru, Narumoto, Osamu, Nagai, Hideaki, Ooshima, Nobuharu, Motegi, Mitsuru, Sagara, Hironori, Tanaka, Akihiko, Ohta, Shin, Shibata, Yoko, Tanino, Yoshinori, Sato, Yuki, Yamada, Yuichiro, Hashino, Takuya, Shinoki, Masato, Iwagoe, Hajime, Imamura, Tomonori, Umeda, Akira, Shimada, Hisato, Endo, Mayu, Hayashi, Shinichi, Takahashi, Mai, Nakano, Shigefumi, Yatomi, Masakiyo, Maeno, Toshitaka, Ishii, Tomoo, Utsugi, Mitsuyoshi, Ono, Akihiro, Kanaoka, Kensuke, Ihara, Shoichi, Komuta, Kiyoshi, Boezen, Marike, Claringbould, Annique, Lopera, Esteban, Warmerdam, Robert, Vonk, Judith. M., van Blokland, Irene, Lanting, Pauline, Ori, Anil P. S., Obeidat, Ma’En, Hernández Cordero, Ana I., Sin, Don D., Bossé, Yohan, Joubert, Philippe, Hao, Ke, Nickle, David, Timens, Wim, van den Berge, Maarten, Feng, Yen-Chen Anne, Mercader, Josep, Weiss, Scott T., Karlson, Elizabeth W., Smoller, Jordan W., Murphy, Shawn N., Meigs, James B., Woolley, Ann E., Green, Robert C., Perez, Emma F., Zöllner, Sebastian, Wang, Jiongming, Beck, Andrew, Sloofman, Laura G., Ascolillo, Steven, Sebra, Robert P., Collins, Brett L., Levy, Te, Sealfon, Stuart C., Jordan, Daniel M., Thompson, Ryan C., Gettler, Kyle, Chaudhary, Kumardeep, Belbin, Gillian M., Preuss, Michael, Hoggart, Clive, Choi, Sam, Underwood, Slayton J., Salib, Irene, Britvan, Bari, Keller, Katherine, Tang, Lara, Peruggia, Michael, Hiester, Liam L., Niblo, Kristi, Aksentijevich, Alexandra, Labkowsky, Alexander, Karp, Avromie, Zlatopolsky, Menachem, Zyndorf, Marissa, Charney, Alexander W., Beckmann, Noam D., Schadt, Eric E., Abul-Husn, Noura S., Cho, Judy H., Itan, Yuval, Kenny, Eimear E., Loos, Ruth J. F., Nadkarni, Girish N., Do, Ron, O’Reilly, Paul, Huckins, Laura M., Ferreira, Manuel A. R., Abecasis, Goncalo R., Leader, Joseph B., Cantor, Michael N., Justice, Anne E., Carey, Dave J., Chittoor, Geetha, Josyula, Navya Shilpa, Kosmicki, Jack A., Horowitz, Julie E., Baras, Ari, Gass, Matthew C., Yadav, Ashish, Mirshahi, Tooraj, Jan Hottenga, Jouke, Bartels, Meike, de Geus, Eco J. C., Nivard, Michel G., Verma, Anurag, Ritchie, Marylyn D., Rader, Daniel, Li, Binglan, Verma, Shefali S., Lucas, Anastasia, Bradford, Yuki, Zara, Federico, Salpietro, Vincenzo, Scala, Marcello, Iacomino, Michele, Scudieri, Paolo, Bocciardi, Renata, Minetti, Carlo, Riva, Antonella, Vari, Maria Stella, Rahier, Jean-Françoi, Giorgio, Elisa, Carli, Diana, Louis, Edouad, Bulik, Cynthia M., Landén, Mikael, Brusco, Alfredo, Ferrero, Giovanni Battista, Madia, Francesca, Fundín, Bengt, Ismail, Said I., Saad, Chadi, Al-Sarraj, Yaser, Badji, Radja Messai, Al-Muftah, Wadha, Al Thani, Asma, Afifi, Nahla, Klovins, Jani, Rovite, Vita, Rescenko, Raimond, Peculis, Raiti, Ustinova, Monta, Zeberg, Hugo, Frithiof, Robert, Hultström, Michael, Lipcsey, Miklo, Johnson, Ruth, Geschwind, Daniel H., Freimer, Nelson, Butte, Manish J., Ding, Yi, Chiu, Alec, Chang, Timothy S., Boutros, Paul, Moutsianas, Louka, Caulfield, Mark J., Scott, Richard H., Walker, Susan, Stuckey, Alex, Odhams, Christopher A., Rhodes, Daniel, Fowler, Tom, Rendon, Augusto, Chan, Georgia, Arumugam, Prabhu, Karczewski, Konrad J., Wilson, Daniel J., Spencer, Chris A., Crook, Derrick W., Wyllie, David H., O’Connell, Anne Marie, Atkinson, Elizabeth G., Tsuo, Kristin, Baya, Nikola, Turley, Patrick, Gupta, Rahul, Walters, Raymond K., Palmer, Duncan S., Sarma, Gopal, Cheng, Nathan, Lu, Wenhan, Churchhouse, Claire, Goldstein, Jacqueline I., King, Daniel, Seed, Cotton, Daly, Mark J., Bryant, Sam, Satterstrom, F. Kyle, Band, Gavin, Earle, Sarah G., Lin, Shang-Kuan, Arning, Nicola, Armstrong, Jacob, Rudkin, Justine K., Callier, Shawneequa, Cusick, Caroline, Soranzo, Nicole, Zhao, Jing Hua, Danesh, John, Di Angelantonio, Emanuele, Butterworth, Adam S., Sun, Yan V., Huffman, Jennifer E., Cho, Kelly, O’Donnell, Christopher J., Tsao, Phil, Gaziano, J. Michael, Peloso, Gina, Ho, Yuk-Lam, Mian, Michael, Scaggiante, Federica, Chang, Xiao, Glessner, Joseph R., Hakonarson, Hakon, Mcguigan, Peter J., Prockter Moore, Luke Stephen, Vizcaychipi, Marcela Paola, Hall, Kathryn, Campbell, Andy, Nichol, Ailstair, Ward, Geraldine, Page, Valerie Joan, Semple, Malcolm G., Adeniji, Kayode, Agranoff, Daniel, Agwuh, Ken, Ail, Dhiraj, Aldera, Erin L., Alegria, Ana, Angus, Brian, Ashish, Abdul, Atkinson, Dougal, Bari, Shahedal, Barlow, Gavin, Barnass, Stella, Barrett, Nichola, Bassford, Christopher, Basude, Sneha, Baxter, David, Beadsworth, Michael, Bernatoniene, Jolanta, Berridge, John, Best, Nicola, Bothma, Pieter, Chadwick, David, Brittain-Long, Robin, Bulteel, Naomi, Burden, Tom, Burtenshaw, Andrew, Caruth, Vikki, Chambler, Duncan, Chee, Nigel, Child, Jenny, Chukkambotla, Srikanth, Clark, Tom, Collini, Paul, Cosgrove, Catherine, Cupitt, Jason, Cutino-Moguel, Maria-Teresa, Dark, Paul, Dawson, Chri, Dervisevic, Samir, Donnison, Phil, Douthwaite, Sam, Drummond, Andrew, Durand, Ingrid, Dushianthan, Ahilanadan, Dyer, Tristan, Evans, Cariad, Eziefula, Chi, Fegan, Christopher, Finn, Adam, Fullerton, Duncan, Garg, Sanjeev, Garg, Atul, Gkrania-Klotsas, Effrossyni, Godden, Jo, Goldsmith, Arthur, Graham, Clive, Hardy, Elaine, Hartshorn, Stuart, Harvey, Daniel, Havalda, Peter, Hawcutt, Daniel B., Hobrok, Maria, Hodgson, Luke, Hormis, Anil, Jacobs, Michael, Jain, Susan, Jennings, Paul, Kaliappan, Agilan, Kasipandian, Vidya, Kegg, Stephen, Kelsey, Michael, Kendall, Jason, Kerrison, Caroline, Kerslake, Ian, Koch, Oliver, Koduri, Gouri, Koshy, George, Laha, Shondipon, Laird, Steven, Larkin, Susan, Leiner, Tama, Lillie, Patrick, Limb, Jame, Linnett, Vanessa, Little, Jeff, Lyttle, Mark, Macmahon, Michael, Macnaughton, Emily, Mankregod, Ravish, Masson, Huw, Matovu, Elijah, Mccullough, Katherine, Mcewen, Ruth, Meda, Manjula, Mills, Gary H., Minton, Jane, Ward, Karl, Mirfenderesky, Mariyam, Mohandas, Kavya, Mok, Quen, Moon, Jame, Moore, Elinoor, Morgan, Patrick, Morris, Craig, Mortimore, Katherine, Moses, Samuel, Mpenge, Mbiye, Mulla, Rohinton, Murphy, Michael, Nagel, Megan, Nagarajan, Thapa, Nelson, Mark, O’Shea, Matthew K., Otahal, Igor, Ostermann, Marlie, Pais, Mark, Panchatsharam, Selva, Papakonstantinou, Danai, Paraiso, Hassan, Patel, Brij, Pattison, Natalie, Pepperell, Justin, Peters, Mark, Phull, Mandeep, Pintus, Stefania, Pooni, Jagtur Singh, Post, Frank, Price, David, Prout, Rachel, Rae, Nikola, Reschreiter, Henrik, Reynolds, Tim, Richardson, Neil, Roberts, Mark, Roberts, Devender, Rose, Alistair, Rousseau, Guy, Ryan, Brendan, Saluja, Taranprit, Shah, Aarti, Shanmuga, Prad, Sharma, Anil, Shawcross, Anna, Sizer, Jeremy, Shankar-Hari, Manu, Smith, Richard, Snelson, Catherine, Spittle, Nick, Staines, Nikki, Stambach, Tom, Stewart, Richard, Subudhi, Pradeep, Szakmany, Tama, Tatham, Kate, Thomas, Jo, Thompson, Chri, Thompson, Robert, Tridente, Ascanio, Tupper-Carey, Darell, Twagira, Mary, Ustianowski, Andrew, Vallotton, Nick, Vincent-Smith, Lisa, Visuvanathan, Shico, Vuylsteke, Alan, Waddy, Sam, Wake, Rachel, Walden, Andrew, Welters, Ingeborg, Whitehouse, Tony, Whittaker, Paul, Whittington, Ashley, Papineni, Padmasayee, Wijesinghe, Meme, Williams, Martin, Wilson, Lawrence, Cole, Sarah, Winchester, Stephen, Wiselka, Martin, Wolverson, Adam, Wooton, Daniel G., Workman, Andrew, Yates, Bryan, Young, Peter, Beale, Rupert, Bretherick, Andrew D., Clohisey, Sara, Fourman, Max Head, Furniss, Jame, Gountouna, Elvina, Grimes, Graeme, Haley, Chri, Harrison, David, Hayward, Caroline, Keating, Sean, Klaric, Lucija, Klenerman, Paul, Law, Andy, Meynert, Alison M., Millar, Jonathan, Pairo-Castineira, Erola, Parkinson, Nichola, Ponting, Chris P., Porteous, David J., Rawlik, Konrad, Richmond, Anne, Rowan, Kathy, Russell, Clark D., Shen, Xia, Shih, Barbara, Tenesa, Albert, Vitart, Veronique, Wang, Bo, Wilson, James F., Wu, Yang, Yang, Jian, Yang, Zhijian, Zechner, Marie, Zhai, Ranran, Zheng, Chenqing, Norman, Lisa, Pius, Riinu, Drake, Thomas M., Fairfield, Cameron J., Knight, Stephen R., Mclean, Kenneth A., Murphy, Derek, Shaw, Catherine A., Dalton, Jo, Girvan, Michelle, Saviciute, Egle, Roberts, Stephanie, Harrison, Janet, Marsh, Laura, Connor, Marie, Halpin, Sophie, Jackson, Clare, Gamble, Carrol, Leeming, Gary, Law, Andrew, Wham, Murray, Hendry, Ro, Scott-Brown, Jame, Begg, Colin, Hinds, Charle, Wai Ho, Antonia Ying, Horby, Peter W., Knight, Julian, Ling, Lowell, Maslove, David, Mcauley, Danny, Montgomery, Hugh, Nichol, Alistair, Openshaw, Peter J. M., Summers, Charlotte, Walsh, Timothy, Armstrong, Lisa, Bates, Hayley, Dooks, Emma, Farquhar, Fiona, Hairsine, Brigid, Mcparland, C., Packham, Sophie, Alldis, Zoe, Astin-Chamberlain, Raine, Bibi, Fatima, Biddle, Jack, Blow, Sarah, Bolton, Matthew, Borra, Catherine, Bowles, Ruth, Burton, Maudrian, Choudhury, Yasmin, Collier, David, Cox, Amber, Easthope, Amy, Ebano, Patrizia, Fotiadis, Stavro, Gurasashvili, Jana, Halls, Rosslyn, Hartridge, Pippa, Kallon, Delordson, Kassam, Jamila, Lancoma-Malcolm, Ivone, Matharu, Maninderpal, May, Peter, Mitchelmore, Oliver, Newman, Tabitha, Patel, Mital, Pheby, Jane, Pinzuti, Irene, Prime, Zoe, Prysyazhna, Oleksandra, Shiel, Julian, Taylor, Melanie, Tierney, Carey, Wood, Suzanne, Zak, Anne, Zongo, Olivier, Forsey, Miranda, Nicholson, Anne, Riches, Joanne, Vertue, Mark, Wasson, Christopher, Finn, Stephanie, Green, Jackie, Collins, Erin, King, Bernadette, Grauslyte, Lina, Hussain, Musarat, Pogreban, Tatiana, Rosaroso, Lace, Salciute, Erika, Franke, George, Wong, Joanna, George, Aparna, Akeroyd, Louise, Bano, Shereen, Bromley, Matt, Gurr, Lucy, Lawton, Tom, Morgan, Jame, Sellick, Kirsten, Warren, Deborah, Wilkinson, Brian, Mcgowan, Janet, Ledgard, Camilla, Stacey, Amelia, Pye, Kate, Bellwood, Ruth, Bentley, Michael, Loosley, Ronda, Mcguinness, Heather, Tench, Helen, Wolf-Roberts, Rebecca, Gibson, Sian, Lyle, Amanda, Mcneela, Fiona, Radhakrishnan, Jayachandran, Hughes, Alistair, Ali, Asifa, Brady, Megan, Dale, Sam, Dance, Annalisa, Gledhill, Lisa, Greig, Jill, Hanson, Kathryn, Holdroyd, Kelly, Home, Marie, Kelly, Diane, Kitson, Ro, Matapure, Lear, Melia, Deborah, Mellor, Samantha, Nortcliffe, Tonicha, Pinnell, Jez, Robinson, Matthew, Shaw, Lisa, Shaw, Ryan, Thomis, Lesley, Wilson, Alison, Wood, Tracy, Bayo, Lee-Ann, Merwaha, Ekta, Ishaq, Tahira, Hanley, Sarah, Antcliffe, David, Banach, Dorota, Brett, Stephen, Coghlan, Phoebe, Fernandez, Ziortza, Gordon, Anthony, Rojo, Roceld, Arias, Sonia Sousa, Templeton, Maie, Jha, Rajeev, Krishnamurthy, Vinodh, Lim, Lai, Bi, Rehana, Scholefield, Barney, Ashton, Lydia, Williams, Alison, Cheyne, Claire, Saunderson, Anne, Allan, Angela, Anderson, Felicity, Kaye, Callum, Liew, Jade, Medhora, Jasmine, Scott, Teresa, Trumper, Erin, Botello, Adriana, Polgarova, Petra, Stroud, Katerina, Meaney, Eoghan, Jones, Megan, Ng, Anthony, Agrawal, Shruti, Pathan, Nazima, White, Deborah, Daubney, Esther, Elston, Kay, Parker, Robert, Reddy, Amie, Turner-Bone, Ian, Wilding, Laura, Harding, Peter, Jacob, Reni, Jones, Cathy, Denmade, Craig, Croft, Maria, White, Ian, Lim, Li, Griffin, Denise, Muchenje, Nycola, Mupudzi, Mcdonald, Partridge, Richard, Conyngham, Jo-Anna, Thomas, Rachel, Wright, Mary, Corral, Maria Alvarez, Bastion, Victoria, Clarke, Daphene, David, Beena, Kent, Harriet, Lorusso, Rachel, Lubimbi, Gamu, Murdoch, Sophie, Penacerrada, Melchizedek, Thomas, Alastair, Valentine, Jennifer, Vochin, Ana, Wulandari, Retno, Djeugam, Brice, Dawson, Joy, Garrioch, Sweyn, Tolson, Melanie, Aldridge, Jonathan, de Almeida Martins, Laura Gome, Carungcong, Jaime, Beavis, Sarah, Dale, Katie, Gascoyne, Rachel, Hawes, Joanne, Pritchard, Kelly, Stevenson, Lesley, Whileman, Amanda, Cowley, Anne, Highgate, Judith, Crawley, Rikki, Crew, Abigail, Cunningham, Mishell, Daniels, Allison, Harrison, Laura, Hope, Susan, Inweregbu, Ken, Jones, Sian, Lancaster, Nicola, Matthews, Jamie, Nicholson, Alice, Wray, Gemma, Benham, Leonie, Bradshaw, Zena, Brown, Joanna, Caswell, Melanie, Melling, Sarah, Preston, Stephen, Slawson, Nicola, Stoddard, Emma, Warden, Scott, Combes, Edward, Joefield, Teishel, Monnery, Sonja, Beech, Valerie, Trotman, Sallyanne, Hopkins, Bridget, Scriven, Jame, Thrasyvoulou, Laura, Willis, Heather, Anderson, Susan, Birch, Janine, Collins, Emma, Hammerton, Kate, O’Leary, Ryan, Abernathy, Caroline, Foster, Louise, Gratrix, Andrew, Martinson, Vicky, Parkinson, Priyai, Stones, Elizabeth, Carbral-Ortega, Llucia, Kapoor, Ritoo, Loader, David, Castle, Karen, Brandwood, Craig, Smith, Lara, Clark, Richard, Birchall, Katie, Kolakaluri, Laurel, Baines, Deborah, Sukumaran, Anila, Mapfunde, Isheunesu, Meredith, Megan, Morris, Lucy, Ryan, Lucy, Clark, Amy, Sampson, Julia, Peters, Cecilia, Dent, Martin, Langley, Margaret, Ashraf, Saima, Wei, Shuying, Andrew, Angela, Chablani, Manish, Kirkby, Amy, Netherton, Kimberley, Bates, Michelle, Dasgin, Jo, Gill, Jaspret, Nilsson, Annette, Apetri, Elena, Basikolo, Cathrine, Blackledge, Bethan, Catlow, Laura, Charles, Bethan, Doonan, Reece, Harris, Jade, Harvey, Alice, Horner, Daniel, Knowles, Karen, Lee, Stephanie, Lomas, Diane, Lyons, Chloe, Marsden, Tracy, Mclaughlan, Danielle, Mcmorrow, Liam, Pendlebury, Jessica, Perez, Jane, Poulaka, Maria, Proudfoot, Nicola, Slaughter, Melanie, Slevin, Kathryn, Thomas, Vicky, Walker, Danielle, Michael, Angiy, Collis, Matthew, Clark, Martyn, Coulding, Martina, Jude, Edward, Mccormick, Jacqueline, Mercer, Oliver, Potla, Darsh, Rehman, Hafiz, Savill, Heather, Turner, Victoria, Davey, Miriam, Golden, David, Seaman, Rebecca, Hunt, Jodie, Dearden, Joy, Dobson, Emma, Mulcahy, Michelle, Munt, Sheila, O’Connor, Grainne, Philbin, Jennifer, Rishton, Chloe, Tully, Redmond, Winnard, Sarah, Cagova, Lenka, Fofano, Adama, Garner, Lucie, Holcombe, Helen, Mepham, Sue, Mitchell, Alice Michael, Mwaura, Lucy, Praman, K., Vuylsteke, Alain, Zamikula, Julie, Bercades, Georgia, Brealey, David, Hass, Ingrid, Maccallum, Niall, Martir, Glady, Raith, Eamon, Reyes, Anna, Smyth, Deborah, Taylor, Abigail, Hughes, Rachel Anne, Thomas, Helen, Rees, Alun, Duskova, Michaela, Phipps, Janet, Brooks, Suzanne, Edwards, Michelle, Alexander, Peter, Allen, Schvearn, Bradley-Potts, Joanne, Brantwood, Craig, Egan, Jasmine, Felton, Timothy, Padden, Grace, Ward, Luke, Moss, Stuart, Glasgow, Susannah, Beesley, Kate, Board, Sarah, Kubisz-Pudelko, Agnieszka, Lewis, Alison, Perry, Je, Pippard, Lucy, Wood, Di, Buckley, Clare, Brown, Alison, Gregory, Jane, O’Connell, Susan, Smith, Tim, Belagodu, Zakaula, Fuller, Bridget, Gherman, Anca, Olufuwa, Olumide, Paramsothy, Remi, Stuart, Carmel, Oakley, Naomi, Kamundi, Charlotte, Tyl, David, Collins, Katy, Silva, Pedro, Taylor, June, King, Laura, Coates, Charlotte, Crowley, Maria, Wakefield, Phillipa, Beadle, Jane, Johnson, Laura, Sargeant, Janet, Anderson, Madeleine, Jardine, Catherine, Williams, Dewi, Parris, Victoria, Quaid, Sheena, Watson, Ekaterina, Melville, Julie, Naisbitt, Jay, Joseph, Rosane, Lazo, Maria, Walton, Olivia, Neal, Alan, Hill, Michaela, Kannan, Thogulava, Wild, Laura, Allan, Elizabeth, Darlington, Kate, Davies, Ffyon, Easton, Jack, Kumar, Sumit, Lean, Richard, Menzies, Daniel, Pugh, Richard, Qiu, Xinyi, Davies, Llino, Williams, Hannah, Scanlon, Jeremy, Davies, Gwyneth, Mackay, Callum, Lewis, Joannne, Rees, Stephanie, Coetzee, Samantha, Gales, Alistair, Raj, Meena, Sell, Craig, Langton, Helen, Watters, Malcolm, Novis, Catherine, Arbane, Gill, Bociek, Aneta, Campos, Sara, Grau, Neu, Jones, Tim Owen, Lim, Rosario, Marotti, Martina, Whitton, Christopher, Barron, Anthony, Collins, Ciara, Kaul, Sundeep, Passmore, Heather, Prendergast, Claire, Reed, Anna, Rogers, Paula, Shokkar, Rajvinder, Woodruff, Meriel, Middleton, Hayley, Polgar, Oliver, Nolan, Claire, Thwaites, Vicky, Mahay, Kanta, Sri-Chandana, Chunda, Scherewode, Joslan, Stephenson, Lorraine, Marsh, Sarah, Bancroft, Hollie, Bellamy, Mary, Carmody, Margaret, Daglish, Jacqueline, Moore, Faye, Rhodes, Joanne, Sangombe, Mirriam, Kadiri, Salma, Ayers, Amanda, Harrison, Wendy, North, Julie, Cavazza, Anna, Cockrell, Maeve, Corcoran, Eleanor, Depante, Maria, Finney, Clare, Jerome, Ellen, Mcphail, Mark, Nayak, Monalisa, Noble, Harriet, O’Reilly, Kevin, Pappa, Evita, Saha, Rohit, Saha, Sian, Smith, John, Knighton, Abigail, Gill, Mandy, Paul, Paul, Ratnam, Valli, Shelton, Sarah, Wynter, Inez, Baptista, David, Crowe, Rebecca, Fernandes, Rita, Herdman-Grant, Rosaleen, Joseph, Anna, Loveridge, Adam, Mckenley, India, Morino, Eriko, Naranjo, Andre, Simms, Richard, Sollesta, Kathryn, Swain, Andrew, Venkatesh, Harish, Khera, Jacyntha, Fox, Jonathan, Barber, Russell, Hewitt, Claire, Hilldrith, Annette, Jackson-Lawrence, Karen, Shepardson, Sarah, Wills, Maryanne, Butler, Susan, Tavares, Silvia, Cunningham, Amy, Hindale, Julia, Arif, Sarwat, George, Linsha, Twiss, Sophie, Wright, David, Holland, Maureen, Keenan, Natalie, Lyons, Marc, Wassall, Helen, Marsh, Chri, Mahenthran, Mervin, Carter, Emma, Kong, Thoma, Adanini, Oluronke, Bhatia, Nikhil, Msiska, Maine, Mew, Louise, Mwaura, Esther, Williams, Felicity, Wren, Lynn, Sutherland, Sara-Beth, Battle, Ceri, Brinkworth, Elaine, Harford, Rachel, Murphy, Carl, Newey, Luke, Rees, Tabitha, Williams, Marie, Arnold, Sophie, Hardy, John, Houlden, Henry, Moncur, Eleanor, Tariq, Ambreen, Tucci, Arianna, Convery, Karen, Fottrell-Gould, Deirdre, Hudig, Lisa, Keshet-Price, Jocelyn, Randell, Georgina, Stammers, Katie, Abdelrazik, Marwa, Bakthavatsalam, Dhanalakshmi, Elhassan, Munzir, Ganesan, Arunkumar, Haldeos, Anne, Moreno-Cuesta, Jeronimo, Purohit, Dharam, Vincent, Rachel, Xavier, Kugan, Rohit, Kumar, Alasdair, Frater, Saleem, Malik, David, Carter, Jenkins, Samuel, Lamond, Zoe, Wall, Alanna, Reynolds, Jessica, Campbell, Helen, Thompsom, Maria, Dodds, Steve, Duffy, Stacey, Butcher, Deborah, O’Sullivan, Susie, Butterworth-Cowin, Nicola, Deacon, Bethan, Hibbert, Meg, Pothecary, Carla, Tetla, Dariusz, Woodford, Christopher, Durga, Latha, Kennard-Holden, Gareth, de Gordoa, Laura Ortiz-Ruiz, Peasgood, Emily, Phillips, Claire, Skinner, Denise, Gaylard, Jane, Mullan, Dee, Newman, Julie, Davies, Ellie, Roche, Lisa, Sathe, Sonia, Brimfield, Lutece, Daly, Zoe, Pogson, David, Rose, Steve, Collins, Amy, Khaliq, Waqa, Gude, Estefania Treu, Allen, Louise, Beranova, Eva, Crisp, Nikki, Deery, Joanne, Hazelton, Tracy, Knight, Alicia, Price, Carly, Tilbey, Sorrell, Turki, Salah, Turney, Sharon, Giles, Julian, Booth, Simon, Bell, Gillian, English, Katy, Katary, Amro, Wilcox, Louise, Campbell, Rachael, Clarke, Noreen, Whiteside, Jonathan, Mascarenhas, Mairi, Donaldson, Avril, Matheson, Joanna, Barrett, Fiona, O’Hara, Marianne, O’Keefe, Laura, Bradley, Clare, Collier, Dawn, Walker, Rachel, Maynard, Victoria, Patel, Tahera, Smith, Matthew, Kazi, Aayesha, Hartley, Janice, Dykes, Joseph, Hijazi, Muhammad, Keith, Sarah, Khan, Meherunnisa, Ryan-Smith, Janet, Springle, Philippa, Thomas, Jacqueline, Truman, Nick, Saad, Samuel, Coleman, Dabheoc, Fine, Christopher, Matt, Roseanna, Gay, Bethan, Dalziel, Jack, Ali, Syamlan, Goodchild, Drew, Harling, Rhiannan, Bhatterjee, Ravi, Goddard, Wendy, Davison, Chloe, Duberly, Stephen, Hargreaves, Jeanette, Bolton, Rachel, Verlander, Mark, Williams, Alexandra, Blackman, Helen, Creagh-Brown, Ben, Donlon, Sinead, Michalak-Glinska, Natalia, Mtuwa, Sheila, Pristopan, Veronika, Salberg, Armorel, Smith, Eleanor, Stone, Sarah, Piercy, Charle, Verula, Jerik, Burda, Dorota, Montaser, Rugia, Harden, Lesley, Mayangao, Irving, Marriott, Cheryl, Bradley, Paul, Harris, Celia, Cooper, Joshua, Finch, Cheryl, Liderth, Sarah, Quinn, Alison, Waddington, Natalia, Fidler, Katy, Tagliavini, Emma, Donnelly, Kevin, Abel, Lynn, Brett, Michael, Digby, Brian, Gemmell, Lisa, Hornsby, Jame, Macgoey, Patrick, O’Neil, Pauline, Price, Richard, Rodden, Natalie, Rooney, Kevin, Sundaram, Radha, Thomson, Nicola, Flanagan, Rebecca, Hughes, Gareth, Latham, Scott, Mckenna, Emma, Anderson, Jennifer, Hull, Robert, Rhead, Kat, Branney, Debbie, Frankham, Jordan, Pitts, Sally, White, Nigel, Cristiano, Daniele, Dormand, Natalie, Farzad, Zohreh, Gummadi, Mahitha, Liyanage, Kamal, Patel, Brijesh V., Salmi, Sara, Sloane, Geraldine, Varghese, Mathew, Zborowski, Anelise C., Bean, Sarah, Burt, Karen, Spivey, Michael, Eastgate-Jackson, Christine, Filipe, Helder, Martin, Daniel, Maharajh, Amitaa, Garcia, Sara Mingo, De Neef, Mark, Lynch, Ceri, Howe, Gwenllian Sera, Singh, Jayaprakash, Turner, Keri, Ellis, Hannah, Stroud, Natalie, Cherian, Shiney, Cutler, Sean, Heron, Anne Emma, Roynon-Reed, Anna, Williams, Gemma, Richards, Owen, Cheema, Yusuf, Ahmad, Norfaizan, Barker, Joann, Bauchmuller, Kri, Bird, Sarah, Cawthron, Kay, Harrington, Kate, Jackson, Yvonne, Kibutu, Faith, Lenagh, Becky, Masuko, Shamiso, Raithatha, Ajay, Wiles, Matthew, Willson, Jayne, Newell, Helen, Lye, Alison, Nwafor, Lorenza, Jarman, Claire, Rowland-Jones, Sarah, Foote, David, Cole, Joby, Thompson, Roger, Watson, Jame, Hesseldon, Lisa, Macharia, Irene, Chetam, Luke, Smith, Jacqui, Ford, Amber, Anderson, Samantha, Birchall, Kathryn, Housley, Kay, Walker, Sara, Milner, Leanne, Hanratty, Helena, Trower, Helen, Phillips, Patrick, Oxspring, Simon, Donne, Ben, Bevan, Emily, Martin, Jane, Trodd, Dawn, Watson, Geoff, Brown, Caroline Wrey, Bunni, Lara, Jennings, Claire, Latif, Monica, Marshall, Rebecca, Subramanian, Gayathri, Bandla, Nageswar, Gellamucho, Minnie, Davies, Michelle, Thompson, Christopher, Trim, Fiona, Eapen, Beena, Ahmed, Cecilia, Baines, Balvinder, Clamp, Sarah, Colley, Julie, Haq, Risna, Hayes, Anne, Hulme, Jonathan, Hussain, Samia, Joseph, Sibet, Kumar, Rita, Maqsood, Zahira, Purewal, Manjit, Chandler, Ben, Elliott, Kerry, Mallinson, Janine, Turnbull, Alison, Dent, Kathy, Horsley, Elizabeth, Akhtar, Muhmmad Nauman, Pearson, Sandra, Potoczna, Dorota, Spencer, Sue, Blakemore, Hayley, Borislavova, Borislava, Faulkner, Beverley, Gendall, Emma, Goff, Elizabeth, Hayes, Kati, Thomas, Matt, Worner, Ruth, Smith, Kerry, Stephens, Deanna, Delgado, Carlos Castro, Dawson, Deborah, Ding, Lijun, Durrant, Georgia, Ezeobu, Obiageri, Farnell-Ward, Sarah, Harrison, Abiola, Kanu, Rebecca, Leaver, Susannah, Maccacari, Elena, Manna, Soumendu, Saluzzio, Romina Peperman, Queiroz, Joana, Samakomva, Tinashe, Sicat, Christine, Texeira, Joana, Da Gloria, Edna Fernande, Lisboa, Ana, Rawlins, John, Mathew, Jisha, Kinch, Ashley, Hurt, William Jame, Shah, Nirav, Clark, Victoria, Thanasi, Maria, Yun, Nikki, Patel, Kamal, Crickmore, Vikki, Debreceni, Gabor, Wilkins, Joy, Nicol, Liz, Burn, Iona, Hambrook, Geraldine, Manso, Katarina, Penn, Ruth, Shanmugasundaram, Pradeep, Tebbutt, Julie, Thornton, Danielle, Rostron, Anthony, Roy, Alistair, Woods, Lindsey, Cornell, Sarah, Wakinshaw, Fiona, Rogerson, Kimberley, Jarmain, Jordan, Anderson, Peter, Archer, Katie, Austin, Karen, Davis, Caroline, Durie, Alison, Kelsall, Olivia, Thrush, Jessica, Vigurs, Charlie, Wood, Hannah-Louise, Tranter, Helen, Harrison, Alison, Cowley, Nichola, Mcalindon, Michael, Digby, Stephen, Low, Emma, Morgan, Aled, Cother, Naiara, Rankin, Tobia, Clayton, Sarah, Mccurdy, Alex, Allibone, Suzanne, Mary-Genetu, Roman, Patel, Amit, Mac, Ainhi, Murphy, Anthony, Mahjoob, Parisa, Nazari, Roonak, Worsley, Lucy, Fagan, Andrew, Mohamed Ali, Inthakab Ali, Beaumont, Karen, Blunt, Mark, Coton, Zoe, Curgenven, Hollie, Elsaadany, Mohamed, Fernandes, Kay, Ally, Sameena Mohamed, Rangarajan, Harini, Sarathy, Varun, Selvanayagam, Sivarupan, Vedage, Dave, White, Matthew, Fernandez-Roman, Jaime, Hamilton, David O., Johnson, Emily, Johnston, Brian, Martinez, Maria Lopez, Mulla, Suleman, Shaw, David, Waite, Alicia A. C., Waugh, Victoria, Welters, Ingeborg D., Williams, Karen, Bemand, Thoma, Black, Ethel, Rosa, Arnold Dela, Howle, Ryan, Jhanji, Shaman, Baikady, Ravishankar Rao, Tatham, Kate Colette, Thomas, Benjamin, Halkes, Matthew, Mercer, Pauline, Thornton, Lorraine, West, Joe, Baird, Tracy, Ruddy, Jim, Reece-Anthony, Rosie, Birt, Mark, Cowton, Amanda, Kay, Andrea, Kent, Melanie, Potts, Kathryn, Wilkinson, Ami, Naylor, Suzanne, Brown, Ellen, Clark, Michele, Purvis, Sarah, Cole, Jade, Davies, Rhy, Duffin, Donna, Hill, Helen, Player, Ben, Thomas, Emma, Williams, Angharad, Beith, Claire Marie, Black, Karen, Clements, Suzanne, Morrison, Alan, Strachan, Dominic, Taylor, Margaret, Clarkson, Michelle, D’Sylva, Stuart, Norman, Kathryn, Coventry, Tina, Fowler, Susan, Mcgregor, Amanda, Brady, Ailbhe, Chan, Rebekah, Mcivor, Shane, Prady, Helena, Whittle, Helen, Mathew, Bijoy, Clapham, Melanie, Harper, Rosemary, Poultney, Una, Rice, Polly, Mutch, Rachel, Baird, Yolanda, Butler, Aaron, Chadbourn, Indra, Folkes, Linda, Fox, Heather, Gardner, Amy, Gomez, Raquel, Hobden, Gillian, King, Kirsten, Margarson, Michael, Martindale, Tim, Meadows, Emma, Raynard, Dana, Thirlwall, Yvette, Helm, David, Margalef, Jordi, Greer, Sandra, Shuker, Karen, Smuts, Sara, Duffield, Joseph, Smith, Oliver, Mallon, Lewi, Claire, Watkin, Birkinshaw, Isobel, Carter, Joseph, Howard, Kate, Ingham, Joanne, Joy, Rosie, Pearson, Harriet, Roche, Samantha, Scott, Zoe, Knights, Ellen, Price, Alicia, Thomas, Alice, Thorpe, Chri, Abraheem, Azmerelda, Bamford, Peter, Cawley, Kathryn, Dunmore, Charlie, Faulkner, Maria, Girach, Rumanah, Jeffrey, Helen, Jones, Rhianna, London, Emily, Nagra, Imrun, Nasir, Farah, Sainsbury, Hannah, Smedley, Clare, Khade, Reena, Sundar, Ashok, Tsinaslanidis, George, Behan, Teresa, Burnett, Caroline, Hatton, Jonathan, Heeney, Elaine, Mitra, Atideb, Newton, Maria, Pollard, Rachel, Stead, Rachael, Birch, Jenny, Bough, Laura, Goodsell, Josie, Tutton, Rebecca, Williams, Patricia, Williams, Sarah, Winter-Goodwin, Barbara, Auld, Fiona, Donnachie, Joanne, Edmond, Ian, Prentice, Lynn, Runciman, Nikole, Salutous, Dario, Symon, Lesley, Todd, Anne, Turner, Patricia, Short, Abigail, Sweeney, Laura, Murdoch, Euan, Senaratne, Dhaneesha, Burns, Karen, Higham, Andrew, Anderson, Taya, Hawcutt, Dan, O’Malley, Laura, Rad, Laura, Rogers, Naomi, Saunderson, Paula, Allison, Kathryn Sian, Afolabi, Deborah, Whitbread, Jennifer, Jones, Dawn, Dore, Rachael, Lankester, Liana, Nikitas, Nikita, Wells, Colin, Stowe, Bethan, Spencer, Kayleigh, Cathcart, Susanne, Duffy, Katharine, Puxty, Alex, Puxty, Kathryn, Turner, Lynne, Ireland, Jane, Semple, Gary, Barry, Peter, Hilltout, Paula, Evitts, Jayne, Tyler, Amanda, Waldron, Joanne, Irvine, Val, Shelley, Benjamin, Akinkugbe, Olugbenga, Bamford, Alasdair, Beech, Emily, Belfield, Holly, Bell, Michael, Davies, Charlene, Jones, Gareth A. L., Mchugh, Tara, Meghari, Hamza, O’Neill, Lauran, Peters, Mark J., Ray, Samiran, Tomas, Ana Luisa, Gorman, Claire, Gupta, Abhinav, Timlick, Elizabeth, Brady, Rebecca, Bonner, Stephen, Hugill, Keith, Jones, Jessica, Liggett, Steven, Bashyal, Archana, Davidson, Neil, Hutton, Paula, Mckechnie, Stuart, Wilson, Jean, Flint, Neil, Rekha, Patel, Hales, Dawn, Cruz, Carina, Gopal, Shameer, Harris, Nichola, Lake, Victoria, Metherell, Stella, Radford, Elizabeth, Clement, Ian, Patel, Bijal, Gulati, A., Hays, Carole, Webster, K., Hudson, Anne, Webster, Andrea, Stephenson, Elaine, Mccormack, Louise, Slater, Victoria, Nixon, Rachel, Hanson, Helen, Fearby, Maggie, Kelly, Sinead, Bridgett, Victoria, Robinson, Philip, Almaden-Boyle, Christine, Austin, Pauline, Cabrelli, Louise, Cole, Stephen, Casey, Matt, Chapman, Susan, Whyte, Clare, Brayne, Adam, Fisher, Emma, Hunt, Jane, Jackson, Peter, Kaye, Duncan, Love, Nichola, Parkin, Juliet, Tuckey, Victoria, van Koutrik, Lynne, Carter, Sasha, Andrew, Benedict, Findlay, Louise, Adams, Katie, Bruce, Michelle, Connolly, Karen, Duncan, Tracy, T. -Michael, Helen, Lindergard, Gabriella, Hey, Samuel, Fox, Claire, Alfonso, Jordan, Durrans, Laura Jayne, Guerin, Jacinta, Hruska, Martin, Eltayeb, Ayaa, Lamb, Thoma, Hodgkiss, Tracey, Cooper, Lisa, Rothwell, Joanne, Dennis, Catherine, Mcgregor, Alastair, Srikaran, Sinduya, Sukha, Anisha, Davies, Kim, O’Brien, Linda, Omar, Zohra, Perkins, Emma, Lewis, Tracy, Sutherland, Isobel, Brooke, Hollie, Buckley, Sarah, Suarez, Jose Cebrian, Charlesworth, Ruth, Hansson, Karen, Norris, John, Poole, Alice, Rose, Alastair, Sandhu, Rajdeep, Sloan, Brendan, Smithson, Elizabeth, Thirumaran, Muthu, Wagstaff, Veronica, Metcalfe, Alexandra, Camsooksai, Julie, Humphrey, Charlotte, Jenkins, Sarah, Wadams, Beverley, Death, Yasmin, Adams, Colene, Agasou, Anita, Arden, Tracie, Bowes, Amy, Boyle, Pauline, Beekes, Mandy, Button, Heather, Capps, Nigel, Carnahan, Mandy, Carter, Anne, Childs, Danielle, Donaldson, Denise, Hard, Kelly, Hurford, Fran, Hussain, Yasmin, Javaid, Ayesha, Jones, Jame, Jose, Sanal, Leigh, Michael, Martin, Terry, Millward, Helen, Motherwell, Nichola, Rikunenko, Rachel, Stickley, Jo, Summers, Julie, Ting, Louise, Tivenan, Helen, Tonks, Louise, Wilcox, Rebecca, Bokhari, Maria, Lucas, Rachael, Mccormick, Wendy, Ritzema, Jenny, Sanderson, Amanda, Wild, Helen, Baxter, Nicola, Henderson, Steven, Kennedy-Hay, Sophie, Mcparland, Christopher, Rooney, Laura, Sim, Malcolm, Mccreath, Gordan, Brunton, Mark, Caterson, Je, Coles, Holly, Frise, Matthew, Rai, Sabi Gurung, Keating, Liza, Tilney, Emma, Bartley, Shauna, Bhuie, Parminder, Downes, Charlotte, Holding, Kathleen, Riches, Katie, Hilton, Mary, Hayman, Mel, Subramanian, Deepak, Daniel, Priya, Zitter, Letizia, Benyon, Sarah, Marriott, Suzie, Park, Linda, Keenan, Samantha, Gordon, Elizabeth, Quinn, Helen, Baines, Kizzy, Andrew, Gillian, Barclay, Lucy, Callaghan, Marie, Clark, Sarah, Hope, Dave, Marshall, Lucy, Mcculloch, Corrienne, Briton, Kate, Singleton, Jo, Birch, Sophie, Simpson, Kerry, Craig, Jayne, Demetriou, Carrie, Eckbad, Charlotte, Hierons, Sarah, Howie, Lucy, Mitchard, Sarah, Ramos, Lidia, Serrano-Ruiz, Alfredo, White, Katie, Kelly, Fiona, Amin, Vishal, Anastasescu, Elena, Anumakonda, Vikram, Karthik, Komala, Kausar, Rizwana, Reid, Karen, Smith, Jacqueline, Imeson-Wood, Janet, Bellini, Arianna, Bryant, Jade, Mayer, Anton, Pickard, Amy, Roe, Nichola, Sowter, Jason, Howlett, Alex, Criste, Kristine, Cusack, Rebecca, Golder, Kim, Golding, Hannah, Jones, Oliver, Leggett, Samantha, Male, Michelle, Marani, Martyna, Prager, Kirsty, Williams, Toran, Roberts, Belinda, Salmon, Karen, Gondo, Prisca, Hadebe, B., Kayani, Abdul, Masunda, Bridgett, Ahmed, Ashar, Morris, Anna, Jakkula, Sriniva, Long, Kate, Whiteley, Simon, Wilby, Elizabeth, Ogg, Bethan, Moultrie, Sam, Odam, M., Bewley, Jeremy, Garland, Zoe, Grimmer, Lisa, Gumbrill, Bethany, Johnson, Rebekah, Sweet, Katie, Webster, Denise, Efford, Georgia, Bennett, Sara, Goodwin, Emma, Jackson, Matthew, Kent, Alissa, Tibke, Clare, Woodyatt, Wiesia, Zaki, Ahmed, Daniel, Amelia, Finn, Joanne, Saha, Rajnish, Bremmer, Pamela, Allan, J., Geary, T., Houston, Gordon, Meikle, A., O’Brien, P., Bell, Dina, Boyle, Rosalind, Douglas, Katie, Glass, Lynn, Lee, Emma, Lennon, Liz, Rattray, Austin, Charnock, Rob, Mcfarland, Denise, Cosgrove, Denise, Attwood, Ben, Parsons, Penny, Carmody, Siobhain, Oblak, Metod, Popescu, Monica, Thankachen, Mini, Baruah, Rosie, Morris, Sheila, Ferguson, Susie, Shepherd, Amy, Altabaibeh, Abdelhakim, Alvaro, Ana, Gilbert, Kayleigh, Ma, Louise, Mostoles, Loreta, Parmar, Chetan, Simpson, Kathryn, Jetha, Champa, Booker, Lauren, Pratley, Anezka, Cosier, Tracey, Millen, Gemma, Schumacher, Natasha, Weston, Heather, Rand, Jame, Alex, Beatrice, Bach, Benjamin, Barclay, Wendy S., Bogaert, Debby, Chand, Meera, Cooke, Graham S., Docherty, Annemarie B., Dunning, Jake, da Silva Filipe, Ana, Fletcher, Tom, Green, Christoper A., Harrison, Ewen M., Hiscox, Julian A., Ijaz, Samreen, Khoo, Saye, Lim, Wei Shen, Mentzer, Alexander J., Merson, Laura, Noursadeghi, Mahdad, Moore, Shona C., Palmarini, Massimo, Paxton, William A., Pollakis, Georgio, Price, Nichola, Rambaut, Andrew, Robertson, David L., Sancho-Shimizu, Vanessa, Scott, Janet T., de Silva, Thushan, Sigfrid, Louise, Solomon, Tom, Sriskandan, Shiranee, Stuart, David, Tedder, Richard S., Thomson, Emma C., Roger Thompson, A. A., Thwaites, Ryan S., Turtle, Lance C. W., Gupta, Rishi K., Palmieri, Carlo, Swann, Olivia V., Zambon, Maria, Dumas, Marc-Emmanuel, Griffin, Julian L., Takats, Zoltan, Chechi, Kanta, Andrikopoulos, Petro, Osagie, Anthonia, Olanipekun, Michael, Liggi, Sonia, Lewis, Matthew R., Correia, Gonçalo dos Santo, Sands, Caroline J., Takis, Panteleimon, Maslen, Lynn, Greenhalf, William, Shaw, Victoria, Mcdonald, Sarah E., Keating, Seán, Ahmed, Katie A., Armstrong, Jane A., Ashworth, Milton, Asiimwe, Innocent G., Bakshi, Siddharth, Barlow, Samantha L., Booth, Laura, Brennan, Benjamin, Bullock, Katie, Catterall, Benjamin W. A., Clark, Jordan J., Clarke, Emily A., Cooper, Louise, Cox, Helen, Davis, Christopher, Dincarslan, Oslem, Dunn, Chri, Dyer, Philip, Elliott, Angela, Evans, Anthony, Finch, Lorna, Fisher, Lewis W. S., Foster, Terry, Garcia-Dorival, Isabel, Gunning, Philip, Hartley, Catherine, Jensen, Rebecca L., Jones, Christopher B., Jones, Trevor R., Khandaker, Shadia, King, Katharine, Kiy, Robyn T., Koukorava, Chrysa, Lake, Annette, Lant, Suzannah, Latawiec, Diane, Lavelle-Langham, Lara, Lefteri, Daniella, Lett, Lauren, Livoti, Lucia A., Mancini, Maria, Mcdonald, Sarah, Mcevoy, Laurence, Mclauchlan, John, Metelmann, Soeren, Miah, Nahida S., Middleton, Joanna, Mitchell, Joyce, Murphy, Ellen G., Penrice-Randal, Rebekah, Pilgrim, Jack, Prince, Tessa, Reynolds, Will, Ridley, P. Matthew, Sales, Debby, Shaw, Victoria E., Shears, Rebecca K., Small, Benjamin, Subramaniam, Krishanthi S., Szemiel, Agnieska, Taggart, Aislynn, Tanianis-Hughes, Jolanta, Thomas, Jordan, Trochu, Erwan, van Tonder, Libby, Wilcock, Eve, Zhang, J. Eunice, Flaherty, Lisa, Maziere, Nicole, Cass, Emily, Carracedo, Alejandra Doce, Carlucci, Nicola, Holmes, Anthony, Massey, Hannah, Murphy, Lee, Wrobel, Nicola, Mccafferty, Sarah, Morrice, Kirstie, Maclean, Alan, Armstrong, Ruth, Boz, Ceilia, Brown, Adam, Coutts, Audrey, Cullum, Louise, Day, Nicky, Donnelly, Lorna, Duncan, Esther, Fawkes, Angie, Finernan, Paul, Gilchrist, Tammy, Golightly, Ailsa, Hafezi, Katarzyna, Law, Dawn, Law, Rachel, Law, Sarah, Macgillivray, Louise, Mal, Hanning, Mcmaster, Ellie, Meikle, Jen, Oosthuyzen, Wilna, Paterson, Trevor, Stenhouse, Andrew, Swets, Maaike, Szoor-McElhinney, Helen, Taneski, Filip, Wackett, Tony, Ward, Mairi, Weaver, Jane, Coyle, Judy, Gallagher, Bernadette, Lidstone-Scott, Rebecca, Hamilton, Debbie, Schon, Katherine, Furlong, Anita, Biggs, Heather, Griffiths, Fiona, Andrews, Eleanor, Brickell, Kathy, Smyth, Michelle, Murphy, Lorna, Carson, Gail, Hardwick, Hayley, Donohue, Chloe, Pérez-Tur, Jordi [0000-0002-9111-1712], Martín, Javier [0000-0002-2202-0622], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], A list of authors and their affiliations appears in the Supplementary Information, Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-20-COVI-0003,GENCOVID,Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé(2020), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (MGD) Service de gastro-entérologie, Niemi, M, Karjalainen, J, Liao, R, Neale, B, Daly, M, Ganna, A, Pathak, G, Andrews, S, Kanai, M, Veerapen, K, Fernandez-Cadenas, I, Schulte, E, Striano, P, Marttila, M, Minica, C, Marouli, E, Karim, M, Wendt, F, Savage, J, Sloofman, L, Butler-Laporte, G, Kim, H, Kanoni, S, Okada, Y, Byun, J, Han, Y, Uddin, M, Smith, G, Willer, C, Buxbaum, J, Mehtonen, J, Finucane, H, Cordioli, M, Martin, A, Zhou, W, Pasaniuc, B, Julienne, H, Aschard, H, Shi, H, Yengo, L, Polimanti, R, Ghoussaini, M, Schwartzentruber, J, Dunham, I, Chwialkowska, K, Francescatto, M, Trankiem, A, Balaconis, M, Davis, L, Lee, S, Priest, J, Renieri, A, Sankaran, V, van Heel, D, Deelen, P, Richards, J, Nakanishi, T, Biesecker, L, Kerchberger, V, Baillie, J, Mari, F, Bernasconi, A, Baillie, S, Canakoglu, A, 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McCormack, L., Slater, V., Nixon, R., Hanson, H., Fearby, M., Kelly, S., Bridgett, V., Robinson, P., Almaden-Boyle, C., Austin, P., Cabrelli, L., Casey, M., Chapman, S., Whyte, C., Brayne, A., Fisher, E., Jackson, P., Kaye, D., Love, N., Parkin, J., Tuckey, V., van Koutrik, L., Carter, S., Andrew, B., Findlay, L., Adams, K., Bruce, M., Connolly, K., Duncan, T., T-Michael, H., Lindergard, G., Hey, S., Fox, C., Alfonso, J., Durrans, L.J., Guerin, J., Hruska, M., Eltayeb, A., Lamb, T., Hodgkiss, T., Cooper, L., Rothwell, J., Dennis, C., Srikaran, S., Sukha, A., Davies, K., O'Brien, L., Omar, Z., Perkins, E., Lewis, T., Sutherland, I., Brooke, H., Buckley, S., Suarez, J.C., Charlesworth, R., Hansson, K., Norris, J., Poole, A., Sandhu, R., Sloan, B., Smithson, E., Thirumaran, M., Wagstaff, V., Metcalfe, A., Camsooksai, J., Humphrey, C., Wadams, B., DeAth, Y., Adams, C., Agasou, A., Arden, T., Bowes, A., Boyle, P., Beekes, M., Button, H., Capps, N., Carnahan, M., Carter, A., Childs, D., Donaldson, D., Hard, K., Hurford, F., Hussain, Y., Javaid, A., Jose, S., Leigh, M., Martin, T., Millward, H., Motherwell, N., Rikunenko, R., Stickley, J., Summers, J., Ting, L., Tivenan, H., Tonks, L., Wilcox, R., Bokhari, M., Lucas, R., McCormick, W., Ritzema, J., Sanderson, A., Wild, H., Baxter, N., Henderson, S., Kennedy-Hay, S., Rooney, L., Sim, M., McCreath, G., Brunton, M., Caterson, J., Coles, H., Frise, M., Rai, S.G., Keating, L., Tilney, E., Bartley, S., Bhuie, P., Downes, C., Holding, K., Riches, K., Hilton, M., Hayman, M., Subramanian, D., Daniel, P., Zitter, L., Benyon, S., Marriott, S., Park, L., Keenan, S., Gordon, E., Quinn, H., Baines, K., Andrew, G., Barclay, L., Callaghan, M., Clark, S., Hope, D., Marshall, L., McCulloch, C., Briton, K., Singleton, J., Birch, S., Simpson, K., Craig, J., Demetriou, C., Eckbad, C., Hierons, S., Howie, L., Mitchard, S., Ramos, L., Serrano-Ruiz, A., White, K., Kelly, F., Amin, V., Anastasescu, E., Anumakonda, V., Karthik, K., Kausar, R., Reid, K., Imeson-Wood, J., Bellini, A., Bryant, J., Pickard, A., Roe, N., Sowter, J., Howlett, A., Criste, K., Cusack, R., Golder, K., Golding, H., Jones, O., Leggett, S., Male, M., Marani, M., Prager, K., Williams, T., Roberts, B., Salmon, K., Gondo, P., Kayani, A., Masunda, B., Ahmed, A., Morris, A., Jakkula, S., Long, K., Whiteley, S., Wilby, E., Ogg, B., Moultrie, S., Bewley, J., Garland, Z., Grimmer, L., Gumbrill, B., Sweet, K., Webster, D., Efford, G., Bennett, S., Goodwin, E., Jackson, M., Kent, A., Tibke, C., Woodyatt, W., Zaki, A., Daniel, A., Finn, J., Bremmer, P., Houston, G., O'Brien, P., Bell, D., Boyle, R., Douglas, K., Glass, L., Lee, E., Lennon, L., Rattray, A., Charnock, R., McFarland, D., Cosgrove, D., Attwood, B., Parsons, P., Carmody, S., Oblak, M., Popescu, M., Thankachen, M., Baruah, R., Morris, S., Ferguson, S., Shepherd, A., Altabaibeh, A., Alvaro, A., Gilbert, K., Ma, L., Mostoles, L., Parmar, C., Jetha, C., Booker, L., Pratley, A., Cosier, T., Millen, G., Schumacher, N., Weston, H., Rand, J., Alex, B., Bach, B., Barclay, W.S., Bogaert, D., Chand, M., Cooke, G.S., Docherty, A.B., Dunning, J., da Silva Filipe, A., Fletcher, T., Green, C.A., Harrison, E.M., Hiscox, J.A., Ijaz, S., Khoo, S., Lim, W.S., Mentzer, A.J., Merson, L., Noursadeghi, M., Moore, S.C., Palmarini, M., Paxton, W.A., Pollakis, G., Price, N., Rambaut, A., Robertson, D.L., Sancho-Shimizu, V., Scott, J.T., de Silva, T., Sigfrid, L., Solomon, T., Sriskandan, S., Stuart, D., Tedder, R.S., Thomson, E.C., Roger Thompson, A.A., Thwaites, R.S., Turtle, LCW, Gupta, R.K., Palmieri, C., Swann, O.V., Zambon, M., Dumas, M.E., Griffin, J.L., Takats, Z., Chechi, K., Andrikopoulos, P., Osagie, A., Olanipekun, M., Liggi, S., Lewis, M.R., Correia, GDS, Sands, C.J., Takis, P., Maslen, L., Greenhalf, W., Shaw, V., McDonald, S.E., Ahmed, K.A., Armstrong, J.A., Ashworth, M., Asiimwe, I.G., Bakshi, S., Barlow, S.L., Booth, L., Brennan, B., Bullock, K., Catterall, BWA, Clark, J.J., Clarke, E.A., Cox, H., Dincarslan, O., Dunn, C., Dyer, P., Elliott, A., Evans, A., Finch, L., Fisher, LWS, Foster, T., Garcia-Dorival, I., Gunning, P., Hartley, C., Jensen, R.L., Jones, C.B., Jones, T.R., Khandaker, S., Kiy, R.T., Koukorava, C., Lake, A., Lant, S., Latawiec, D., Lavelle-Langham, L., Lefteri, D., Lett, L., Livoti, L.A., Mancini, M., McDonald, S., McEvoy, L., McLauchlan, J., Metelmann, S., Miah, N.S., Middleton, J., Mitchell, J., Murphy, E.G., Penrice-Randal, R., Pilgrim, J., Prince, T., Reynolds, W., Ridley, P.M., Sales, D., Shaw, V.E., Shears, R.K., Small, B., Subramaniam, K.S., Szemiel, A., Taggart, A., Tanianis-Hughes, J., Trochu, E., van Tonder, L., Wilcock, E., Zhang, J.E., Flaherty, L., Maziere, N., Cass, E., Carracedo, A.D., Carlucci, N., Holmes, A., Massey, H., Murphy, L., Wrobel, N., McCafferty, S., Morrice, K., MacLean, A., Armstrong, R., Boz, C., Coutts, A., Cullum, L., Day, N., Donnelly, L., Duncan, E., Fawkes, A., Finernan, P., Gilchrist, T., Golightly, A., Hafezi, K., Law, D., Law, R., Law, S., Macgillivray, L., Maclean, A., Mal, H., Mcmaster, E., Meikle, J., Oosthuyzen, W., Paterson, T., Stenhouse, A., Swets, M., Szoor-McElhinney, H., Taneski, F., Wackett, T., Ward, M., Weaver, J., Coyle, J., Gallagher, B., Lidstone-Scott, R., Hamilton, D., Schon, K., Furlong, A., Biggs, H., Griffiths, F., Andrews, E., Brickell, K., Smyth, M., Carson, G., Hardwick, H., Donohue, C., Neale, Benjamin M. [0000-0003-1513-6077], Apollo - University of Cambridge Repository, Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Groningen Research Institute for Asthma and COPD (GRIAC), Guided Treatment in Optimal Selected Cancer Patients (GUTS), AII - Infectious diseases, Amsterdam Neuroscience - Neuroinfection & -inflammation, Neurology, Infectious diseases, Center of Experimental and Molecular Medicine, APH - Aging & Later Life, APH - Global Health, APH - Quality of Care, Amsterdam institute for Infection and Immunity, APH - Health Behaviors & Chronic Diseases, Global Health, APH - Methodology, Graduate School, ACS - Heart failure & arrhythmias, Anesthesiology, ACS - Diabetes & metabolism, APH - Digital Health, APH - Personalized Medicine, ACS - Microcirculation, Niemi, M. E. K., Liao, R. G., Neale, B. M., Pathak, G. A., Andrews, S. J., Schulte, E. C., Karim, M. A., Wendt, F. R., Kim, H. -N., Uddin, M. J., Smith, G. D., Willer, C. J., Buxbaum, J. D., Martin, A. R., Balaconis, M. K., Sankaran, V. G., Brent Richards, J., Eric Kerchberger, V., Kenneth Baillie, J., Dutta, A. K., Uddin, M. M., Perez-Tur, J., Verdugo, R. A., Zarate, R., Medina-Gomez, C., Gomez-Cabrero, D., Cadilla, C. L., Boua, P. R., Fave, M. -J., Lemacon, A., Szentpeteri, J. L., Ahmad, H. F., Kornilov, S. A., Prokic, I., Pearson, N. M., Shelton, J. F., Shastri, A. J., Weldon, C. H., Brouwer, M. C., Vlaar, A. P. J., Joost Wiersinga, W., Algera, A. G., Bogaard, H. J., Bonta, P. I., Grobusch, M. P., Hermans, S. M., Hovius, J. W., de Jong, M. D., Nossent, E. J., Prins, J. M., Schultz, M. J., Stijnis, C. S., Minnaar, R. P., van Uffelen, K. W. J., Wolterman, R. A., Ball, C. A., Mccurdy, S., Hong, E. L., Baltzell, A. H., Goffard, J. -C., Peree, H., Leonard, P., Giot, J. -B., Sauvage, A. -S., Wery, M., Morrison, D. R., Chasse, M., Kaufmann, D. E., Mark Lathrop, G., Davis, L. K., Cox, N. J., Below, J. E., Sealock, J. M., Faucon, A. B., Shuey, M. M., Polikowsky, H. G., Petty, L. E., Shaw, D. M., Chen, H. -H., Ludwig, K. U., Schroder, J., Nothen, M. M., Jensen, B. -E. O., Altmuller, J., Berger, M. M., Gogele, M., Gignoux, C. R., Wicks, S. J., Barnes, K. C., Goldstein, D. B., Reilly, M. P., Gharavi, A. G., O'Byrne, S. M., So, Y. S., Park, S. -K., Kim, H. -L., Kang, C. K., Lee, H. -J., Song, K. -H., Yoon, K. J., Paik, N. -J., Joo, E. -J., Park, W. B., Park, J. S., Park, K. U., Ham, S. Y., Kim, E. S., Kim, H. B., Caceres, M., Lenz, T. L., Julia, A., Holter, J. C., Fernandez, J., Sander, L. E., Banales, J. M., Romero-Gomez, M., Hov, J. R., Karlsen, T. H., Wacker, E. M., Elabd, H., Ruhlemann, M. C., Vadla, M. S., Lenning, O. B., Ozer, O., Kassens, J., Figuera Basso, M. E., Ortiz, A. B., Chercoles, A. G., Holten, A. R., Kildal, A. B., Gluck, A., Nolla, A. C., Dyrhol-Riise, A. M., Spinner, C. D., Hoff, D. A. L., Jimenez, D., Pestana, D., Helbig, E. T., Paraboschi, E. M., Sanchez, F. G., Hernandez, I., Galvan-Femenia, I., Badia, J. R., Muller, K. E., Gaede, K. I., Lippert, L. J., Tellez, L., Gutierrez-Stampa, M. A., Vehreschild, M. J. G. T., Marquie, M., Seilmaier, M. J., Rodriguez-Gandia, M., Ayo, N. I., Martinez, N., Cornely, O. A., Rodrigues, P. M., Espana, P. P., Garcia-Fernandez, A. -E., Fracanzani, A. L., Muniz-Diaz, E., Calderon, E. J., Solligard, E., Medrano, F. J., Muller, F., Afset, J. E., Damas, J. K., Ferrusquia-Acosta, J., Quero, J. H., Guerrero, J. M., Bettini, L. R., Gustad, L. T., Valsecchi, M. G., D'Angio, M., Gallego-Duran, R., Cejudo, T. G., Grimsrud, M. M., Gudbjartsson, D. F., Moore, K. H. S., Alarcon-Riquelme, M. E., Martinez-Bueno, M., Rello, S. R., Lall, K., Bochud, P. -Y., Nussle, S. G., Meyer zu Bentrup, F., Merlet Viollet, R., Guery, B., Hugli, O., Gonseth Nussle, S., Estoppey Younes, S., Rochat Negro, T., Mercader, J. M., Castano-Vinyals, G., Dobano, C., Mondelli, M. U., Mazzei, M. A., Caldarelli, G. P., Monforte, A. D., Scotton, P. G., Monica, M. D., Mandala, M., Coviello, D. A., La Rovere, M. T., Segala, F. V., Mencarelli, M. A., Pinto, A. M., Carriero, M. L., Ann Belli, M., Antoni, M. D., Miraglia, F. G., Parisi, S. G., Squeo, G. M., Botta, G., Hunt, K. A., Trembath, R. C., Martin, H. C., Griffiths, C. J., Curtis, C. J., Huang, Q. Q., Lee, S. H., Macarthur, D., Maclaughlin, B., Smith, A. V., Boughton, A. P., Li, K. W., Lefaive, J., Jannes, C. E., Krieger, J. E., Pereira, A. C., Lima, I. R., Tada, M. T., Mccarthy, M., Lee, J. E., Lee, H. S., Jang, H. Y., Kim, Y. -S., Kwon, K. T., Kim, S. -W., Kim, J. Y., Jang, Y. R., Kim, H., Lee, J. Y., Choe, K. -W., Kang, Y. M., Jee, S. H., Jung, K. J., Schroth, G. P., Desouza, F., Cirulli, E. T., Schiabor Barrett, K. M., Washington, N. L., Lu, J. T., Ramirez, J. M., Grzymski, J. J., Minano, J. I. E., Aguirre, L. A., Lopez-Collazo, E., Lozano-Rodriguez, R., Avendano-Ortiz, J., Arcos, V. T., Montalban-Hernandez, K. M., Quiroga, J. V., Martin-Quiros, A., Nakada, T. -A., Vonk, J. M., Ori, A. P. S., Hernandez Cordero, A. I., Sin, D. D., Bosse, Y., Feng, Y. -C. A., Weiss, S. T., Karlson, E. W., Smoller, J. W., Murphy, S. N., Meigs, J. B., Woolley, A. E., Green, R. C., Perez, E. F., Zollner, S., Sloofman, L. G., Sebra, R. P., Collins, B. L., Sealfon, S. C., Jordan, D. M., Thompson, R. C., Belbin, G. M., Underwood, S. J., Hiester, L. L., Charney, A. W., Beckmann, N. D., Schadt, E. E., Abul-Husn, N. S., Cho, J. H., Kenny, E. E., Loos, R. J. F., Nadkarni, G. N., Huckins, L. M., Ferreira, M. A. R., Abecasis, G. R., Leader, J. B., Cantor, M. N., Justice, A. E., Carey, D. J., Josyula, N. S., Kosmicki, J. A., Horowitz, J. E., Gass, M. C., Hottenga, J. J., de Geus, E. J. C., Nivard, M. G., Ritchie, M. D., Verma, S. S., Vari, M. S., Rahier, J. -F., Bulik, C. M., Landen, M., Ferrero, G. B., Fundin, B., Ismail, S. I., Badji, R. M., Hultstrom, M., Geschwind, D. H., Butte, M. J., Chang, T. S., Caulfield, M. J., Scott, R. H., Odhams, C. A., Karczewski, K. J., Wilson, D. J., Spencer, C. A., Crook, D. W., Wyllie, D. H., O'Connell, A. M., Atkinson, E. G., Walters, R. K., Palmer, D. S., Goldstein, J. I., Kyle Satterstrom, F., Earle, S. G., Lin, S. -K., Rudkin, J. K., Zhao, J. H., Butterworth, A. S., Sun, Y. V., Huffman, J. E., O'Donnell, C. J., Michael Gaziano, J., Ho, Y. -L., Glessner, J. R., Mcguigan, P. J., Moore, L. S. P., Vizcaychipi, M. P., Page, V. J., Aldera, E. L., Cutino-Moguel, M. -T., Durand, I., Hawcutt, D. B., Macmahon, M., Macnaughton, E., Mccullough, K., Mcewen, R., O'Shea, M. K., Pooni, J. S., Wooton, D. G., Bretherick, A. D., Fourman, M. H., Meynert, A. M., Ponting, C. P., Porteous, D. J., Russell, C. D., Wilson, J. F., Drake, T. M., Fairfield, C. J., Knight, S. R., Mclean, K. A., Shaw, C. A., Ho, A. Y. W., Horby, P. W., Mcauley, D., Openshaw, P. J. M., Semple, M. G., Mcgowan, J., Mcguinness, H., Mcneela, F., Bayo, L. -A., Arias, S. S., Conyngham, J. -A., Corral, M. A., de Almeida Martins, L. G., Mclaughlan, D., Mcmorrow, L., Mccormick, J., Mitchell, A. M., Maccallum, N., Hughes, R. A., Jones, T. O., Mcphail, M., Mckenley, I., Sutherland, S. -B., de Gordoa, L. O. -R., Gude, E. T., Macgoey, P., Mckenna, E., Patel, B. V., Zborowski, A. C., Garcia, S. M., Howe, G. S., Heron, A. E., Mills, G. H., Brown, C. W., Akhtar, M. N., Delgado, C. C., Saluzzio, R. P., Da Gloria, E. F., Hurt, W. J., Wood, H. -L., Mcalindon, M., Mccurdy, A., Ali, I. A. M., Ally, S. M., Hamilton, D. O., Lopez Martinez, M., Waite, A. A. C., Welters, I. D., Rosa, A. D., Baikady, R. R., Tatham, K. C., Beith, C. M., Mcgregor, A., Mcivor, S., Allison, K. S., Jones, G. A. L., Mchugh, T., Peters, M. J., Tomas, A. L., Mckechnie, S., Mccormack, L., Michael, H. T., Durrans, L. J., Suarez, J. C., Death, Y., Mccormick, W., Mccreath, G., Rai, S. G., Mcculloch, C., Mcfarland, D., Barclay, W. S., Cooke, G. S., Docherty, A. B., Green, C. A., Harrison, E. M., Hiscox, J. A., Lim, W. S., Mentzer, A. J., Paxton, W. A., Robertson, D. L., Scott, J. T., Tedder, R. S., Thomson, E. C., Thwaites, R. S., Gupta, R. K., Swann, O. V., Dumas, M. -E., Griffin, J. L., Lewis, M. R., dos Santos Correia, G., Sands, C. J., Mcdonald, S. E., Ahmed, K. A., Armstrong, J. A., Asiimwe, I. G., Barlow, S. L., Catterall, B. W. A., Clark, J. J., Clarke, E. A., Fisher, L. W. S., Jensen, R. L., Jones, C. B., Jones, T. R., Kiy, R. T., Livoti, L. A., Mcdonald, S., Mcevoy, L., Mclauchlan, J., Miah, N. S., Moore, S. C., Murphy, E. G., Matthew Ridley, P., Shaw, V. E., Shears, R. K., Subramaniam, K. S., Eunice Zhang, J., Carracedo, A. D., Mccafferty, S., Turtle, L. C. W., Data Science Genetic Epidemiology Lab, Institute for Molecular Medicine Finland, HUS Helsinki and Uusimaa Hospital District, University of Helsinki, Research Programs Unit, Doctoral Programme in Population Health, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, and University of Zurich
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Male ,45/43 ,Autoimmunity ,Autoimmunity/genetics ,Body Mass Index ,COVID-19/genetics ,COVID-19/virology ,Critical Illness ,Female ,Genetic Loci/genetics ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Geographic Mapping ,Hospitalization ,Host-Pathogen Interactions/genetics ,Humans ,Inflammation/complications ,Information Dissemination ,Multifactorial Inheritance ,Racial Groups/genetics ,SARS-CoV-2/pathogenicity ,Smoking ,environmental risk factors ,Q1 ,631/208 ,0302 clinical medicine ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Genetics, Genome-wide association studies, SARS-CoV-2, Viral infection ,GWAS ,Aetiology ,Lung ,QC ,0303 health sciences ,HERITABILITY ,3. Good health ,covid-19 ,Science & Technology - Other Topics ,Identification (biology) ,Infection ,Human ,631/208/205/2138 ,Settore BIO/11 - Biologia Molecolare ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Clinical Research ,Biodefense ,Genetics ,GENOME-WIDE ASSOCIATION ,Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714 [VDP] ,METAANALYSIS ,1000 Multidisciplinary ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Science & Technology ,Prevention ,Racial Groups ,Pneumonia ,genetic architecture ,Human genetics ,Genetic Loci ,genetic factors ,570 Life sciences ,biology ,030217 neurology & neurosurgery ,Medizin ,Infektionsmedicin ,Genome-wide association studies ,Settore BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA ,Pandemic ,2.1 Biological and endogenous factors ,pandemi ,Multidisciplinary ,article ,Public Health, Global Health, Social Medicine and Epidemiology ,Racial Group ,10124 Institute of Molecular Life Sciences ,Host-Pathogen Interaction ,Multidisciplinary Sciences ,Infectious Diseases ,Host-Pathogen Interactions ,Critical Illne ,COVID-19, GWAS, genetic factors, environmental risk factors, therapy ,Infectious Medicine ,Coronavirus disease 2019 (COVID-19) ,SUSCEPTIBILITY LOCI ,General Science & Technology ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Computational biology ,Biology ,Vaccine Related ,692/699/255/2514 ,Environmental risk ,Mendelian randomization ,COVID-19 Host Genetics Initiative ,QH426 ,631/326/596/4130 ,030304 developmental biology ,Inflammation ,therapy ,SARS-CoV-2 ,Human Genome ,COVID-19 ,Genetic architecture ,Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi ,Emerging Infectious Diseases ,Good Health and Well Being ,Viral infection ,3111 Biomedicine - Abstract
Niemi, Mari E. K. et al. 39 páginas, figuras y tablas. Contiene material suplementario., The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3-7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
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- 2021
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7. Structural basis for Glycan-receptor binding by mumps virus hemagglutinin-neuraminidase
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Cristina Di Carluccio, Rosa Ester Forgione, Alba Silipo, Roberta Marchetti, Marie Kubota, Takao Hashiguchi, Yoshiyuki Manabe, Koichi Fukase, Antonio Molinaro, Forgione, R. E., Di Carluccio, C., Kubota, M., Manabe, Y., Fukase, K., Molinaro, A., Hashiguchi, T., Marchetti, R., and Silipo, A.
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0301 basic medicine ,Glycan ,Magnetic Resonance Spectroscopy ,Protein Conformation ,Neuraminidase ,Organic chemistry ,lcsh:Medicine ,Mumps virus ,medicine.disease_cause ,01 natural sciences ,Article ,03 medical and health sciences ,Polysaccharides ,Viral entry ,medicine ,Humans ,Binding site ,lcsh:Science ,Viral Structural Proteins ,Host cell surface ,Binding Sites ,Multidisciplinary ,biology ,010405 organic chemistry ,Chemistry ,lcsh:R ,Chemical biology ,3. Good health ,0104 chemical sciences ,Molecular Docking Simulation ,Kinetics ,Hemagglutinins ,030104 developmental biology ,Biochemistry ,Docking (molecular) ,biology.protein ,lcsh:Q ,Hemagglutinin-neuraminidase - Abstract
Mumps virus is one of the main cause of respiratory illnesses in humans, especially children. Among the viral surface glycoproteins, the hemagglutinin – neuraminidase, MuV-HN, plays key roles in virus entry into host cells and infectivity, thus representing an ideal target for the design of novel inhibitors. Here we report the detailed analysis of the molecular recognition of host cell surface sialylated glycans by the viral glycoprotein MuV-HN. By a combined use of NMR, docking, molecular modelling and CORCEMA-ST, the structural features of sialoglycans/MuV-HN complexes were revealed. Evidence for a different enzyme activity toward longer and complex substrates compared to unbranched ligands was also examined by an accurate NMR kinetic analysis. Our results provide the basis for the structure-based design of effective drugs against mumps-induced diseases.
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- 2020
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8. The core fucose on an IgG antibody is an endogenous ligand of Dectin-1
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Shinya Hanashima, Yoshiki Yamaguchi, Yoshihiro Kamada, Tomoyuki Takebe, Masahiro Nagasaki, Naohito Ohno, Roberta Marchetti, Alba Silipo, Yoshiyuki Adachi, Yoshiyuki Manabe, Fabrizio Chiodo, Wataru Nihei, Kazuya Kabayama, Katsunori Tanaka, Yohei Takakura, Antonio Molinaro, Eiji Miyoshi, Hari Prasad Dulal, Hiroshi Tanaka, Koichi Fukase, Manabe, Yoshiyuki, Marchetti, Roberta, Takakura, Yohei, Nagasaki, Masahiro, Nihei, Wataru, Takebe, Tomoyuki, Tanaka, Katsunori, Kabayama, Kazuya, Chiodo, Fabrizio, Hanashima, Shinya, Kamada, Yoshihiro, Miyoshi, Eiji, Dulal, Hari Prasad, Yamaguchi, Yoshiki, Adachi, Yoshiyuki, Ohno, Naohito, Tanaka, Hiroshi, Silipo, Alba, Fukase, Koichi, Molinaro, Antonio, and Molecular cell biology and Immunology
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Glycosylation ,Ligands ,010402 general chemistry ,01 natural sciences ,Catalysis ,Fucose ,chemistry.chemical_compound ,Molecular recognition ,Aromatic amino acids ,Humans ,Lectins, C-Type ,Asparagine ,Cytotoxicity ,core fucose * N-glycan * Dectin-1 * IgG * Molecular recognition ,biology ,010405 organic chemistry ,Lectin ,General Medicine ,General Chemistry ,0104 chemical sciences ,chemistry ,Biochemistry ,Immunoglobulin G ,biology.protein ,Antibody - Abstract
The core fucose, a major modification of N -glycans, is implicated in immune regulation, such as the attenuation of the antibody-dependent cell-mediated cytotoxicity of antibody drugs and the inhibition of anti-tumor responses via promotion of PD-1 expression on T cells. Although the core fucose regulates many biological processes, no core fucose recognition molecule has been identified in mammals. In the present study, we discovered that Dectin-1, a known anti- b -glucan lectin, recognizes the core fucose on IgGs. A combination of biophysical experiments further suggested that Dectin-1 recognizes aromatic amino acids adjacent to the N -terminal asparagine residue at the glycosylation site as well as core fucose residue. Thus, Dectin-1 appears to be the first lectin-like molecule involved in the hetero-valent and specific recognition of characteristic N -glycans on antibodies.
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- 2019
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9. Sporadic Amyotrophic Lateral Sclerosis Due to a FUS P525L Mutation with Asymmetric Muscle Weakness and Anti-ganglioside Antibodies
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Masanobu Tanemoto, Kazuna Ikeda, Kazuki Yokokawa, Akihiro Matsumura, Tatsuo Manabe, Takashi Matsushita, Shun Shimohama, Shin Hisahara, Reiko Tsuda, Syuuichirou Suzuki, and Daisuke Yamamoto
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Adult ,amyotrophic lateral sclerosis ,Pathology ,medicine.medical_specialty ,anti-ganglioside antibody ,Mismatch negativity ,Case Report ,030204 cardiovascular system & hematology ,fused in sarcoma ,03 medical and health sciences ,0302 clinical medicine ,Gangliosides ,Internal Medicine ,Humans ,Medicine ,Amyotrophic lateral sclerosis ,FUS ,Muscle Weakness ,Ganglioside ,biology ,business.industry ,Muscle weakness ,General Medicine ,medicine.disease ,P525L mutation ,Mutation ,Mutation (genetic algorithm) ,biology.protein ,RNA-Binding Protein FUS ,Female ,030211 gastroenterology & hepatology ,Sarcoma ,medicine.symptom ,Antibody ,business ,Multifocal motor neuropathy - Abstract
Amyotrophic lateral sclerosis (ALS) due to a fused in sarcoma (FUS) P525L mutation is characterized by a rapidly progressive course. Multifocal motor neuropathy (MMN) may resemble ALS in early stage and is associated with anti-ganglioside antibodies. A 38-year-old woman was admitted to our hospital because of progressive muscle weakness in the right limbs. She had mild mental retardation and minor deformities. Initially, we suspected MMN given the asymmetric muscle weakness and detection of anti-ganglioside antibodies. However, physical and electrophysiological tests did not support MMN, instead suggesting ALS. We confirmed a heterozygous P525L mutation and finally diagnosed this case as ALS due to an FUS mutation.
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- 2021
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10. A Case of Miller-Fisher Syndrome with Syndrome of Inappropriate Secretion of Antidiuretic Hormone
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Yoshio Omote, Yasuhiro Manabe, Yumiko Nakano, Hisashi Narai, Koji Abe, and Shunya Fujiwara
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Osmole ,medicine.medical_specialty ,Ataxia ,biology ,hyponatremia ,business.industry ,Respiratory infection ,medicine.disease ,Immunoglobulin G ,syndrome of inappropriate secretion of antidiuretic hormone ,Intravenous Immunoglobulin Therapy ,Endocrinology ,Internal medicine ,Urine osmolality ,biology.protein ,Medicine ,Neurology (clinical) ,Neurology. Diseases of the nervous system ,medicine.symptom ,business ,Hyponatremia ,RC346-429 ,Antidiuretic ,Single Case − General Neurology ,miller-fisher syndrome - Abstract
We report a 72-year-old woman with Miller-Fisher syndrome (MFS) with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). She developed diplopia and unsteady gait a week after an upper respiratory infection. Neurologic examination revealed ophthalmoplegia, ataxia, symmetrical weakness, numbness, and areflexia. She underwent intravenous immunoglobulin therapy. Her serum sodium concentration decreased to 119 mEq/L on day 12. She had low plasma osmolarity (254 mosm/kg), high urine osmolarity (457 mosm/kg), and high urine sodium level (73 mEq/L), while the blood level of antidiuretic hormone was normal. Anti-GD1b immunoglobulin G (IgG), -GQ1b IgG, -GT1a IgG, and -Gal-C IgM antibodies were positive. We diagnosed her with MFS overlapping with SIADH. Four weeks after onset, her symptoms recovered. The elevation of anti-GD1b, -GQ1b, and -GT1a antibodies that recognize disialosyl residue may be pathologically related to SIADH.
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- 2021
11. Chemical Biology Study on N-glycans
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Yoshiyuki Manabe
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chemistry.chemical_classification ,Glycan ,Glycan array ,biology ,Biochemistry ,Chemistry ,Organic Chemistry ,biology.protein ,Chemical biology ,Glycoprotein - Published
- 2021
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12. Shelter effect of the gaps within rock piles to reduce the predation on Japanese eel Anguilla japonica
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Kazuki Matsushige, Rei Sakanoue, Miyuki Manabe, Shun Satoh, Yusuke Hibino, Yoshiya Yasutake, Noritaka Mochioka, and Kazuo Utida
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Fishery ,biology ,Japanese eel ,Aquatic Science ,biology.organism_classification ,Japonica ,Predation - Published
- 2021
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13. Quantitative evaluation of COVID-19 pneumonia severity by CT pneumonia analysis algorithm using deep learning technology and blood test results
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Akishige Taniguchi, Kyoko Hirakawa, Shinichi Hamamoto, Katsuko Murata, Tetsunori Maebayashi, Yukio Miki, Shu Matsushita, Kazuki Matsushita, Tomohisa Okuma, and Takao Manabe
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Prothrombin time ,Creatinine ,medicine.diagnostic_test ,biology ,business.industry ,Renal function ,medicine.disease ,Procalcitonin ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Pneumonia ,chemistry.chemical_compound ,0302 clinical medicine ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,White blood cell ,medicine ,biology.protein ,Blood test ,Radiology, Nuclear Medicine and imaging ,Creatine kinase ,business ,Algorithm - Abstract
To evaluate whether early chest computed tomography (CT) lesions quantified by an artificial intelligence (AI)-based commercial software and blood test values at the initial presentation can differentiate the severity of COVID-19 pneumonia. This retrospective study included 100 SARS-CoV-2-positive patients with mild (n = 23), moderate (n = 37) or severe (n = 40) pneumonia classified according to the Japanese guidelines. Univariate Kruskal–Wallis and multivariate ordinal logistic analyses were used to examine whether CT parameters (opacity score, volume of opacity, % opacity, volume of high opacity, % high opacity and mean HU total on CT) as well as blood test parameters [procalcitonin, estimated glomerular filtration rate (eGFR), C-reactive protein, % lymphocyte, ferritin, aspartate aminotransferase, lactate dehydrogenase, alanine aminotransferase, creatine kinase, hemoglobin A1c, prothrombin time, activated partial prothrombin time (APTT), white blood cell count and creatinine] differed by disease severity. All CT parameters and all blood test parameters except procalcitonin and APPT were significantly different among mild, moderate and severe groups. By multivariate analysis, mean HU total and eGFR were two independent factors associated with severity (p
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- 2021
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14. Clonal evidence for the development of neuroblastoma with extensive copy‐neutral loss of heterozygosity arising in a mature teratoma
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Satoko Takahashi, Junko Takita, Hiroki Yoshihara, Kenichi Yoshida, Seishi Ogawa, Ryunosuke Saiki, Koyu Suzuki, Taiki Nozaki, Rintaro Ono, Daisuke Hasegawa, Hiroo Ueno, Masafumi Seki, Atsuko Nakazawa, and Atsushi Manabe
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0301 basic medicine ,malignant transformation ,endocrine system ,Cancer Research ,endocrine system diseases ,Case Report ,Ovary ,Biology ,Germline ,Malignant transformation ,law.invention ,Loss of heterozygosity ,neuroblastoma ,03 medical and health sciences ,0302 clinical medicine ,law ,Neuroblastoma ,medicine ,teratoma ,neoplasms ,Gene ,copy‐neutral loss of heterozygosity ,General Medicine ,medicine.disease ,female genital diseases and pregnancy complications ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,genomic analysis ,030220 oncology & carcinogenesis ,cancer genome/genetics ,Cancer research ,Suppressor ,Teratoma - Abstract
Mature teratomas are usually benign tumors that rarely undergo malignant transformation. We report an advanced neuroblastoma arising in a mature teratoma of the ovary. Whole‐exome sequencing identified extensive copy‐neutral loss of heterozygosity (LOH) in both neuroblastoma and teratoma elements, suggesting that the neuroblastoma evolved from the teratoma. In addition, several truncating germline heterozygous variants in tumor suppressor genes, including RBL2 and FBXW12, became homozygous as a result of LOH. Collectively, we speculate that extensive LOH in teratoma cells may force heterozygous germline variants to become homozygous, which, in turn, may contribute to the development of neuroblastoma with the acquisition of additional chromosomal changes., A model of malignant transformation from teratoma to neuroblastoma.
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- 2021
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15. Inflammatory Cell Numbers in the Stomach of Japanese Subjects with Endoscopically Normal Mucosa without Helicobacter pylori Infection
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Akiko Shiotani, Noriaki Manabe, Tomoari Kamada, Sohachi Fujimoto, Takashi Akiyama, Mitsuhiko Suehiro, Toshihiro Takao, Ken Haruma, Yoshiyuki Yamanaka, and Naoki Sumi
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medicine.medical_specialty ,Helicobacter pylori infection ,biology ,business.industry ,Stomach ,Gastroenterology ,Fundic Gland ,Inflammation ,Histology ,General Medicine ,Helicobacter pylori ,biology.organism_classification ,medicine.anatomical_structure ,Internal medicine ,Gastric mucosa ,Medicine ,medicine.symptom ,Gastritis ,business - Abstract
Introduction: Since inflammatory cells, such as lymphocytes and plasma cells, normally inhabit the stomach, the border between normal and mild inflammation is difficult to visually determine using the updated Sydney system scale of gastritis. Additionally, eosinophils in the gastric mucosa must be counted to diagnose eosinophilic gastritis. We aimed to determine the normal number of inflammatory cells in patients with endoscopically normal mucosa and without Helicobacter pylori infections. Methods: We assessed patients aged 20–79 years, who had undergone upper gastrointestinal endoscopy at Kawasaki Medical School Hospital between January 2010 and December 2014. Inflammatory cells were counted in 1,000 μm2 fields of pyloric and fundic gland mucosal biopsy specimens. We finally included 325 (male, n = 141; female, n = 184; average age = 49.3 years) patients without inflammation who had H. pylori-negative endoscopic results and negative histological findings interpreted based on the updated Sydney System and the Kyoto classification of gastritis. Results: The average numbers of nucleated cells were 83.3 ± 14.2 and 65.4 ± 12.6/mm2 in the pyloric and fundic gland mucosae, respectively. Inflammatory cells were significantly more abundant in the pyloric mucosa than in the fundic gland mucosa (p < 0.05). Age and sex distribution did not significantly differ. Eosinophils were absent or scanty in the gastric mucosae of both glands in all patients. Conclusion: We determined the absolute values of inflammatory cells, including eosinophils, in normal mucosae of pyloric and fundic glands. These findings could be important in defining gastric mucosal inflammation, including eosinophilic gastritis diagnosis.
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- 2021
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16. Chemical Synthesis of Sialyl N-Glycans and Analysis of Their Recognition by Neuraminidase
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Asuka Shirakawa, Kumpei Yano, Seiji Masui, Koichi Fukase, Antonio Molinaro, Yoshiyuki Manabe, Roberta Marchetti, Alba Silipo, Shirakawa, A., Manabe, Y., Marchetti, R., Yano, K., Masui, S., Silipo, A., Molinaro, A., and Fukase, K.
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Steric effects ,Glycan ,Glycosylation ,Stereochemistry ,Oxocarbenium ,Mannose ,Neuraminidase ,Chemical synthesis ,Catalysis ,Mass Spectrometry ,chemistry.chemical_compound ,Sialic Acid ,Influenza A Virus, H1N1 Subtype ,Polysaccharides ,deuterium labeling ,Polysaccharide ,biology ,General Chemistry ,Deuterium ,Sialic acid ,carbohydrates (lipids) ,chemistry ,N-glycan ,biology.protein ,Sialic Acids ,Spectrophotometry, Ultraviolet - Abstract
The chemical synthesis of a fully sialylated tetraantennary N-glycan has been achieved for the first time by using the diacetyl strategy, in which NHAc is protected as NAc2 to improve reactivity by preventing intermolecular hydrogen bonds. Another key was the glycosylation to the branched mannose in an ether solvent, which promoted the desired glycosylation by stabilizing the oxocarbenium ion intermediate. Furthermore, high α-selectivity of these glycosylation reactions was realized by utilizing remote participation. Two asymmetrically deuterium labeled sialyl N-glycans were also synthesized by the same strategy. The synthesized N-glycans were used to probe the molecular basis of H1N1 neuraminidase recognition. The asymmetrically deuterated N-glycans revealed a difference in the recognition of sialic acid on each branch. Meanwhile, the tetraantennary N-glycan was used to evaluate the effects of multivalency and steric hinderance by forming branching structures.
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- 2021
17. Characterisation of the dynamic interactions between complex N-glycans and human CD22
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Roberta Marchetti, Jussara Amato, Sonsoles Martín-Santamaría, Alessandra Lacetera, Koichi Fukase, Alba Silipo, Antonio Randazzo, Antonio Molinaro, Bruno Pagano, Angela Zampella, Cristina Di Carluccio, Paul R. Crocker, Rosa Ester Forgione, Rosa Lanzetta, Enrique Crisman, Yoshiyuki Manabe, European Commission, Mizutani Foundation for Glycoscience, Di Carluccio, Cristina, Manabe, Yoshiyuki, Forgione, Rosa Ester, Lacetera, Alessandra, Amato, Jussara, Pagano, Bruno, Randazzo, Antonio, Zampella, Angela, Lanzetta, Rosa, Fukase, Koichi, Molinaro, Antonio, Crocker, Paul R., Martín-Santamaría, Sonsoles, Marchetti, Roberta, Silipo, A., Di Carluccio, Cristina [0000-0001-5895-9829], Manabe, Yoshiyuki [0000-0002-5515-3923], Forgione, Rosa Ester [0000-0002-3306-2377], Lacetera, Alessandra [0000-0003-3926-2684], Amato, Jussara [0000-0001-6096-3544], Pagano, Bruno [0000-0002-7716-9010], Randazzo, Antonio [0000-0002-9192-7586], Zampella, Angela [0000-0002-6170-279X], Lanzetta, Rosa [0000-0002-1472-5825], Fukase, Koichi [0000-0001-8844-0710], Molinaro, Antonio [0000-0002-3456-7369], Crocker, Paul R. [0000-0001-6230-0293], Martín-Santamaría, Sonsoles [0000-0002-7679-0155], Marchetti, Roberta [0000-0002-7173-7099], Silipo, A. [0000-0002-5394-6532], DI CARLUCCIO, Cristina, Crisman, Enrique, Manabe Manabey Chem Sci Osaka-U Ac J, Yoshiyuki Manabe Manabey Chem Sci Osaka-U Ac J, Koichi, Fukase, Crocker, Paul R, Martin-Santamaria, Sonsole, and Silipo, Alba
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Glycan ,Sialic Acid Binding Ig-like Lectin 2 ,N-glycans ,Autoimmune responses ,Sialic acids ,Molecular Dynamics Simulation ,010402 general chemistry ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Molecular recognition ,NMR spectroscopy ,immune system diseases ,Polysaccharides ,hemic and lymphatic diseases ,Carbohydrate Conformation ,Humans ,Molecular Biology ,B-Lymphocytes ,biology ,010405 organic chemistry ,Organic Chemistry ,CD22 ,Galactose ,Nuclear magnetic resonance spectroscopy ,NMR ,0104 chemical sciences ,3. Good health ,Sialic acid ,chemistry ,Siglec ,Siglecs ,N-glycan ,biology.protein ,Molecular Medicine - Abstract
12 p.-6 fig.-1 schem., CD22 (Siglec-2) is a B-cell surface inhibitory protein capable of selectively recognising sialylated glycans, thus dampening autoimmune responses against self-antigens. Here we have characterised the dynamic recognition of complex-type N-glycans by human CD22 by means of orthogonal approaches including NMR spectroscopy, computational methods and biophysical assays. We provide new molecular insights into the binding mode of sialoglycans in complex with h-CD22, highlighting the role of the sialic acid galactose moieties in the recognition process, elucidating the conformational behaviour of complex-type N-glycans bound to Siglec-2 and dissecting the formation of CD22 homo-oligomers on the B-cell surface. Our results could enable the development of additional therapeutics capable of modulating the activity of h-CD22 in autoimmune diseases and malignancies derived from B-cells., H2020 Marie Skłodowska-Curie Actions. Grant Numbers: 642157, 814102 Mizutani Foundation for Glycoscience. Grant Number: 2014-2015
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- 2020
18. Synthesis of ABO blood group antigens and functional glycan display on the cell surface
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Yoshiyuki Manabe, Kazuya Kabayama, Masato Tsutsui, and Koichi Fukase
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Glycan ,medicine.anatomical_structure ,Antigen ,biology ,Biochemistry ,Chemistry ,ABO blood group system ,Organic Chemistry ,Cell ,biology.protein ,medicine - Published
- 2020
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19. The 'caterpillar sign': a novel endoscopic indicator of eosinophilic esophagitis
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Noriaki Manabe, Jun Nakamura, Ken Haruma, Maki Ayaki, Tomoari Kamada, Kazuhiko Inoue, Kazumi Imamura, and Minoru Fujita
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medicine.medical_specialty ,Severity of Illness Index ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Clinical significance ,In patient ,Esophagus ,Caterpillar ,Eosinophilic esophagitis ,Retrospective Studies ,Esophageal mucosa ,biology ,business.industry ,fungi ,Eosinophilic Esophagitis ,biology.organism_classification ,medicine.disease ,medicine.anatomical_structure ,Cardiothoracic surgery ,030220 oncology & carcinogenesis ,030211 gastroenterology & hepatology ,Esophagoscopy ,business ,Sign (mathematics) - Abstract
Although several endoscopic findings of eosinophilic esophagitis (EoE), such as the EoE endoscopic reference score (EREFS), have been reported thus far, these endoscopic findings exhibit low specificity. Furthermore, most of these endoscopic findings were evaluated solely in patients from Western nations. We have recently noted a fragile, protruded mucosal lesion sandwiched between longitudinal furrows (similar to caterpillar tracks) on the esophagus in patients with EoE. We have termed this novel finding the "caterpillar sign". This study evaluated the clinical significance of the caterpillar sign and the EREFS for diagnosis of EoE in Japanese patients.We retrospectively analyzed endoscopic images from 165 consecutive patients who underwent tissue collection on suspicion of EoE. We compared the clinical significance between the EREFS and the caterpillar sign. We defined EoE as the presence of ≥ 15 eosinophils on esophageal mucosa per high-power field; control images had 15 eosinophils per high-power field. For evaluation of endoscopic diagnosis capacity using the total EREFS, 2 points was set as the cutoff value. The presence or absence of the caterpillar sign was evaluated.The sensitivity, specificity, positive predictive value, and negative predictive value of total EREFS ≥ 2 for the diagnosis of EoE were 100%, 56.2%, 56.6%, and 100%; for the caterpillar sign, those values were 83.3%, 98.1%, 96.2%, and 91.2%, respectively. Interobserver agreement for identification of the caterpillar sign was substantial (κ = 0.80) CONCLUSIONS: The caterpillar sign could be a novel reliable indicator for endoscopic diagnosis of EoE.
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- 2020
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20. MicroRNA‐200b is a potential biomarker of the expression of PD‐L1 in patients with lung cancer
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Nobuaki Kobayashi, Yu Hara, Chisato Kamimaki, Sousuke Kubo, Katsushi Tanaka, Hongmei Piao, Shuhei Teranishi, Seigo Katakura, Keisuke Watanabe, Kentaro Nakashima, Makoto Kudo, Takeshi Kaneko, Hisashi Hashimoto, Masaki Yamamoto, Nobuyuki Horita, and Saki Manabe
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Male ,non‐small cell lung cancer ,Lung Neoplasms ,exosomes ,lcsh:RC254-282 ,B7-H1 Antigen ,03 medical and health sciences ,0302 clinical medicine ,PD-L1 ,Cell Line, Tumor ,microRNA ,medicine ,Biomarkers, Tumor ,Gene silencing ,Humans ,Liquid biopsy ,programmed cell death 1 ligand 1 ,Lung cancer ,Aged ,miRNA ,Aged, 80 and over ,Gene knockdown ,biology ,business.industry ,General Medicine ,Original Articles ,Middle Aged ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,MicroRNAs ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Cancer research ,Biomarker (medicine) ,Original Article ,Female ,business ,Biomarkers - Abstract
Background Advanced non‐small cell lung cancer (NSCLC) has a high mortality rate and poor prognosis. However, outcomes have gradually improved after the introduction of novel immunotherapies, including immune checkpoint inhibitors (ICIs). Although programmed death‐ligand 1 (PD‐L1) expression in tumor tissues is a known biomarker for guiding ICI treatment of NSCLC, challenges such as difficulty of liquid biopsy and heterogeneous results during treatment persist. This study evaluated the potential of miR200b as a surrogate biomarker for PD‐L1 expression. Methods We used the human lung cancer cell lines H226, H460, H520, A549, and H1975. miR200b expression in blood and bronchoscopy specimens of NSCLC patients was evaluated using reverse‐transcription‐quantitative PCR. Using flow cytometry, PD‐L1 expression in vitro, as well as in tumor tissues, was evaluated after transfection with a mimic miR200b or siRNA. Results miR200b expression negatively correlated with PD‐L1 expression in all cell lines. The induction or knockdown of miR200b also altered PD‐L1 expression in vitro. The patient group with a PD‐L1 tumor proportion score ≥ 50% had significantly lower miR200b expression in the bronchoscopy specimens (P = 0.025) and serum‐derived exosomes (P = 0.022) than that with PD‐L1 tumor proportion score, Relative to patients with a PD‐L1 tumor proportion score of
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- 2020
21. Concise and reliable synthesis of glycodendrimers via self-activating click chemistry: Robust strategy for mimicking multivalent glycan-pathogen interactions
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Kindi Farabi, Katsunori Tanaka, Shuto Miyake, Shang-Cheng Hung, Toshiyuki Yamaji, Masato Tsutsui, Kazuya Kabayama, Yoshiyuki Manabe, Hiroaki Ichikawa, and Koichi Fukase
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Glycan ,Dendrimers ,biology ,Chemistry ,Organic Chemistry ,Hemagglutinin (influenza) ,Shiga toxin ,Biochemistry ,Polysaccharides ,Dendrimer ,biology.protein ,Click chemistry ,Avidity ,Click Chemistry ,Pathogen - Abstract
Individual interactions between glycans and their receptors are usually weak, although these weak interactions can combine to realize a strong interaction (multivalency). Such multivalency plays a crucial role in the recognition of host cells by pathogens. Glycodendrimers are useful materials for the reconstruction of this multivalent interaction. However, the introduction of a large number of glycans to a dendrimer core is fraught with difficulties. We herein synthesized antipathogenic glycodendrimers using the self-activating click chemistry (SACC) method developed by our group. The excellent reactivity of SACC enabled the efficient preparation of sialyl glycan and Gb3 glycan dendrimers, which exhibited strong avidity toward hemagglutinin on influenza virus and Shiga toxin B subunit produced by Escherichia coli, respectively. We demonstrated the usefulness of SACC-based glycodendrimers as antipathogenic compounds.
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- 2020
22. Contribution of the retronasal odor of soy sauce to salt reduction
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Ryoichi Sakaue, Mariko Manabe, and Akio Obata
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Taste ,Hot Temperature ,Seasoning ,030309 nutrition & dietetics ,Umami ,Sensory analysis ,Gas Chromatography-Mass Spectrometry ,03 medical and health sciences ,0404 agricultural biotechnology ,Olfactometry ,Humans ,Cooking ,Palatability ,Food science ,Sodium Chloride, Dietary ,Flavor ,Aroma ,0303 health sciences ,biology ,Chemistry ,Soy Foods ,04 agricultural and veterinary sciences ,biology.organism_classification ,040401 food science ,Flavoring Agents ,Odor ,Odorants ,Food Science - Abstract
The characteristic odor of soy sauce has been reported to enhance saltiness. However, soy sauce is used not only as a sauce that is added directly to food, but also as a seasoning. In addition, some of the aromatic compounds that contribute to the soy sauce odor change during cooking or heating. In the present study, the effects of the retronasal odor of uncooked and cooked soy sauce on the enhancement of saltiness and palatability of a low-salt solution were sensory evaluated. A probit analysis indicated that the saltiness-enhancing effect of the odor of 15% uncooked soy sauce was lost by heating. The odors of soy sauce boiled for 10 min (cooked SS) and the residue of soy sauce heated at 200 °C for 1 min improved the palatability of the low-salt solution. Gas chromatography (GC) analyses, namely, GC-olfactometry and GC-mass spectrometry, showed that one active candidate aromatic component of soy sauce contributing to saltiness enhancement was 3-methyl-1-butanol (3-Me-BuOH). The saltiness-enhancing effects of cooked SS could be restored by adding 3-Me-BuOH, as assessed by the sensory evaluation. These data demonstrated that 3-Me-BuOH contributes to saltiness enhancement. PRACTICAL APPLICATION: We found that the odor of cooked soy sauce could improve the palatability of low-salt food. Although the saltiness-enhancing effect provided by the odor of uncooked soy sauce was lost, the saltiness-enhancing effect of the odor of cooked soy sauce can be partially restored by adding 3-methyl butanol. Thus, not only the odor of unheated soy sauce but also the odor of heated soy sauce following addition of 3-methyl butanol may be useful for developing palatable salt-reduced food.
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- 2020
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23. Afatinib + bevacizumab combination therapy in <scp> EGFR </scp> ‐mutant <scp>NSCLC</scp> patients with osimertinib resistance: Protocol of an <scp>open‐label</scp> , phase <scp>II</scp> , multicenter, <scp>single‐arm</scp> trial
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Hiroki Watanabe, Sousuke Kubo, Katsushi Tanaka, Nobuyuki Hirama, Ryo Nagasawa, Keisuke Watanabe, Kentaro Nakashima, Chisato Kamimaki, Hongmei Piao, Makoto Kudo, Shuhei Teranishi, Ayako Aoki, Nobuaki Kobayashi, Yu Hara, Saki Manabe, Ryota Ushio, Seigo Katakura, Hao Chen, Nobuyuki Horita, Takeshi Kaneko, Hisashi Hashimoto, and Masaki Yamamoto
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Bevacizumab ,Combination therapy ,Afatinib ,Salvage therapy ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Osimertinib ,Epidermal growth factor receptor ,Lung cancer ,biology ,business.industry ,General Medicine ,medicine.disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,business ,Progressive disease ,medicine.drug - Abstract
Introduction As most patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) develop progressive disease after treatment with osimertinib, it is important to develop more effective treatment options. Afatinib has been shown to be more effective in in vitro studies than osimertinib when used in cancer cell lines containing some specific EGFR mutations. Therefore, afatinib may be an effective solution, especially when used in combination with an anti-VEGF agent such as bevacizumab. Methods A phase II multicenter, open-label, single-arm trial has been initiated to evaluate the efficacy and safety of afatinib and bevacizumab combination as salvage therapy for EGFR-mutated lung cancer in patients previously treated with osimertinib. The primary endpoint will be the objective response rate (ORR) and secondary endpoints are progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs). Discussion A previous study indicated that afatinib inhibits lung cancer cells with specific EGFR mutations more effectively than other EGFR-TKIs such as osimertinib. Therefore, we expect that combination therapy using afatinib and bevacizumab will be effective in patients previously treated with osimertinib (registration no. jRCTs031190077).
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- 2020
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24. Tensin2 is important for podocyte-glomerular basement membrane interaction and integrity of the glomerular filtration barrier
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Osamu Suzuki, Keiko Yasuda, Noboru Manabe, Kozue Uchio-Yamada, Ken-ichi Akagi, and Yoko Monobe
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0301 basic medicine ,Physiology ,Integrin ,030232 urology & nephrology ,Glomerulus (kidney) ,urologic and male genital diseases ,Podocyte ,03 medical and health sciences ,0302 clinical medicine ,Tensins ,Glomerular Basement Membrane ,Cell Adhesion ,medicine ,Animals ,Cells, Cultured ,Mice, Knockout ,biology ,Podocytes ,urogenital system ,Chemistry ,Glomerular basement membrane ,Age Factors ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Animals, Newborn ,biology.protein ,Glomerular Filtration Barrier ,Laminin ,Stress, Mechanical ,Thickening ,Glomerular Filtration Rate - Abstract
Tensin2 (Tns2), an integrin-linked protein, is enriched in podocytes within the glomerulus. Previous studies have revealed that Tns2-deficient mice exhibit defects of the glomerular basement membrane (GBM) soon after birth in a strain-dependent manner. However, the mechanisms for the onset of defects caused by Tns2 deficiency remains unidentified. Here, we aimed to determine the role of Tns2 using newborn Tns2-deficient mice and murine primary podocytes. Ultrastructural analysis revealed that developing glomeruli during postnatal nephrogenesis exhibited abnormal GBM processing due to ectopic laminin-α2accumulation followed by GBM thickening. In addition, analysis of primary podocytes revealed that Tns2 deficiency led to impaired podocyte-GBM interaction and massive expression of laminin-α2in podocytes. Our study suggests that weakened podocyte-GBM interaction due to Tns2 deficiency causes increased mechanical stress on podocytes by continuous daily filtration after birth, resulting in stressed podocytes ectopically producing laminin-α2, which interrupts GBM processing. We conclude that Tns2 plays important roles in the podocyte-GBM interaction and maintenance of the glomerular filtration barrier.
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- 2020
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25. Siphonaxanthin, a carotenoid from green algae Codium cylindricum, protects Ob/Ob mice fed on a high-fat diet against lipotoxicity by ameliorating somatic stresses and restoring anti-oxidative capacity
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Yuki Manabe, Tatsuya Sugawara, and Jiawen Zheng
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0301 basic medicine ,Male ,Antioxidant ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Mice, Obese ,Xanthophylls ,medicine.disease_cause ,Kidney ,Antioxidants ,0302 clinical medicine ,Endocrinology ,Chlorophyta ,Non-alcoholic Fatty Liver Disease ,Carotenoid ,Nutrition and Dietetics ,Fatty liver ,Hep G2 Cells ,Endoplasmic Reticulum Stress ,medicine.anatomical_structure ,Lipotoxicity ,Liver ,Hepatocyte ,Lipogenesis ,Oxidation-Reduction ,Signal Transduction ,medicine.medical_specialty ,NF-E2-Related Factor 2 ,Endothelium reticulum stress ,030209 endocrinology & metabolism ,Protein degradation ,Biology ,Diet, High-Fat ,Thiobarbituric Acid Reactive Substances ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,Humans ,Obesity ,Non-alcoholic fatty liver diseases ,030109 nutrition & dietetics ,Membrane Proteins ,medicine.disease ,Lipid Metabolism ,Gene Expression Regulation ,Oxidative stress ,Dietary Supplements ,Steatosis ,Heme Oxygenase-1 - Abstract
Oxidative stress is implicated in the pathogenesis of many diseases including obesity, non-alcoholic fatty liver disease, and diabetes mellitus. Previously, we reported that siphonaxanthin, a carotenoid from green algae, elicited a potent inhibitory effect on hepatic de novo lipogenesis, and an anti-obesity effect in both 3T3L1 cells and KKAy mice. Thus, we hypothesized that consumption of siphonaxanthin could improve metabolic disorders including hepatic steatosis and systemic adiposity, as well as ameliorate somatic stress under obese conditions. Both the hepatocyte cell line HepG2 and a mouse model of severe obesity, produced by feeding Ob/Ob mice on a high-fat diet (HFD), were used to test this hypothesis. In obese mice, siphonaxanthin intake did not improve liver steatosis or systemic adiposity. However, intake did lower plasma glucose and alanine aminotransferase (ALT) levels and diminished hepatic lipid peroxidation products and antioxidant gene expression, which increased significantly in control group obese mice. Renal protein carbonyl content decreased significantly in the siphonaxanthin group, which might also indicate an ameliorated oxidative stress. Siphonaxanthin restored gene expression related to antioxidant signaling, lipid β-oxidation, and endoplasmic-reticulum-associated protein degradation in the kidney, which decreased significantly in obese mice. Liver and kidney responded to obesity-induced somatic stress in a divergent pattern. In addition, we confirmed that siphonaxanthin potently induced Nrf2-regulated antioxidant signaling in HepG2 cells. In conclusion, our results indicated that siphonaxanthin might protect obesity-leading somatic stress through restoration of Nrf2-regulated antioxidant signaling, and might be a promising nutritional supplement.
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- 2020
26. Validation of a Method for Quantification of Lutein in Spinach Using High-Performance Liquid Chromatography: Interlaboratory Study
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H. Maeda, L Yonekura, Akemi Yasui, K Mizuta, Tomohiro Koiwa, M Miyamoto, F Takahashi, Eiichi Kotake, K Iwamaru, E Watanabe, Y Manabe, Yusuke Hiejima, R Yamoto, Takefumi Sonoda, H Ueda, Masahiro Asano, T Sugawara, M Morioka, and M Kumagai
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Lutein ,030309 nutrition & dietetics ,High-performance liquid chromatography ,Analytical Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Human health ,0302 clinical medicine ,Spinacia oleracea ,Humans ,Environmental Chemistry ,Chromatography, High Pressure Liquid ,Pharmacology ,Detection limit ,0303 health sciences ,Reproducibility ,Measurement method ,Chromatography ,biology ,Chemistry ,Reproducibility of Results ,Repeatability ,biology.organism_classification ,Food ,030221 ophthalmology & optometry ,Spinach ,Agronomy and Crop Science ,Food Science - Abstract
Background Lutein is gaining attention as a strong antioxidant contained in foods. It accumulates in the human blood and retina, and is considered to play an important role in the body, especially in the eyes. Objective A method to determine the lutein content of raw spinach (Spinacia oleracea L.) was developed with the aim of its enactment as a Japanese agricultural standard (JAS) measurement method for components beneficial to human health. Methods An interlaboratory study was conducted to evaluate an analytical method for the determination of lutein in spinach. The detection limit and quantification limit of lutein for this method were 0.2 and 0.7 mg/kg, respectively. Twelve participating laboratories independently analyzed test samples (five pairs of blind duplicates) using high-performance liquid chromatography (HPLC). Results After removal of a few outliers, the repeatability relative standard deviation (RSDr), reproducibility (RSDR), and predicted RSDR of the evaluated method were 3.4–7.5, 4.6–13, and 7.5–8.5%, respectively, in a concentration range from 64.9–150 mg/kg. Conclusions The HorRat values (RSDR/predicted RSDR) of the lutein concentration were calculated to be 0.61–1.6. Highlights The study results indicate the acceptable precision of this method.
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- 2020
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27. Expression and localization of cellular FLICE-like inhibitory protein (cFLIP), an anti-apoptotic factor, in corpora lutea during the estrous cycle and pregnancy in Thai swamp buffalo (Bubalus bubalis)
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Noboru Manabe and Kannika Wongpanit
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Estrous cycle ,endocrine system ,0303 health sciences ,Messenger RNA ,Pregnancy ,030219 obstetrics & reproductive medicine ,urogenital system ,media_common.quotation_subject ,Proteolytic enzymes ,Biology ,medicine.disease ,Blot ,Andrology ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Apoptosis ,medicine ,Animal Science and Zoology ,Ovulation ,Corpus luteum ,hormones, hormone substitutes, and hormone antagonists ,reproductive and urinary physiology ,030304 developmental biology ,media_common - Abstract
In female mammals, luteal cells rapidly proliferate and form corpora lutea (CLs) after ovulation. The corpus luteum (CL) plays crucial roles in establishing and maintaining pregnancy. To gain further insights into the role of cellular FLICE-like inhibitory protein (cFLIP), an anti-apoptosis factor that is structurally similar to procaspase-8 but lacks proteolytic enzyme activity, we examined the expression in CLs of Thai swamp buffalos (Bubalus bubalis) during the early, mid, and late stage of the estrous cycle and pregnancy. cFLIP short form and long form (cFLIP S and cFLIP L , respectively) mRNA and protein levels were assessed by reverse transcription-polymerase chain reaction and western blotting, respectively. cFLIP S mRNA levels were low in the mid and late stages of the estrous cycle and increased during pregnancy (P L mRNA was highly expressed in CLs during pregnancy and was lower in the mid and late stages of the estrous cycle. The level of cFLIP S protein was high in CLs during pregnancy and low levels were noted in the mid stage of the estrous cycle (P L protein were demonstrated in CLs during pregnancy and lower levels were found in CLs during the early stage of the estrous cycle. Strong positive immunohistochemical staining for cFLIP S/L proteins was observed in luteal cells during pregnancy. The present findings revealed that cFLIP was at the highest level in CLs during pregnancy, and this may act as a dominant survival anti-apoptotic factor by inhibiting intracellular apoptosis signal transduction in luteal cells of CLs during pregnancy.
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- 2020
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28. Return to play in professional baseball players following transforaminal endoscopic decompressive spine surgery under local anesthesia
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Toshinori Sakai, Hiroaki Manabe, Koichi Sairyo, Yoichiro Takata, Yasuyuki Omichi, Nobutoshi Takamatsu, Kosuke Sugiura, Toru Maeda, Ayaka Hashimoto, Yoshihiro Ishihama, and Kazuta Yamashita
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Sciatica ,030222 orthopedics ,medicine.medical_specialty ,biology ,Pulsed radiofrequency ,business.industry ,Decompression ,Athletes ,Case Report ,biology.organism_classification ,Surgery ,03 medical and health sciences ,Dissection ,0302 clinical medicine ,Spine surgery ,030220 oncology & carcinogenesis ,medicine ,Back pain ,Orthopedics and Sports Medicine ,Local anesthesia ,medicine.symptom ,business ,human activities - Abstract
Transforaminal endoscopic discectomy has been established as the least minimally invasive spine surgical procedure because it avoids the surgical morbidity from surgical dissection and denervation of normal anatomy responsible for the functional stability of the spine. There have been few reports on endoscopic spine surgery for professional athletes who are dependent on the preservation of vital anatomy to maintain the highest level of function. This report is on five Japanese professional baseball players who underwent transforaminal endoscopic foraminoplasty-discectomy with pulsed radiofrequency thermal annuloplasty under the local anesthesia. There were no adverse surgical events nor complications. Three athletes suffered from discogenic back pain, one from symptomatic herniated nucleus pulposus (HNP), and another player from sciatica due to foraminal stenosis. Three players decided to undergo surgery at the beginning of the off-season. Therefore, they returned to professional play at the beginning of the following season. The remaining two players underwent surgery just before the beginning of the next season. They all returned to play sooner than with traditional open decompression. Two players returned to play about one month after the start of the season. All five players quickly returned to their sport within three months despite the rigors required of their sport to maintain high proficiency and were able to complete the season.
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- 2020
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29. Upregulation of cancer-associated gene expression in activated fibroblasts in a mouse model of non-alcoholic steatohepatitis
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Yoshihiro Ogawa, Yutaka Inagaki, Takayoshi Suganami, Sayaka Kanai, Tomomi Hatayama, Shinji Tanaka, Masahiro Asakawa, Xunmei Yuan, Takeru Sakai, Shu Shimada, Katsuhito Fujiu, Ichiro Manabe, Ibuki Shirakawa, Shoji Yamaoka, Yoshimitsu Akiyama, Tetsuya Yamada, and Michiko Itoh
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Liver Cirrhosis ,Male ,0301 basic medicine ,lcsh:Medicine ,Apoptosis ,medicine.disease_cause ,Mice ,0302 clinical medicine ,Cell Movement ,Non-alcoholic Fatty Liver Disease ,Fibrosis ,Neoplasms ,Gene expression ,lcsh:Science ,Non-alcoholic steatohepatitis ,Mice, Knockout ,Regulation of gene expression ,Multidisciplinary ,Liver Neoplasms ,Metabolic syndrome ,Up-Regulation ,Experimental models of disease ,Gene Expression Regulation, Neoplastic ,Liver ,030220 oncology & carcinogenesis ,Disease Progression ,Fibroblast Growth Factor 9 ,Carcinoma, Hepatocellular ,Biology ,Article ,03 medical and health sciences ,FGF9 ,Downregulation and upregulation ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Cell Proliferation ,Gene Expression Profiling ,lcsh:R ,Fibroblasts ,medicine.disease ,digestive system diseases ,Mice, Inbred C57BL ,Gene expression profiling ,030104 developmental biology ,Cancer research ,lcsh:Q ,Steatohepatitis ,Carcinogenesis ,Neoplasm Transplantation - Abstract
Non-alcoholic steatohepatitis (NASH), characterized by chronic inflammation and fibrosis, is predicted to be the leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the next decade. Although recent evidence suggests the importance of fibrosis as the strongest determinant of HCC development, the molecular mechanisms underlying NASH-induced carcinogenesis still remain unclear. Here we performed RNA sequencing analysis to compare gene expression profiles of activated fibroblasts prepared from two distinct liver fibrosis models: carbon tetrachloride–induced fibrosis as a model without obesity and HCC and genetically obese melanocortin 4 receptor–deficient (MC4R-KO) mice fed Western diet, which develop steatosis, NASH, and eventually HCC. Our data showed that activated fibroblasts exhibited distinct gene expression patterns in each etiology, and that the ‘pathways in cancer’ were selectively upregulated in the activated fibroblasts from MC4R-KO mice. The most upregulated gene in these pathways was fibroblast growth factor 9 (FGF9), which was induced by metabolic stress such as palmitate. FGF9 exerted anti-apoptotic and pro-migratory effects in fibroblasts and hepatoma cells in vitro and accelerated tumor growth in a subcutaneous xenograft model. This study reveals upregulation of cancer-associated gene expression in activated fibroblasts in NASH, which would contribute to the progression from NASH to HCC.
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- 2019
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30. Histopathological analysis of the differential diagnosis of peripheral odontogenic fibroma from fibrous epulis
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Juri Saruta, Mayumi Yakeishi, Keiichi Tsukinoki, Wakako Sakaguchi, and Kei Manabe
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,endocrine system diseases ,Gingiva ,CD34 ,Medicine (miscellaneous) ,Peripheral odontogenic fibroma ,Odontogenic Tumors ,Fibroma ,General Biochemistry, Genetics and Molecular Biology ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,B-cell lymphoma ,General Dentistry ,Gingival Neoplasms ,biology ,business.industry ,Odontogenic tumor ,030206 dentistry ,medicine.disease ,female genital diseases and pregnancy complications ,030104 developmental biology ,Ki-67 ,biology.protein ,Immunohistochemistry ,Fibrous epulis ,Differential diagnosis ,business - Abstract
Objectives Peripheral odontogenic fibroma (POF) is a relatively rare odontogenic tumor of the gingiva. Although its histological differential diagnosis from fibrous epulis (FE) is important, no study has reported the differences in their expression of immunohistochemical markers. Here, we compared the expression of tumor markers that are frequently used for the differential diagnosis of fibroproliferative lesions between POF and FE. Methods Forty cases were selected, including 20 POF and 20 FE cases. CD34, B cell lymphoma (Bcl)-2, and Ki-67 were used as markers for immunohistochemical examination. The positive cell ratio was calculated, and Mann-Whitney U test was performed for statistical analysis. Results POF and FE were negative for CD34 expression but showed Bcl-2 and Ki-67 expression. The ratio of Bcl-2- and Ki-67-positive cells was significantly higher in POF than in FE (p Conclusions POF is CD34 negative, and Bcl-2 and Ki-67 positive-cell ratio differs between POF and FE, suggesting that these proteins may serve as immunohistochemical markers for the differential diagnosis of POF.
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- 2019
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31. Behaviour of glycolylated sialoglycans in the binding pockets of murine and human CD22
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Giovanni Smaldone, Monica Civera, Roberta Marchetti, Sara Sattin, Alba Silipo, Yoshiyuki Manabe, Rosa Ester Forgione, Cristina Di Carluccio, Marco Montefiori, Paul R. Crocker, Antonio Molinaro, Koichi Fukase, Di Carluccio, Cristina, Forgione, Rosa Ester, Montefiori, Marco, Civera, Monica, Sattin, Sara, Smaldone, Giovanni, Fukase, K., Manabe, Y., Crocker, Paul R., Molinaro, Antonio, Marchetti, Roberta, and Silipo, Alba
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0301 basic medicine ,Immunology ,02 engineering and technology ,Sialic acid binding ,Biochemistry ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Immune system ,Structural Biology ,Neuraminic acid ,lcsh:Science ,Multidisciplinary ,Innate immune system ,biology ,Chemistry ,CD22 ,Lectin ,021001 nanoscience & nanotechnology ,3. Good health ,Cell biology ,030104 developmental biology ,Structural biology ,biology.protein ,lcsh:Q ,Antibody ,0210 nano-technology - Abstract
Summary Siglecs (sialic acid binding immunoglobulin (Ig)-like lectins) constitute a group of 15 human and 9 murine cell-surface transmembrane receptors belonging to the I-type lectin family, mostly expressed on innate immune cells and characterized by broadly similar structural features. Here, the prominent inhibitory CD22 (Siglec-2), well known in maintaining tolerance and preventing autoimmune responses on B cells, is studied in its human and murine forms in complex with sialoglycans. In detail, the role of the N-glycolyl neuraminic acid (Neu5Gc) moiety in the interaction with both orthologues was explored. The analysis of the binding mode was carried out by the combination of NMR spectroscopy, computational approaches, and CORCEMA-ST calculations. Our findings provide a first model of Neu5Gc recognition by h-CD22 and show a comparable molecular recognition profile by h- and m-CD22. These data open the way to innovative diagnostic and/or therapeutic methodologies to be used in the modulation of the immune responses., Graphical abstract, Highlights • The structural basis of sialoglycans recognition by h/m CD22 has been investigated • The binding modes of Neu5Gc-/Neu5Ac-containing ligands to m/h-CD22 were compared • The bioactive conformation of sialoglycans has been derived • Our findings may help in the regulation of immune response and cancer prevention, Biochemistry; Immunology; Structural Biology
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- 2021
32. Evaluation of a Novel Immunochromatographic Assay Using Monoclonal Antibodies against the Matrix Protein of Human Metapneumovirus
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Noboru Sakai, Yasuhisa Odagawa, Atsushi Tame, Atsushi Manabe, Daisuke Sato, Hideaki Kikuta, Akiko Okamura, Akihito Ishizaka, Yasushi Akutsu, Takehiro Togashi, Tatsuhiro Tohmoto, Koichi Yasoshima, Nobuhisa Ishiguro, Keisuke Morita, Katsura Ishizu, Motoharu Yonekawa, Tatsuru Yamanaka, Naoko Nagano, Katsuki Azuma, Fujio Kakuya, and Akira Tsuchida
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Myeloma protein ,medicine.drug_class ,viruses ,Monoclonal antibody ,General Biochemistry, Genetics and Molecular Biology ,Viral Matrix Proteins ,Human metapneumovirus ,Nasopharynx ,Medicine ,Humans ,Respiratory Tract Infections ,Immunoassay ,Viral matrix protein ,Paramyxoviridae Infections ,Respiratory tract infections ,biology ,medicine.diagnostic_test ,business.industry ,virus diseases ,Antibodies, Monoclonal ,Infant ,biology.organism_classification ,Virology ,respiratory tract diseases ,Monoclonal ,biology.protein ,Metapneumovirus ,Antibody ,business - Abstract
Background The aim of this study was to determine the sensitivity and specificity of a novel immunochromatographic (IC) assay (APD1806) using monoclonal antibodies against the matrix (M) protein of human metapneumovirus (hMPV) for detection of hMPV from nasopharyngeal swab samples based on the results of real-time RT-PCR. Methods Nasopharyngeal swab samples taken from 189 patients aged 0 - 5 years who were suspected of having respiratory tract infections associated with hMPV were used in this study. The samples were tested both by the IC assay and by real-time RT-PCR for detection of hMPV. Results The sensitivity and specificity of the IC assay for detection of hMPV were 88.8% (95/107) and 92.7% (76/82), respectively. Conclusions The IC assay using monoclonal antibodies against the M protein of hMPV is an accurate and fast assay that is suitable as a diagnostic tool for hMPV infection. The optimal timing of the IC assay is 12 hours or more after the onset of fever due to hMPV infection.
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- 2021
33. A tetracycline antibiotic minocycline prevents early aging phenotypes in mice heterozygous for RP58
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Tomoko Tanaka, Shinobu Hirai, Hiroyuki Manabe, Kentaro Endo, Yasumasa Nishito, Hiroko Shimbo, Hikari Yoshitane, and Haruo Okado
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Microglia ,DNA damage ,DNA repair ,Hippocampus ,Endogeny ,DNA Repair Pathway ,Biology ,Cell biology ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Cerebral cortex ,medicine ,DNA - Abstract
SummaryIn humans, cognitive and motor functions develop in association with maturation, followed by a decline in advancing age. In this study, we aimed to provide a method for extending healthy lifespan by preventing age-related phenomena. Therefore, we focused on RP58, a transcriptional repressor, whose expression is reduced during aging in the human cortex. In the Rp58 hetero-knockout (KO) mice, object location memory was impaired even at 4–5 months, while it was normal in the wild-type mice at 4–5 months but was impaired at 12–18 months. These results indicate an early onset of impaired spatial memory in the mutant mice. As the underlying mechanism, the Rp58 hetero-KO mice showed early onset of DNA damage accumulation and microglial activation in the dentate gyrus due to a DNA repair defect that is generally observed with aging. As another hallmark of aging, we focused on mitochondrial function and detected mitochondrial abnormalities in the Rp58 hetero-KO mice at 4–5 months. Notably, continuous treatments with minocycline, a neuroprotective and anti-inflammatory antibiotic, prevented the facilitation of age-related phenomena in the Rp58 hetero-KO mice. These results suggest the availability of the Rp58 hetero-KO mice as a novel mouse model of human-like early aging and provide a therapeutic strategy to prevent age-related phenomena using minocycline.HighlightRp58 hetero-KO mice exhibit early aging phenotypes including impairment of spatial cognitionRp58 hetero-KO mice show early accumulation of DNA damage due to a defect in the DNA repair systemTreatment with minocycline prevented cognitive dysfunction observed in Rp58 hetero-KO mice
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- 2021
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34. Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network
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Grapotte M., Saraswat M., Bessiere C., Menichelli C., Ramilowski J. A., Severin J., Hayashizaki Y., Itoh M., Tagami M., Murata M., Kojima-Ishiyama M., Noma S., Noguchi S., Kasukawa T., Hasegawa A., Suzuki H., Nishiyori-Sueki H., Frith M. C., Abugessaisa I., Aitken S., Aken B. L., Alam I., Alam T., Alasiri R., Alhendi A. M. N., Alinejad-Rokny H., Alvarez M. J., Andersson R., Arakawa T., Araki M., Arbel T., Archer J., Archibald A. L., Arner E., Arner P., Asai K., Ashoor H., Astrom G., Babina M., Baillie J. K., Bajic V. B., Bajpai A., Baker S., Baldarelli R. M., Balic A., Bansal M., Batagov A. O., Batzoglou S., Beckhouse A. G., Beltrami A. P., Beltrami C. A., Bertin N., Bhattacharya S., Bickel P. J., Blake J. A., Blanchette M., Bodega B., Bonetti A., Bono H., Bornholdt J., Bttcher M., Bougouffa S., Boyd M., Breda J., Brombacher F., Brown J. B., Bult C. J., Burroughs A. M., Burt D. W., Busch A., Caglio G., Califano A., Cameron C. J., Cannistraci C. V., Carbone A., Carlisle A. J., Carninci P., Carter K. W., Cesselli D., Chang J. -C., Chen J. C., Chen Y., Chierici M., Christodoulou J., Ciani Y., Clark E. L., Coskun M., Dalby M., Dalla E., Daub C. O., Davis C. A., de Hoon M. J. L., de Rie D., Denisenko E., Deplancke B., Detmar M., Deviatiiarov R., Di Bernardo D., Diehl A. D., Dieterich L. C., Dimont E., Djebali S., Dohi T., Dostie J., Drablos F., Edge A. S. B., Edinger M., Ehrlund A., Ekwall K., Elofsson A., Endoh M., Enomoto H., Enomoto S., Faghihi M., Fagiolini M., Farach-Carson M. C., Faulkner G. J., Favorov A., Fernandes A. M., Ferrai C., Forrest A. R. R., Forrester L. M., Forsberg M., Fort A., Francescatto M., Freeman T. C., Frith M., Fukuda S., Funayama M., Furlanello C., Furuno M., Furusawa C., Gao H., Gazova I., Gebhard C., Geier F., Geijtenbeek T. B. H., Ghosh S., Ghosheh Y., Gingeras T. R., Gojobori T., Goldberg T., Goldowitz D., Gough J., Greco D., Gruber A. J., Guhl S., Guigo R., Guler R., Gusev O., Gustincich S., Ha T. J., Haberle V., Hale P., Hallstrom B. M., Hamada M., Handoko L., Hara M., Harbers M., Harrow J., Harshbarger J., Hase T., Hashimoto K., Hatano T., Hattori N., Hayashi R., Herlyn M., Hettne K., Heutink P., Hide W., Hitchens K. J., Sui S. H., 't Hoen P. A. C., Hon C. C., Hori F., Horie M., Horimoto K., Horton P., Hou R., Huang E., Huang Y., Hugues R., Hume D., Ienasescu H., Iida K., Ikawa T., Ikemura T., Ikeo K., Inoue N., Ishizu Y., Ito Y., Ivshina A. V., Jankovic B. R., Jenjaroenpun P., Johnson R., Jorgensen M., Jorjani H., Joshi A., Jurman G., Kaczkowski B., Kai C., Kaida K., Kajiyama K., Kaliyaperumal R., Kaminuma E., Kanaya T., Kaneda H., Kapranov P., Kasianov A. S., Katayama T., Kato S., Kawaguchi S., Kawai J., Kawaji H., Kawamoto H., Kawamura Y. I., Kawasaki S., Kawashima T., Kempfle J. S., Kenna T. J., Kere J., Khachigian L., Kiryu H., Kishima M., Kitajima H., Kitamura T., Kitano H., Klaric E., Klepper K., Klinken S. P., Kloppmann E., Knox A. J., Kodama Y., Kogo Y., Kojima M., Kojima S., Komatsu N., Komiyama H., Kono T., Koseki H., Koyasu S., Kratz A., Kukalev A., Kulakovskiy I., Kundaje A., Kunikata H., Kuo R., Kuo T., Kuraku S., Kuznetsov V. A., Kwon T. J., Larouche M., Lassmann T., Law A., Le-Cao K. -A., Lecellier C. -H., Lee W., Lenhard B., Lennartsson A., Li K., Li R., Lilje B., Lipovich L., Lizio M., Lopez G., Magi S., Mak G. K., Makeev V., Manabe R., Mandai M., Mar J., Maruyama K., Maruyama T., Mason E., Mathelier A., Matsuda H., Medvedeva Y. A., Meehan T. F., Mejhert N., Meynert A., Mikami N., Minoda A., Miura H., Miyagi Y., Miyawaki A., Mizuno Y., Morikawa H., Morimoto M., Morioka M., Morishita S., Moro K., Motakis E., Motohashi H., Mukarram A. K., Mummery C. L., Mungall C. J., Murakawa Y., Muramatsu M., Nagasaka K., Nagase T., Nakachi Y., Nakahara F., Nakai K., Nakamura K., Nakamura Y., Nakazawa T., Nason G. P., Nepal C., Nguyen Q. H., Nielsen L. K., Nishida K., Nishiguchi K. M., Nishiyori H., Nitta K., Notredame C., Ogishima S., Ohkura N., Ohno H., Ohshima M., Ohtsu T., Okada Y., Okada-Hatakeyama M., Okazaki Y., Oksvold P., Orlando V., Ow G. S., Ozturk M., Pachkov M., Paparountas T., Parihar S. P., Park S. -J., Pascarella G., Passier R., Persson H., Philippens I. H., Piazza S., Plessy C., Pombo A., Ponten F., Poulain S., Poulsen T. M., Pradhan S., Prezioso C., Pridans C., Qin X. -Y., Quackenbush J., Rackham O., Ramilowski J., Ravasi T., Rehli M., Rennie S., Rito T., Rizzu P., Robert C., Roos M., Rost B., Roudnicky F., Roy R., Rye M. B., Sachenkova O., Saetrom P., Sai H., Saiki S., Saito M., Saito A., Sakaguchi S., Sakai M., Sakaue S., Sakaue-Sawano A., Sandelin A., Sano H., Sasamoto Y., Sato H., Saxena A., Saya H., Schafferhans A., Schmeier S., Schmidl C., Schmocker D., Schneider C., Schueler M., Schultes E. A., Schulze-Tanzil G., Semple C. A., Seno S., Seo W., Sese J., Sheng G., Shi J., Shimoni Y., Shin J. W., SimonSanchez J., Sivertsson A., Sjostedt E., Soderhall C., Laurent G. S., Stoiber M. H., Sugiyama D., Summers K. M., Suzuki A. M., Suzuki K., Suzuki M., Suzuki N., Suzuki T., Swanson D. J., Swoboda R. K., Taguchi A., Takahashi H., Takahashi M., Takamochi K., Takeda S., Takenaka Y., Tam K. T., Tanaka H., Tanaka R., Tanaka Y., Tang D., Taniuchi I., Tanzer A., Tarui H., Taylor M. S., Terada A., Terao Y., Testa A. C., Thomas M., Thongjuea S., Tomii K., Triglia E. T., Toyoda H., Tsang H. G., Tsujikawa M., Uhlen M., Valen E., van de Wetering M., van Nimwegen E., Velmeshev D., Verardo R., Vitezic M., Vitting-Seerup K., von Feilitzen K., Voolstra C. R., Vorontsov I. E., Wahlestedt C., Wasserman W. W., Watanabe K., Watanabe S., Wells C. A., Winteringham L. N., Wolvetang E., Yabukami H., Yagi K., Yamada T., Yamaguchi Y., Yamamoto M., Yamamoto Y., Yamanaka Y., Yano K., Yasuzawa K., Yatsuka Y., Yo M., Yokokura S., Yoneda M., Yoshida E., Yoshida Y., Yoshihara M., Young R., Young R. S., Yu N. Y., Yumoto N., Zabierowski S. E., Zhang P. G., Zucchelli S., Zwahlen M., Chatelain C., Brehelin L., Grapotte, M., Saraswat, M., Bessiere, C., Menichelli, C., Ramilowski, J. A., Severin, J., Hayashizaki, Y., Itoh, M., Tagami, M., Murata, M., Kojima-Ishiyama, M., Noma, S., Noguchi, S., Kasukawa, T., Hasegawa, A., Suzuki, H., Nishiyori-Sueki, H., Frith, M. C., Abugessaisa, I., Aitken, S., Aken, B. L., Alam, I., Alam, T., Alasiri, R., Alhendi, A. M. N., Alinejad-Rokny, H., Alvarez, M. J., Andersson, R., Arakawa, T., Araki, M., Arbel, T., Archer, J., Archibald, A. L., Arner, E., Arner, P., Asai, K., Ashoor, H., Astrom, G., Babina, M., Baillie, J. K., Bajic, V. B., Bajpai, A., Baker, S., Baldarelli, R. M., Balic, A., Bansal, M., Batagov, A. O., Batzoglou, S., Beckhouse, A. G., Beltrami, A. P., Beltrami, C. A., Bertin, N., Bhattacharya, S., Bickel, P. J., Blake, J. A., Blanchette, M., Bodega, B., Bonetti, A., Bono, H., Bornholdt, J., Bttcher, M., Bougouffa, S., Boyd, M., Breda, J., Brombacher, F., Brown, J. B., Bult, C. J., Burroughs, A. M., Burt, D. W., Busch, A., Caglio, G., Califano, A., Cameron, C. J., Cannistraci, C. V., Carbone, A., Carlisle, A. J., Carninci, P., Carter, K. W., Cesselli, D., Chang, J. -C., Chen, J. C., Chen, Y., Chierici, M., Christodoulou, J., Ciani, Y., Clark, E. L., Coskun, M., Dalby, M., Dalla, E., Daub, C. O., Davis, C. A., de Hoon, M. J. L., de Rie, D., Denisenko, E., Deplancke, B., Detmar, M., Deviatiiarov, R., Di Bernardo, D., Diehl, A. D., Dieterich, L. C., Dimont, E., Djebali, S., Dohi, T., Dostie, J., Drablos, F., Edge, A. S. B., Edinger, M., Ehrlund, A., Ekwall, K., Elofsson, A., Endoh, M., Enomoto, H., Enomoto, S., Faghihi, M., Fagiolini, M., Farach-Carson, M. C., Faulkner, G. J., Favorov, A., Fernandes, A. M., Ferrai, C., Forrest, A. R. R., Forrester, L. M., Forsberg, M., Fort, A., Francescatto, M., Freeman, T. C., Frith, M., Fukuda, S., Funayama, M., Furlanello, C., Furuno, M., Furusawa, C., Gao, H., Gazova, I., Gebhard, C., Geier, F., Geijtenbeek, T. B. H., Ghosh, S., Ghosheh, Y., Gingeras, T. R., Gojobori, T., Goldberg, T., Goldowitz, D., Gough, J., Greco, D., Gruber, A. J., Guhl, S., Guigo, R., Guler, R., Gusev, O., Gustincich, S., Ha, T. J., Haberle, V., Hale, P., Hallstrom, B. M., Hamada, M., Handoko, L., Hara, M., Harbers, M., Harrow, J., Harshbarger, J., Hase, T., Hashimoto, K., Hatano, T., Hattori, N., Hayashi, R., Herlyn, M., Hettne, K., Heutink, P., Hide, W., Hitchens, K. J., Sui, S. H., 't Hoen, P. A. C., Hon, C. C., Hori, F., Horie, M., Horimoto, K., Horton, P., Hou, R., Huang, E., Huang, Y., Hugues, R., Hume, D., Ienasescu, H., Iida, K., Ikawa, T., Ikemura, T., Ikeo, K., Inoue, N., Ishizu, Y., Ito, Y., Ivshina, A. V., Jankovic, B. R., Jenjaroenpun, P., Johnson, R., Jorgensen, M., Jorjani, H., Joshi, A., Jurman, G., Kaczkowski, B., Kai, C., Kaida, K., Kajiyama, K., Kaliyaperumal, R., Kaminuma, E., Kanaya, T., Kaneda, H., Kapranov, P., Kasianov, A. S., Katayama, T., Kato, S., Kawaguchi, S., Kawai, J., Kawaji, H., Kawamoto, H., Kawamura, Y. I., Kawasaki, S., Kawashima, T., Kempfle, J. S., Kenna, T. J., Kere, J., Khachigian, L., Kiryu, H., Kishima, M., Kitajima, H., Kitamura, T., Kitano, H., Klaric, E., Klepper, K., Klinken, S. P., Kloppmann, E., Knox, A. J., Kodama, Y., Kogo, Y., Kojima, M., Kojima, S., Komatsu, N., Komiyama, H., Kono, T., Koseki, H., Koyasu, S., Kratz, A., Kukalev, A., Kulakovskiy, I., Kundaje, A., Kunikata, H., Kuo, R., Kuo, T., Kuraku, S., Kuznetsov, V. A., Kwon, T. J., Larouche, M., Lassmann, T., Law, A., Le-Cao, K. -A., Lecellier, C. -H., Lee, W., Lenhard, B., Lennartsson, A., Li, K., Li, R., Lilje, B., Lipovich, L., Lizio, M., Lopez, G., Magi, S., Mak, G. K., Makeev, V., Manabe, R., Mandai, M., Mar, J., Maruyama, K., Maruyama, T., Mason, E., Mathelier, A., Matsuda, H., Medvedeva, Y. A., Meehan, T. F., Mejhert, N., Meynert, A., Mikami, N., Minoda, A., Miura, H., Miyagi, Y., Miyawaki, A., Mizuno, Y., Morikawa, H., Morimoto, M., Morioka, M., Morishita, S., Moro, K., Motakis, E., Motohashi, H., Mukarram, A. K., Mummery, C. L., Mungall, C. J., Murakawa, Y., Muramatsu, M., Nagasaka, K., Nagase, T., Nakachi, Y., Nakahara, F., Nakai, K., Nakamura, K., Nakamura, Y., Nakazawa, T., Nason, G. P., Nepal, C., Nguyen, Q. H., Nielsen, L. K., Nishida, K., Nishiguchi, K. M., Nishiyori, H., Nitta, K., Notredame, C., Ogishima, S., Ohkura, N., Ohno, H., Ohshima, M., Ohtsu, T., Okada, Y., Okada-Hatakeyama, M., Okazaki, Y., Oksvold, P., Orlando, V., Ow, G. S., Ozturk, M., Pachkov, M., Paparountas, T., Parihar, S. P., Park, S. -J., Pascarella, G., Passier, R., Persson, H., Philippens, I. H., Piazza, S., Plessy, C., Pombo, A., Ponten, F., Poulain, S., Poulsen, T. M., Pradhan, S., Prezioso, C., Pridans, C., Qin, X. -Y., Quackenbush, J., Rackham, O., Ramilowski, J., Ravasi, T., Rehli, M., Rennie, S., Rito, T., Rizzu, P., Robert, C., Roos, M., Rost, B., Roudnicky, F., Roy, R., Rye, M. B., Sachenkova, O., Saetrom, P., Sai, H., Saiki, S., Saito, M., Saito, A., Sakaguchi, S., Sakai, M., Sakaue, S., Sakaue-Sawano, A., Sandelin, A., Sano, H., Sasamoto, Y., Sato, H., Saxena, A., Saya, H., Schafferhans, A., Schmeier, S., Schmidl, C., Schmocker, D., Schneider, C., Schueler, M., Schultes, E. A., Schulze-Tanzil, G., Semple, C. A., Seno, S., Seo, W., Sese, J., Sheng, G., Shi, J., Shimoni, Y., Shin, J. W., Simonsanchez, J., Sivertsson, A., Sjostedt, E., Soderhall, C., Laurent, G. S., Stoiber, M. H., Sugiyama, D., Summers, K. M., Suzuki, A. M., Suzuki, K., Suzuki, M., Suzuki, N., Suzuki, T., Swanson, D. J., Swoboda, R. K., Taguchi, A., Takahashi, H., Takahashi, M., Takamochi, K., Takeda, S., Takenaka, Y., Tam, K. T., Tanaka, H., Tanaka, R., Tanaka, Y., Tang, D., Taniuchi, I., Tanzer, A., Tarui, H., Taylor, M. S., Terada, A., Terao, Y., Testa, A. C., Thomas, M., Thongjuea, S., Tomii, K., Triglia, E. T., Toyoda, H., Tsang, H. G., Tsujikawa, M., Uhlen, M., Valen, E., van de Wetering, M., van Nimwegen, E., Velmeshev, D., Verardo, R., Vitezic, M., Vitting-Seerup, K., von Feilitzen, K., Voolstra, C. R., Vorontsov, I. E., Wahlestedt, C., Wasserman, W. W., Watanabe, K., Watanabe, S., Wells, C. A., Winteringham, L. N., Wolvetang, E., Yabukami, H., Yagi, K., Yamada, T., Yamaguchi, Y., Yamamoto, M., Yamamoto, Y., Yamanaka, Y., Yano, K., Yasuzawa, K., Yatsuka, Y., Yo, M., Yokokura, S., Yoneda, M., Yoshida, E., Yoshida, Y., Yoshihara, M., Young, R., Young, R. S., Yu, N. Y., Yumoto, N., Zabierowski, S. E., Zhang, P. G., Zucchelli, S., Zwahlen, M., Chatelain, C., Brehelin, L., Institute of Biotechnology, Biosciences, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Computationnelle (IBC), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Méthodes et Algorithmes pour la Bioinformatique (MAB), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), National Institute of Advanced Industrial Science and Technology (AIST), SANOFI Recherche, University of British Columbia (UBC), Experimental Immunology, Infectious diseases, AII - Infectious diseases, Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)
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0301 basic medicine ,General Physics and Astronomy ,Genome ,Mice ,0302 clinical medicine ,Transcription (biology) ,Promoter Regions, Genetic ,Transcription Initiation, Genetic ,0303 health sciences ,Multidisciplinary ,1184 Genetics, developmental biology, physiology ,High-Throughput Nucleotide Sequencing ,Neurodegenerative Diseases ,222 Other engineering and technologies ,Genomics ,[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,humanities ,Enhancer Elements, Genetic ,Microsatellite Repeat ,Transcription Initiation Site ,Sequence motif ,Transcription Initiation ,Human ,Enhancer Elements ,Neural Networks ,Science ,610 Medicine & health ,Computational biology ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Promoter Regions ,03 medical and health sciences ,Computer ,Deep Learning ,Tandem repeat ,Genetic ,Clinical Research ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Machine learning ,Genetics ,Animals ,Humans ,Polymorphism ,Enhancer ,Transcriptomics ,Gene ,A549 Cell ,030304 developmental biology ,Polymorphism, Genetic ,Neurodegenerative Disease ,Base Sequence ,Animal ,Genome, Human ,Human Genome ,Computational Biology ,Promoter ,General Chemistry ,113 Computer and information sciences ,Cap analysis gene expression ,030104 developmental biology ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Cardiovascular and Metabolic Diseases ,A549 Cells ,Minion ,Generic health relevance ,3111 Biomedicine ,Neural Networks, Computer ,610 Medizin und Gesundheit ,030217 neurology & neurosurgery ,FANTOM consortium ,Microsatellite Repeats - Abstract
Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism., Nature Communications, 12 (1), ISSN:2041-1723
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- 2020
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35. Convergent Synthesis of a BisectingN-Acetylglucosamine (GlcNAc)-Containing N-Glycan
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Naoya Minamoto, Alba Silipo, Antonio Molinaro, Koichi Fukase, Katsunori Tanaka, Yohei Takakura, Hiroki Shomura, Masahiro Nagasaki, Yoshiyuki Manabe, Manabe, Yoshiyuki, Shomura, Hiroki, Minamoto, Naoya, Nagasaki, Masahiro, Takakura, Yohei, Tanaka, Katsunori, Silipo, Alba, Molinaro, Antonio, and Fukase, Koichi
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Steric effects ,Convergent synthesi ,Glycan ,Glycosylation ,animal structures ,Stereochemistry ,Oxocarbenium ,Convergent synthesis ,Ether ,macromolecular substances ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Chemical synthesis ,Oligosaccharide ,chemistry.chemical_compound ,Protecting group ,Glycosyl donor ,biology ,010405 organic chemistry ,Chemistry ,Chemistry (all) ,Organic Chemistry ,General Chemistry ,0104 chemical sciences ,carbohydrates (lipids) ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Synthesis design - Abstract
The chemical synthesis of a bisecting N-acetylglucosamine (GlcNAc)-containing N-glycan was achieved by a convergent synthetic route through [4+2] and [6+2] glycosylations. This synthetic route reduced the number of reaction steps, although the key glycosylations were challenging in terms of yields and selectivities owing to steric hindrance at the glycosylation site and a lack of neighboring group participation. The yields of these glycosylations were enhanced by stabilizing the oxocarbenium ion intermediate through ether coordination. Glycosyl donor protecting groups were explored in an effort to realize perfect α selectivity by manipulating remote participation. The simultaneous glycosylations of a tetrasaccharide with two disaccharides was investigated to efficiently construct a bisecting GlcNAc-containing N-glycan.
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- 2018
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36. Identification of a KLF5-dependent program and drug development for skeletal muscle atrophy
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Shinichiro Hayashi, Tomoki Nakashima, Fujimi Kudo, Lin Liu, Ichiro Manabe, Atsushi Kaneda, Takehito Ono, Hiroyuki Kagechika, Yumiko Oishi, and Hiroyuki Koike
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Male ,medicine.medical_specialty ,Tetrahydronaphthalenes ,Ubiquitin-Protein Ligases ,Kruppel-Like Transcription Factors ,Muscle Proteins ,Benzoates ,Dexamethasone ,Cachexia ,Tripartite Motif Proteins ,Mice ,Atrophy ,Drug Development ,Internal medicine ,medicine ,Animals ,Muscle, Skeletal ,Glucocorticoids ,Mice, Knockout ,SKP Cullin F-Box Protein Ligases ,Multidisciplinary ,biology ,business.industry ,Myogenesis ,Skeletal muscle ,Biological Sciences ,medicine.disease ,Muscle atrophy ,Ubiquitin ligase ,Mice, Inbred C57BL ,Muscular Atrophy ,Retinoic acid receptor ,Endocrinology ,medicine.anatomical_structure ,Gene Expression Regulation ,Sarcopenia ,biology.protein ,medicine.symptom ,business ,Signal Transduction - Abstract
Skeletal muscle atrophy is caused by various conditions, including aging, disuse related to a sedentary lifestyle and lack of physical activity, and cachexia. Our insufficient understanding of the molecular mechanism underlying muscle atrophy limits the targets for the development of effective pharmacologic treatments and preventions. Here, we identified Krüppel-like factor 5 (KLF5), a zinc-finger transcription factor, as a key mediator of the early muscle atrophy program. KLF5 was up-regulated in atrophying myotubes as an early response to dexamethasone or simulated microgravity in vitro. Skeletal muscle–selective deletion of Klf5 significantly attenuated muscle atrophy induced by mechanical unloading in mice. Transcriptome- and genome-wide chromatin accessibility analyses revealed that KLF5 regulates atrophy-related programs, including metabolic changes and E3-ubiquitin ligase-mediated proteolysis, in coordination with Foxo1. The synthetic retinoic acid receptor agonist Am80, a KLF5 inhibitor, suppressed both dexamethasone- and microgravity-induced muscle atrophy in vitro and oral Am80 ameliorated disuse– and dexamethasone-induced atrophy in mice. Moreover, in three independent sets of transcriptomic data from human skeletal muscle, KLF5 expression significantly increased with age and the presence of sarcopenia and correlated positively with the expression of the atrophy-related ubiquitin ligase genes FBXO32 and TRIM63. These findings demonstrate that KLF5 is a key transcriptional regulator mediating muscle atrophy and that pharmacological intervention with Am80 is a potentially preventive treatment.
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- 2021
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37. Epidemiological Review of Gastroesophageal Junction Adenocarcinoma in Asian Countries
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Ken Haruma, Noriaki Manabe, and Kazuhiro Matsueda
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medicine.medical_specialty ,Esophageal Neoplasms ,Gastroesophageal Junction Adenocarcinoma ,Adenocarcinoma ,Gastroenterology ,Helicobacter Infections ,Barrett Esophagus ,Internal medicine ,Medicine ,Humans ,Esophagus ,Risk factor ,biology ,Helicobacter pylori ,business.industry ,Incidence (epidemiology) ,Cancer ,medicine.disease ,biology.organism_classification ,digestive system diseases ,medicine.anatomical_structure ,GERD ,Esophagogastric Junction ,business - Abstract
Background: Similar trends in the prevalence of gastroesophageal reflux disease (GERD), obesity, and Helicobacter pylori infection have been observed in Asian and Western countries despite their time differences. However, it is unclear whether the prevalence of gastroesophageal junction adenocarcinomas in Asian countries is increasing. In this review, we discuss the epidemiological trends of gastroesophageal junction adenocarcinoma in Asian countries. Summary: The prevalence of GERD is increasing in Asian countries, but most cases are considered mild. Obesity is a serious problem worldwide, but it is considered less serious in Asia than in Western countries. In Asian countries where gastric cancer is common, both cardiac and noncardiac cancers are associated with high rates of H. pylori infection, which is considered a carcinogenic risk factor for both sites of cancer. The widespread use of H. pylori eradication therapy for chronic gastritis in several Asian countries has not directly led to an increased prevalence of esophageal adenocarcinoma. One of the originating sites of junctional adenocarcinoma in most Asian countries is Barrett’s esophagus, with short-segment Barrett’s esophagus having much lower carcinogenicity than long-segment Barrett’s esophagus. Key Messages: Considering the future trends of several risk factors for gastroesophageal junction adenocarcinoma in Asian countries, it is likely that the incidence of gastroesophageal junction adenocarcinoma will gradually increase, but not at a rate that exceeds that of squamous cell carcinoma, as in Western countries.
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- 2021
38. Daily sampling of early SARS-CoV-2 infection reveals substantial heterogeneity in infectiousness
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John Broach, William J Heetderks, Richard Fredrickson, Peter Lazar, Chun Huai Luo, Crystal Reinhart, Laura Gibson, Jessica Quicksall, Darci C Edmonson, Agha Mirza, Stacy L Gloss, Melinda E Baughman, Heba H. Mostafa, Kimberly K. O. Walden, Yukari C. Manabe, Bruce A. Barton, Shannon Bradley, Ruian Ke, Nicholas Gallagher, Matthew L Robinson, Rebecca L. Smith, Gloria Rendon, Karen K Chiu, Pamela P. Martinez, Jagadeesh Yedetore, Abigail Conte, Tongyu Liu, Hannah Choi, David D. McManus, Junko Jarrett, Christopher B. Brooke, Alyssa N Owens, Mireille Farjo, Christopher J. Fields, Leyi Wang, Andrew Pekosz, Madison Conte, and Kevin R Scardina
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Saliva ,SARS-CoV-2 ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,viruses ,Acute infection ,COVID-19 ,Biology ,Viral Load ,Virology ,Article ,Virus Shedding ,Viral replication ,Humans ,Viral rna ,Clearance rate ,Viral load ,Infectious virus - Abstract
The dynamics of SARS-CoV-2 replication and shedding in humans remain poorly understood. We captured the dynamics of infectious virus and viral RNA shedding during acute infection through daily longitudinal sampling of 60 individuals for up to 14 days. By fitting mechanistic models, we directly estimated viral expansion and clearance rates and overall infectiousness for each individual. Significant person-to-person variation in infectious virus shedding suggests that individual-level heterogeneity in viral dynamics contributes to 'superspreading'. Viral genome loads often peaked days earlier in saliva than in nasal swabs, indicating strong tissue compartmentalization and suggesting that saliva may serve as a superior sampling site for early detection of infection. Viral loads and clearance kinetics of Alpha (B.1.1.7) and previously circulating non-variant-of-concern viruses were mostly indistinguishable, indicating that the enhanced transmissibility of this variant cannot be explained simply by higher viral loads or delayed clearance. These results provide a high-resolution portrait of SARS-CoV-2 infection dynamics and implicate individual-level heterogeneity in infectiousness in superspreading.
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- 2021
39. P150 Characterization of pharyngeal gonorrhea in Ugandan men with urethral discharge syndrome
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Emmanuel Mande, P Kyambadde, A Onzia, Matthew M. Hamill, Mohammed Lamorde, Yukari C. Manabe, and Johan H. Melendez
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medicine.medical_specialty ,biology ,Genitourinary system ,business.industry ,Gonorrhea ,medicine.disease_cause ,biology.organism_classification ,medicine.disease ,Ciprofloxacin ,Internal medicine ,parasitic diseases ,Epidemiology ,Ceftriaxone ,medicine ,Neisseria gonorrhoeae ,Chlamydia trachomatis ,Mycoplasma genitalium ,business ,medicine.drug - Abstract
Background Multi-drug resistant Neisseria gonorrhoeae (NG) threatens the effectiveness of gonorrhea treatment and control globally. Pharyngeal NG (pNG) infections are hypothesized to play a role in the emergence of antimicrobial resistance (AMR) in NG, yet the epidemiology of pNG infections is poorly understood, especially in resource-limited settings (RLS). We report on pNG in men with concurrent urogenital NG infections in Kampala, Uganda. Methods Penile-meatal and pharyngeal samples were collected from Ugandan men with urethral discharge syndrome (UDS), cultured for NG, and tested by nucleic acid amplification tests (NAATs) for NG and other STIs. Antimicrobial susceptibility testing was performed on all NG isolates. Results Of the 83 participants (mean age 29.5 years) who provided urogenital and pharyngeal samples, 22.9% (19/83) were living with HIV, and 57.8% (48/83) were positive for urogenital gonorrhea. NG was detected in 8.6% (7/81) of pharyngeal samples by NAAT; 57.1% (4/7) were also positive by culture. Participants with pNG had concurrent urogenital NG, were HIV-negative, heterosexual (71.4%), reported transactional sex (85.7%), did not report oral sex (85.7%), and were younger (median – 24 years, IQR=21–28; p=0.013) than pNG-negative participants (median – 29 years, IQR=27–32). The paired (n = 4) urogenital-pharyngeal isolates displayed the same antimicrobial susceptibility profile: ciprofloxacin-, tetracycline-, and penicillin-resistant and ceftriaxone- and cefixime-susceptible. None of the pharyngeal samples were positive for Chlamydia trachomatis and one sample was positive for Mycoplasma genitalium. Conclusions To our knowledge, this is the first report of pNG in Ugandan men. NAATs were more sensitive than cultures for detection of pNG. In this pilot study, there was no difference in the susceptibility profiles of paired pharyngeal and urogenital NG isolates. Differences by age might be explained by differences in sexual behaviors or mucosal immunity. Additional studies are warranted to better define the epidemiology and microbiology of pNG infections in RLS.
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- 2021
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40. Dimeric IgA is a specific biomarker of recent SARS-CoV-2 infection
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Heidi E Drummer, Huy Van, Ethan Klock, Shuning Zheng, Zihui Wei, Irene Boo, Rob J Center, Fan Li, Purnima Bhat, Rosemary Ffrench, Jillian SY Lau, James McMahon, Oliver Laeyendecker, Reinaldo E. Fernandez, Yukari C. Manabe, Sabra L. Klein, Thomas C. Quinn, and David A. Anderson
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Plasma samples ,Coronavirus disease 2019 (COVID-19) ,Secretory component ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,fungi ,Biology ,Highly selective ,Article ,body regions ,Biotinylation ,Immunology ,biology.protein ,Biomarker (medicine) ,Antibody - Abstract
Current tests for SARS-CoV-2 antibodies (IgG, IgM, IgA) cannot differentiate recent and past infections. We describe a point of care, lateral flow assay for SARS-CoV-2 dIgA based on the highly selective binding of dIgA to a chimeric form of secretory component (CSC), that distinguishes dIgA from monomeric IgA. Detection of specific dIgA uses a complex of biotinylated SARS-CoV-2 receptor binding domain and streptavidin-colloidal gold. SARS-CoV-2-specific dIgA was measured both in 112 cross-sectional samples and a longitudinal panel of 362 plasma samples from 45 patients with PCR-confirmed SARS-CoV-2 infection, and 193 discrete pre-COVID-19 or PCR-negative patient samples. The assay demonstrated 100% sensitivity from 11 days post-symptom onset, and a specificity of 98.2%. With an estimated half-life of 6.3 days, dIgA provides a unique biomarker for the detection of recent SARS-CoV-2 infections with potential to enhance diagnosis and management of COVID-19 at point-of-care.
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- 2021
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41. P261 Follow-up assessment of participants with urethral discharge syndrome in Kampala, Uganda: Lessons learned for future STI control Interventions
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P Kyambadde, Agnes Kiragga, Aminah Zawedde, Edith Nakku-Joloba, A Onzia Aketoko, Charlotte A. Gaydos, Matthew M. Hamill, Yukari C. Manabe, Johan H. Melendez, and Rosalind Parkes-Ratanshi
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medicine.medical_specialty ,biology ,Genitourinary system ,business.industry ,Psychological intervention ,medicine.disease_cause ,biology.organism_classification ,law.invention ,Condom ,law ,Penile discharge ,Internal medicine ,medicine ,Dysuria ,Trichomonas vaginalis ,medicine.symptom ,Chlamydia trachomatis ,Mycoplasma genitalium ,business - Abstract
Background After effective treatment, persons diagnosed with a sexually transmitted infections (STI) are encouraged to modify behavior and notify partners. In resource-limited settings (RLS), follow-up assessment is limited by a variety of factors, including access to knowledge, material resources, and reliable communication. Methods A study conducted in 2019 within the existing WHO-based Enhanced Gonococcal Antimicrobial Surveillance Program (EGASP) collected urogenital samples and blood from men with urethral discharge syndrome (UDS). Samples were tested for Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), Trichomonas vaginalis (TV) and Mycoplasma genitalium (MG), and HIV. Participants received treatment and were then followed up using phone calls on days 7, 14 and 21 post-enrolment. Results Of the 250 participants recruited for this study, 66.7%, 20.5%, 11.6%, and 2.0% were positive for NG, CT, MG, TV, respectively, and 20% (50/250) were HIV-positive. Follow-up visits on days 7, 14, and 21 were completed by 98.8%, 96.0%, and 96.4% of participants, respectively. The majority (94.5%) of participants completed their prescribed treatment regimen. Resolution of symptoms (penile discharge and dysuria) was reported by 76.7% of participants 3–5 days post-treatment while 7.5% reported no resolution of symptoms. The majority (77.2%) reported sexual activity while on treatment; 31.6% of those reported condom use, and 15.1% reported multiple partners. PN was reported by 66.9% of participants; 16.8% of participants reported that they had no intention of notifying their partners. Conclusions The prevalence of STIs was high in this group of men with UDS who also reported low condom use and multiple sex partners. While completion rate of follow-up visits was very high, innovative ways to follow-up patients to ensure response to treatment and to incentivize PN are necessary in future STI control interventions.
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- 2021
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42. P1 gene of Mycoplasma pneumoniae isolated from 2016 to 2019 and relationship between genotyping and macrolide resistance in Hokkaido, Japan
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Tsuyoshi Kenri, Akihito Ishizaka, Kyosuke Hazama, Yasuhisa Odagawa, Rikako Sato, Atsushi Manabe, Keisuke Morita, Takehiro Togashi, Masanori Nakanishi, Atsuko Horino, Mutsuko Konno, Hideaki Kikuta, Nobuhisa Ishiguro, Hiroshi Tanaka, Toshihiko Mori, Katsumi Azuma, Satoshi Sasaki, Hayato Aoyagi, Naoko Nagano, Akira Tsuchida, Yuichi Tabata, Mitsuo Narita, and Tatsuru Yamanaka
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Microbiology (medical) ,Mycoplasma pneumoniae ,antibiotic resistance ,Lineage (genetic) ,Gene type ,macrolides ,Strain (biology) ,General Medicine ,Biology ,medicine.disease_cause ,Microbiology ,Antibiotic resistance ,Japan ,Macrolide resistance ,medicine ,Genotyping ,Gene - Abstract
We characterized 515 Mycoplasma pneumoniae specimens in Hokkaido. In 2013 and 2014, the p1 gene type 1 strain, mostly macrolide-resistant, was dominant and the prevalence of macrolide resistance was over 50 %. After 2017, the p1 gene type 2 lineage, mostly macrolide-sensitive, increased and the prevalence of macrolide resistance became 31.0 % in 2017, 5.3 % in 2018 and 16.3 % in 2019.
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- 2021
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43. Molecular cloning and characterization of common marmoset SULT1C subfamily members that catalyze the sulfation of thyroid hormones
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Ming-Cheh Liu, Yoko Manabe, Masahito Suiko, Yoichi Sakakibara, and Katsuhisa Kurogi
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Genetics ,Gene isoform ,Subfamily ,biology ,Pseudogene ,Organic Chemistry ,Marmoset ,Callithrix ,General Medicine ,biology.organism_classification ,Applied Microbiology and Biotechnology ,Biochemistry ,Genome ,Analytical Chemistry ,Kinetics ,biology.animal ,Regular Paper ,Animals ,Humans ,Cloning, Molecular ,Molecular Biology ,Gene ,Orthologous Gene ,Biotechnology - Abstract
Cytosolic sulfotransferase SULT1C subfamily is one of the most flexible gene subfamilies during mammalian evolution. The physiological functions of SULT1C enzymes still remain to be fully understood. In this study, common marmoset (Callithrix jacchus), a promising primate animal model, was used to investigate the functional relevance of the SULT1C subfamily. Gene database search revealed 3 intact SULT1C genes and a pseudogene in its genome. These 4 genes were named SULT1C1, SULT1C2, SULT1C3P, and SULT1C5, according to the sequence homology and gene location. Since SULT1C5 is the orthologous gene for human SULT1C2P, we propose, here, to revisit the designation of human SULT1C2P to SULT1C5P. Purified recombinant SULT1C enzymes showed sulfating activities toward a variety of xenobiotic compounds and thyroid hormones. Kinetic analysis revealed high catalytic activities of SULT1C1 and SULT1C5 for 3,3′-T2. It appears therefore that SULT1C isoforms may play a role in the thyroid hormone metabolism in common marmoset.
- Published
- 2021
44. Baseline Xpert MTB/RIF ct values predict sputum conversion during the intensive phase of anti-TB treatment in HIV infected patients in Kampala, Uganda: a retrospective study
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Joan N. Kalyango, Barbara Castelnouvo, Emmanuel Sendaula, Yukari C. Manabe, Andrew Kambugu, Juliet Namugenyi, Christine Sekaggya-Wiltshire, Willy Ssengooba, Jan Fehr, Achilles Katamba, Joseph Musaazi, University of Zurich, and Sekaggya-Wiltshire, Christine
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Male ,0301 basic medicine ,Antitubercular Agents ,Colony Count, Microbial ,Human immunodeficiency virus (HIV) ,HIV Infections ,Infectious and parasitic diseases ,RC109-216 ,medicine.disease_cause ,Gee ,10234 Clinic for Infectious Diseases ,0302 clinical medicine ,Odds Ratio ,Uganda ,030212 general & internal medicine ,biology ,Time to positivity ,Infectious Diseases ,Anti-Retroviral Agents ,Female ,medicine.symptom ,Nucleic Acid Amplification Techniques ,Research Article ,Adult ,medicine.medical_specialty ,Xpert MTB/RIF ,030106 microbiology ,610 Medicine & health ,Sensitivity and Specificity ,Mycobacterium tuberculosis ,03 medical and health sciences ,Intensive Phase ,Internal medicine ,medicine ,Humans ,Tuberculosis, Pulmonary ,Retrospective Studies ,Receiver operating characteristic ,business.industry ,Colony count ,Sputum ,HIV ,Retrospective cohort study ,10060 Epidemiology, Biostatistics and Prevention Institute (EBPI) ,2725 Infectious Diseases ,biology.organism_classification ,Bacterial Load ,CD4 Lymphocyte Count ,Baseline ct values ,business - Abstract
Background In resource-limited settings, sputum smear conversion is used to document treatment response. Many People living with HIV (PLHIV) are smear-negative at baseline. The Xpert MTB/RIF test can indirectly measure bacterial load through cycle threshold (ct) values. This study aimed to determine if baseline Xpert MTB/RIF could predict time to culture negativity in PLHIV with newly diagnosed TB. Methods A subset of 138 PLHIV from the ‘SOUTH’ study on outcomes related to TB and antiretroviral drug concentrations were included. Bacterial load was estimated by Mycobacterium Growth Indicator Tubes (MGIT) culture time-to-positivity (TTP) and Lowenstein Jensen (LJ) colony counts. Changes in TTP and colony counts were analyzed with Poisson Generalised Estimating Equations (GEE) and multilevel ordered logistic regression models, respectively, while time to culture negativity analysed with Cox proportional hazard models. ROC curves were used to explore the accuracy of the ct value in predicting culture negativity. Results A total of 81 patients (58.7%) were males, median age 34 (IQR 29 ̶ 40) years, median CD4 cell count of 180 (IQR 68 ̶ 345) cells/μL and 77.5% were ART naive. The median baseline ct value was 25.1 (IQR 21.0 ̶ 30.1). A unit Increase in the ct value was associated with a 5% (IRR = 1.05 95% CI 1.04 ̶ 1.06) and 3% (IRR = 1.03 95% CI 1.03 ̶ 1.04) increase in TTP at week 2 and 4 respectively. With LJ culture, a patient’s colony grade was reduced by 0.86 times (0R = 0.86 95% CI 0.74 ̶ 0.97) at week 2 and 0.84 times (OR = 0.84 95% CI 0.79 ̶ 0.95 P = 0.002) at week 4 for every unit increase in the baseline ct value. There was a 3% higher likelihood of earlier conversion to negativity for every unit increase in the ct value. A ct cut point ≥28 best predicted culture negativity at week 4 with a sensitivity of 91. 7% & specificity 53.7% while a cut point ≥23 best predicted culture negativity at week 8. Conclusion Baseline Xpert MTB/RIF ct values predict sputum conversion in PLHIV on anti-TB treatment. Surrogate biomarkers for sputum conversion in PLHIV are still a research priority.
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- 2021
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45. Campylobacter fetus Meningitis and Pyogenic Spondylodiscitis in a Healthy Young Woman
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Yasuhiro Manabe, Hisashi Narai, Kenta Ikeda, Yoshio Omote, Koji Abe, and Shunya Fujiwara
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medicine.medical_specialty ,medicine.diagnostic_test ,biology ,business.industry ,Magnetic resonance imaging ,medicine.disease ,biology.organism_classification ,Low back pain ,Gastroenterology ,Lesion ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Ampicillin ,Medicine ,Medical history ,Blood culture ,030212 general & internal medicine ,Neurology (clinical) ,Campylobacter fetus ,medicine.symptom ,business ,Meningitis ,030217 neurology & neurosurgery ,medicine.drug - Abstract
We report a rare case of Campylobacter fetus meningitis and pyogenic spondylodiscitis in a healthy young woman. A 35-year-old woman without significant medical history presented with fever, headache, and low back pain. C. fetus was detected from the blood culture. Cerebrospinal fluid analysis showed bacterial meningitis 2 days after onset. Although initial magnetic resonance imaging (MRI) did not reveal abnormal findings, repeated MRI showed a low-signal-intensity lesion on T1-weighted image (T1WI) and a high-signal-intensity lesion on T2WI between the L5 and S1 vertebral bodies 11 days after onset. The mode of infection was considered to be the consumption of raw chicken meat. After antibiotic treatment with 12 g/day ampicillin following 6 g/day meropenem, she was discharged 51 days after onset. As the inflammatory signs on MRI improved, oral antibiotic therapy was discontinued 85 days after onset. Although the initial MRI showed no abnormal findings, repeat MRI should be performed for patients who have persistent low back pain and fever.
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- 2019
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46. DNA methylation-based classification reveals difference between pediatric T-cell acute lymphoblastic leukemia and normal thymocytes
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Kentaro Watanabe, Akira Ohara, Atsushi Manabe, Masao Kobayashi, Akira Oka, Tomoko Kawai, Atsushi Sato, Seishi Ogawa, Katsuyoshi Koh, Satoru Miyano, Yusuke Shiozawa, Hiromichi Suzuki, Motohiro Kato, Shunsuke Kimura, Yoshiko Hashii, Masashi Sanada, Yasuo Kubota, Keizo Horibe, Hiroo Ueno, Junko Takita, Yasuhide Hayashi, Yasuhito Nannya, Nobutaka Kiyokawa, Yuichi Shiraishi, Ryoji Kobayashi, Masafumi Seki, Hiroaki Goto, Marc R. Mansour, Masahiro Sekiguchi, Kenichiro Hata, Takao Deguchi, Toshihiko Imamura, Kenichi Yoshida, Tomoya Isobe, and Kentaro Ohki
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Regulation of gene expression ,Cancer Research ,medicine.anatomical_structure ,Oncology ,T cell ,Lymphoblastic Leukemia ,DNA methylation ,medicine ,Cancer research ,Hematology ,Biology ,Epigenesis - Published
- 2019
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47. Glial pathology in a novel spontaneous mutant mouse of the Eif2b5 gene: a vanishing white matter disease model
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Takuhiro Ito, Yasuko Toyoshima, Anna Simankova, Norikazu Hara, Shiho Ominato, Hironaka Igarashi, Shigeharu Wakana, Kazuhiro Kashiwagi, Muraki Yoshiko, Toshiya Manabe, Hirohide Takebayashi, Yuji Kiyama, Akiyoshi Kakita, Hiroki Kitaura, Mika Terumitsu-Tsujita, Norihisa Bizen, Ikuo Miura, and Fumiko Goto
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Male ,0301 basic medicine ,Protein subunit ,Mutant ,Biology ,Biochemistry ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Myelin ,0302 clinical medicine ,Leukoencephalopathies ,medicine ,Animals ,Point Mutation ,eIF2 ,Glial fibrillary acidic protein ,Point mutation ,Endoplasmic reticulum ,Brain ,Mice, Mutant Strains ,Cell biology ,Mice, Inbred C57BL ,Disease Models, Animal ,Eukaryotic Initiation Factor-2B ,030104 developmental biology ,medicine.anatomical_structure ,eIF2B ,biology.protein ,Female ,Neuroglia ,030217 neurology & neurosurgery - Abstract
Vanishing white matter disease (VWM) is an autosomal recessive neurological disorder caused by mutation(s) in any subunit of eukaryotic translation initiation factor 2B (eIF2B), an activator of translation initiation factor eIF2. VWM occurs with mutation of the genes encoding eIF2B subunits (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5). However, little is known regarding the underlying pathogenetic mechanisms or how to treat patients with VWM. Here we describe the identification and detailed analysis of a new spontaneous mutant mouse harboring a point mutation in the Eif2b5 gene (p.Ile98Met). Homozygous Eif2b5I98M mutant mice exhibited a small body, abnormal gait, male and female infertility, epileptic seizures, and a shortened lifespan. Biochemical analyses indicated that the mutant eIF2B protein with the Eif2b5I98M mutation decreased guanine nucleotide exchange activity on eIF2, and the level of the endoplasmic reticulum stress marker activating transcription factor 4 was elevated in the 1-month-old Eif2b5I98M brain. Histological analyses indicated up-regulated glial fibrillary acidic protein immunoreactivity in the astrocytes of the Eif2b5I98M forebrain and translocation of Bergmann glia in the Eif2b5I98M cerebellum, as well as increased mRNA expression of an endoplasmic reticulum stress marker, C/EBP homologous protein. Disruption of myelin and clustering of oligodendrocyte progenitor cells were also indicated in the white matter of the Eif2b5I98M spinal cord at 8 months old. Our data show that Eif2b5I98M mutants are a good model for understanding VWM pathogenesis and therapy development. Cover Image for this issue: doi: 10.1111/jnc.14751.
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- 2019
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48. A PQ-loop protein Ypq2 is involved in the exchange of arginine and histidine across the vacuolar membrane of Saccharomyces cerevisiae
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Yoshimi Kakinuma, Yuki Harada, Kunio Manabe, Takayuki Sekito, Koichi Ikeda, Miyuki Kawano-Kawada, Shiho Tanaka, T. Kimura, and Haruka Ichimura
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Cell biology ,Saccharomyces cerevisiae Proteins ,Proline ,Arginine ,Molecular biology ,Amino Acid Motifs ,Saccharomyces cerevisiae ,lcsh:Medicine ,Vacuole ,Biochemistry ,Article ,Adenosine Triphosphate ,Histidine ,Amino Acid Sequence ,lcsh:Science ,Peptide sequence ,Multidisciplinary ,biology ,Chemistry ,Vesicle ,lcsh:R ,Membrane Transport Proteins ,Transporter ,Intracellular Membranes ,biology.organism_classification ,Mutation ,Vacuoles ,lcsh:Q ,Protons - Abstract
In nutrient-rich conditions, basic amino acids are actively accumulated into the vacuoles by H+-coupled transporters in Saccharomyces cerevisiae. In addition to the H+-coupled systems, the existence of an exchanger for arginine and histidine was indicated by kinetic analysis using isolated vacuolar membrane vesicles; however, the gene(s) involved in the activity has not been identified. Here, we show that the uptake activity of arginine driven by an artificially imposed histidine gradient decreased significantly by the disruption of the gene encoding vacuolar PQ-loop protein Ypq2, but not by those of Ypq1 and Ypq3. The exchange activity was restored by the expression of YPQ2. Furthermore, the substitution of a conserved proline residue, Pro29, in Ypq2 greatly decreased the exchange activity. These results suggest that Ypq2 is responsible for the exchange activity of arginine and histidine across the vacuolar membrane, and the conserved proline residue in the PQ-loop motif is required for the activity.
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- 2019
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49. Therapeutic targeting of mitochondrial ROS ameliorates murine model of volume overload cardiomyopathy
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Kenichi Okamura, Yasutaka Hirata, Issei Komuro, Yasutoshi Kido, Katsura Soma, Takayuki Isagawa, Minoru Ono, Yu Nakagama, Masaya Sakamoto, Ichiro Manabe, Tatsuyuki Sato, and Norihiko Takeda
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Male ,0301 basic medicine ,Mitochondrial ROS ,medicine.medical_specialty ,medicine.medical_treatment ,Management of heart failure ,Volume overload ,Cardiomyopathy ,Antioxidants ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Citrate synthase ,Myocytes, Cardiac ,Molecular Targeted Therapy ,Heart Failure ,Pharmacology ,biology ,business.industry ,lcsh:RM1-950 ,medicine.disease ,Acetylcysteine ,Mitochondria ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,lcsh:Therapeutics. Pharmacology ,Heart failure ,biology.protein ,Cardiology ,Molecular Medicine ,Hemodialysis ,Cardiomyopathies ,Reactive Oxygen Species ,business ,030217 neurology & neurosurgery - Abstract
Concomitant heart failure is associated with poor clinical outcome in dialysis patients. The arteriovenous shunt, created as vascular access for hemodialysis, increases ventricular volume-overload, predisposing patients to developing cardiac dysfunction. The integral function of mitochondrial respiration is critically important for the heart to cope with hemodynamic overload. The involvement, however, of mitochondrial activity or reactive oxygen species (ROS) in the pathogenesis of ventricular-overload-induced heart failure has not been fully elucidated.We herein report that disorganization of mitochondrial respiration increases mitochondrial ROS production in the volume-overloaded heart, leading to ventricular dysfunction. We adopted the murine arteriovenous fistula (AVF) model, which replicates the cardinal features of volume-overload-induced ventricular dysfunction. Enzymatic assays of cardiac mitochondria revealed that the activities of citrate synthase and NADH-quinone reductase (complex Ⅰ) were preserved in the AVF heart. In contrast, the activity of NADH oxidase supercomplex was significantly compromised, resulting in elevated ROS production. Importantly, the antioxidant N-acetylcysteine prevented the development of ventricular dilatation and cardiac dysfunction, suggesting a pathogenic role for ROS in dialysis-related cardiomyopathy. A cardioprotective effect was also observed in metformin-treated mice, illuminating its potential use in the management of heart failure complicating diabetic patients on dialysis. Keywords: Heart failure, Volume-overload, ROS, N-acetylcysteine, Metformin
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- 2019
50. Efficient Syntheses of Complex-Type N-Glycans using Microflow Systems and Convergent Synthetic Routes
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Yoshiyuki Manabe
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chemistry.chemical_compound ,Glycan ,Glycosylation ,chemistry ,biology ,Stereochemistry ,Organic Chemistry ,biology.protein ,Convergent synthesis ,Complex type ,Biochemistry - Published
- 2019
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