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6. First Search for Gravitational Waves from Known Pulsars with Advanced LIGO

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Abbott, B. P., Abbott, R., Abbott, T. D., Abernathy, M. R., Acernese, F., Ackley, K., Adams, C., Phythian-Adams, A.T., Addesso, P., Adhikari, R. X., Adya, V. B., Affeldt, C., Agathos, M., Agatsuma, K., Aggarwal, N.T., Aguiar, O. D., Aiello, L., Ain, A., Ajith, P., Allen, B., Allocca, A., Altin, P. A., Ananyeva, A., Anderson, S. B., Anderson, W. G., Appert, S., Arai, K., Araya, M. C., Areeda, J. S., Arnaud, N., Arun, K. G., Ascenzi, S., Ashton, G., Ast, M., Aston, S. M., Astone, P., Aufmuth, P., Aulbert, C., Avila-Alvarez, A., Babak, S., Bacon, P., Bader, M. K. M., Baker, P. T., Baldaccini, F., Ballardin, G., Ballmer, S. W., Barayoga, J. C., Barclay, S. E., Barish, B. C., Barker, R.D., Barone, F., Barr, B., Barsotti, L., Barsuglia, M., Barta, D., Bartlett, J., Bartos, I., Bassiri, R., Basti, A., Batch, J. C., Baune, C., Bavigadda, V., Bazzan, M., Beer, C., Bejger, M., Belahcene, I., Belgin, M., Bell, A. S., Berger, B. K., Bergmann, G., Berry, C. P. L., Bersanetti, D., Bertolini, A., Betzwieser, J., Bhagwat, S., Bhandare, R., Bilenko, I. A., Billingsley, G., Billman, C. R., Birch, M.J., Birney, R., Birnholtz, O., Biscans, S., Bisht, A., Bitossi, M., Biwer, C., Bizouard, M. A., Blackburn, J. K., Blackman, J., Blair, C. D., Blair, D. G., Blair, R. M., Bloemen, A.L.S., Bock, O., Boer, M., Bogaert, J.G., Bohe, A., Bondu, F., Bonnand, R., Boom, B. A., Bork, R., Boschi, V., Bose, S., Bouffanais, Y., Bozzi, A., Bradaschia, C., Brady, P. R., Braginsky, V. B., Branchesi, M., Brau, J. E., Briant, T., Brillet, A., Brinkmann, M., Brisson, V., Brockill, P., Broida, J. E., Brooks, A. F., Brown, A.D., Brown, D., Brown, N. M., Brunett, S., Buchanan, C. C., Buikema, A., Bulik, T., Bulten, H. J., Buonanno, A., Buskulic, D., Buy, C., Byer, R. L., Cabero, M., Cadonati, L., Cagnoli, G., Cahillane, C., Bustillo, J. Calderon, Callister, T. A., Calloni, E., Camp, J. B., Canepa, M., Cannon, K. C., Cao, H., Cao, J., Capano, C. D., Capocasa, E., Carbognani, F., Caride, S., Diaz, J. Casanueva, Casentini, C., Caudill, S., Cavaglia, M., Cavalier, F., Cavalieri, R., Cella, G., Cepeda, C. B., Baiardi, L. Cerboni, Cerretani, G., Cesarini, E., Chamberlin, S. J., Chan, M., Chao, D. S., Charlton, P., Chassande-Mottin, E., Cheeseboro, B. D., Chen, H. Y., Chen, Y, Cheng, H. -P., Chincarini, A., Chiummo, A., Chmiel, T., Cho, H. S., Cho, M., Chow, J. H., Christensen, N., Chu, Qian, Chua, A. J. K., Chua, S. S. Y., Chung, E.S., Ciani, G., Clara, F., Clark, J. A., Cleva, F., Cocchieri, C., Coccia, E., Cohadon, P. -F., Colla, A., Collette, C. G., Cominsky, L., Constancio, M., Jr., Conti, L., Cooper, S. J., Corbitt, T. R., Cornish, N., Corsi, A., Cortese, S., Costa, A.C., Coughlin, M. W., Coughlin, S. B., Coulon, J. -P., Countryman, S. T., Couvares, P., Covas, P. B., Cowan, E. E., Coward, D. M., Cowart, M. J., Coyne, D. C., Coyne, R., Creighton, J. D. E., Creighton, T. D., Cripe, J., Crowder, S. G., Cullen, T. J., Cumming, A., Cunningham, Laura, Cuoco, E., Dal Canton, T., Danilishin, S. L., D'Antonio, S., Danzmann, K., Dasgupta, A., Costa, C. F. Da Silva, Dattilo, V., Dave, I., Davier, M., Davies, G. S., Davis, D., Daw, E. J., Day, B., Day, R., De, S., Debra, D., Debreczeni, G., Degallaix, J., De laurentis, M., Deleglise, S., Del Pozzo, W., Denker, T., Dent, T., Dergachev, V.A., Rosa, R., DeRosa, R. T., DeSalvo, R., Devenson, J., Devine, R. C., Dhurandhar, S., Diaz, M. C., Di Fiore, L., Giovanni, M. Di, Di Girolamo, T., Di Lieto, A., Di Pace, S., Di Palma, I., Di Virgilio, A., Doctor, Z., Dolique, V., Donovan, F., Dooley, K. L., Doravari, S., Dorrington, I., Douglas, R., Alvarez, M. Dovale, Downes, T. P., Drago, M., Drever, R. W. P., Driggers, J. C., Du, Z., Ducrot, M., Dwyer, S. E., Edo, T. B., Edwards, M. C., Effler, A., Eggenstein, H. -B., Ehrens, P., Eichholz, J., Eikenberry, S. S., Eisenstein, R. A., Essick, R. C., Etienne, Z., Etzel, T., Evans, T. M., Everett, R., Factourovich, M., Fafone, V., Fair, H., Fairhurst, S., Fan, X.M., Farinon, S., Farr, B., Farr, W. M., Fauchon-Jones, E. J., Favata, M., Fays, M., Fehrmann, H., Fejer, M. M., Galiana, A. Fernandez, Ferrante, I., Ferreira, E. C., Ferrini, F., Fidecaro, F., Fiori, I., Fiorucci, D., Fisher, R. P., Flaminio, R., Fletcher, M, Fong, H., Forsyth, S. S., Fournier, J. -D., Frasca, S., Frasconi, F., Frei, Z., Freise, A., Frey, R., Frey, V., Fries, E. M., Fritschel, P., Frolov, V. V., Fulda, P., Fyffe, M., Gabbard, H., Gadre, B. U., Gaebel, S. M., Gair, J. R., Gammaitoni, L., Gaonkar, S. G., Garufi, F., Gaur, G., Gayathri, V., Gehrels, N., Gemme, G., Genin, E., Gennai, A., George, J., Gergely, L., Germain, V., Ghonge, S., Ghosh, Abhirup, Ghosh, Archisman, Ghosh, S., Giaime, J. A., Giardina, K. D., Giazotto, A., Gill, K.P., Glaefke, A., Goetz, E., Goetz, R., Gondan, L., Gonzalez, Idelmis G., Castro, J. M. Gonzalez, Gopakumar, A., Gorodetsky, M. L., Gossan, S. E., Lee-Gosselin, M., Gouaty, R., Grado, A., Graef, C., Granata, M., Grant, A., Gras, S., Gray, C.M., Greco, G., Green, A. C., Groot, P., Grote, H., Grunewald, S., Guidi, G. M., Guo, X., Gupta, A., Gupta, M. K., Gushwa, K. E., Gustafson, E. K., Gustafson, R., Hacker, J. J., Buffoni-Hall, R., Hall, E. D., Hammond, G.L., Haney, M., Hanke, M. M., Hanks, J., Hanna, C., Hanson, P.J., Hardwick, T., Harms, J., Harry, G. M., Harry, I. W., Hart, M. J., Hartman, M. T., Haster, C. -J., Haughian, K., Healy, J., Heidmann, A., Heintze, M. C., Heitmann, H., Hello, P., Hemming, G., Hendry, M., Heng, I. S., Hennig, J., Henry, J.A., Heptonstall, A. W., Heurs, M., Hild, S., Hoak, D., Hofman, D., Holt, K., Holz, D. E., Hopkins, P., Hough, J., Houston, E. A., Howell, E. J., Hu, Y. M., Huerta, E. A., Huet, D., Hughey, B., Husa, S., Huttner, S. H., Huynh-Dinh, T., Indik, N., Ingram, D. R., Inta, R., Isa, H. N., Isac, J. -M., Isi, M., Isogai, T., Iyer, B. R., Izumi, K., Jacqmin, T., Jani, K., Jaranowski, P., Jawahar, S., Jimenez-Forteza, F., Johnson, W., Jones, I.D., Jones, R., Jonker, R. J. G., Ju, L., Junker, J., Kalaghatgi, C. V., Kalogera, V., Kandhasamy, S., Kang, G.H., Kanner, J. B., Karki, S., Karvinen, K. S., Kasprzack, M., Katsavounidis, E., Katzman, W., Kaufer, S., Kaur, T., Kawabe, K., Kefelian, F., Keitel, D., Kelley, D. B., Kennedy, R.E., Key, J. S., Khalili, F. Y., Khan, I., Khan., S., Khan, Z., Khazanov, E. A., Kijbunchoo, N., Kim, Chunglee, Kim, J. C., Kim, Whansun, Kim, W., Kim, Y.M., Kimbrell, S. J., King, E. J., King, P. J., Kirchhoff, R., Kissel, J. S., Klein, B., Kleybolte, L., Klimenko, S., Koch, P., Koehlenbeck, S. M., Koley, S., Kondrashov, V., Kontos, A., Korobko, M., Korth, W. Z., Kowalska, I., Kozak, D. B., Kraemer, H.C., Kringel, V., Krishnan, B., Krolak, A., Kuehn, G., Kumar, P., Kumar, R., Kuo, L., Kutynia, A., Lackey, B. D., Landry, M., Lang, R. N., Lange, J., Lantz, B., Lanza, R. K., Lartaux-Vollard, A., Lasky, P. D., Laxen, M., Lazzarini, A., Lazzaro, C., Leaci, P., Leavey, S., Lebigot, E. O., Lee, C.H., Lee, K.H., Lee, M.H., Lee, K., Lehmann, J., Lenon, A., Leonardi, M., Leong, J. R., Leroy, N., Letendre, N., Levin, Y., Li, T. G. F., Libson, A., Littenberg, T. B., Liu, J., Lockerbie, N. A., Lombardi, A. L., London, L. T., Lord, J. E., Lorenzini, M., Loriette, V., Lormand, M., Losurdo, G., Lough, J. D., Lousto, C. O., Lovelace, G., Lueck, H., Lundgren, A. P., Lynch, R., Ma, Y., Macfoy, S., Machenschalk, B., MacInnis, M., Macleod, D. M., Magana-Sandoval, F., Majorana, E., Maksimovic, I., Malvezzi, V., Man, N., Mandic, V., Mangano, V., Mansell, G. L., Manske, M., Mantovani, M., Marchesoni, F., Marion, F., Marka, S., Marka, Z., Markosyan, A. S., Maros, E., Martelli, F., Martellini, L., Martin, I. W., Martynov, D. V., Mason, K., Masserot, A., Massinger, T. J., Masso-Reid, M., Mastrogiovanni, S., Matichard, F., Matone, L., Mavalvala, N., Mazumder, N., McCarthy, R., McClelland, D. E., McCormick, S., McGrath Hoareau, C., McGuire, S. C., McIntyre, G., McIver, J., McManus, D. J., McRae, T., McWilliams, S. T., Meacher, D., Meador, G. D., Meidam, J., Melatos, A., Mendell, G., Mendoza-Gandara, D., Mercer, R. A., Merilh, E. L., Merzougui, M., Meshkov, S., Messenger, C., Messick, C., Metzdorff, R., Meyers, P. M., Mezzani, F., Miao, H., Michel, C., Middleton, H., Mikhailov, E. E., Milano, L., Miller, A. L., Miller, B., Miller, J., Millhouse, M., Minenkov, Y., Ming, J., Mirshekari, S., Mishra, C., Mitra, S., Mitrofanov, V. P., Mitselmakher, G., Mittleman, R., Moggi, A., Mohan, M., Mohapatra, S. R. P., Montani, M., Moore, B.C., Moore, J.C., Moraru, D., Gutierrez Moreno, M., Morriss, S. R., Mours, B., Mow-Lowry, C. M., Mueller, G., Muir, A. W., Mukherjee, Arunava, Mukherjee, S.D., Mukherjee, S., Mukund, N., Mullavey, A., Munch, J., Muniz, E. A. M., Murray, P.G., Mytidis, A., Napier, K., Nardecchia, I., Naticchioni, L., Nelemans, G., Nelson, T. J. N., Gutierrez-Neri, M., Nery, M., Neunzert, A., Newport, J. M., Newton-Howes, G., Nguyen, T. T., Nielsen, A. B., Nissanke, S., Nitz, A., Noack, A., Nocera, F., Nolting, D., Normandin, M. E. N., Nuttall, L. K., Oberling, J., Ochsner, E., Oelker, E., Ogin, G. H., Oh, J., Oh, S. H., Ohme, F., Oliver, M. B., Oppermann, P., Oram, Richard J., O'Reilly, B., O'Shaughnessy, R., Ottaway, D. J., Overmier, H., Owen, B. J., Pace, A. E., Page, J., Pai, A., Pai, S. A., Palamos, J. R., Palashov, O., Palomba, C., Pal-Singh, A., Pan, H., Pankow, C., Pannarale, F., Pant, B. C., Paoletti, F., Paoli, A., Papa, M. A., Paris, H. R., Parker, W.S, Pascucci, D., Pasqualetti, A., Passaquieti, R., Passuello, D., Patricelli, B., Pearlstone, B. L., Pedraza, M., Pedurand, R., Pekowsky, L., Pele, A., Penn, S., Castro-Perez, J., Perreca, A., Perri, L. M., Pfeiffer, H. P., Phelps, M., Piccinni, O. J., Pichot, M., Piergiovanni, F., Pierro, V., Pillant, G., Pinard, L., Pinto, I. M., Pitkin, M., Poe, M., Poggiani, R., Popolizio, P., Post, A., Powell, J., Prasad, J., Pratt, J. W. W., Predoi, V., Prestegard, T., Prijatelj, M., Principe, M., Privitera, S., Prix, R., Prodi, G. A., Prokhorov, L. G., Puncken, O., Punturo, M., Puppo, P., Puerrer, M., Qi, H., Qin, J., Qiu, S., Quetschke, V., Quintero, E. A., Quitzow-James, R., Raab, F. J., Rabeling, D. S., Radkins, H., Raffai, P., Raja, S., Rajan, C., Rakhmanov, M., Rapagnani, P., Raymond, V., Razzano, M., Re, V., Read, J., Regimbau, T., Rei, L., Reid, S., Reitze, D. H., Rew, H., Reyes, S. D., Rhoades, E., Ricci, F., Riles, K., Rizzo, D.M., Robertson, N. A., Robie, R., Robinet, F., Rocchi, A., Rolland, L., Rollins, J. G., Roma, V. J., Romano, R., Romie, J. H., Rosinska, D., Rowan, S., Ruediger, A., Ruggi, P., Ryan, K.A., Sachdev, Perminder S, Sadecki, T., Sadeghian, L., Sakellariadou, M., Salconi, L., Saleem, M., Salemi, F., Samajdar, A., Sammut, L., Sampson, L. M., Sanchez, E. J., Sandberg, V., Sanders, J. R., Sassolas, B., Sathyaprakash, B. S., Saulson, P. R., Sauter, O., Savage, R. L., Sawadsky, A., Schale, P., Scheuer, J., Schmidt, E., Schmidt, J, Schmidt, P., Schnabel, R.B., Schofield, R. M. S., Schoenbeck, A., Schreiber, K.E.C., Schuette, D., Schutz, B. F., Schwalbe, S. G., Scott, J., Scott, M.S., Sellers, D., Sengupta, A. S., Sentenac, D., Sequino, V., Sergeev, A., Setyawati, Y., Shaddock, D. A., Shaffer, T. J., Shahriar, M. S., Shapiro, B., Shawhan, P., Sheperd, A., Shoemaker, D. H., Shoemaker, D. M., Siellez, K., Siemens, X., Sieniawska, M., Sigg, D., Silva, António Dias da, Singer, A, Singer, L. P., Singh, A., Singh, R., Singhal, A., Sintes, A. M., Slagmolen, B. J. J., Smith, B., Smith, R. J. E., Son, E. J., Sorazu, B., Sorrentino, F., Souradeep, T., Spencer, A. P., Srivastava, A. K., Staley, A., Steinke, M., Steinlechner, J., Steinlechner, S., Steinmeyer, D., Stephens, B. C., Stevenson-Moore, P., Stone, J.R., Strain, K. A., Straniero, N., Stratta, G., Strigin, S. E., Sturani, R., Stuver, A. L., Summerscales, T. Z., Sun, L., Sunil, S., Sutton, P. J., Swinkels, B. L., Szczepanczyk, M. J., Tacca, M.D., Talukder, D., Tanner, D. B., Tapai, M., Taracchini, A., Taylor, W.R., Theeg, T., Thomas, E. G., Thomas, M., Thomas, P., Thorne, K. A., Thrane, E., Tippens, T., Tiwari, S., Tiwari, V., Tokmakov, K. V., Toland, K., Tomlinson, C., Tonelli, M., Tornasi, Z., Torrie, C. I., Toeyrae, D., Travasso, F., Traylor, G., Trifiro, D., Trinastic, J., Tringali, M. C., Trozzo, L., Tse, M., Tso, R., Turconi, M., Tuyenbayev, D., Ugolini, D., Unnikrishnan, C. S., Urban, A. L., Usman, S. A., Vahlbruch, H., Vajente, G., Valdes, G., van Bakel, N., Van Beuzekom, Martin, van den Brand, J. F. J., Van Den Broeck, C.F.F., Vander-Hyde, D. C., van der Schaaf, L., van Heijningen, J. V., van Veggel, A. A., Vardaro, M., Varma, V., Vass, S., Vasuth, M., Vecchio, A., Vedovato, G., Veitch, J., Veitch, P.J., Venkateswara, K., Venugopalan, G., Verkindt, D., Vetrano, F., Vicere, A., Viets, A. D., Vinciguerra, S., Vine, D. J., Vinet, J. -Y., Vitale, S., Vo, T., Vocca, H., Vorvick, C., Voss, D. V., Vousden, W. D., Vyatchanin, S. P., Wade, A. R., Wade, L. E., Wade, MT, Walker, M., Wallace, L., Walsh, S., Wang, G., Wang, H., Wang, M., Wang, Y., Ward, R. L., Warner, J., Was, M., Watchi, J., Weaver, B., Wei, L. -W., Weinert, M., Weinstein, A. J., Weiss, R., Wen, L.M., Wessels, P., Westphal, T., Wette, K., Whelan, J. T., Whiting, B. F., Whittle, C., Williams, D., Williams, D.R., Williamson, A. R., Willis, J. L., Willke, B., Wimmer, M. H., Winkler, W., Wipf, C. C., Wittel, H., Woan, G., Woehler, J., Worden, J., Wright, J.L., Wu, D.S., Wu, G., Yam, W., Yamamoto, H., Yancey, C. C., Yap, M. J., Yu, Hang, Yu, Haocun, Yvert, M., Zadrozny, A., Zangrando, L., Zanolin, M., Zendri, J. -P., Zevin, M., Zhang, L., Zhang, M., Zhang, T., Zhang, Y., Zhao, C., Zhou, M., Zhou, Z., Zhu, S.J., Zhu, X. J., Zucker, M. E., Zweizig, J., Buchner, S., Cognard, I., Corongiu, A., Freire, P. C.C., Guillemot, L., Hobbs, G. B., Kerr, M., Lyne, A. G., Possenti, A., Ridolfi, A., Shannon, R. M., Stappers, B. W., Weltevrede, P., Abbott, B. P., Abbott, R., Abbott, T. D., Abernathy, M. R., Acernese, F., Ackley, K., Adams, C., Phythian-Adams, A.T., Addesso, P., Adhikari, R. X., Adya, V. B., Affeldt, C., Agathos, M., Agatsuma, K., Aggarwal, N.T., Aguiar, O. D., Aiello, L., Ain, A., Ajith, P., Allen, B., Allocca, A., Altin, P. A., Ananyeva, A., Anderson, S. B., Anderson, W. G., Appert, S., Arai, K., Araya, M. C., Areeda, J. S., Arnaud, N., Arun, K. G., Ascenzi, S., Ashton, G., Ast, M., Aston, S. M., Astone, P., Aufmuth, P., Aulbert, C., Avila-Alvarez, A., Babak, S., Bacon, P., Bader, M. K. M., Baker, P. T., Baldaccini, F., Ballardin, G., Ballmer, S. W., Barayoga, J. C., Barclay, S. E., Barish, B. C., Barker, R.D., Barone, F., Barr, B., Barsotti, L., Barsuglia, M., Barta, D., Bartlett, J., Bartos, I., Bassiri, R., Basti, A., Batch, J. C., Baune, C., Bavigadda, V., Bazzan, M., Beer, C., Bejger, M., Belahcene, I., Belgin, M., Bell, A. S., Berger, B. K., Bergmann, G., Berry, C. P. L., Bersanetti, D., Bertolini, A., Betzwieser, J., Bhagwat, S., Bhandare, R., Bilenko, I. A., Billingsley, G., Billman, C. R., Birch, M.J., Birney, R., Birnholtz, O., Biscans, S., Bisht, A., Bitossi, M., Biwer, C., Bizouard, M. A., Blackburn, J. K., Blackman, J., Blair, C. D., Blair, D. G., Blair, R. M., Bloemen, A.L.S., Bock, O., Boer, M., Bogaert, J.G., Bohe, A., Bondu, F., Bonnand, R., Boom, B. A., Bork, R., Boschi, V., Bose, S., Bouffanais, Y., Bozzi, A., Bradaschia, C., Brady, P. R., Braginsky, V. B., Branchesi, M., Brau, J. E., Briant, T., Brillet, A., Brinkmann, M., Brisson, V., Brockill, P., Broida, J. E., Brooks, A. F., Brown, A.D., Brown, D., Brown, N. M., Brunett, S., Buchanan, C. C., Buikema, A., Bulik, T., Bulten, H. J., Buonanno, A., Buskulic, D., Buy, C., Byer, R. L., Cabero, M., Cadonati, L., Cagnoli, G., Cahillane, C., Bustillo, J. Calderon, Callister, T. A., Calloni, E., Camp, J. B., Canepa, M., Cannon, K. C., Cao, H., Cao, J., Capano, C. D., Capocasa, E., Carbognani, F., Caride, S., Diaz, J. Casanueva, Casentini, C., Caudill, S., Cavaglia, M., Cavalier, F., Cavalieri, R., Cella, G., Cepeda, C. B., Baiardi, L. Cerboni, Cerretani, G., Cesarini, E., Chamberlin, S. J., Chan, M., Chao, D. S., Charlton, P., Chassande-Mottin, E., Cheeseboro, B. D., Chen, H. Y., Chen, Y, Cheng, H. -P., Chincarini, A., Chiummo, A., Chmiel, T., Cho, H. S., Cho, M., Chow, J. H., Christensen, N., Chu, Qian, Chua, A. J. K., Chua, S. S. Y., Chung, E.S., Ciani, G., Clara, F., Clark, J. A., Cleva, F., Cocchieri, C., Coccia, E., Cohadon, P. -F., Colla, A., Collette, C. G., Cominsky, L., Constancio, M., Jr., Conti, L., Cooper, S. J., Corbitt, T. R., Cornish, N., Corsi, A., Cortese, S., Costa, A.C., Coughlin, M. W., Coughlin, S. B., Coulon, J. -P., Countryman, S. T., Couvares, P., Covas, P. B., Cowan, E. E., Coward, D. M., Cowart, M. J., Coyne, D. C., Coyne, R., Creighton, J. D. E., Creighton, T. D., Cripe, J., Crowder, S. G., Cullen, T. J., Cumming, A., Cunningham, Laura, Cuoco, E., Dal Canton, T., Danilishin, S. L., D'Antonio, S., Danzmann, K., Dasgupta, A., Costa, C. F. Da Silva, Dattilo, V., Dave, I., Davier, M., Davies, G. S., Davis, D., Daw, E. J., Day, B., Day, R., De, S., Debra, D., Debreczeni, G., Degallaix, J., De laurentis, M., Deleglise, S., Del Pozzo, W., Denker, T., Dent, T., Dergachev, V.A., Rosa, R., DeRosa, R. T., DeSalvo, R., Devenson, J., Devine, R. C., Dhurandhar, S., Diaz, M. C., Di Fiore, L., Giovanni, M. Di, Di Girolamo, T., Di Lieto, A., Di Pace, S., Di Palma, I., Di Virgilio, A., Doctor, Z., Dolique, V., Donovan, F., Dooley, K. L., Doravari, S., Dorrington, I., Douglas, R., Alvarez, M. Dovale, Downes, T. P., Drago, M., Drever, R. W. P., Driggers, J. C., Du, Z., Ducrot, M., Dwyer, S. E., Edo, T. B., Edwards, M. C., Effler, A., Eggenstein, H. -B., Ehrens, P., Eichholz, J., Eikenberry, S. S., Eisenstein, R. A., Essick, R. C., Etienne, Z., Etzel, T., Evans, T. M., Everett, R., Factourovich, M., Fafone, V., Fair, H., Fairhurst, S., Fan, X.M., Farinon, S., Farr, B., Farr, W. M., Fauchon-Jones, E. J., Favata, M., Fays, M., Fehrmann, H., Fejer, M. M., Galiana, A. Fernandez, Ferrante, I., Ferreira, E. C., Ferrini, F., Fidecaro, F., Fiori, I., Fiorucci, D., Fisher, R. P., Flaminio, R., Fletcher, M, Fong, H., Forsyth, S. S., Fournier, J. -D., Frasca, S., Frasconi, F., Frei, Z., Freise, A., Frey, R., Frey, V., Fries, E. M., Fritschel, P., Frolov, V. 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Abstract

We present the result of searches for gravitational waves from 200 pulsars using data from the first observing run of the Advanced LIGO detectors. We find no significant evidence for a gravitational-wave signal from any of these pulsars, but we are able to set the most constraining upper limits yet on their gravitational-wave amplitudes and ellipticities. For eight of these pulsars, our upper limits give bounds that are improvements over the indirect spindown limit values. For another 32, we are within a factor of 10 of the spin-down limit, and it is likely that some of these will be reachable in future runs of the advanced detector. Taken as a whole, these new results improve on previous limits by more than a factor of two.

Published
2017
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7. Effects of waveform model systematics on the interpretation of GW150914

Author

Abbott, B. P., Abbott, R., Abbott, T. D., Abernathy, M. R., Acernese, F., Ackley, K., Adams, C., Phythian-Adams, A.T., Addesso, P., Adhikari, R. X., Adya, V. B., Affeldt, C., Agathos, M., Agatsuma, K., Aggarwal, N.T., Aguiar, O. D., Aiello, L., Ain, A., Ajith, P., Allen, B., Allocca, A., Altin, P. A., Ananyeva, A., Anderson, S. B., Anderson, W. G., Appert, S., Arai, K., Araya, M. C., Areeda, J. S., Arnaud, N., Arun, K. G., Ascenzi, S., Ashton, G., Ast, M., Aston, S. M., Astone, P., Aufmuth, P., Aulbert, C., Avila-Alvarez, A., Babak, S., Bacon, P., Bader, M. K.M., Baker, P. T., Baldaccini, F., Ballardin, G., Ballmer, S. W., Barayoga, J. C., Barclay, S. E., Barish, B. C., Barker, R.D., Barone, F., Barr, B., Barsotti, L., Barsuglia, M., Barta, D., Bartlett, J., Bartos, I., Bassiri, R., Basti, A., Batch, J. C., Baune, C., Bavigadda, V., Bazzan, M., Beer, C., Bejger, M., Belahcene, I., Belgin, M., Bell, A. S., Berger, B. K., Bergmann, G., Berry, C. P. L., Bersanetti, D., Bertolini, A., Betzwieser, J., Bhagwat, S., Bhandare, R., Bilenko, I. A., Billingsley, G., Billman, C. R., Birch, M.J., Birney, R., Birnholtz, O., Biscans, S., Bisht, A., Bitossi, M., Biwer, C., Bizouard, M. A., Blackburn, J. K., Blackman, J., Blair, C. D., Blair, D. G., Blair, R. M., Bloemen, A.L.S., Bock, O., Boer, M., Bogaert, J.G., Bohe, A., Bondu, F., Bonnand, R., Boom, B. A., Bork, R., Boschi, V., Bose, S., Bouffanais, Y., Bozzi, A., Bradaschia, C., Brady, P. R., Braginsky, V. B., Branchesi, M., Brau, J. E., Briant, T., Brillet, A., Brinkmann, M., Brisson, V., Brockill, P., Broida, J. E., Brooks, A. F., Brown, A.D., Brown, D., Brown, N. M., Brunett, S., Buchanan, C. C., Buikema, A., Bulik, T., Bulten, H. J., Buonanno, A., Buskulic, D., Buy, C., Byer, R. L., Cabero, M., Cadonati, L., Cagnoli, G., Cahillane, C., Calderón Bustillo, J., Callister, T. A., Calloni, E., Camp, J. B., Cannon, K. C., Cao, H., Cao, J., Capano, C. 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J., Cumming, A., Cunningham, Laura, Cuoco, E., Dal Canton, T., Danilishin, S. L., D'Antonio, S., Danzmann, K., Dasgupta, A., Da Silva Costa, C. F., Dattilo, V., Dave, I., Davier, M., Davies, G. S., Davis, D., Daw, E. J., Day, B., Day, R., De, S., Debra, D., Debreczeni, G., Degallaix, J., De laurentis, M., Deléglise, S., Del Pozzo, W., Denker, T., Dent, T., Dergachev, V.A., Rosa, R., DeRosa, R. T., DeSalvo, R., Devenson, J., Devine, R. C., Dhurandhar, S., Díaz, M. C., Di Fiore, L., Giovanni, M. Di, Di Girolamo, T., Di Lieto, A., Di Pace, S., Di Palma, I., Di Virgilio, A., Doctor, Z., Dolique, V., Donovan, F., Dooley, K. L., Doravari, S., Dorrington, I., Douglas, R., Dovale Álvarez, M., Downes, T. P., Drago, M., Drever, R. W. P., Driggers, J. C., Du, Z., Ducrot, M., Dwyer, S. E., Edo, T. B., Edwards, M. C., Effler, A., Eggenstein, H. -B., Ehrens, P., Eichholz, J., Eikenberry, S. S., Eisenstein, R. A., Essick, R. C., Etienne, Z., Etzel, T., Evans, T. M., Everett, R., Factourovich, M., Fafone, V., Fair, H., Fairhurst, S., Fan, X.M., Farinon, S., Farr, B., Farr, W. M., Fauchon-Jones, E. J., Favata, M., Fays, M., Fehrmann, H., Fejer, M. M., Fernández Galiana, A., Ferrante, I., Ferreira, E. C., Ferrini, F., Fidecaro, F., Fiori, I., Fiorucci, D., Fisher, R. P., Flaminio, R., Fletcher, M, Fong, H., Forsyth, S. S., Fournier, J. -D., Frasca, S., Frasconi, F., Frei, Z., Freise, A., Frey, R., Frey, V., Fries, E. M., Fritschel, P., Frolov, V. V., Fulda, P., Fyffe, M., Gabbard, H., Gadre, B. U., Gaebel, S. M., Gair, J. R., Gammaitoni, L., Gaonkar, S. G., Garufi, F., Gaur, G., Gayathri, V., Gehrels, N., Gemme, G., Genin, E., Gennai, A., George, J., Gergely, L., Germain, V., Ghonge, S., Ghosh, Abhirup, Ghosh, Archisman, Ghosh, S., Giaime, J. A., Giardina, K. D., Giazotto, A., Gill, K.P., Glaefke, A., Goetz, E., Goetz, R., Gondan, L., González, G., Gonzalez Castro, J. M., Gopakumar, A., Gorodetsky, M. L., Gossan, S. E., Lee-Gosselin, M., Gouaty, R., Grado, A., Graef, C., Granata, M., Grant, A., Gras, S., Gray, C.M., Greco, G., Green, A. C., Groot, P., Grote, H., Grunewald, S., Guidi, G. M., Guo, X., Gupta, A., Gupta, M. K., Gushwa, K. E., Gustafson, E. K., Gustafson, R., Hacker, J. J., Buffoni-Hall, R., Hall, E. D., Hammond, G.L., Haney, M., Hanke, M. M., Hanks, J., Hanna, C., Hannam, M. D., Hanson, P.J., Hardwick, T., Harms, J., Harry, G. M., Harry, I. W., Hart, M. J., Hartman, M. T., Haster, C. -J., Haughian, K., Healy, J., Heidmann, A., Heintze, M. C., Heitmann, H., Hello, P., Hemming, G., Hendry, M., Heng, I. S., Hennig, J., Henry, J.A., Heptonstall, A. W., Heurs, M., Hild, S., Hoak, D., Hofman, D., Holt, K., Holz, D. E., Hopkins, P., Hough, J., Houston, E. A., Howell, E. J., Hu, Y. M., Huerta, E. A., Huet, D., Hughey, B., Husa, S., Huttner, S. H., Huynh-Dinh, T., Indik, N., Ingram, D. R., Inta, R., Isa, H. N., Isac, J. -M., Isi, M., Isogai, T., Iyer, B. 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S., Klein, B., Kleybolte, L., Klimenko, S., Koch, P., Koehlenbeck, S. M., Koley, S., Kondrashov, V., Kontos, A., Korobko, M., Korth, W. Z., Kowalska, I., Kozak, D. B., Krämer, C., Kringel, V., Krishnan, B., Królak, A., Kuehn, G., Kumar, P., Kumar, R., Kuo, L., Kutynia, A., Lackey, B. D., Landry, M., Lang, R. N., Lange, J., Lantz, B., Lanza, R. K., Lartaux-Vollard, A., Lasky, P. D., Laxen, M., Lazzarini, A., Lazzaro, C., Leaci, P., Leavey, S., Lebigot, E. O., Lee, C.H., Lee, K.H., Lee, M.H., Lee, K., Lehmann, J., Lenon, A., Leonardi, M., Leong, J. R., Leroy, N., Letendre, N., Levin, Y., Li, T. G.F., Libson, A., Littenberg, T. B., Liu, J., Lockerbie, N. A., Lombardi, A. L., London, L. T., Lord, J. E., Lorenzini, M., Loriette, V., Lormand, M., Losurdo, G., Lough, J. D., Lovelace, G., Lück, H., Lundgren, A. P., Lynch, R., Ma, Y., Macfoy, S., Machenschalk, B., MacInnis, M., Macleod, D. M., Magaña-Sandoval, F., Majorana, E., Maksimovic, I., Malvezzi, V., Man, N., Mandic, V., Mangano, V., Mansell, G. L., Manske, M., Mantovani, M., Marchesoni, F., Marion, F., Márka, S., Márka, Z., Markosyan, A. S., Maros, E., Martelli, F., Martellini, L., Martin, I. W., Martynov, D. V., Mason, K., Masserot, A., Massinger, T. J., Masso-Reid, M., Mastrogiovanni, S., Matichard, F., Matone, L., Mavalvala, N., Mazumder, N., McCarthy, R., McClelland, D. E., McCormick, S., McGrath Hoareau, C., McGuire, S. C., McIntyre, G., McIver, J., McManus, D. J., McRae, T., McWilliams, S. T., Meacher, D., Meadors, G. D., Meidam, J., Melatos, A., Mendell, G., Mendoza-Gandara, D., Mercer, R. A., Merilh, E. L., Merzougui, M., Meshkov, S., Messenger, C., Messick, C., Metzdorff, R., Meyers, P. M., Mezzani, F., Miao, H., Michel, C., Middleton, H., Mikhailov, E. E., Milano, L., Miller, A. L., Miller, B., Miller, J., Millhouse, M., Minenkov, Y., Ming, J., Mirshekari, S., Mishra, C., Mitra, S., Mitrofanov, V. 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C., Paoletti, F., Paoli, A., Papa, M. A., Paris, H. R., Parker, W.S, Pascucci, D., Pasqualetti, A., Passaquieti, R., Passuello, D., Patricelli, B., Pearlstone, B. L., Pedraza, M., Pedurand, R., Pekowsky, L., Pele, A., Penn, S., Castro-Perez, J., Perreca, A., Perri, L. M., Pfeiffer, H. P., Phelps, M., Piccinni, O. J., Pichot, M., Piergiovanni, F., Pierro, V., Pillant, G., Pinard, L., Pinto, I. M., Pitkin, M., Poe, M., Poggiani, R., Popolizio, P., Post, A., Powell, J., Prasad, J., Pratt, J. W. W., Predoi, V., Prestegard, T., Prijatelj, M., Principe, M., Privitera, S., Prodi, G. A., Prokhorov, L. G., Puncken, O., Punturo, M., Puppo, P., Pürrer, M., Qi, H., Qin, J., Qiu, S., Quetschke, V., Quintero, E. A., Quitzow-James, R., Raab, F. J., Rabeling, D. S., Radkins, H., Raffai, P., Raja, S., Rajan, C., Rakhmanov, M., Rapagnani, P., Raymond, V., Razzano, M., Re, V., Read, J., Regimbau, T., Rei, L., Reid, S., Reitze, D. H., Rew, H., Reyes, S. D., Rhoades, E., Ricci, F., Riles, K., Rizzo, D.M., Robertson, N. A., Robie, R., Robinet, F., Rocchi, A., Rolland, L., Rollins, J. G., Roma, V. J., Romano, J. D., Romano, R., Romie, J. H., Rosińska, D., Rowan, S., Rüdiger, A., Ruggi, P., Ryan, K.A., Sachdev, Perminder S, Sadecki, T., Sadeghian, L., Sakellariadou, M., Salconi, L., Saleem, M., Salemi, F., Samajdar, A., Sammut, L., Sampson, L. M., Sanchez, E. J., Sandberg, V., Sanders, J. R., Sassolas, B., Sathyaprakash, B. S., Saulson, P. R., Sauter, O., Savage, R. L., Sawadsky, A., Schale, P., Scheuer, J., Schmidt, E., Schmidt, J, Schmidt, P., Schnabel, R.B., Schofield, R. M. S., Schönbeck, A., Schreiber, K.E.C., Schuette, D., Schutz, B. F., Schwalbe, S. G., Scott, J., Scott, M.S., Sellers, D., Sengupta, A. S., Sentenac, D., Sequino, V., Sergeev, A., Setyawati, Y., Shaddock, D. A., Shaffer, T. J., Shahriar, M. S., Shapiro, B., Shawhan, P., Sheperd, A., Shoemaker, D. H., Shoemaker, D. 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C., Trozzo, L., Tse, M., Tso, R., Turconi, M., Tuyenbayev, D., Ugolini, D., Unnikrishnan, C. S., Urban, A. L., Usman, S. A., Vahlbruch, H., Vajente, G., Valdes, G., Van Bakel, N., Van Beuzekom, Martin, Van Den Brand, J. F.J., Van Den Broeck, C.F.F., Vander-Hyde, D. C., van der Schaaf, L., van Heijningen, J. V., van Veggel, A. A., Vardaro, M., Varma, V., Vass, S., Vasúth, M., Vecchio, A., Vedovato, G., Veitch, J., Veitch, P.J., Venkateswara, K., Venugopalan, G., Verkindt, D., Vetrano, F., Viceré, A., Viets, A. D., Vinciguerra, S., Vine, D. J., Vinet, J. -Y., Vitale, S., Vo, T., Vocca, H., Vorvick, C., Voss, D. V., Vousden, W. D., Vyatchanin, S. P., Wade, A. R., Wade, L. E., Wade, MT, Walker, M., Wallace, L., Walsh, S., Wang, G., Wang, H., Wang, M., Wang, Y., Ward, R. L., Warner, J., Was, M., Watchi, J., Weaver, B., Wei, L. -W., Weinert, M., Weinstein, A. J., Weiss, R., Wen, L.M., Weßels, P., Westphal, T., Wette, K., Whelan, J. T., Whiting, B. 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Abstract

Parameter estimates of GW150914 were obtained using Bayesian inference, based on three semi-analytic waveform models for binary black hole coalescences. These waveform models differ from each other in their treatment of black hole spins, and all three models make some simplifying assumptions, notably to neglect sub-dominant waveform harmonic modes and orbital eccentricity. Furthermore, while the models are calibrated to agree with waveforms obtained by full numerical solutions of Einstein's equations, any such calibration is accurate only to some non-zero tolerance and is limited by the accuracy of the underlying phenomenology, availability, quality, and parameter-space coverage of numerical simulations. This paper complements the original analyses of GW150914 with an investigation of the effects of possible systematic errors in the waveform models on estimates of its source parameters. To test for systematic errors we repeat the original Bayesian analysis on mock signals from numerical simulations of a series of binary configurations with parameters similar to those found for GW150914. Overall, we find no evidence for a systematic bias relative to the statistical error of the original parameter recovery of GW150914 due to modeling approximations or modeling inaccuracies. However, parameter biases are found to occur for some configurations disfavored by the data of GW150914: for binaries inclined edge-on to the detector over a small range of choices of polarization angles, and also for eccentricities greater than ∼0.05. For signals with higher signal-to-noise ratio than GW150914, or in other regions of the binary parameter space (lower masses, larger mass ratios, or higher spins), we expect that systematic errors in current waveform models may impact gravitational-wave measurements, making more accurate models desirable for future observations.

Published
2017
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8. Localization of Fatty Acyl and Double Bond Positions in Phosphatidylcholines Using a Dual Stage CID Fragmentation Coupled with Ion Mobility Mass Spectrometry

Author

Castro-Perez, J., Roddy, T.P., Nibbering, N.M.M., Shah, V., McLaren, D.G., Previs, S., Attygalle, A.B., Herath, K., Chen, Z., Wang, S.P., Mitnaul, L., Hubbard, B.K., Vreeken, R.J., Johns, D.G., Hankemeier, Th., Castro-Perez, J., Roddy, T.P., Nibbering, N.M.M., Shah, V., McLaren, D.G., Previs, S., Attygalle, A.B., Herath, K., Chen, Z., Wang, S.P., Mitnaul, L., Hubbard, B.K., Vreeken, R.J., Johns, D.G., and Hankemeier, Th.

Abstract

A high content molecular fragmentation for the analysis of phosphatidylcholines (PC) was achieved utilizing a two-stage [trap (first generation fragmentation) and transfer (second generation fragmentation)] collision-induced dissociation (CID) in combination with travelling-wave ion mobility spectrometry (TWIMS). The novel aspects of this work reside in the fact that a TWIMS arrangement was used to obtain a high level structural information including location of fatty acyl substituents and double bonds for PCs in plasma, and the presence of alkali metal adduct ions such as [M + Li]

Published
2011
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9. Erratum to: Localization of Fatty Acyl and Double Bond Positions in Phosphatidylcholines Using a Dual Stage CID Fragmentation Coupled with Ion Mobility Mass Spectrometry.

Author

Castro-Perez, J., Roddy, T.P., Nibbering, N.M.M., Shah, V., McLaren, D.G., Previs, S., Attygalle, A.B., Herath, K., Chen, Z., Wang, S.P., Mitnaul, L., Hubbard, B.K., Vreeken, R.J., Johns, D.G., Hankemeier, T., Castro-Perez, J., Roddy, T.P., Nibbering, N.M.M., Shah, V., McLaren, D.G., Previs, S., Attygalle, A.B., Herath, K., Chen, Z., Wang, S.P., Mitnaul, L., Hubbard, B.K., Vreeken, R.J., Johns, D.G., and Hankemeier, T.

Published
2011
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12. UPLC-MS, HPLC-radiometric, and NMR-spectroscopic studies on the metabolic fate of 3-fluoro-[U-14C]-aniline in the bile-cannulated rat.

Author

Athersuch, T. J., Castro-Perez, J., Rodgers, C., Nicholson, J. K., and Wilson, I. D.

Subjects
*RADIATION measurements, *NUCLEAR magnetic resonance, *ANILINE, *METABOLITES, *LIQUID chromatography
Abstract

1. A study of the rates and routes of excretion of 3-fluoro-[U-14C]aniline following intraperitoneal administration to male bile-cannulated rats by liquid scintillation counting (LSC) gave a total recovery of ~ 90% in the 48 h following dosing, with the majority of the dose being excreted in the urine during the first 24 h (~ 49%). 2. The total recovery as determined by 19F-nuclear magnetic resonance (19F-NMR) was ~ 49%, with the majority of the dose excreted in the first 24 h (~ 41%). The comparatively low recovery in comparison to that obtained from LSC was due to matrix effects in bile and a contribution from metabolic defluorination. 3. High-performance liquid chromatography with radiometric profiling of urine and bile revealed a complex pattern of metabolites with the bulk of the dose excreted as a single peak. 4. Ultra-performance liquid chromatography-orthogonal acceleration time of flight mass spectrometry profiling also showed a complex pattern of metabolites, detecting ~ 21 metabolites of 3-fluoroaniline (3-FA) with six of these detected only in urine and four solely in bile. 5. 19F-NMR revealed the presence of the parent compound and 15 metabolites in urine collected during the first 24 h after -dosing. The matrix effects of bile on 19F-NMR spectroscopy made metabolite profiling impractical for this biofluid. 6. The major metabolite of 3-FA was identified as 2-fluoro-4-acetamidophenol-sulfate. [ABSTRACT FROM AUTHOR]

Published
2010
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13. High Resolution “Ultra Performance” Liquid Chromatography Coupled to oa-TOF Mass Spectrometry as a Tool for Differential Metabolic Pathway Profiling in Functional Genomic Studies

Author

Wilson, I. D., Nicholson, J. K., Castro-Perez, J., Granger, J. H., Johnson, K. A., Smith, B. W., and Plumb, R. S.

Abstract

The combination of a new 1.7 μm reversed-phase packing material, and a chromatographic system, operating at ca. 12 000 psi, (so-called ultra performance liquid chromatography, UPLC) has enabled dramatic increases in chromatographic performance to be obtained for complex mixture separation. This increase in performance is manifested in improved peak resolution, together with increased speed and sensitivity. Here, we show that UPLC offers significant advantages over conventional reversed-phase HPLC amounting to a more than doubling of peak capacity, an almost 10-fold increase in speed and a 3- to 5-fold increase in sensitivity compared to that generated with a conventional 3.5 μm stationary phase. The first functional genomic application of UPLC−MS technology is illustrated here with respect to multivariate metabolic profiling of urines from males and females of two groups of phenotypically normal mouse strains (C57BL19J and Alpk:ApfCD) and a “nude mouse” strain. We have also compared this technology to conventional HPLC−MS under similar analytical conditions and show improved phenotypic classification capability of UPLC−MS analysis together with increased ability to probe differential pathway activities between strains as a result of improved analytical sensitivity and resolution. Keywords: metabolic profile • metabonomics • C57BL19J mouse • Alpk:ApfCD mouse • nude mouse • chemometrics • UPLC−MS • functional genomics

Published
2005

15. Volumetric absorptive microsampling as an effective microsampling technique for LC-MS/MS bioanalysis of biomarkers in drug discovery.

Author

Kapadnis U, Locuson C, Okamura H, Rienzo G, Cotter C, Zhu D, Narayanaswami R, Castro-Perez J, Marathe P, and Yang WC

Subjects
Animals, Mice, Chromatography, Liquid methods, Dried Blood Spot Testing methods, Drug Discovery, Tandem Mass Spectrometry methods, Blood Specimen Collection methods
Abstract

Aim: Develop and validate a volumetric absorptive microsampling (VAMS)-based LC-MS/MS method to support the bioanalysis of amino acid and carboxylic acid biomarkers in mouse whole blood. Method: Mouse whole blood was collected using a 10 μl VAMS device. The analytes in VAMS were extracted and analyzed using an LC-MS/MS method. Results: The VAMS-based LC-MS/MS assay exhibited a linearity range of 10.0-10,000 ng/ml with acceptable precision and accuracy and consistent recovery. The analyte stability in mouse whole blood VAMS was shown for 7 days at ambient conditions and at -80°C, as well as with three freeze/thaw cycles. Conclusion: A simple and robust VAMS-based LC-MS/MS method was developed and further validated for simultaneous bioanalysis of nine biomarkers in mouse whole blood.

Published
2023
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16. Reconstruction of Glutathione Metabolism in the Neuronal Model of Rotenone-Induced Neurodegeneration Using Mass Isotopologue Analysis with Hydrophilic Interaction Liquid Chromatography-Zeno High-Resolution Multiple Reaction Monitoring.

Author

Huang L, Drouin N, Causon J, Wegrzyn A, Castro-Perez J, Fleming R, Harms A, and Hankemeier T

Subjects
Humans, Carbon Isotopes chemistry, Chromatography, Liquid methods, Neurons metabolism, Hydrophobic and Hydrophilic Interactions, Isotope Labeling methods, Rotenone, Metabolomics methods
Abstract

Accurate reconstruction of metabolic pathways is an important prerequisite for interpreting metabolomics changes and understanding the diverse biological processes in disease models. A tracer-based metabolomics strategy utilizes stable isotope-labeled precursors to resolve complex pathways by tracing the labeled atom(s) to downstream metabolites through enzymatic reactions. Isotope enrichment analysis is informative and achieved by counting total labeled atoms and acquiring the mass isotopologue distribution (MID) of the intact metabolite. However, quantitative analysis of labeled metabolite substructures/moieties (MS 2 fragments) can offer more valuable insights into the reaction connections through measuring metabolite transformation. In order to acquire the isotopic labeling information at the intact metabolite and moiety level simultaneously, we developed a method that couples hydrophilic interaction liquid chromatography (HILIC) with Zeno trap-enabled high-resolution multiple reaction monitoring (MRM HR ). The method enabled accurate and reproducible MID quantification for intact metabolites as well as their fragmented moieties, with notably high sensitivity in the MS 2 fragmentation mode based on the measurement of 13 C- or 15 N-labeled cellular samples. The method was applied to human-induced pluripotent stem cell-derived neurons to trace the fate of 13 C/ 15 N atoms from D- 13 C 6 -glucose/L- 15 N 2 -glutamine added to the media. With the MID analysis of both intact metabolites and fragmented moieties, we validated the pathway reconstruction of de novo glutathione synthesis in mid-brain neurons. We discovered increased glutathione oxidization from both basal and newly synthesized glutathione pools under neuronal oxidative stress. Furthermore, the significantly decreased de novo glutathione synthesis was investigated and associated with altered activities of several key enzymes, as evidenced by suppressed glutamate supply via glucose metabolism and a diminished flux of glutathione synthetic reaction in the neuronal model of rotenone-induced neurodegeneration.

Published
2023
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17. High-throughput proteomics of nanogram-scale samples with Zeno SWATH MS.

Author

Wang Z, Mülleder M, Batruch I, Chelur A, Textoris-Taube K, Schwecke T, Hartl J, Causon J, Castro-Perez J, Demichev V, Tate S, and Ralser M

Subjects
Humans, Proteome, Systems Biology, Drug Discovery, Proteomics, Biomedical Research
Abstract

The possibility to record proteomes in high throughput and at high quality has opened new avenues for biomedical research, drug discovery, systems biology, and clinical translation. However, high-throughput proteomic experiments often require high sample amounts and can be less sensitive compared to conventional proteomic experiments. Here, we introduce and benchmark Zeno SWATH MS, a data-independent acquisition technique that employs a linear ion trap pulsing (Zeno trap pulsing) to increase the sensitivity in high-throughput proteomic experiments. We demonstrate that when combined with fast micro- or analytical flow-rate chromatography, Zeno SWATH MS increases protein identification with low sample amounts. For instance, using 20 min micro-flow-rate chromatography, Zeno SWATH MS identified more than 5000 proteins consistently, and with a coefficient of variation of 6%, from a 62.5 ng load of human cell line tryptic digest. Using 5 min analytical flow-rate chromatography (800 µl/min), Zeno SWATH MS identified 4907 proteins from a triplicate injection of 2 µg of a human cell lysate, or more than 3000 proteins from a 250 ng tryptic digest. Zeno SWATH MS hence facilitates sensitive high-throughput proteomic experiments with low sample amounts, mitigating the current bottlenecks of high-throughput proteomics., Competing Interests: ZW, MM, KT, TS, JH, VD, MR No competing interests declared, IB, AC, JC, JC, ST Employee of Sciex, (© 2022, Wang et al.)

Published
2022
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18. Relation of plasma ceramides to visceral adiposity, insulin resistance and the development of type 2 diabetes mellitus: the Dallas Heart Study.

Author

Neeland IJ, Singh S, McGuire DK, Vega GL, Roddy T, Reilly DF, Castro-Perez J, Kozlitina J, and Scherer PE

Subjects
Adiposity physiology, Adult, Body Mass Index, Chromatography, Liquid, Female, Humans, Magnetic Resonance Spectroscopy, Male, Mass Spectrometry, Middle Aged, Ceramides blood, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 physiopathology, Insulin Resistance physiology, Intra-Abdominal Fat metabolism
Abstract

Aims/hypothesis: Ceramides are sphingolipids that contribute to insulin resistance in preclinical studies. We hypothesised that plasma ceramides would be associated with body fat distribution, insulin resistance and incident type 2 diabetes in a multi-ethnic cohort., Methods: A total of 1557 participants in the Dallas Heart Study without type 2 diabetes underwent measurements of metabolic biomarkers, fat depots by MRI and plasma ceramides by liquid chromatography-mass spectrometry. Diabetes outcomes were assessed after 7 years. Associations of body fat and insulin resistance with ceramides at baseline and of ceramides with incident diabetes outcomes were analysed., Results: The cohort had a mean age of 43 years, with 58% women, 45% black participants and a mean BMI of 28 kg/m 2 . Total cholesterol levels were associated with all ceramides, but higher triacylglycerols and lower HDL-cholesterol and adiponectin were associated only with saturated fatty acid chain ceramides (p < 0.0003). After adjusting for clinical characteristics and total body fat, visceral adipose tissue was positively associated with saturated fatty acid ceramides (per SD, β = 0.16 to 0.18) and inversely associated with polyunsaturated fatty acid ceramides (β = -0.14 to -0.16, p < 0.001 for all). Lower-body subcutaneous fat showed an opposite pattern to that for visceral fat. HOMA-IR was positively associated with saturated (β = 0.08 to 0.09, p < 0.001) and inversely with polyunsaturated ceramides (β = -0.06 to -0.07, p < 0.05). Ceramides were not associated with incident type 2 diabetes after adjustment for clinical factors., Conclusions/interpretation: Plasma ceramides demonstrate a biologically complex relationship with metabolic and imaging indicators of dysfunctional adiposity. The role of ceramides in a shared pathway of metabolic dysfunction linking visceral adiposity and insulin resistance requires further investigation.

Published
2018
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19. Cyp8b1 ablation prevents Western diet-induced weight gain and hepatic steatosis because of impaired fat absorption.

Author

Bertaggia E, Jensen KK, Castro-Perez J, Xu Y, Di Paolo G, Chan RB, Wang L, and Haeusler RA

Subjects
Animals, Bile Acids and Salts metabolism, Diet, High-Fat, Fatty Liver metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Diet, Western adverse effects, Dietary Fats metabolism, Fatty Liver genetics, Intestinal Absorption genetics, Lipid Metabolism genetics, Steroid 12-alpha-Hydroxylase genetics, Weight Gain genetics
Abstract

Bile acids (BAs) are cholesterol derivatives that regulate lipid metabolism, through their dual abilities to promote lipid absorption and activate BA receptors. However, different BA species have varying abilities to perform these functions. Eliminating 12α-hydroxy BAs in mice via Cyp8b1 knockout causes low body weight and improved glucose tolerance. The goal of this study was to determine mechanisms of low body weight in Cyp8b1 -/- mice. We challenged Cyp8b1 -/- mice with a Western-type diet and assessed body weight and composition. We measured energy expenditure, fecal calories, and lipid absorption and performed lipidomic studies on feces and intestine. We investigated the requirement for dietary fat in the phenotype using a fat-free diet. Cyp8b1 -/- mice were resistant to Western diet-induced body weight gain, hepatic steatosis, and insulin resistance. These changes were associated with increased fecal calories, due to malabsorption of hydrolyzed dietary triglycerides. This was reversed by treating the mice with taurocholic acid, the major 12α-hydroxylated BA species. The improvements in body weight and steatosis were normalized by feeding mice a fat-free diet. The effects of BA composition on intestinal lipid handling are important for whole body energy homeostasis. Thus modulating BA composition is a potential tool for obesity or diabetes therapy., (Copyright © 2017 the American Physiological Society.)

Published
2017
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20. The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent.

Author

Mancina RM, Dongiovanni P, Petta S, Pingitore P, Meroni M, Rametta R, Borén J, Montalcini T, Pujia A, Wiklund O, Hindy G, Spagnuolo R, Motta BM, Pipitone RM, Craxì A, Fargion S, Nobili V, Käkelä P, Kärjä V, Männistö V, Pihlajamäki J, Reilly DF, Castro-Perez J, Kozlitina J, Valenti L, and Romeo S

Subjects
Acetyltransferases metabolism, Acyltransferases metabolism, Biopsy, Case-Control Studies, Cross-Sectional Studies, Europe epidemiology, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Liver metabolism, Liver pathology, Liver Cirrhosis diagnosis, Liver Cirrhosis ethnology, Liver Cirrhosis metabolism, Male, Membrane Proteins metabolism, Non-alcoholic Fatty Liver Disease diagnosis, Non-alcoholic Fatty Liver Disease ethnology, Non-alcoholic Fatty Liver Disease metabolism, Phenotype, Phosphatidylinositols metabolism, Proton Magnetic Resonance Spectroscopy, Risk Factors, Severity of Illness Index, Texas epidemiology, Triglycerides metabolism, Acetyltransferases genetics, Acyltransferases genetics, Liver Cirrhosis genetics, Membrane Proteins genetics, Non-alcoholic Fatty Liver Disease genetics, Polymorphism, Genetic, White People genetics
Abstract

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7, also called LPIAT1) and transmembrane channel-like 4 gene (TMC4) increased the risk for cirrhosis in alcohol abusers. We investigated whether the MBOAT7-TMC4 is a susceptibility locus for the development and progression of NAFLD., Methods: We genotyped rs641738 in DNA collected from 3854 participants from the Dallas Heart Study (a multi-ethnic population-based probability sample of Dallas County residents) and 1149 European individuals from the Liver Biopsy Cross-Sectional Cohort. Clinical and anthropometric data were collected, and biochemical and lipidomics were measured in plasma samples from participants. A total of 2736 participants from the Dallas Heart Study also underwent proton magnetic resonance spectroscopy to measure hepatic triglyceride content. In the Liver Biopsy Cross-Sectional Cohort, a total of 1149 individuals underwent liver biopsy to diagnose liver disease and disease severity., Results: The genotype rs641738 at the MBOAT7-TMC4 locus associated with increased hepatic fat content in the 2 cohorts, and with more severe liver damage and increased risk of fibrosis compared with subjects without the variant. MBOAT7, but not TMC4, was found to be highly expressed in the liver. The MBOAT7 rs641738 T allele was associated with lower protein expression in the liver and changes in plasma phosphatidylinositol species consistent with decreased MBOAT7 function., Conclusions: We provide evidence for an association between the MBOAT7 rs641738 variant and the development and severity of NAFLD in individuals of European descent. This association seems to be mediated by changes in the hepatic phosphatidylinositol acyl-chain remodeling., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Published
2016
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21. Increased Bile Acid Synthesis and Impaired Bile Acid Transport in Human Obesity.

Author

Haeusler RA, Camastra S, Nannipieri M, Astiarraga B, Castro-Perez J, Xie D, Wang L, Chakravarthy M, and Ferrannini E

Subjects
Adult, Bile Acids and Salts biosynthesis, Biological Transport, Female, Glucose Clamp Technique, Humans, Male, Bile Acids and Salts metabolism, Carrier Proteins metabolism, Intestinal Mucosa metabolism, Liver metabolism, Membrane Glycoproteins metabolism, Obesity metabolism, Pancreas metabolism
Abstract

Context: Alterations in bile acid (BA) synthesis and transport have the potential to affect multiple metabolic pathways in the pathophysiology of obesity., Objective: The objective of the study was to investigate the effects of obesity on serum fluctuations of BAs and markers of BA synthesis., Design: We measured BA fluctuations in 11 nonobese and 32 obese subjects and BA transporter expression in liver specimens from 42 individuals and specimens of duodenum, jejunum, ileum, colon, and pancreas from nine individuals., Main Outcome Measures: We analyzed serum BAs and markers of BA synthesis after overnight fasting, during a hyperinsulinemic-euglycemic clamp, or a mixed-meal tolerance test and the association of BA transporter expression with body mass index., Results: BA synthesis markers were 2-fold higher (P < .01) and preferentially 12α-hydroxylated (P < .05) in obese subjects, and both measures were correlated with clamp-derived insulin sensitivity (r = -0.62, P < .0001, and r = -0.39, P = .01, respectively). Insulin infusion acutely reduced serum BAs in nonobese subjects, but this effect was blunted in obese subjects (δBAs -44.2% vs -4.2%, P < .05). The rise in serum BAs postprandially was also relatively blunted in obese subjects (δBAs +402% vs +133%, P < .01). Liver expression of the Na+-taurocholate cotransporting polypeptide and the bile salt export pump were negatively correlated with body mass index (r = -0.37, P = .02, and r = -0.48, P = .001, respectively)., Conclusions: Obesity is associated with increased BA synthesis, preferential 12α-hydroxylation, and impaired serum BA fluctuations. The findings reveal new pathophysiological aspects of BA action in obesity that may lend themselves to therapeutic targeting in metabolic disease.

Published
2016
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22. Multiplexed Quantification of Proglucagon-Derived Peptides by Immunoaffinity Enrichment and Tandem Mass Spectrometry after a Meal Tolerance Test.

Author

Lee AY, Chappell DL, Bak MJ, Judo M, Liang L, Churakova T, Ayanoglu G, Castro-Perez J, Zhou H, Previs S, Souza SC, Lassman ME, and Laterza OF

Subjects
Animals, Chromatography, High Pressure Liquid, Glucagon immunology, Glucagon-Like Peptide 1 immunology, Humans, Mice, Mice, Inbred BALB C, Oxyntomodulin immunology, Fasting, Glucagon blood, Glucagon-Like Peptide 1 blood, Immunoassay, Oxyntomodulin blood, Tandem Mass Spectrometry
Abstract

Background: Proglucagon-derived peptides (PGDPs), which include glucagon-like peptide (GLP)-1, glucagon, and oxyntomodulin, are key regulators of glucose homeostasis and satiety. These peptide hormones are typically measured with immuno-based assays (e.g., ELISA, RIA), which often suffer from issues of selectivity., Methods: We developed a multiplexed assay for measuring PGDPs including GLP-1 (7-36) amide, GLP-1 (9-36) amide, glucagon, and oxyntomodulin by mass spectrometry and used this assay to examine the effect of a meal tolerance test on circulating concentrations of these hormones. Participants fasted overnight and were either given a meal (n = 8) or continued to fast (n = 4), with multiple blood collections over the course of 3 h. Plasma samples were analyzed by microflow immunoaffinity (IA)-LC-MS/MS with an isotope dilution strategy., Results: Assay performance characteristics were examined and established during analytical validation for all peptides. Intra- and interassay imprecision were found to be 2.2%-10.7% and 6.8%-22.5%, respectively. Spike recovery was >76%, and dilution linearity was established up to a 16-fold dilution. Immediately after the meal tolerance test, GLP-1 and oxyntomodulin concentrations increased and had an almost identical temporal relationship, and glucagon concentrations increased with a slight delay., Conclusions: IA-LC-MS/MS was used for the simultaneous and selective measurement of PGDPs. This work includes the first indication of the physiological concentrations and modulation of oxyntomodulin after a meal., (© 2015 American Association for Clinical Chemistry.)

Published
2016
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23. Increased Bile Acid Synthesis and Deconjugation After Biliopancreatic Diversion.

Author

Ferrannini E, Camastra S, Astiarraga B, Nannipieri M, Castro-Perez J, Xie D, Wang L, Chakravarthy M, and Haeusler RA

Subjects
Adult, Bile Acids and Salts blood, Blood Glucose, Cholesterol blood, Female, Glucose Clamp Technique, Humans, Male, Middle Aged, Bile Acids and Salts biosynthesis, Biliopancreatic Diversion, Diabetes Mellitus, Type 2 metabolism, Gastric Bypass
Abstract

Biliopancreatic diversion (BPD) improves insulin sensitivity and decreases serum cholesterol out of proportion with weight loss. Mechanisms of these effects are unknown. One set of proposed contributors to metabolic improvements after bariatric surgeries is bile acids (BAs). We investigated the early and late effects of BPD on plasma BA levels, composition, and markers of BA synthesis in 15 patients with type 2 diabetes (T2D). We compared these to the early and late effects of Roux-en-Y gastric bypass (RYGB) in 22 patients with T2D and 16 with normal glucose tolerance. Seven weeks after BPD, insulin sensitivity had doubled and serum cholesterol had halved. At this time, BA synthesis markers and total plasma BAs, particularly unconjugated BAs, had markedly risen; this effect could not be entirely explained by low FGF19. In contrast, after RYGB, insulin sensitivity improved gradually with weight loss and cholesterol levels declined marginally; BA synthesis markers were decreased at an early time point (2 weeks) after surgery and returned to the normal range 1 year later. These findings indicate that BA synthesis contributes to the decreased serum cholesterol after BPD. Moreover, they suggest a potential role for altered enterohepatic circulation of BAs in improving insulin sensitivity and cholesterol metabolism after BPD., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Published
2015
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24. Inhibition of cholesteryl ester transfer protein increases cholesteryl ester content of large HDL independently of HDL-to-HDL homotypic transfer: in vitro vs in vivo comparison using anacetrapib and dalcetrapib.

Author

Johns DG, Chen Y, Wang SP, Castro-Perez J, Previs SF, and Roddy TP

Subjects
Amides, Animals, Cholesterol, VLDL metabolism, Esters, Humans, Male, Mice, Mice, Inbred C57BL, Anticholesteremic Agents pharmacology, Cholesterol Ester Transfer Proteins antagonists & inhibitors, Cholesterol Esters metabolism, Cholesterol, HDL chemistry, Cholesterol, HDL metabolism, Oxazolidinones pharmacology, Sulfhydryl Compounds pharmacology
Abstract

The increase in high density lipoprotein (HDL)-cholesterol observed with cholesteryl ester transfer protein (CETP) inhibition is commonly attributed to blockade of cholesteryl ester (CE) transfer from HDL to low density lipoprotein particles. In vitro, it has been observed that CETP can mediate transfer of CE between HDL particles ("homotypic transfer"), and it is postulated that this contributes to HDL remodeling and generation of anti-atherogenic pre-beta HDL. Inhibition of CETP could limit this beneficial remodeling and reduce pre-beta HDL levels. We observed that anacetrapib does not reduce pre-beta HDL in vivo, but the role of HDL homotypic transfer was not examined. This study evaluated the effects of anacetrapib on homotypic transfer from HDL3 to HDL2 in vivo using deuterium-labeled HDL3, and compared this to in vitro settings, where homotypic transfer was previously described. In vitro, both anacetrapib and dalcetrapib inhibited transfer of CE from HDL3 to HDL2 particles. In CETP transgenic mice, anacetrapib did not inhibit the appearance of labeled CE derived from HDL3 in HDL2 particles, but rather promoted the appearance of labeled CE in HDL2. We concluded that inhibition of CETP by anacetrapib promoted HDL particle remodeling, and does not impair the flux of cholesterol ester into larger HDL particles when studied in vivo, which is not consistent with in vitro observations. We further conclude, therefore, that the in vitro conditions used to examine HDL-to-HDL homotypic transfer may not recapitulate the in vivo condition, where multiple mechanisms contribute to cholesteryl ester flux into and out of the HDL pool., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Published
2015
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25. Discovery of Triazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys.

Author

Hoyt SB, Petrilli W, London C, Liang GB, Tata J, Hu Q, Yin L, van Koppen CJ, Hartmann RW, Struthers M, Wisniewski T, Ren N, Bopp C, Sok A, Cai TQ, Stribling S, Pai LY, Ma X, Metzger J, Verras A, McMasters D, Chen Q, Tung E, Tang W, Salituro G, Buist N, Clemas J, Zhou G, Gibson J, Maxwell CA, Lassman M, McLaughlin T, Castro-Perez J, Szeto D, Forrest G, Hajdu R, Rosenbach M, and Xiong Y

Abstract

Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

Published
2015
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26. Evaluation of cynomolgus monkeys for the identification of endogenous biomarkers for hepatic transporter inhibition and as a translatable model to predict pharmacokinetic interactions with statins in humans.

Author

Chu X, Shih SJ, Shaw R, Hentze H, Chan GH, Owens K, Wang S, Cai X, Newton D, Castro-Perez J, Salituro G, Palamanda J, Fernandis A, Ng CK, Liaw A, Savage MJ, and Evers R

Subjects
Administration, Oral, Animals, Bilirubin analogs & derivatives, Bilirubin blood, Bilirubin metabolism, Biomarkers blood, Biomarkers metabolism, Cytochrome P-450 Enzyme Inducers administration & dosage, Drug Evaluation, Preclinical, Drug Interactions, HEK293 Cells, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Hydroxymethylglutaryl-CoA Reductase Inhibitors blood, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Injections, Intravenous, Macaca fascicularis, Male, Membrane Transport Modulators administration & dosage, Metabolic Clearance Rate, Microsomes, Liver enzymology, Microsomes, Liver metabolism, Organic Anion Transporters genetics, Organic Anion Transporters metabolism, Protein Isoforms antagonists & inhibitors, Protein Isoforms genetics, Protein Isoforms metabolism, Random Allocation, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Species Specificity, Cytochrome P-450 Enzyme Inducers adverse effects, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacokinetics, Membrane Transport Modulators adverse effects, Microsomes, Liver drug effects, Models, Biological, Organic Anion Transporters antagonists & inhibitors
Abstract

Inhibition of hepatic transporters such as organic anion transporting polypeptides (OATPs) 1B can cause drug-drug interactions (DDIs). Determining the impact of perpetrator drugs on the plasma exposure of endogenous substrates for OATP1B could be valuable to assess the risk for DDIs early in drug development. As OATP1B orthologs are well conserved between human and monkey, we assessed in cynomolgus monkeys the endogenous OATP1B substrates that are potentially suitable to assess DDI risk in humans. The effect of rifampin (RIF), a potent inhibitor for OATP1B, on plasma exposure of endogenous substrates of hepatic transporters was measured. From the 18 biomarkers tested, RIF (18 mg/kg, oral) caused significant elevation of plasma unconjugated and conjugated bilirubin, which may be attributed to inhibition of cOATP1B1 and cOATP1B3 based on in vitro to in vivo extrapolation analysis. To further evaluate whether cynomolgus monkeys are a suitable translational model to study OATP1B-mediated DDIs, we determined the inhibitory effect of RIF on in vitro transport and pharmacokinetics of rosuvastatin (RSV) and atorvastatin (ATV). RIF strongly inhibited the uptake of RSV and ATV by cOATP1B1 and cOATP1B3 in vitro. In agreement with clinical observations, RIF (18 mg/kg, oral) significantly decreased plasma clearance and increased the area under the plasma concentration curve (AUC) of intravenously administered RSV by 2.8- and 2.7-fold, and increased the AUC and maximum plasma concentration of orally administered RSV by 6- and 10.3-fold, respectively. In contrast to clinical findings, RIF did not significantly increase plasma exposure of either intravenous or orally administered ATV, indicating species differences in the rate-limiting elimination pathways., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

Published
2015
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27. Discovery of Benzimidazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys.

Author

Hoyt SB, Park MK, London C, Xiong Y, Tata J, Bennett DJ, Cooke A, Cai J, Carswell E, Robinson J, MacLean J, Brown L, Belshaw S, Clarkson TR, Liu K, Liang GB, Struthers M, Cully D, Wisniewski T, Ren N, Bopp C, Sok A, Cai TQ, Stribling S, Pai LY, Ma X, Metzger J, Verras A, McMasters D, Chen Q, Tung E, Tang W, Salituro G, Buist N, Kuethe J, Rivera N, Clemas J, Zhou G, Gibson J, Maxwell CA, Lassman M, McLaughlin T, Castro-Perez J, Szeto D, Forrest G, Hajdu R, Rosenbach M, and Ali A

Abstract

We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

Published
2015
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28. Effect of Error Propagation in Stable Isotope Tracer Studies: An Approach for Estimating Impact on Apparent Biochemical Flux.

Author

Previs SF, Herath K, Castro-Perez J, Mahsut A, Zhou H, McLaren DG, Shah V, Rohm RJ, Stout SJ, Zhong W, Wang SP, Johns DG, Hubbard BK, Cleary MA, and Roddy TP

Subjects
Animals, Carbon Isotopes, Chromatography, Gas methods, Chromatography, Liquid methods, Deuterium Oxide, Humans, Signal-To-Noise Ratio, Isotope Labeling methods, Mass Spectrometry methods, Metabolism
Abstract

Stable isotope tracers are widely used to quantify metabolic rates, and yet a limited number of studies have considered the impact of analytical error on estimates of flux. For example, when estimating the contribution of de novo lipogenesis, one typically measures a minimum of four isotope ratios, i.e., the precursor and product labeling pre- and posttracer administration. This seemingly simple problem has 1 correct solution and 80 erroneous outcomes. In this report, we outline a methodology for evaluating the effect of error propagation on apparent physiological endpoints. We demonstrate examples of how to evaluate the influence of analytical error in case studies concerning lipid and protein synthesis; we have focused on (2)H2O as a tracer and contrast different mass spectrometry platforms including GC-quadrupole-MS, GC-pyrolysis-IRMS, LC-quadrupole-MS, and high-resolution FT-ICR-MS. The method outlined herein can be used to determine how to minimize variations in the apparent biology by altering the dose and/or the type of tracer. Likewise, one can facilitate biological studies by estimating the reduction in the noise of an outcome that is expected for a given increase in the number of replicate injections., (© 2015 Elsevier Inc. All rights reserved.)

Published
2015
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29. In vivo isotopically labeled atherosclerotic aorta plaques in ApoE KO mice and molecular profiling by matrix-assisted laser desorption/ionization mass spectrometric imaging.

Author

Castro-Perez J, Hatcher N, Kofi Karikari N, Wang SP, Mendoza V, Shion H, Millar A, Shockcor J, Towers M, McLaren D, Shah V, Previs S, Akinsanya K, Cleary M, Roddy TP, and Johns DG

Abstract

Rationale: The ability to quantify rates of formation, regression and/or remodeling of atherosclerotic plaque should facilitate a better understanding of the pathogenesis and management of cardiovascular disease. In the current study, we coupled a stable isotope labeled tracer protocol with matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to examine spatial and temporal lipid dynamics in atherosclerotic plaque., Methods: To promote plaque formation in the aorta region, ApoE KO mice were fed a high cholesterol diet (0.15% cholesterol) and orally dosed with (2,2,3,4,4,6-d(6))-cholesterol over several weeks. Tissue sections of ~10 µm thickness were analyzed by MALDI-MSI using matrix deposition by either chemical sublimation or acoustic droplet ejection., Results: MALDI-MSI yielded distinct spatial distribution information for a variety of lipid classes including specific lysophosphatidylcholines typically associated with atherosclerosis-related tissue damage such as phospholipase 2 (Lp-PLA(2)) that mediate chemotactic responses to inflammation (e.g. LPC 16:0, LPC 18:0 and LPC 18:1) as well as free cholesterol and cholesteryl esters that contribute to atheroma formation. MALDI mass spectra acquired from aorta tissue sections clearly distinguished non-esterified and esterified versions of (2,2,3,4,4,6-d(6))-cholesterol within aortic plaque regions and showed distinct spatial accumulation of the cholesterol tracer., Conclusions: The ability to couple stable isotope based protocols with MALDI-MSI enables a novel strategy to characterize the effects of therapeutic treatments on atherosclerotic plaque formation, regression and potential remodeling of the complex lipid components with high chemical specificity and spatiotemporal information., (Copyright © 2014 John Wiley & Sons, Ltd.)

Published
2014
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30. Static and turnover kinetic measurement of protein biomarkers involved in triglyceride metabolism including apoB48 and apoA5 by LC/MS/MS.

Author

Pan Y, Zhou H, Mahsut A, Rohm RJ, Berejnaia O, Price O, Chen Y, Castro-Perez J, Lassman ME, McLaren D, Conway J, Jensen KK, Thomas T, Reyes-Soffer G, Ginsberg HN, Gutstein DE, Cleary M, Previs SF, and Roddy TP

Subjects
Biomarkers blood, Chromatography, Liquid methods, Female, Humans, Male, Mass Spectrometry methods, Apolipoprotein A-V blood, Apolipoprotein B-48 blood, Triglycerides blood
Abstract

LC/MS quantification of multiple plasma proteins that differ by several orders of magnitude in concentration from a single sample is challenging. We present a strategy that allows the simultaneous determination of the concentration and turnover kinetics of higher and lower abundant proteins from a single digestion mixture. Our attention was directed at a cluster of proteins that interact to affect the absorption and interorgan lipid trafficking. We demonstrate that apos involved in TG metabolism such as apoC2, C3, E, and A4 (micromolar concentration), and apoB48 and apoA5 (single-digit nanomolar concentration) can be quantified from a single digestion mixture. A high degree of correlation between LC/MS and immunobased measurements for apoC2, C3, E, and B48 was observed. Moreover, apoA5 fractional synthesis rate was measured in humans for the first time. Finally, the method can be directly applied to studies involving nonhuman primates because peptide sequences used in the method are conserved between humans and nonhuman primates., (Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.)

Published
2014
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31. New methodologies for studying lipid synthesis and turnover: looking backwards to enable moving forwards.

Author

Previs SF, McLaren DG, Wang SP, Stout SJ, Zhou H, Herath K, Shah V, Miller PL, Wilsie L, Castro-Perez J, Johns DG, Cleary MA, and Roddy TP

Subjects
Body Fat Distribution, Cholesterol biosynthesis, Cholesterol metabolism, Energy Metabolism, Humans, Kinetics, Triglycerides chemistry, Adipose Tissue metabolism, Lipid Metabolism, Lipids biosynthesis, Triglycerides metabolism
Abstract

Our ability to understand the pathogenesis of problems surrounding lipid accretion requires attention towards quantifying lipid kinetics. In addition, studies of metabolic flux should also help unravel mechanisms that lead to imbalances in inter-organ lipid trafficking which contribute to dyslipidemia and/or peripheral lipid accumulation (e.g. hepatic fat deposits). This review aims to outline the development and use of novel methods for studying lipid kinetics in vivo. Although our focus is directed towards some of the approaches that are currently reported in the literature, we include a discussion of the older literature in order to put "new" methods in better perspective and inform readers of valuable historical research. Presumably, future advances in understanding lipid dynamics will benefit from a careful consideration of the past efforts, where possible we have tried to identify seminal papers or those that provide clear data to emphasize essential points. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Published
2014
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32. Determination of low levels of 2H-labeling using high-resolution mass spectrometry: application in studies of lipid flux and beyond.

Author

Herath KB, Zhong W, Yang J, Mahsut A, Rohm RJ, Shah V, Castro-Perez J, Zhou H, Attygalle AB, Kang L, Singh S, Johns DG, Cleary MA, Hubbard BK, Previs SF, and Roddy TP

Subjects
Animals, Chlorocebus aethiops, Deuterium chemistry, Deuterium metabolism, Deuterium Oxide administration & dosage, Fatty Acids metabolism, Female, Linear Models, Macaca mulatta, Male, Peptides chemistry, Peptides metabolism, Deuterium analysis, Fatty Acids chemistry, Isotope Labeling methods, Mass Spectrometry methods
Abstract

Rationale: The ability to measure low levels of (2)H-labeling is important in studies of metabolic flux, e.g. one can estimate lipid synthesis by administering (2)H2O and then measuring the incorporation of (2)H into fatty acids. Unfortunately, the analyses are complicated by the presence of more abundant naturally occurring stable isotopes, e.g. (13)C. Conventional approaches rely on coupling gas chromatographic separation of lipids with either quadrupole-mass spectrometry (q-MS) and/or pyrolysis-isotope ratio mass spectrometry (IRMS). The former is limited by high background labeling (primarily from (13)C) whereas the latter is not suitable for routine high-throughput analyses., Methods: We have contrasted the use of continuous flow-pyrolysis-IRMS against high-resolution mass spectrometry (i.e. Qq-FT-ICR MS) for measuring the (2)H-enrichment of fatty acids and peptides., Results: In contrast to IRMS, which requires ~30 min per analysis, it is possible to measure the (2)H-enrichment of palmitate via direct infusion high-resolution mass spectrometry (HRMS) in ~3 min per sample. In addition, Qq-FT-ICR MS enabled measurements of the (2)H-enrichment of peptides (which is not possible using IRMS)., Conclusions: High-resolution mass spectrometry can be used to measure low levels of (2)H-labeling so we expect that this approach will enhance studies of metabolic flux that rely on (2)H-labeled tracers, e.g. (2)H2O. However, since the high-resolution analyses require greater amounts of a given analyte one potential limitation centers on the overall sensitivity. Presumably, future advances can overcome this barrier., (Copyright © 2013 John Wiley & Sons, Ltd.)

Published
2014
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33. An ultrasensitive method for the quantitation of active and inactive GLP-1 in human plasma via immunoaffinity LC-MS/MS.

Author

Chappell DL, Lee AY, Castro-Perez J, Zhou H, Roddy TP, Lassman ME, Shankar SS, Yates NA, Wang W, and Laterza OF

Subjects
Amides chemistry, Animals, Antibodies chemistry, Calibration, Eating physiology, Humans, Immunoassay instrumentation, Rabbits, Reproducibility of Results, Sensitivity and Specificity, Chromatography, Liquid methods, Glucagon-Like Peptide 1 blood, Immunoassay standards, Tandem Mass Spectrometry methods
Abstract

Background: Measuring endogenous levels of incretin hormones, like GLP-1, is critical in the development of antidiabetic compounds. However, the assays used to measure these molecules often have analytical issues., Results: We have developed an ultrasensitive, highly-selective immunoaffinity LC-MS/MS (IA LC-MS/MS) assay capable of quantitating endogenous levels of active (7-36 amide) and inactive (9-36 amide) GLP-1 in human plasma. We performed fit-for-purpose validation of the assay by assessing the following assay performance characteristics: inter-assay precision, sensitivity, spike recovery, dilution linearity, absolute recovery, matrix effect, immunoprecipitation efficiency, and food effect., Conclusion: We have developed a robust analytical method for the quantitation of endogenous active and inactive GLP-1 in human plasma. In addition, we employed this method to measure the typical changes in GLP-1 levels after food intake. The sensitivity of this assay is better than another LC-MS/MS GLP-1 assay previously reported and many commercially available immunoassays. This important analytical tool could be used to qualify and/or harmonize the different immunoassays used for the quantitation of GLP-1.

Published
2014
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34. In vivo effects of anacetrapib on preβ HDL: improvement in HDL remodeling without effects on cholesterol absorption.

Author

Wang SP, Daniels E, Chen Y, Castro-Perez J, Zhou H, Akinsanya KO, Previs SF, Roddy TP, and Johns DG

Subjects
Amides, Animals, Anticholesteremic Agents therapeutic use, Area Under Curve, Azetidines pharmacology, Azetidines therapeutic use, Cholesterol Ester Transfer Proteins antagonists & inhibitors, Cholesterol Ester Transfer Proteins metabolism, Cricetinae, Diet, High-Fat adverse effects, Drug Evaluation, Preclinical, Dyslipidemias blood, Dyslipidemias etiology, Esters, Ezetimibe, Humans, Male, Mesocricetus, Oxazolidinones therapeutic use, Sulfhydryl Compounds pharmacology, Sulfhydryl Compounds therapeutic use, Anticholesteremic Agents pharmacology, Cholesterol metabolism, Dyslipidemias drug therapy, High-Density Lipoproteins, Pre-beta blood, Intestinal Absorption drug effects, Oxazolidinones pharmacology
Abstract

Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester and triglyceride between HDL and apoB-containing lipoproteins. Anacetrapib (ANA), a reversible inhibitor of CETP, raises HDL cholesterol and lowers LDL cholesterol in dyslipidemic patients. We previously demonstrated that ANA increases macrophage-to-feces reverse cholesterol transport and fecal cholesterol excretion in hamsters, and increased preβ HDL-dependent cholesterol efflux via ABCA1 in vitro. However, the effects of ANA on in vivo preβ HDL have not been characterized. In vitro, ANA inhibited the formation of preβ, however in ANA-treated dyslipidemic hamsters, preβ HDL levels (measured by two-dimensional gel electrophoresis) were increased, in contrast to in vitro findings. Because changes in plasma preβ HDL have been proposed to potentially affect markers of cholesterol absorption with other CETP inhibitors, a dual stable isotope method was used to directly measure cholesterol absorption in hamsters. ANA treatment of hamsters (on either dyslipidemic or normal diet) had no effect on cholesterol absorption, while dalcetrapib-treated hamsters displayed an increase in cholesterol absorption. Taken together, these data support the notion that ANA promotes preβ HDL functionality in vivo, with no effects on cholesterol absorption.

Published
2013
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35. Measurement of apo(a) kinetics in human subjects using a microfluidic device with tandem mass spectrometry.

Author

Zhou H, Castro-Perez J, Lassman ME, Thomas T, Li W, McLaughlin T, Dan X, Jumes P, Wagner JA, Gutstein DE, Hubbard BK, Rader DJ, Millar JS, Ginsberg HN, Reyes-Soffer G, Cleary M, Previs SF, and Roddy TP

Subjects
Humans, Kinetics, Apolipoproteins A chemistry, Microfluidic Analytical Techniques methods, Tandem Mass Spectrometry methods
Abstract

Rationale: Apolipoprotein(a) [apo(a)] is the defining protein component of lipoprotein(a) [Lp(a)], an independent risk factor for cardiovascular disease. The regulation of Lp(a) levels in blood is poorly understood in part due to technical challenges in measuring Lp(a) kinetics. Improvements in the ability to readily and reliably measure the kinetics of apo(a) using a stable isotope labeled tracer is expected to facilitate studies of the role of Lp(a) in cardiovascular disease. Since investigators typically determine the isotopic labeling of protein-bound amino acids following acid-catalyzed hydrolysis of a protein of interest [e.g., apo(a)], studies of protein synthesis require extensive protein purification which limits throughput and often requires large sample volumes. We aimed to develop a rapid and efficient method for studying apo(a) kinetics that is suitable for use in studies involving human subjects., Methods: Microfluidic device and tandem mass spectrometry were used to quantify the incorporation of [(2)H3]-leucine tracer into protein-derived peptides., Results: We demonstrated that it is feasible to quantify the incorporation of [(2)H3]-leucine tracer into a proteolytic peptide from the non-kringle repeat region of apo(a) in human subjects. Specific attention was directed toward optimizing the multiple reaction monitoring (MRM) transitions, mass spectrometer settings, and chromatography (i.e., critical parameters that affect the sensitivity and reproducibility of isotopic enrichment measurements). The results demonstrated significant advantages with the use of a microfluidic device technology for studying apo(a) kinetics, including enhanced sensitivity relative to conventional micro-flow chromatography, a virtually drift-free elution profile, and a stable and robust electrospray., Conclusions: The technological advances described herein enabled the implementation of a novel method for studying the kinetics of apo(a) in human subjects infused with [(2)H3]-leucine., (Copyright © 2013 John Wiley & Sons, Ltd.)

Published
2013
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36. The impact of partial and complete loss-of-function mutations in endothelial lipase on high-density lipoprotein levels and functionality in humans.

Author

Singaraja RR, Sivapalaratnam S, Hovingh K, Dubé MP, Castro-Perez J, Collins HL, Adelman SJ, Riwanto M, Manz J, Hubbard B, Tietjen I, Wong K, Mitnaul LJ, van Heek M, Lin L, Roddy TA, McEwen J, Dallinge-Thie G, van Vark-van der Zee L, Verwoert G, Winther M, van Duijn C, Hofman A, Trip MD, Marais AD, Asztalos B, Landmesser U, Sijbrands E, Kastelein JJ, and Hayden MR

Subjects
Cohort Studies, Coronary Artery Disease metabolism, Heterozygote, Humans, Lipase metabolism, Cholesterol, HDL blood, Coronary Artery Disease enzymology, Coronary Artery Disease genetics, Lipase genetics, Mutation, Missense
Abstract

Background: Endothelial lipase is a phospholipase with activity against high-density lipoprotein. Although a small number of mutations in LIPG have been described, the role of LIPG in protection against atherosclerosis is unclear., Methods and Results: We identified 8 loss-of-function (LOF) mutations in LIPG in individuals with high-density lipoprotein cholesterol. Functional analysis confirmed that most rare mutations abolish lipase activity in vitro, indicating complete LOF, whereas 2 more common mutations N396S and R476W reduce activity by ≈50%, indicating partial LOF and implying ≈50% and ≈75% remaining endothelial lipase function in heterozygous complete LOF and partial LOF mutation carriers, respectively. complete LOF mutation carriers had significantly higher plasma high-density lipoprotein cholesterol levels compared with partial LOF mutation carriers. Apolipoprotein B-depleted serum from complete LOF carriers showed significantly enhanced cholesterol efflux acceptor capacity, whereas only trends were observed in partial LOF carriers. Carriers of LIPG mutations exhibited trends toward reduced coronary artery disease in 4 independent cohorts (meta-analysis odds ratio, 0.7; P=0.04)., Conclusions: Our data suggest that the impact of LIPG mutations is directly related to their effect on endothelial lipase function and support that antagonism of endothelial lipase function improves cardioprotection.

Published
2013
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37. Tracking fatty acid kinetics in distinct lipoprotein fractions in vivo: a novel high-throughput approach for studying dyslipidemia in rodent models.

Author

McLaren DG, Wang SP, Stout SJ, Xie D, Miller PL, Mendoza V, Rosa R, Castro-Perez J, Previs SF, Johns DG, and Roddy TP

Subjects
Animals, Biological Transport, Disease Models, Animal, Humans, Isotope Labeling, Lipoproteins chemistry, Male, Mice, Mice, Inbred C57BL, Chemical Fractionation methods, Dyslipidemias metabolism, Fatty Acids metabolism, Lipoproteins isolation & purification, Lipoproteins metabolism
Abstract

Isotopic tracers have been used to examine lipid trafficking for many years, and data from those studies have typically yielded novel insight regarding the pathophysiology of dyslipidemia. Previous experimental designs were suitable for studies in humans because relatively large volumes of plasma could be regularly sampled. We have expanded on the earlier logic by applying high-throughput analytical methods that require reduced sample volumes. Specifically, we have examined the possibility of coupling gel-based separations of lipoproteins (e.g., lipoprint) with LC-MS/MS analyses of complex lipid mixtures as a way to routinely measure the labeling profiles of distinct lipids in discrete lipoprotein subfractions. We demonstrate the ability to measure the incorporation of [U-(13)C]oleate into triglycerides (TG), PLs (PL), and cholesterol esters (CE) in VLDL, LDL, and HDL particles in mice. Although rodent models of dyslipidemia are inherently different from humans because of alterations in enzyme activities and underlying metabolism, rodent models can be used to screen novel compounds for efficacy in altering a given biochemical pathway and therein enable studies of target engagement in vivo. We expect that it is possible to translate our approach for application in other systems, including studies in humans.

Published
2013
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38. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis.

Author

Li JZ, Huang Y, Karaman R, Ivanova PT, Brown HA, Roddy T, Castro-Perez J, Cohen JC, and Hobbs HH

Subjects
Adipose Tissue enzymology, Adipose Tissue pathology, Amino Acid Substitution, Animals, Fatty Acids genetics, Fatty Acids metabolism, Fatty Liver genetics, Fatty Liver pathology, Humans, Liver pathology, Mice, Mice, Transgenic, Non-alcoholic Fatty Liver Disease, Phospholipases A2, Calcium-Independent genetics, Triglycerides genetics, Fatty Liver enzymology, Lipid Metabolism, Liver enzymology, Mutation, Missense, Phospholipases A2, Calcium-Independent biosynthesis, Triglycerides metabolism
Abstract

A genetic variant in PNPLA3 (PNPLA3(I148M)), a triacylglycerol (TAG) hydrolase, is a major risk factor for nonalcoholic fatty liver disease (NAFLD); however, the mechanism underlying this association is not known. To develop an animal model of PNPLA3-induced fatty liver disease, we generated transgenic mice that overexpress similar amounts of wild-type PNPLA3 (PNPLA3(WT)) or mutant PNPLA3 (PNPLA3(I148M)) either in liver or adipose tissue. Overexpression of the transgenes in adipose tissue did not affect liver fat content. Expression of PNPLA3(I148M), but not PNPLA3(WT), in liver recapitulated the fatty liver phenotype as well as other metabolic features associated with this allele in humans. Metabolic studies provided evidence for 3 distinct alterations in hepatic TAG metabolism in PNPLA3(I148M) transgenic mice: increased formation of fatty acids and TAG, impaired hydrolysis of TAG, and relative depletion of TAG long-chain polyunsaturated fatty acids. These findings suggest that PNPLA3 plays a role in remodeling TAG in lipid droplets, as they accumulate in response to food intake, and that the increase in hepatic TAG levels associated with the I148M substitution results from multiple changes in hepatic TAG metabolism. The development of an animal model that recapitulates the metabolic phenotype of the allele in humans provides a new platform in which to elucidate the role of PNLPA3(I148M) in NAFLD.

Published
2012
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39. Small molecule activation of lecithin cholesterol acyltransferase modulates lipoprotein metabolism in mice and hamsters.

Author

Chen Z, Wang SP, Krsmanovic ML, Castro-Perez J, Gagen K, Mendoza V, Rosa R, Shah V, He T, Stout SJ, Geoghagen NS, Lee SH, McLaren DG, Wang L, Roddy TP, Plump AS, Hubbard BK, Sinz CJ, and Johns DG

Subjects
Animals, Bile Acids and Salts blood, Cholesterol blood, Cholesterol Esters blood, Cricetinae, Enzyme Activation drug effects, Female, Lipoproteins, HDL blood, Liver enzymology, Magnetic Resonance Spectroscopy, Mass Spectrometry, Mesocricetus, Mice, Mice, Inbred C57BL, Thiadiazoles chemistry, Triglycerides blood, Enzyme Activation physiology, Lipoproteins metabolism, Liver metabolism, Phosphatidylcholine-Sterol O-Acyltransferase metabolism, Thiadiazoles pharmacology
Abstract

The objective was to assess whether pharmacological activation of lecithin cholesterol acyltransferase (LCAT) could exert beneficial effects on lipoprotein metabolism. A putative small molecule activator (compound A) was used as a tool compound in in vitro and in vivo studies. Compound A increased LCAT activity in vitro in plasma from mouse, hamster, rhesus monkey, and human. To assess the acute pharmacodynamic effects of compound A, C57Bl/6 mice and hamsters received a single dose (20 mg/kg) of compound A. Both species displayed a significant increase in high-density lipoprotein cholesterol (HDLc) and a significant decrease in non-HDLc and triglycerides acutely after dosing; these changes tracked with ex vivo plasma LCAT activity. To examine compound A's chronic effect on lipoprotein metabolism, hamsters received a daily dosing of vehicle or of 20 or 60 mg/kg of compound A for 2 weeks. At study termination, compound treatment resulted in a significant increase in HDLc, HDL particle size, plasma apolipoprotein A-I level, and plasma cholesteryl ester (CE) to free cholesterol ratio, and a significant reduction in very low-density lipoprotein cholesterol. The increase in plasma CE mirrored the increase in HDL CE. Triglycerides trended toward a dose-dependent decrease in very low-density lipoprotein and HDL, with multiple triglyceride species reaching statistical significance. Gallbladder bile acids content displayed a significant and more than 2-fold increase with the 60 mg/kg treatment. We characterized pharmacological activation of LCAT by a small molecule extensively for the first time, and our findings support the potential of this approach in treating dyslipidemia and atherosclerosis; our analyses also provide mechanistic insight on LCAT's role in lipoprotein metabolism., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Published
2012
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40. Anacetrapib promotes reverse cholesterol transport and bulk cholesterol excretion in Syrian golden hamsters.

Author

Castro-Perez J, Briand F, Gagen K, Wang SP, Chen Y, McLaren DG, Shah V, Vreeken RJ, Hankemeier T, Sulpice T, Roddy TP, Hubbard BK, and Johns DG

Subjects
Animals, Biological Transport drug effects, Cell Line, Cholesterol chemistry, Cholesterol Ester Transfer Proteins antagonists & inhibitors, Cholesterol Ester Transfer Proteins metabolism, Cricetinae, Dyslipidemias metabolism, Feces, Lipoproteins, HDL metabolism, Macrophages drug effects, Macrophages metabolism, Male, Mice, Cholesterol metabolism, Oxazolidinones pharmacology
Abstract

Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester (CE) and triglyceride between HDL and apoB-containing lipoproteins. Anacetrapib (ANA), a reversible inhibitor of CETP, raises HDL cholesterol (HDL-C) and lowers LDL cholesterol in dyslipidemic patients; however, the effects of ANA on cholesterol/lipoprotein metabolism in a dyslipidemic hamster model have not been demonstrated. To test whether ANA (60 mg/kg/day, 2 weeks) promoted reverse cholesterol transport (RCT), ³H-cholesterol-loaded macrophages were injected and (3)H-tracer levels were measured in HDL, liver, and feces. Compared to controls, ANA inhibited CETP (94%) and increased HDL-C (47%). ³H-tracer in HDL increased by 69% in hamsters treated with ANA, suggesting increased cholesterol efflux from macrophages to HDL. ³H-tracer in fecal cholesterol and bile acids increased by 90% and 57%, respectively, indicating increased macrophage-to-feces RCT. Mass spectrometry analysis of HDL from ANA-treated hamsters revealed an increase in free unlabeled cholesterol and CE. Furthermore, bulk cholesterol and cholic acid were increased in feces from ANA-treated hamsters. Using two independent approaches to assess cholesterol metabolism, the current study demonstrates that CETP inhibition with ANA promotes macrophage-to-feces RCT and results in increased fecal cholesterol/bile acid excretion, further supporting its development as a novel lipid therapy for the treatment of dyslipidemia and atherosclerotic vascular disease.

Published
2011
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41. ApoB siRNA-induced liver steatosis is resistant to clearance by the loss of fatty acid transport protein 5 (Fatp5).

Author

Ason B, Castro-Perez J, Tep S, Stefanni A, Tadin-Strapps M, Roddy T, Hankemeier T, Hubbard B, Sachs AB, Michael Flanagan W, Kuklin NA, and Mitnaul LJ

Subjects
Animals, Apolipoproteins B blood, Bile Acids and Salts metabolism, Cholesterol blood, Cholesterol, HDL blood, Female, Gene Expression Profiling, Gene Knockdown Techniques, Lipid Metabolism genetics, Liver metabolism, Liver pathology, Mice, Mice, Inbred C57BL, RNA, Small Interfering, Triglycerides blood, Apolipoproteins B genetics, Fatty Acid Transport Proteins genetics, Fatty Liver genetics
Abstract

The association between hypercholesterolemia and elevated serum apolipoprotein B (APOB) has generated interest in APOB as a therapeutic target for patients at risk of developing cardiovascular disease. In the clinic, mipomersen, an antisense oligonucleotide (ASO) APOB inhibitor, was associated with a trend toward increased hepatic triglycerides, and liver steatosis remains a concern. We found that siRNA-mediated knockdown of ApoB led to elevated hepatic triglycerides and liver steatosis in mice engineered to exhibit a human-like lipid profile. Many genes required for fatty acid synthesis were reduced, suggesting that the observed elevation in hepatic triglycerides is maintained by the cell through fatty acid uptake as opposed to fatty acid synthesis. Fatty acid transport protein 5 (Fatp5/Slc27a5) is required for long chain fatty acid (LCFA) uptake and bile acid reconjugation by the liver. Fatp5 knockout mice exhibited lower levels of hepatic triglycerides due to decreased fatty acid uptake, and shRNA-mediated knockdown of Fatp5 protected mice from diet-induced liver steatosis. Here, we evaluated if siRNA-mediated knockdown of Fatp5 was sufficient to alleviate ApoB knockdown-induced steatosis. We determined that, although Fatp5 siRNA treatment was sufficient to increase the proportion of unconjugated bile acids 100-fold, consistent with FATP5's role in bile acid reconjugation, Fatp5 knockdown failed to influence the degree, zonal distribution, or composition of the hepatic triglycerides that accumulated following ApoB siRNA treatment.

Published
2011
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42. Localization of fatty acyl and double bond positions in phosphatidylcholines using a dual stage CID fragmentation coupled with ion mobility mass spectrometry.

Author

Castro-Perez J, Roddy TP, Nibbering NM, Shah V, McLaren DG, Previs S, Attygalle AB, Herath K, Chen Z, Wang SP, Mitnaul L, Hubbard BK, Vreeken RJ, Johns DG, and Hankemeier T

Subjects
Animals, Ceramides blood, Ceramides chemistry, Ions chemistry, Male, Mice, Mice, Inbred C57BL, Molecular Structure, Molecular Weight, Phosphatidylcholines blood, Phospholipids blood, Phospholipids chemistry, Sphingomyelins blood, Sphingomyelins chemistry, Water chemistry, Phosphatidylcholines chemistry, Spectrometry, Mass, Electrospray Ionization methods
Abstract

A high content molecular fragmentation for the analysis of phosphatidylcholines (PC) was achieved utilizing a two-stage [trap (first generation fragmentation) and transfer (second generation fragmentation)] collision-induced dissociation (CID) in combination with travelling-wave ion mobility spectrometry (TWIMS). The novel aspects of this work reside in the fact that a TWIMS arrangement was used to obtain a high level structural information including location of fatty acyl substituents and double bonds for PCs in plasma, and the presence of alkali metal adduct ions such as [M + Li](+) was not required to obtain double bond positions. Elemental compositions for fragment ions were confirmed by accurate mass measurements. A very specific first generation fragment ion m/z 577 (M-phosphoryl choline) from the PC [16:0/18:1 (9Z)] was produced, which by further CID generated acylium ions containing either the fatty acyl 16:0 (C(15)H(31)CO(+), m/z 239) or 18:1 (9Z) (C(17)H(33)CO(+), m/z 265) substituent. Subsequent water loss from these acylium ions was key in producing hydrocarbon fragment ions mainly from the α-proximal position of the carbonyl group such as the hydrocarbon ion m/z 67 (+H(2)C-HC = CH-CH = CH(2)). Formation of these ions was of important significance for determining double bonds in the fatty acyl chains. In addition to this, and with the aid of (13)C labeled lyso-phosphatidylcholine (LPC) 18:1 (9Z) in the ω-position (methyl) TAP fragmentation produced the ion at m/z 57. And was proven to be derived from the α-proximal (carboxylate) or distant ω-position (methyl) in the LPC.

Published
2011
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43. siRNA-induced liver ApoB knockdown lowers serum LDL-cholesterol in a mouse model with human-like serum lipids.

Author

Tadin-Strapps M, Peterson LB, Cumiskey AM, Rosa RL, Mendoza VH, Castro-Perez J, Puig O, Zhang L, Strapps WR, Yendluri S, Andrews L, Pickering V, Rice J, Luo L, Chen Z, Tep S, Ason B, Somers EP, Sachs AB, Bartz SR, Tian J, Chin J, Hubbard BK, Wong KK, and Mitnaul LJ

Subjects
Animals, Apolipoproteins B blood, Apolipoproteins E blood, Apolipoproteins E genetics, Atherosclerosis pathology, Cell Line, Tumor, Cholesterol Ester Transfer Proteins metabolism, Founder Effect, Gene Expression Profiling, Gene Knockdown Techniques, Hemizygote, Humans, Lipid Metabolism genetics, Liposomes metabolism, Liver drug effects, Liver metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nanoparticles administration & dosage, RNA, Messenger analysis, RNA, Messenger biosynthesis, RNA, Small Interfering metabolism, RNA, Small Interfering pharmacology, Receptors, LDL metabolism, Triglycerides blood, Apolipoproteins B genetics, Atherosclerosis genetics, Atherosclerosis metabolism, Cholesterol Ester Transfer Proteins genetics, Cholesterol, LDL blood, Disease Models, Animal, Receptors, LDL genetics
Abstract

Increased serum apolipoprotein (apo)B and associated LDL levels are well-correlated with an increased risk of coronary disease. ApoE⁻/⁻ and low density lipoprotein receptor (LDLr)⁻/⁻ mice have been extensively used for studies of coronary atherosclerosis. These animals show atherosclerotic lesions similar to those in humans, but their serum lipids are low in apoB-containing LDL particles. We describe the development of a new mouse model with a human-like lipid profile. Ldlr CETP⁺/⁻ hemizygous mice carry a single copy of the human CETP transgene and a single copy of a LDL receptor mutation. To evaluate the apoB pathways in this mouse model, we used novel short-interfering RNAs (siRNA) formulated in lipid nanoparticles (LNP). ApoB siRNAs induced up to 95% reduction of liver ApoB mRNA and serum apoB protein, and a significant lowering of serum LDL in Ldlr CETP⁺/⁻ mice. ApoB targeting is specific and dose-dependent, and it shows lipid-lowering effects for over three weeks. Although specific triglycerides (TG) were affected by ApoB mRNA knockdown (KD) and the total plasma lipid levels were decreased by 70%, the overall lipid distribution did not change. Results presented here demonstrate a new mouse model for investigating additional targets within the ApoB pathways using the siRNA modality.

Published
2011
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44. In vivo D2O labeling to quantify static and dynamic changes in cholesterol and cholesterol esters by high resolution LC/MS.

Author

Castro-Perez J, Previs SF, McLaren DG, Shah V, Herath K, Bhat G, Johns DG, Wang SP, Mitnaul L, Jensen K, Vreeken R, Hankemeier T, Roddy TP, and Hubbard BK

Subjects
Animals, Cholesterol blood, Cholesterol metabolism, Cholesterol Esters metabolism, Isotopes, Male, Mice, Mice, Inbred C57BL, Palmitates blood, Stearoyl-CoA Desaturase metabolism, Cholesterol analysis, Cholesterol Esters analysis, Chromatography, Liquid methods, Deuterium Oxide chemistry, Mass Spectrometry methods
Abstract

High resolution LC/MS-MS and LC/APPI-MS methods have been established for the quantitation of flux in the turnover of cholesterol and cholesterol ester. Attention was directed toward quantifying the monoisotopic mass (M0) and that of the singly deuterated labeled (M+1) isotope. A good degree of isotopic dynamic range has been achieved by LC/MS-MS ranging from 3-4 orders of magnitude. Correlation between the linearity of GC/MS and LC atmospheric pressure photoionization (APPI)-MS are complimentary (r² = 0.9409). To prove the viability of this particular approach, male C57Bl/6 mice on either a high carbohydrate (HC) or a high fat (HF) diet were treated with ²H₂O for 96 h. Gene expression analysis showed an increase in the activity of stearoyl-CoA desaturase (Scd1) in the HC diet up to 69-fold (P < 0.0008) compared with the HF diet. This result was supported by the quantitative flux measurement of the isotopic incorporation of ²H into the respective cholesterol and cholesterol ester (CE) pools. We concluded that it is possible to readily obtain static and dynamic measurement of cholesterol and CEs in vivo by coupling novel LC/MS methods with stable isotope-based protocols.

Published
2011
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45. Collision cross-section determination and tandem mass spectrometric analysis of isomeric carotenoids using electrospray ion mobility time-of-flight mass spectrometry.

Author

Dong L, Shion H, Davis RG, Terry-Penak B, Castro-Perez J, and van Breemen RB

Subjects
Antioxidants analysis, Isomerism, Lycopene, beta Carotene analysis, Carotenoids analysis, Tandem Mass Spectrometry methods
Abstract

Carotenoids are natural pigments with provitamin A and antioxidant activities. Biosynthesized in plants as their all-trans isomers, carotenoids isomerize in solution and in humans to multiple cis isomers which can have different bioavailabilities and functions. Since separation and characterization of isomeric carotenoids using high-pressure liquid chromatography (HPLC) or liquid chromatography-tandem mass spectrometry (LC-MS/MS) is time-consuming, the potential for ion mobility mass spectrometry (IM-MS) to resolve and characterize carotenoid isomers rapidly without chromatography was investigated using traveling-wave ion mobility spectrometry on a quadrupole time-of-flight mass spectrometer. The all-trans isomers of lycopene and β-carotene were separated by several milliseconds from the cis-isomers which were detected as partially overlapping peaks. The collision cross-section values of these carotenoid isomers were determined using IM-MS to be 180 and 236 Å(2) for cis-lycopene and all-trans-lycopene, and 181 and 225 Å(2) for cis-β-carotene and all-trans-β-carotene, respectively. Collision-induced dissociation MS/MS of ion mobility-resolved isomers indicated that cis and all-trans carotenoid isomers can be distinguished by their fragmentation patterns. Previous MS/MS studies of cis- and all trans-carotenoids had suggested that they produced identical tandem mass spectra, but this appears to have been the result of isomerization during ionization. Introduction of specific cis or trans isomers by infusion or HPLC resulted in cis/trans isomerization in the ion source during electrospray, and the relative levels of cis carotenoids forming in the ion source compared to the all-trans isomers were temperature dependent.

Published
2010
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46. Fractional mass filtering as a means to assess circulating metabolites in early human clinical studies.

Author

Tiller PR, Yu S, Bateman KP, Castro-Perez J, McIntosh IS, Kuo Y, and Baillie TA

Subjects
Animals, Anti-HIV Agents analysis, Anti-HIV Agents blood, Chromatography, Liquid methods, Dogs, Humans, Mass Spectrometry methods, Microsomes, Liver metabolism, Pharmaceutical Preparations analysis, Pharmaceutical Preparations blood, Pharmaceutical Preparations metabolism, Rats, Anti-HIV Agents metabolism, Drug Evaluation, Preclinical, Software, Tandem Mass Spectrometry methods
Abstract

Recent changes in the regulatory environment have led to a need for new methods to assess circulating human drug metabolites in early clinical studies with respect to their potential toxicological impact. The specific goals of such studies are to determine if the metabolites present in human plasma following administration of a drug candidate also are observed in plasma from the animal studies employed for preclinical toxicological evaluation, and to estimate corresponding exposure margins (animal:human) for the major metabolites. Until recently, the accepted best practice for the characterization of circulating drug metabolites utilized liquid chromatography/tandem mass spectrometry (LC/MS/MS)-based methodologies, in conjunction with authentic chemical standards, for the detection and quantitative analyses of metabolites predicted from both animal studies and experiments with human liver preparations in vitro. While this approach is satisfactory for anticipated biotransformation products, metabolites that were not expected to circulate in human plasma frequently escape detection. Current accurate mass instruments enable the use of the technique of fractional mass filtering to detect both expected and unexpected metabolites in a rapid, less resource-intensive and more robust manner. Application of this technology to several clinical development programs at Merck Research Laboratories has demonstrated the value of fractional mass filtering in the assessment of circulating drug metabolites in early clinical trials.

Published
2008
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47. High-throughput, accurate mass liquid chromatography/tandem mass spectrometry on a quadrupole time-of-flight system as a 'first-line' approach for metabolite identification studies.

Author

Tiller PR, Yu S, Castro-Perez J, Fillgrove KL, and Baillie TA

Subjects
Animals, Dogs, Humans, Rats, Reproducibility of Results, Sensitivity and Specificity, Chromatography, High Pressure Liquid methods, Gene Expression Profiling methods, Glutathione pharmacokinetics, Microsomes, Liver metabolism, Spectrometry, Mass, Electrospray Ionization methods, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization methods
Abstract

Throughput for drug metabolite identification studies has been increased significantly by the combined use of accurate mass liquid chromatography/tandem mass spectrometry (LC/MS/MS) data on a quadrupole time-of-flight (QTOF) system and targeted data analysis procedures. Employed in concert, these tools have led to the implementation of a semi-automated high-throughput metabolite identification strategy that has been incorporated successfully into lead optimization efforts in drug discovery. The availability of elemental composition data on precursor and all fragment ions in each spectrum has greatly enhanced confidence in ion structure assignments, while computer-based algorithms for defining sites of biotransformation based upon mass shifts of diagnostic fragment ions have facilitated identification of positions of metabolic transformation in drug candidates. Adoption of this technology as the 'first-line' approach for in vitro metabolite profiling has resulted in the analysis of as many as 21 new chemical entities on one day from diverse structural classes and therapeutic programs., ((c) 2008 John Wiley & Sons, Ltd.)

Published
2008
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48. MSE with mass defect filtering for in vitro and in vivo metabolite identification.

Author

Bateman KP, Castro-Perez J, Wrona M, Shockcor JP, Yu K, Oballa R, and Nicoll-Griffith DA

Subjects
Animals, Biotransformation, HIV Protease Inhibitors blood, Hepatocytes drug effects, Hepatocytes metabolism, Indinavir blood, Male, Molecular Structure, Rats, Rats, Sprague-Dawley, Drug Evaluation, Preclinical, HIV Protease Inhibitors pharmacokinetics, Indinavir pharmacokinetics, Spectrometry, Mass, Electrospray Ionization methods
Abstract

Metabolite identification studies involve the detection and structural characterization of the biotransformation products of drug candidates. These experiments are necessary throughout the drug discovery and development process. The use of high-resolution chromatography and high-resolution mass spectrometry together with data processing using mass defect filtering is described for in vitro and in vivo metabolite identification studies. Data collection was done using UPLC coupled with an orthogonal hybrid quadrupole time-of-flight mass spectrometer. This experimental approach enabled the use of MS(E) data collection (where E represents collision energy) which has previously been shown to be a powerful approach for metabolite identification studies. Post-acquisition processing with a prototype mass defect filtering program was used to eliminate endogenous interferences in the study samples, greatly enhancing the discovery of metabolites. The ease of this approach is illustrated by results showing the detection and structural characterization of metabolites in plasma from a preclinical rat pharmacokinetic study., (Copyright 2007 John Wiley & Sons, Ltd.)

Published
2007
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49. Generation of ultrahigh peak capacity LC separations via elevated temperatures and high linear mobile-phase velocities.

Author

Plumb RS, Rainville P, Smith BW, Johnson KA, Castro-Perez J, Wilson ID, and Nicholson JK

Subjects
Acetaminophen chemistry, Acetaminophen urine, Animals, Glucuronides chemistry, Glucuronides urine, Humans, Male, Rats, Rats, Wistar, Temperature, Urine chemistry, Chromatography, Liquid methods
Abstract

The use of a combination of ultraperformance liquid chromatography at approximately 11,000 psi on sub 2-microm particles combined with reversed-phase gradient chromatography at a temperature of 90 degrees C is described as applied to the analysis of endogenous and drug metabolites in human and animal urine. By using elevated temperatures, back pressures can be reduced while maintaining high flow rates and chromatographic efficiency, with peaks 1-3 s wide at the base. Application to urine samples provided a peak capacity of approximately 700 for a 10-min analysis and greater than approximately 1000 in 1 h. Despite the narrow nature of the peaks, good quality mass spectra were also obtained, allowing the identification of typical drug and endogenous metabolites. These ultra-high-resolution chromatograms should be ideal for the analysis of complex samples in, for example, metabolite identification, impurity identification, and metabonomic/metabolomic studies. Applications in natural product analysis and proteomics can also be envisaged.

Published
2006
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50. Narrow-bore sample trapping and chromatography combined with quadrupole/time-of-flight mass spectrometry for ultra-sensitive identification of in vivo and in vitro metabolites.

Author

Foltz DJ, Castro-Perez J, Riley P, Entwisle JR, and Baker TR

Subjects
Chromatography, High Pressure Liquid instrumentation, Humans, Pharmaceutical Preparations blood, Sensitivity and Specificity, Chromatography, High Pressure Liquid methods, Mass Spectrometry methods, Pharmaceutical Preparations metabolism
Abstract

The identification of in vitro and in vivo metabolites is vital to the discovery and development of new pharmaceutical therapies. Analytical strategies to identify metabolites at different stages of this process vary, but all involve the use of liquid chromatography separations combined with detection via mass spectrometry (HPLC/MS). Reported here is the use of narrow-bore column (0.5-1.0 mm i.d.) trapping of metabolites, followed by back-flushing onto a matching analytical column. Separated metabolites were then identified using quadrupole time-of-flight mass spectrometry (MS) and tandem MS. Metabolites in human plasma and from low-level in vitro incubations, that were not identified using standard HPLC/MS approaches, were characterized using the instrumental configuration described here.

Published
2005
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