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On February 23, 2018, PubMed Central Canada (PMC Canada) will be taken offline permanently. No author manuscripts will be deleted, and the approximately 2,900 manuscripts authored by Canadian Institutes of Health Research (CIHR)-funded researchers currently in the archive will be copied to the National Research Council’s (NRC) Digital Repository over the coming months. These manuscripts along with all other content will also remain publicly searchable on PubMed Central (US) and Europe PubMed Central, meaning such manuscripts will continue to be compliant with the Tri-Agency Open Access Policy on Publications.

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1.  Ahnak functions as a tumor suppressor via modulation of TGFβ/Smad signaling pathway 
Oncogene  2014;33(38):4675-4684.
We provide detailed mechanisms of Ahnak-mediated potentiation of transforming growth factor β (TGFβ) signaling, which leads to a negative regulation of cell growth. We show that Smad3 interacts with Ahnak through MH2 domain and that Ahnak stimulates Smad3 localization into nucleus leading to potentiating TGFβ-induced transcriptional activity of R-Smad. Moreover, overexpression of Ahnak resulted in growth retardation and cell cycle arrest through downregulation of c-Myc and cyclin D1/D2. We describe results from analyses of Ahnak−/− mouse model expressing middle T antigen in a mammary gland-specific manner (MMTVTg/+Ahnak−/−), which showed significantly progressed hyperplasia of mammary glands compared with MMTVTg/+Ahnak+/+. Finally, we screened multiple human breast cancer tissues and showed that the expression of Ahnak in cancer tissues is lower than that in control tissues by 50%. Taken together, these data indicate that Ahnak mediates a negative regulation of cell growth and acts as novel tumor suppressor through potentiation of TGFβ signaling.
doi:10.1038/onc.2014.69
PMCID: PMC4180639  PMID: 24662814
2.  Scaffold protein FHL2 facilitates MDM2-mediated degradation of IER3 to regulate proliferation of cervical cancer cells 
Oncogene  2016;35(39):5106-5118.
The expression of immediate early response 3 (IER3), a protein with a short half-life, is rapidly induced by various cellular stimuli. We recently reported that IER3 induces the apoptosis of cervical cancer cells and that its expression is downregulated in patients with cervical cancer. However, the molecular mechanism involved in the rapid degradation of IER3 remains unknown. Here, we demonstrate that MDM2 is an E3 ligase that interacts with IER3 and promotes its ubiquitination, followed by proteasomal degradation. Polyubiquitination of the conserved lysine 60 of IER3 is essential for its degradation. In addition, four and a half LIM domains protein 2 (FHL2) binds to both IER3 and MDM2, allowing for efficient MDM2-mediated IER3 degradation by facilitating an association between MDM2 and IER3. Moreover, IER3 induces cell cycle arrest in cervical cancer cells and its activity is further enhanced in cells in which FHL2 or MDM2 was silenced, thereby preventing IER3 degradation. The E6 and E7 oncoproteins of human papilloma virus 18 regulated IER3 expression. FHL2 expression was significantly higher in the squamous epithelium of cervical carcinoma tissues than in non-cancerous cervical tissues, whereas cervical carcinoma expression of IER3 was downregulated in this region. Thus, we determined the molecular mechanism responsible for IER3 degradation, involving a ternary complex of IER3, MDM2 and FHL2, which may contribute to cervical tumor growth. Furthermore, we demonstrated that FHL2 serves as a scaffold for E3 ligase and its substrate during the ubiquitination reaction, a function that has not been previously reported for this protein.
doi:10.1038/onc.2016.54
PMCID: PMC5399145  PMID: 26973248
3.  Prospects for Observing and Localizing Gravitational-Wave Transients with Advanced LIGO and Advanced Virgo 
Abbott, B. P. | Abbott, R. | Abbott, T. D. | Abernathy, M. R. | Acernese, F. | Ackley, K. | Adams, C. | Adams, T. | Addesso, P. | Adhikari, R. X. | Adya, V. B. | Affeldt, C. | Agathos, M. | Agatsuma, K. | Aggarwal, N. | Aguiar, O. D. | Ain, A. | Ajith, P. | Allen, B. | Allocca, A. | Altin, P. A. | Amariutei, D. V. | Anderson, S. B. | Anderson, W. G. | Arai, K. | Araya, M. C. | Arceneaux, C. C. | Areeda, J. S. | Arnaud, N. | Arun, K. G. | Ashton, G. | Ast, M. | Aston, S. M. | Astone, P. | Aufmuth, P. | Aulbert, C. | Babak, S. | Baker, P. T. | Baldaccini, F. | Ballardin, G. | Ballmer, S. W. | Barayoga, J. C. | Barclay, S. E. | Barish, B. C. | Barker, 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. | Behnke, B. | Bejger, M. | Belczynski, C. | Bell, A. S. | Bell, C. J. | Berger, B. K. | Bergman, J. | Bergmann, G. | Berry, C. P. L. | Bersanetti, D. | Bertolini, A. | Betzwieser, J. | Bhagwat, S. | Bhandare, R. | Bilenko, I. A. | Billingsley, G. | Birch, J. | Birney, R. | Biscans, S. | Bisht, A. | Bitossi, M. | Biwer, C. | Bizouard, M. A. | Blackburn, J. K. | Blair, C. D. | Blair, D. | Blair, R. M. | Bloemen, S. | Bock, O. | Bodiya, T. P. | Boer, M. | Bogaert, G. | Bogan, C. | Bohe, A. | Bojtos, P. | Bond, C. | Bondu, F. | Bonnand, R. | Bork, R. | Boschi, V. | Bose, S. | 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. | Brooks, A. F. | Brown, D. A. | Brown, D. D. | Brown, N. M. | Buchanan, C. C. | Buikema, A. | Bulik, T. | Bulten, H. J. | Buonanno, A. | Buskulic, D. | Buy, C. | Byer, R. L. | Cadonati, L. | Cagnoli, G. | Cahillane, C. | Calderón Bustillo, J. | Callister, T. | Calloni, E. | Camp, J. B. | Cannon, K. C. | Cao, J. | Capano, C. D. | Capocasa, E. | Carbognani, F. | Caride, S. | Casanueva Diaz, J. | Casentini, C. | Caudill, S. | Cavaglià, M. | Cavalier, F. | Cavalieri, R. | Cella, G. | Cepeda, C. | Cerboni Baiardi, L. | Cerretani, G. | Cesarini, E. | Chakraborty, R. | Chalermsongsak, T. | Chamberlin, S. J. | Chan, M. | Chao, S. | Charlton, P. | Chassande-Mottin, E. | Chen, H. Y. | Chen, Y. | Cheng, C. | Chincarini, A. | Chiummo, A. | Cho, H. S. | Cho, M. | Chow, J. H. | Christensen, N. | Chu, Q. | Chua, S. | Chung, S. | Ciani, G. | Clara, F. | Clark, J. A. | Cleva, F. | Coccia, E. | Cohadon, P.-F. | Colla, A. | Collette, C. G. | Constancio, M. | Conte, A. | Conti, L. | Cook, D. | Corbitt, T. R. | Cornish, N. | Corsi, A. | Cortese, S. | Costa, C. A. | Coughlin, M. W. | Coughlin, S. B. | Coulon, J.-P. | Countryman, S. T. | Couvares, P. | Coward, D. M. | Cowart, M. J. | Coyne, D. C. | Coyne, R. | Craig, K. | Creighton, J. D. E. | Cripe, J. | Crowder, S. G. | Cumming, A. | Cunningham, L. | Cuoco, E. | Dal Canton, T. | Danilishin, S. L. | D’Antonio, S. | Danzmann, K. | Darman, N. S. | Dattilo, V. | Dave, I. | Daveloza, H. P. | Davier, M. | Davies, G. S. | Daw, E. J. | Day, R. | DeBra, D. | Debreczeni, G. | Degallaix, J. | De Laurentis, M. | Deléglise, S. | Del Pozzo, W. | Denker, T. | Dent, T. | Dereli, H. | Dergachev, V. | DeRosa, R. | De Rosa, R. | DeSalvo, R. | Dhurandhar, S. | Díaz, M. C. | Di Fiore, L. | Di Giovanni, M. | Di Lieto, A. | Di Palma, I. | Di Virgilio, A. | Dojcinoski, G. | Dolique, V. | Donovan, F. | Dooley, K. L. | Doravari, S. | Douglas, R. | 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. M. | Eikenberry, S. S. | Engels, W. | Essick, R. C. | Etzel, T. | Evans, M. | Evans, T. M. | Everett, R. | Factourovich, M. | Fafone, V. | Fair, H. | Fairhurst, S. | Fan, X. | Fang, Q. | Farinon, S. | Farr, B. | Farr, W. M. | Favata, M. | Fays, M. | Fehrmann, H. | Fejer, M. M. | Ferrante, I. | Ferreira, E. C. | Ferrini, F. | Fidecaro, F. | Fiori, I. | Fisher, R. P. | Flaminio, R. | Fletcher, M. | Fournier, J.-D. | Franco, S. | Frasca, S. | Frasconi, F. | Frei, Z. | Freise, A. | Frey, R. | Fricke, T. T. | Fritschel, P. | Frolov, V. V. | Fulda, P. | Fyffe, M. | Gabbard, H. A. G. | Gair, J. R. | Gammaitoni, L. | Gaonkar, S. G. | Garufi, F. | Gatto, A. | Gaur, G. | Gehrels, N. | Gemme, G. | Gendre, B. | Genin, E. | Gennai, A. | George, J. | Gergely, L. | Germain, V. | Ghosh, A. | Ghosh, S. | Giaime, J. A. | Giardina, K. D. | Giazotto, A. | Gill, K. | Glaefke, A. | Goetz, E. | Goetz, R. | Gondan, L. | González, G. | Castro, J. M. Gonzalez | Gopakumar, A. | Gordon, N. A. | Gorodetsky, M. L. | Gossan, S. E. | Gosselin, M. | Gouaty, R. | Graef, C. | Graff, P. B. | Granata, M. | Grant, A. | Gras, S. | Gray, C. | 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. | Hall, B. R. | Hall, E. D. | Hammond, G. | Haney, M. | Hanke, M. M. | Hanks, J. | Hanna, C. | Hannam, M. D. | Hanson, J. | Hardwick, T. | Harms, J. | Harry, G. M. | Harry, I. W. | Hart, M. J. | Hartman, M. T. | Haster, C.-J. | Haughian, K. | Heidmann, A. | Heintze, M. C. | Heitmann, H. | Hello, P. | Hemming, G. | Hendry, M. | Heng, I. S. | Hennig, J. | Heptonstall, A. W. | Heurs, M. | Hild, S. | Hoak, D. | Hodge, K. A. | Hofman, D. | Hollitt, S. E. | Holt, K. | Holz, D. E. | Hopkins, P. | Hosken, D. J. | Hough, J. | Houston, E. A. | Howell, E. J. | Hu, Y. M. | Huang, S. | Huerta, E. A. | Huet, D. | Hughey, B. | Husa, S. | Huttner, S. H. | Huynh-Dinh, T. | Idrisy, A. | Indik, N. | Ingram, D. R. | Inta, R. | Isa, H. N. | Isac, J.-M. | Isi, M. | Islas, G. | Isogai, T. | Iyer, B. R. | Izumi, K. | Jacqmin, T. | Jang, H. | Jani, K. | Jaranowski, P. | Jawahar, S. | Jiménez-Forteza, F. | Johnson, W. W. | Jones, D. I. | Jones, R. | Jonker, R. J. G. | Ju, L. | Haris, K. | Kalaghatgi, C. V. | Kalogera, V. | Kandhasamy, S. | Kang, G. | Kanner, J. B. | Karki, S. | Kasprzack, M. | Katsavounidis, E. | Katzman, W. | Kaufer, S. | Kaur, T. | Kawabe, K. | Kawazoe, F. | Kéfélian, F. | Kehl, M. S. | Keitel, D. | Kelley, D. B. | Kells, W. | Kennedy, R. | Key, J. S. | Khalaidovski, A. | Khalili, F. Y. | Khan, S. | Khan, Z. | Khazanov, E. A. | Kijbunchoo, N. | Kim, C. | Kim, J. | Kim, K. | Kim, N. | Kim, Y.-M. | King, E. J. | King, P. J. | Kinzel, D. L. | Kissel, J. S. | Kleybolte, L. | Klimenko, S. | Koehlenbeck, S. M. | Kokeyama, K. | Koley, S. | Kondrashov, V. | Kontos, A. | Korobko, M. | Korth, W. Z. | Kowalska, I. | Kozak, D. B. | Kringel, V. | Krishnan, B. | Królak, A. | Krueger, C. | Kuehn, G. | Kumar, P. | Kuo, L. | Kutynia, A. | Lackey, B. D. | Landry, M. | Lange, J. | Lantz, B. | Lasky, P. D. | Lazzarini, A. | Lazzaro, C. | Leaci, P. | Leavey, S. | Lebigot, E. | Lee, C. H. | Lee, H. K. | Lee, H. M. | Lee, K. | Lenon, A. | Leonardi, M. | Leong, J. R. | Leroy, N. | Letendre, N. | Levin, Y. | Levine, B. M. | Li, T. G. F. | Libson, A. | Littenberg, T. B. | Lockerbie, N. A. | Logue, J. | Lombardi, A. L. | Lord, J. E. | Lorenzini, M. | Loriette, V. | Lormand, M. | Losurdo, G. | Lough, J. D. | Lück, H. | Lundgren, A. P. | Luo, J. | Lynch, R. | Ma, Y. | MacDonald, T. | Machenschalk, B. | MacInnis, M. | Macleod, D. M. | Magaña-Sandoval, F. | Magee, R. M. | Mageswaran, M. | Majorana, E. | Maksimovic, I. | Malvezzi, V. | Man, N. | Mandel, I. | 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. | Martin, R. M. | Martynov, D. V. | Marx, J. N. | Mason, K. | Masserot, A. | Massinger, T. J. | Masso-Reid, M. | Matichard, F. | Matone, L. | Mavalvala, N. | Mazumder, N. | Mazzolo, G. | McCarthy, R. | McClelland, D. E. | McCormick, S. | McGuire, S. C. | McIntyre, G. | McIver, J. | McManus, D. J. | McWilliams, S. T. | Meacher, D. | Meadors, G. D. | Meidam, J. | Melatos, A. | Mendell, G. | Mendoza-Gandara, D. | Mercer, R. A. | Merilh, E. | Merzougui, M. | Meshkov, S. | Messenger, C. | Messick, C. | Meyers, P. M. | Mezzani, F. | Miao, H. | Michel, C. | Middleton, H. | Mikhailov, E. E. | Milano, L. | 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, C. J. | Moraru, D. | Moreno, G. | Morriss, S. R. | Mossavi, K. | Mours, B. | Mow-Lowry, C. M. | Mueller, C. L. | Mueller, G. | Muir, A. W. | Mukherjee, Arunava | Mukherjee, D. | Mukherjee, S. | Mullavey, A. | Munch, J. | Murphy, D. J. | Murray, P. G. | Mytidis, A. | Nardecchia, I. | Naticchioni, L. | Nayak, R. K. | Necula, V. | Nedkova, K. | Nelemans, G. | Neri, M. | Neunzert, A. | Newton, G. | Nguyen, T. T. | Nielsen, A. B. | Nissanke, S. | Nitz, A. | Nocera, F. | Nolting, D. | Normandin, M. E. N. | Nuttall, L. K. | Oberling, J. | Ochsner, E. | O’Dell, J. | Oelker, E. | Ogin, G. H. | Oh, J. J. | Oh, S. H. | Ohme, F. | Oliver, M. | Oppermann, P. | Oram, R. J. | O’Reilly, B. | O’Shaughnessy, R. | Ott, C. D. | Ottaway, D. J. | Ottens, R. S. | Overmier, H. | Owen, B. 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. | Pascucci, D. | Pasqualetti, A. | Passaquieti, R. | Passuello, D. | Patrick, Z. | Pearlstone, B. L. | Pedraza, M. | Pedurand, R. | Pekowsky, L. | Pele, A. | Penn, S. | Pereira, R. | Perreca, A. | Phelps, M. | Piccinni, O. | Pichot, M. | Piergiovanni, F. | Pierro, V. | Pillant, G. | Pinard, L. | Pinto, I. M. | Pitkin, M. | Poggiani, R. | Post, A. | Powell, J. | Prasad, J. | Predoi, V. | Premachandra, S. S. | Prestegard, T. | Price, L. R. | Prijatelj, M. | Principe, M. | Privitera, S. | Prodi, G. A. | Prokhorov, L. | Punturo, M. | Puppo, P. | Pürrer, M. | Qi, H. | Qin, J. | Quetschke, V. | Quintero, E. A. | Quitzow-James, R. | Raab, F. J. | Rabeling, D. S. | Radkins, H. | Raffai, P. | Raja, S. | Rakhmanov, M. | Rapagnani, P. | Raymond, V. | Razzano, M. | Re, V. | Read, J. | Reed, C. M. | Regimbau, T. | Rei, L. | Reid, S. | Reitze, D. H. | Rew, H. | Ricci, F. | Riles, K. | Robertson, N. A. | Robie, R. | Robinet, F. | Rocchi, A. | Rolland, L. | Rollins, J. G. | Roma, V. J. | Romano, J. D. | Romano, R. | Romanov, G. | Romie, J. H. | Rosińska, D. | Rowan, S. | Rüdiger, A. | Ruggi, P. | Ryan, K. | Sachdev, S. | Sadecki, T. | Sadeghian, L. | Saleem, M. | Salemi, F. | Samajdar, A. | Sammut, L. | Sanchez, E. J. | Sandberg, V. | Sandeen, B. | Sanders, J. R. | Sassolas, B. | Sathyaprakash, B. S. | Saulson, P. R. | Sauter, O. | Savage, R. L. | Sawadsky, A. | Schale, P. | Schilling, R. | Schmidt, J. | Schmidt, P. | Schnabel, R. | Schofield, R. M. S. | Schönbeck, A. | Schreiber, E. | Schuette, D. | Schutz, B. F. | Scott, J. | Scott, S. M. | Sellers, D. | Sentenac, D. | Sequino, V. | Sergeev, A. | Serna, G. | Setyawati, Y. | Sevigny, A. | Shaddock, D. A. | Shah, S. | Shahriar, M. S. | Shaltev, M. | Shao, Z. | Shapiro, B. | Shawhan, P. | Sheperd, A. | Shoemaker, D. H. | Shoemaker, D. M. | Siellez, K. | Siemens, X. | Sigg, D. | Silva, A. D. | Simakov, D. | Singer, A. | Singer, L. P. | Singh, A. | Singh, R. | Sintes, A. M. | Slagmolen, B. J. J. | Smith, J. R. | Smith, N. D. | Smith, R. J. E. | Son, E. J. | Sorazu, B. | Sorrentino, F. | Souradeep, T. | Srivastava, A. K. | Staley, A. | Steinke, M. | Steinlechner, J. | Steinlechner, S. | Steinmeyer, D. | Stephens, B. C. | Stone, R. | Strain, K. A. | Straniero, N. | Stratta, G. | Strauss, N. A. | Strigin, S. | Sturani, R. | Stuver, A. L. | Summerscales, T. Z. | Sun, L. | Sutton, P. J. | Swinkels, B. L. | Szczepanczyk, M. J. | Tacca, M. | Talukder, D. | Tanner, D. B. | Tápai, M. | Tarabrin, S. P. | Taracchini, A. | Taylor, R. | Theeg, T. | Thirugnanasambandam, M. P. | Thomas, E. G. | Thomas, M. | Thomas, P. | Thorne, K. A. | Thorne, K. S. | Thrane, E. | Tiwari, S. | Tiwari, V. | Tokmakov, K. V. | Tomlinson, C. | Tonelli, M. | Torres, C. V. | Torrie, C. I. | Töyrä, D. | Travasso, F. | Traylor, G. | Trifirò, D. | Tringali, M. C. | Trozzo, L. | Tse, M. | 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, M. | van den Brand, J. F. J. | van den Broeck, C. | Vander-Hyde, D. C. | van der Schaaf, L. | van der Sluys, M. V. | van Heijningen, J. V. | van Veggel, A. A. | Vardaro, M. | Vass, S. | Vasúth, M. | Vaulin, R. | Vecchio, A. | Vedovato, G. | Veitch, J. | Veitch, P. J. | Venkateswara, K. | Verkindt, D. | Vetrano, F. | Viceré, A. | Vinciguerra, S. | Vine, D. J. | Vinet, J.-Y. | Vitale, S. | Vo, T. | Vocca, H. | Vorvick, C. | Vousden, W. D. | Vyatchanin, S. P. | Wade, A. R. | Wade, L. E. | Wade, M. | Walker, M. | Wallace, L. | Walsh, S. | Wang, G. | Wang, H. | Wang, M. | Wang, X. | Wang, Y. | Ward, R. L. | Warner, J. | Was, M. | Weaver, B. | Wei, L.-W. | Weinert, M. | Weinstein, A. J. | Weiss, R. | Welborn, T. | Wen, L. | Weßels, P. | Westphal, T. | Wette, K. | Whelan, J. T. | White, D. J. | Whiting, B. F. | Williams, R. D. | Williamson, A. R. | Willis, J. L. | Willke, B. | Wimmer, M. H. | Winkler, W. | Wipf, C. 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We present a possible observing scenario for the Advanced LIGO and Advanced Virgo gravitational-wave detectors over the next decade, with the intention of providing information to the astronomy community to facilitate planning for multi-messenger astronomy with gravitational waves. We determine the expected sensitivity of the network to transient gravitational-wave signals, and study the capability of the network to determine the sky location of the source. We report our findings for gravitational-wave transients, with particular focus on gravitational-wave signals from the inspiral of binary neutron-star systems, which are considered the most promising for multi-messenger astronomy. The ability to localize the sources of the detected signals depends on the geographical distribution of the detectors and their relative sensitivity, and 90% credible regions can be as large as thousands of square degrees when only two sensitive detectors are operational. Determining the sky position of a significant fraction of detected signals to areas of 5 deg2 to 20 deg2 will require at least three detectors of sensitivity within a factor of ∼ 2 of each other and with a broad frequency bandwidth. Should the third LIGO detector be relocated to India as expected, a significant fraction of gravitational-wave signals will be localized to a few square degrees by gravitational-wave observations alone.
doi:10.1007/lrr-2016-1
PMCID: PMC5256041  PMID: 28179853
Gravitational waves; Gravitational-wave detectors; Electromagnetic counterparts; Data analysis
4.  The novel miR-9500 regulates the proliferation and migration of human lung cancer cells by targeting Akt1 
Cell Death and Differentiation  2014;21(7):1150-1159.
MicroRNAs have crucial roles in lung cancer cell development. They regulate cell growth, proliferation and migration by mediating the expression of tumor suppressor genes and oncogenes. We identified and characterized the novel miR-9500 in human lung cancer cells. The miR-9500 forms a stem-loop structure and is conserved in other mammals. The expression levels of miR-9500 were reduced in lung cancer cells and lung cancer tissues compared with normal tissues, as verified by TaqMan miRNA assays. It was confirmed that the putative target gene, Akt1, was directly suppressed by miR-9500, as demonstrated by a luciferase reporter assay. The miR-9500 significantly repressed the protein expression levels of Akt1, as demonstrated via western blot, but did not affect the corresponding mRNA levels. Akt1 has an important role in lung carcinogenesis, and depletion of Akt1 has been shown to have antiproliferative and anti-migratory effects in previous studies. In the current study, the overexpression of miR-9500 inhibited cell proliferation and the expression of cell cycle-related proteins. Likewise, the overexpression of miR-9500 impeded cell migration in human lung cancer cells. In an in vivo assay, miR-9500 significantly suppressed Fluc expression compared with NC and ASO-miR-9500, suggesting that cell proliferation was inhibited in nude mice. Likewise, miR-9500 repressed tumorigenesis and metastasis by targeting Akt1. These data indicate that miR-9500 might be applicable for lung cancer therapy.
doi:10.1038/cdd.2014.33
PMCID: PMC4207482  PMID: 24658401
5.  2,4,5-Trimethoxyldalbergiquinol promotes osteoblastic differentiation and mineralization via the BMP and Wnt/β-catenin pathway 
Cell Death & Disease  2015;6(7):e1819-.
Dalbergia odorifera has been traditionally used as a medicine to treat many diseases. However, the role of 2,4,5-trimethoxyldalbergiquinol (TMDQ) isolated and extracted from D. odorifera in osteoblast function and the underlying molecular mechanisms remain poorly understood. The aim of this study was to investigate the effects and possible underlying mechanisms of TMDQ on osteoblastic differentiation of primary cultures of mouse osteoblasts as an in vitro assay system. TMDQ stimulated osteoblastic differentiation, as assessed by the alkaline phosphatase (ALP) activity, ALP staining, mineralized nodule formation, and the levels of mRNAs encoding the bone differentiation markers, including ALP, bone sialoprotein (BSP), osteopontin, and osteocalcin. TMDQ upregulated the expression of Bmp2 and Bmp4 genes, and increased the protein level of phospho-Smad1/5/8. Furthermore, TMDQ treatment showed the increased mRNA expression of Wnt ligands, phosphorylation of GSK3, and the expression of β-catenin protein. The TMDQ-induced osteogenic effects were abolished by Wnt inhibitor, Dickkopf-1 (DKK1), and bone morphogenetic protein (BMP) antagonist, noggin. TMDQ-induced runt-related transcription factor 2 (Runx2) expression was attenuatted by noggin and DKK1. These data suggest that TMDQ acts through the activation of BMP, Wnt/β-catenin, and Runx2 signaling to promote osteoblast differentiation, and we demonstrate that TMDQ could be a potential agent for the treatment of bone loss-associated diseases such as osteoporosis.
doi:10.1038/cddis.2015.185
PMCID: PMC4650732  PMID: 26181200
6.  Study on Growth Curves of Longissimus dorsi Muscle Area, Backfat Thickness and Body Conformation for Hanwoo (Korean Native) Cows 
The objective of this study was to estimate the parameters of Gompertz growth curves with the measurements of body conformation, real-time ultrasound longissimus dorsi muscle area (LMA) and backfat thickness (BFT) in Hanwoo cows. The Hanwoo cows (n = 3,373) were born in 97 Hanwoo commercial farms in the 17 cities or counties of Gyeongbuk province, Korea, between 2000 and 2007. A total of 5,504 ultrasound measurements were collected for the cows at the age of 13 to 165 months in 2007 and 2008. Wither height (HW), rump height (HR), the horizontal distance between the top of the hips (WH), and girth of chest (GC) were also measured. Analysis of variance was conducted to investigate variables affecting LMA and BFT. The effect of farm nested in location was included in the statistical model, as well as the effects of HW, HR, WH, and GC as covariates. All of the effects were significant in the analysis of variance for LMA and BFT (p<0.01), except for the HR effect for LMA. The two ultrasound measures and the four body conformation traits were fitted to a Gompertz growth curve function to estimate parameters. Upper asymptotic weights were estimated as 54.0 cm2, 7.67 mm, 125.6 cm, 126.4 cm, 29.3 cm, and 184.1 cm, for LMA, BFT, HW, HR, WH, and GC, respectively. Results of ultrasound measurements showed that Hanwoo cows had smaller LMA and greater BFT than other western cattle breeds, suggesting that care must be taken to select for thick BFT rather than an increase of only beef yield. More ultrasound records per cow are needed to get accurate estimates of growth curve, which, thus, helps producers select animals with high accuracy.
doi:10.5713/ajas.2013.13797
PMCID: PMC4150190  PMID: 25178367
Hanwoo; Cows; Growth Curve; Ultrasound; Body Conformation
7.  Estimation of Genetic Parameters for Real-time Ultrasound Measurements for Hanwoo Cows at Different Ages and Pregnancy Status 
The purpose of this study was to estimate genetic parameters of ultrasound measurements for longissimus dorsi muscle area (LMA), backfat thickness (BFT), and marbling score (MS) in Hanwoo cows (N = 3,062) at the ages between 18 and 42 months. Data were collected from 100 Hanwoo breeding farms in Gyeongbuk province, Korea, in 2007 and 2008. The cows were classified into four different age groups, i.e. 18 to 22 months (the first pregnancy period), 23 to 27 (the first parturition), 28 to 32 (the second pregnancy), and 33 to 42 (the second parturition), respectively. For each age group, a multi-trait animal model was used to estimate variance components and heritabilities of the three traits. The averages of LMA, BFT, and MS measurements across the cows of all age groups were 50.1 cm2, 4.62 mm, and 3.04, respectively and heritability estimates were 0.09, 0.10, and 0.08 for the respective traits. However, when the data were analyzed in different age groups, heritability estimates of LMA and BFT were 0.24 and 0.47, respectively, for the cows of 18 to 22 months of age, and 0.21 for MS in the 28 to 32 months old cows. When the cows of all age groups were used, the estimates of genetic (phenotypic) correlations were 0.43 (0.35), −0.06 (0.34) and 0.21 (0.32) between LMA and BFT, LMA and MS, and BFT and MS, respectively. However, in the cow age group between 28 and 32 (18 and 22) months, the estimates of genetic (phenotypic) correlations were 0.05 (0.29), −0.15 (0.24) and 0.38 (0.24), for the respective pairs of traits. These results suggest that genetic, environmental, and phenotypic variations differ depending on cow age, such that care must be taken when ultrasound measurements are applied to selection of cows for meat quality.
doi:10.5713/ajas.2013.13430
PMCID: PMC4093205  PMID: 25049938
Real-time Ultrasound; Heritability; Cows; Hanwoo
8.  Effects of Dietary Protein Levels for Gestating Gilts on Reproductive Performance, Blood Metabolites and Milk Composition 
This experiment was conducted to evaluate the effects of dietary CP levels in gestation under equal lysine content on reproductive performance, blood metabolites and milk composition of gilts. A total of 25 gilts (F1, Yorkshire×Landrace) were allotted to 4 dietary treatments at breeding in a completely randomized design, and fed 1 of 4 experimental diets containing different CP levels (11%, 13%, 15%, or 17%) at 2.0 kg/d throughout the gestation. Body weight of gilts at 24 h postpartum tended to increase linearly (p = 0.09) as dietary CP level increased. In lactation, backfat thickness, ADFI, litter size and weaning to estrus interval (WEI) did not differ among dietary treatments. There were linear increases in litter and piglet weight at 21 d of lactation (p<0.05) and weight gain of litter (p<0.01) and piglet (p<0.05) throughout the lactation as dietary CP level increased. Plasma urea nitrogen levels of gilts in gestation and at 24 h postpartum were linearly elevated as dietary CP level increased (p<0.05). Free fatty acid (FFA) levels in plasma of gestating gilts increased as dietary CP level increased up to 15%, and then decreased with quadratic effects (15 d, p<0.01; 90 d, p<0.05), and a quadratic trend (70 d, p = 0.06). There were no differences in plasma FFA, glucose levels and milk composition in lactation. These results indicate that increasing dietary CP level under equal lysine content in gestation increases BW of gilts and litter performance but does not affect litter size and milk composition. Feeding over 13% CP diet for gestating gilts could be recommended to improve litter growth.
doi:10.5713/ajas.2013.13369
PMCID: PMC4093289  PMID: 25049930
Gilt; Protein; Reproductive Performance; Milk Composition; Litter Growth
9.  National Genetic Evaluation (System) of Hanwoo (Korean Native Cattle) 
Hanwoo (Also known as Korean native cattle; Bos taurus coreanae) have been used for transportation and farming for a long time in South Korea. It has been about 30 yrs since Hanwoo improvement began in earnest as beef cattle for meat yield. The purpose of this study was to determine the trend of improvement as well as to estimate genetic parameters of the traits being used for seedstock selection based on the data collected from the past. Hanwoo proven bulls in South Korea are currently selected through performance and progeny tests. National Hanwoo genetic evaluations are implemented with yearling weight (YW), carcass weight (CW), eye muscle area (EMA), backfat thickness (BF) and marbling score (MS). Yearling weights and MS are used for selecting young bulls, and EMA, BF, and MS are used for selecting proven bulls. One individual per testing room was used for performance tests, and five individuals per room for progeny tests. Individuals tested were not allowed to graze pasture, but there was enough space for them to move around in the testing room. Feeds including roughages and minerals were fed ad libitum, and concentrates were provided at the rate of about 1.8% of individual weight. Overall means of the traits were 352.8±38.56 kg, 335.09±44.61 kg, 77.85±8.838 cm2, 8.6±3.7 mm and 3.293±1.648 for YW, CW, EMA, BF and MS. Heritabilities estimated in this study were 0.30, 0.30, 0.42, 0.50 and 0.63 in YW, CW, EMA, BF and MS, respectively, which are similar to results from previous research. Yearling weight was 315.54 kg in 1998, and had increased to 355.06 kg in 2011, resulting in about 40 kg of improvement over 13 yrs. YW and CW have improved remarkably over the past 15 yrs. Breeding values between 1996 and 2000 decreased or did not change much, but have moved in a desirable direction since 2001. These improvements correspond with the substantial increase in use of animal models since the late 1990s in Korea. Hanwoo testing programs have practically contributed to the improvement in aspects of quality and quantity. In sum, the current selection system is good enough to accommodate circumstances where fewer sires are used on many more cows. Although progeny tests take longer and cost more, they seem to be appropriate under the circumstances of the domestic market with its higher requirement for better meat quality. Consequently, accumulative data collection, genetic evaluation model development, revision of selection indices, as well as cooperation among farms, associations, National Agricultural Cooperative Federation, universities, research institutes, and government agencies must be applied to the Hanwoo selection program. All these efforts will assist the domestic market to secure a competitive position against imported beef under Free Trade Agreement trade system and will provide farmers with higher profits as well as the public with a higher quality of beef.
doi:10.5713/ajas.2012.12439
PMCID: PMC4093164  PMID: 25049770
Hanwoo; Genetic; Trend; Parameter
10.  Comparison of Pork Quality and Sensory Characteristics for Antibiotic Free Yorkshire Crossbreds Raised in Hoop Houses 
The objective of this study was to compare pork characteristics and to determine consumer acceptability of pork chops from antibiotic free Yorkshire crossbreds sired by Berkshire (BY), Large Black (LBY), Tamworth (TY) or Yorkshire (YY) boars and reared in hoop houses. The experiments were conducted at the North Carolina Agricultural and Technical State University (NCA&TSU) Farm in Greensboro, NC and the Cherry Research Station Center for Environmental Farming Systems (CEFS) Alternative Swine Unit in Goldsboro, NC (source of antibiotic free Yorkshire sows used at both places). Twenty-four sows were artificially inseminated at each location in each of three trials. Litters were weaned at 4 wks old, and reared within deep-bedded outdoor hoop houses. To compare pork characteristics, 104 randomly selected animals were harvested at a USDA-inspected abattoir at approximately 200 d of age. Variables measured included pH, color score, L*, a*, b*, marbling score, drip loss, hot carcass weight, backfat thickness (BF), loin muscle area (LMA), and slice shear force. Sensory panel tests were also conducted at two time periods. The data was analyzed with GLM in SAS 9.01 including location, trial, and sire breed as fixed effects. Backfat thickness, LMA, color score and a* were different among breeding groups (p<0.05). The LBY pigs had thicker backfat and smaller LMA than the other breed types. The TY and YY had less backfat than all other breed groups. Color score was lower for YY than BY and LBY but intermediate for TY. The a* was lower for TY than other breeds except LBY which was intermediate. For one sensory panel test, YY pork was more preferred overall as well as for juiciness and texture compared to BY and LBY (p<0.05), but no impact of breed type was noted for the other test, with values similar for BY, LBY, TY and YY pork. This information may help small farmers make decisions about breed types to use for outdoor production.
doi:10.5713/ajas.2012.12296
PMCID: PMC4093026  PMID: 25049527
Outdoor; Antibiotic-Free; Yorkshire; Crossbred; Pork
11.  Comparison of Growth Performance of Antibiotic-free Yorkshire Crossbreds Sired by Berkshire, Large Black, and Tamworth Breeds Raised in Hoop Structures 
The objective of this study was to compare body weight, ADG, and feed:gain ratio of antibiotic-free pigs from Yorkshire dams and sired by Yorkshire (YY), Berkshire (BY), Large Black (LBY) or Tamworth (TY) boars. All the crossbred pigs in each of three trials were raised as one group from weaning to finishing in the same deep-bedded hoop, providing a comfortable environment for the animals which allowed rooting and other natural behaviors. Birth, weaning and litter weights were measured and recorded. From approximately 50 kg to market weight (125 kg), feed intake and body weights were recorded manually (body weight) or using a FIRE (Feed Intake Recording Equipment, Osborne Industries Inc. Osborne, Kansas) system with eight individual feeding stations. Feed intake data for 106 finishing pigs between 140 and 210 d of age and the resulting weights and feed conversion ratios were analyzed by breed type. Least square means for body weights (birth, weaning and to 240 d) were estimated with Proc Mixed in SAS 9.2 for fixed effects such as crossbreed and days of age within the sire breed. The differences within fixed effects were compared using least significant differences with DIFF option. Individual birth weights and weaning weights were influenced by sire breed (p<0.05). For birth weight, BY pigs were the lightest, TY and YY pigs were the heaviest but similar to each other and LBY pigs were intermediate. For weaning weights, BY and LBY pigs were heavier than TY and YY pigs. However, litter birth and weaning weights were not influenced by sire breed, and average daily gain was also not significantly different among breed types. Tamworth sired pigs had lower overall body weight gain, and feed conversion was lower in TY and YY groups than BY and LBY groups (p<0.05), however, number of observations was somewhat limited for feed conversion and for Tamworth pigs. Overall, no convincing differences among breed types were noted for this study, but growth performance in the outdoor environment was satisfactory.
doi:10.5713/ajas.2012.12162
PMCID: PMC4093016  PMID: 25049489
Berkshire; Large Black; Tamworth; Antibiotic-free Yorkshire; Crossbred; Growth
12.  Evaluation of Optimum Genetic Contribution Theory to Control Inbreeding While Maximizing Genetic Response 
Inbreeding is the mating of relatives that produce progeny having more homozygous alleles than non-inbred animals. Inbreeding increases numbers of recessive alleles, which is often associated with decreased performance known as inbreeding depression. The magnitude of inbreeding depression depends on the level of inbreeding in the animal. Level of inbreeding is expressed by the inbreeding coefficient. One breeding goal in livestock is uniform productivity while maintaining acceptable inbreeding levels, especially keeping inbreeding less than 20%. However, in closed herds without the introduction of new genetic sources high levels of inbreeding over time are unavoidable. One method that increases selection response and minimizes inbreeding is selection of individuals by weighting estimated breeding values with average relationships among individuals. Optimum genetic contribution theory (OGC) uses relationships among individuals as weighting factors. The algorithm is as follows: i) Identify the individual having the best EBV; ii) Calculate average relationships ( rj¯) between selected and candidates; iii) Select the individual having the best EBV adjusted for average relationships using the weighting factor k, EBV*=EBVj(1-krj¯). iv) Repeat process until the number of individuals selected equals number required. The objective of this study was to compare simulated results based on OGC selection under different conditions over 30 generations. Individuals (n = 110) were generated for the base population with pseudo random numbers of N~ (0, 3), ten were assumed male, and the remainder female. Each male was mated to ten females, and every female was assumed to have 5 progeny resulting in 500 individuals in the following generation. Results showed the OGC algorithm effectively controlled inbreeding and maintained consistent increases in selection response. Difference in breeding values between selection with OGC algorithm and by EBV only was 8%, however, rate of inbreeding was controlled by 47% after 20 generation. These results indicate that the OGC algorithm can be used effectively in long-term selection programs.
doi:10.5713/ajas.2011.11315
PMCID: PMC4092951  PMID: 25049566
Genetic Contribution Theory; Genetic Response; Breeding Value
13.  Mutant ubiquitin found in Alzheimer’s disease causes neuritic beading of mitochondria in association with neuronal degeneration 
Cell Death and Differentiation  2007;14(10):1721-1732.
A dinucleotide deletion in human ubiquitin (Ub) B messenger RNA leads to formation of polyubiquitin (UbB) + 1, which has been implicated in neuronal cell death in Alzheimer’s and other neurodegenerative diseases. Previous studies demonstrate that UbB + 1 protein causes proteasome dysfunction. However, the molecular mechanism of UbB + 1-mediated neuronal degeneration remains unknown. We now report that UbB + 1 causes neuritic beading, impairment of mitochondrial movements, mitochondrial stress and neuronal degeneration in primary neurons. Transfection of UbB + 1 induced a buildup of mitochondria in neurites and dysregulation of mitochondrial motor proteins, in particular, through detachment of P74, the dynein intermediate chain, from mitochondria and decreased mitochondria–microtubule interactions. Altered distribution of mitochondria was associated with activation of both the mitochondrial stress and p53 cell death pathways. These results support the hypothesis that neuritic clogging of mitochondria by UbB + 1 triggers a cascade of events characterized by local activation of mitochondrial stress followed by global cell death. Furthermore, UbB + 1 small interfering RNA efficiently blocked expression of UbB + 1 protein, attenuated neuritic beading and preserved cellular morphology, suggesting a potential neuroprotective strategy for certain neurodegenerative disorders.
doi:10.1038/sj.cdd.4402180
PMCID: PMC3258508  PMID: 17571083
ubiquitin; ubiquitin B+1; Alzheimer’s disease; mitochondria; mitochondrial stress; axonal transport; neurite; neuronal cell death
14.  Pork Preference for Consumers in China, Japan and South Korea 
Competition in global pork markets has increased as trade barriers have opened as a result of free trade agreements. Japanese prefer both loin and Boston butt, while Chinese prefer pork offal. Frozen pork has increased in terms of imports into China. Japanese consumers consider pork meat origin along with pork price when making purchase decisions. While the Chinese prefer a strong tasting pork product, South Korean consumers show very strong preferences to pork that is higher in fat. Therefore, South Korean consumers have a higher demand for pork belly and Boston butt. Consequently, the supply and demand of pork in Korea is hardly met, which means that importation of high fat parts is inevitable. In Korea there is lower preference toward low fat parts such as loin, picnic shoulder, and ham. During the economic depression in South Korea there have been observable changes in consumer preferences. There remains steep competition among the pork exporting countries in terms of gaining share in the international pork market. If specific consumer preferences would be considered carefully, there is the possibility to increase the amount of pork exported to these countries.
doi:10.5713/ajas.2011.11368
PMCID: PMC4092925  PMID: 25049488
Pork; Preference; China; Japan; South Korea
15.  Growing and equipping the infection control community in Singapore 
BMC Proceedings  2011;5(Suppl 6):P4.
doi:10.1186/1753-6561-5-S6-P4
PMCID: PMC3239772
16.  Association of genetic variations in neurokinin‐2 receptor with enhanced cough sensitivity to capsaicin in chronic cough 
Thorax  2006;61(12):1070-1075.
Background
Chronic cough is associated with increased sensitivity to inhaled capsaicin, and both tachykinins and their receptors play important roles in the cough reflex. However, associations between polymorphisms of the tachykinin receptor genes and cough sensitivity in patients with non‐productive chronic cough have not been reported.
Methods
Direct sequencing was used to identify single nucleotide polymorphisms (SNPs) in the genes for the neurokinin‐1 and neurokinin‐2 receptors (NK‐1R and NK‐2R, respectively). Informative non‐synonymous SNPs were scored using the single base extension method for 312 patients with chronic cough and for 100 age matched healthy controls. The cough response to capsaicin was recorded for 312 patients with chronic cough, and the potential genetic association between cough sensitivity to capsaicin and the NK‐1R and NK‐2R genotypes was evaluated.
Results
Two informative SNPs were identified in NK‐2R (Gly231Glu and Arg375His), whereas no informative SNP was found in NK‐1R. After adjusting for atopy, sex, age, and smoking, the prevalence of enhanced cough sensitivity to capsaicin was higher in the chronic cough patients with the 231Glu allele (p = 0.004; OR 1.69 (95% CI 1.18 to 2.42)) and the 231Glu_375Arg haplotype (p = 0.003; OR 1.71 (95% CI 1.20 to 2.24)]. Moreover, the lowest capsaicin concentration to cause five consecutive coughs (C5) was significantly lower in patients with 231Glu (mean (SD) 44.1 (53.2) v 60.9 (55.8) μM/l, p = 0.04) and those with 231Glu_375Arg (43.2 (52.7) v 69.6 (52.0) μM/l, p = 0.03).
Conclusions
The results of this study suggest that NK‐2R gene polymorphisms are involved in the enhanced cough sensitivity to capsaicin of patients with chronic cough.
doi:10.1136/thx.2005.054429
PMCID: PMC2117043  PMID: 16893949
chronic cough; neurokinin receptors; polymorphism; capsaicin sensitivity
17.  Analysis of the Candida albicans Als2p and Als4p adhesins suggests the potential for compensatory function within the Als family 
Microbiology (Reading, England)  2005;151(Pt 5):1619-1630.
The ALS (agglutinin-like sequence) gene family encodes eight large cell-surface glycoproteins. The work presented here focuses on Als2p and Als4p, and is part of a larger effort to deduce the function of each Als protein. Both ALS4 alleles were deleted from the Candida albicans genome and the phenotype of the mutant strain (als4Δ/als4Δ; named 2034) studied. Loss of Als4p slowed germ tube formation of cells grown in RPMI 1640 medium and resulted in decreased adhesion of C. albicans to vascular endothelial cells. Loss of Als4p did not affect adhesion to buccal epithelial cells, biofilm formation in a catheter model, or adhesion to or destruction of oral reconstituted human epithelium (RHE). Although deletion of one ALS2 allele was achieved readily, a strain lacking the second allele was not identified despite screening thousands of transformants. The remaining ALS2 allele was placed under control of the C. albicans MAL2 promoter to create an als2Δ/PMAL2-ALS2 strain (named 2342). Real-time RT-PCR analysis of strain 2342 grown in glucose-containing medium (non-inducing conditions) showed that although ALS2 transcript levels were greatly reduced compared to wild-type cells, some ALS2 transcript remained. The decreased ALS2 expression levels were sufficient to slow germ tube formation in RPMI 1640 and Lee medium, reduce adhesion to vascular endothelial cells and to RHE, decrease RHE destruction, and impair biofilm formation. Growth of strain 2342 in maltose-containing medium (inducing conditions) restored the wild-type phenotype in all assays. Real-time RT-PCR analysis demonstrated that in maltose-containing medium, strain 2342 overexpressed ALS2 compared to wild-type cells; however no overexpression phenotype was apparent. Microarray analysis revealed little transcriptional response to ALS4 deletion, but showed twofold up-regulation of orf19.4765 in the glucose-medium-grown als2Δ/PMAL2-ALS2 strain. orf19.4765 encodes a protein with features of a glycosylated cell wall protein with similarity to Saccharomyces cerevisiae Ccw12p, although initial analysis suggested functional differences between the two proteins. Real-time RT-PCR measurement of ALS2 and ALS4 transcript copy number showed a 2·8-fold increase in ALS2 expression in the als4Δ/als4Δ strain and a 3·2-fold increase in ALS4 expression in the als2Δ/PMAL2-ALS2 strain, suggesting the potential for compensatory function between these related proteins.
doi:10.1099/mic.0.27763-0
PMCID: PMC2583123  PMID: 15870470
18.  Enterostatin inhibition of angiogenesis: possible role of pAMPK and vascular endothelial growth factor A (VEGF-A) 
Introduction
We utilized a genomic analysis of the response of neuronal GT1–7 cells to enterostatin to identify pathways responsive to this peptide. This information, together with reported properties of the enterostatin receptor, suggested that enterostatin may have an effect on angiogenesis.
Method
To investigate this hypothesis, we studied the effect of enterostatin as an antiangiogenic agent in two angiogenic tissue culture model systems.
Results
Enterostatin induced a 50% or greater inhibition in the angiogenic response of human fat cells and had a U-shaped bimodal dose–response effect in inhibiting angiogenesis in a human placental vein angiogenesis model. To further understand this response, we tested enterostatin’s effect in a human hepatoma cell line (HepG2 cells) that was subjected to glucose deprivation, a condition known to induce angiogenesis in other tumor cell lines. Phosphorylated AMP kinase (pAMPK) levels and vascular endothelial growth factor A (VEGF-A) mRNA expression were elevated robustly after incubation of HepG2 cells in the absence of glucose for 4 h, but 15 min incubation with enterostatin dramatically inhibited this pAMPK activation and reduced VEGF-A gene expression after 1 h incubation with enterostatin. The AMPK activator 5-aminoimidazole-4-carboximide ribonucleoside (AICAR) induced VEGF-A expression.
Summary
These data suggest that enterostatin has an antiangiogenic effect and suggest that it regulates VEGF-A gene expression through inhibition of AMPK activity.
doi:10.1038/ijo.2008.16
PMCID: PMC2505274  PMID: 18301390
angiogenesis; veins; in vitro assays; human adipose tissue
19.  Pinusolide and 15-methoxypinusolidic acid attenuate the neurotoxic effect of staurosporine in primary cultures of rat cortical cells 
British Journal of Pharmacology  2006;150(1):65-71.
Background and purpose:
Apoptosis is a fundamental process required for neuronal development but also occurs in most of the common neurodegenerative disorders. In an attempt to obtain an anti-apoptotic neuroprotective compound from natural products, we isolated the diterpenoids, pinusolide and 15-MPA, from B. orientalis and investigated their neuroprotective activity against staurosporine (STS) -induced neuronal apoptosis. In addition, we determined the anti-apoptotic mechanism of these compounds in rat cortical cells.
Experimental approach:
Primary cultures of rat cortical cells injured by STS were used as an in vitro assay system. Cells were pretreated with pinusolide or 15-MPA before exposure to STS. Anti-apoptotic activities were evaluated by the measurement of cytoplasmic condensation and nuclear fragmentation. The levels of cellular peroxide, malondialdehyde (MDA) and [Ca2+]i , as well as the activities of superoxide dismutase (SOD) and caspase-3/7, were measured.
Key results:
Pinusolide and 15-MPA, at a concentration of 5.0 ìM, reduced the condensed nuclei and rise in [Ca2+]i that accompanies apoptosis induced by 100 nM STS. Pinusolide and 15-MPA also protected the cellular activity of SOD, an antioxidative enzyme reduced by STS insult. Furthermore, the overproduction of reactive oxygen species and lipid peroxidation induced by STS was significantly reduced in pinusolide and 15-MPA treated cells. In addition, pinusolide and 15-MPA inhibited STS-induced caspase-3/7 activation.
Conclusions and Implications:
These results show that pinusolide and 15-MPA protect neuronal cells from STS-induced apoptosis, probably by preventing the increase in [Ca2+]i and cellular oxidation caused by STS, and indicate that they could be used to treat neurodegenerative diseases.
doi:10.1038/sj.bjp.0706944
PMCID: PMC2013848  PMID: 17143305
apoptosis; pinusolide; 15-methoxypinusolidic acid; Biota orientalis; staurosporine; neuroprotective activity
21.  Overlapping Roles of Pocket Proteins in the Myocardium Are Unmasked by Germ Line Deletion of p130 plus Heart-Specific Deletion of Rb 
Molecular and Cellular Biology  2005;25(6):2486-2497.
The pocket protein family of tumor suppressors, and Rb specifically, have been implicated as controlling terminal differentiation in many tissues, including the heart. To establish the biological functions of Rb in the heart and overcome the early lethality caused by germ line deletion of Rb, we used a Cre/loxP system to create conditional, heart-specific Rb-deficient mice. Mice that are deficient in Rb exclusively in cardiac myocytes (CRbL/L) are born with the expected Mendelian distribution, and the adult mice displayed no change in heart size, myocyte cell cycle distribution, myocyte apoptosis, or mechanical function. Since both Rb and p130 are expressed in the adult myocardium, we created double-knockout mice (CRbL/L p130−/−) to determine it these proteins have a shared role in regulating cardiac myocyte cell cycle progression. Adult CRbL/L p130−/− mice demonstrated a threefold increase in the heart weight-to-body weight ratio and showed increased numbers of bromodeoxyuridine- and phosphorylated histone H3-positive nuclei, consistent with persistent myocyte cycling. Likewise, the combined deletion of Rb plus p130 up-regulated myocardial expression of Myc, E2F-1, and G1 cyclin-dependent kinase activities, synergistically. Thus, Rb and p130 have overlapping functional roles in vivo to suppress cell cycle activators, including Myc, and maintain quiescence in postnatal cardiac muscle.
doi:10.1128/MCB.25.6.2486-2497.2005
PMCID: PMC1061608  PMID: 15743840
22.  Relationship between premature mortality and socioeconomic factors in black and white populations of US metropolitan areas. 
Public Health Reports  2001;116(5):464-473.
OBJECTIVE: examined the association of mortality with selected socioeconomic indicators of inequality and segregation among blacks and whites younger than age 65 in 267 US metropolitan areas. The primary aim of the analysis was to operationalize the concept of institutional racism in public health. METHODS: Socioeconomic indicators were drawn from Census and vital statistics data for 1989-1991 and included median household income; two measures of income inequality; percentage of the population that was black; and a measure of residential segregation. RESULTS: Age-adjusted premature mortality was 81% higher in blacks than in whites, and median household income was 40% lower. Income inequality, as measured by the Gini coefficient, was greater within the black population (0.45) than within the white population (0.40; p < 0.001). To confirm that the proxy socioeconomic variables were relevant markers of population health status, regression analysis was performed initially on data for the total population. These variables were all independently and significantly related to premature mortality (p < or = 0.01; R(2) = 0.74). Income inequality for the total population was significantly correlated with premature mortality (r = 0.33). Black (r = 0.26) and white (r = 0.20) population-specific correlations between income inequality and premature mortality, while still significant, were smaller. Residential segregation was significantly related to premature mortality and income inequality for blacks (r = 0.38 for both); among whites, however, segregation was modestly correlated with premature mortality (r = 0.19) and uncorrelated with income inequality. Regional analyses demonstrated that the association of segregation with premature mortality was much more pronounced in the South and in areas with larger black populations. CONCLUSION: Social factors such as income inequality and segregation strongly influence premature mortality in the US. Ecologic studies of the relationships among social factors and population health can measure attributes of the social context that may be relevant for population health, providing the basis for imputing macro-level relationships.
PMCID: PMC1497360  PMID: 12042610
23.  Metabolic characteristics and prevalence of osteoporosis among women in Tae-An area. 
Journal of Korean Medical Science  2001;16(3):323-327.
Understanding the metabolic changes in women is one of the important ways to prevent and treat osteoporosis. To reveal the metabolic characteristics of 289 healthy women aged between 35-65 yr in Tae-An, Korea we evaluated the association between bone mass assessed by broadband ultrasound attenuation (BUA) using quantitative ultrasound 2 (QUS2) and various parameters such as age, body mass index, serum levels of alkaline phosphatase, calcium, phosphorus, parathyroid hormone, 25(OH)D, and urinary ratios of calcium/creatinine and deoxypyridinoline (Dpyd)/creatinine. Among the subjects, 3.0% were osteoporotic, and 40.9% were osteopenic. When the subjects were classified according to their years since menopause (YSM) and age, the prevalence of osteoporosis increased along with an increase of YSM and age. Bone turnover markers such as serum alkaline phosphatase and fasting urinary Dpyd/creatinine were significantly higher in the group with low bone mass than in the normal group. In summary, this study shows, by use of biochemical markers of bone turnover and QUS2, the prevalence of osteoporosis in women aged between 35-65 in Tae-An was 3.0% and the risk of low bone mass increased with the bone turnover markers.
PMCID: PMC3054743  PMID: 11410694
24.  Myelomatous effusion with poor response to chemotherapy. 
Journal of Korean Medical Science  2000;15(2):243-246.
While pleural effusion in multiple myeloma is relatively infrequent, myelomatous pleural effusion is extremely rare. We experienced a 61-year-old woman with IgD-lambda multiple myeloma and pleural effusion. The diagnosis was made originally by pleural biopsy, pleural fluid cytology and immunoelectropheresis of pleural fluid. Transient improvement of the pleural effusion was observed after administration of combination chemotherapy of vincristine, melphalan, cyclophosphamide, prednisone (VMCP)/vincristine, cyclophosphamide, adriamycin, prednisone (VCAP). Two months later, myelomatous pleural effusion recurred and no response to salvage therapy was observed. We reviewed the clinical feature of this case and literature concerning myelomatous pleural effusion.
PMCID: PMC3054621  PMID: 10803706
25.  Ultrastructural changes of the internal elastic lamina in experimental hypercholesterolemic porcine coronary arteries. 
Journal of Korean Medical Science  1998;13(6):603-611.
The internal elastic lamina (IEL) serves as a barrier for cells and macromolecules between the intima and media in the vascular wall. We evaluated the morphological changes and quantitative assessments of the IEL architecture in the coronary circulation of pigs fed with a high cholesterol diet. Transmission electron microscopy (TEM) analysis of the IEL from hypercholesterolemic coronary arteries revealed fragmentation of the IEL associated with a decrease in the thickness. Confocal microscopy and scanning electron microscopy (SEM) revealed an altered pattern characterized by a large oval fenestration in the IEL of hypercholesterolemic vessels. Morphometric analysis of confocal microscopy images demonstrated that the IEL of cholesterol-fed animals were characterized by an increase in the minor diameter of the fenestrae (2.16+/-0.04 microm vs 3.32+/-0.06 microm, p=0.003) and a decrease in the fenestrae density (22,333+/-1,334/mm2 vs 17,552+/-931/mm2, p=0.015) compared to controls. The percentage of the IEL area covered by the fenestrae correlated with the intimal thickness (r=0.79, p=0.004). The immunoreactivity for matrix metalloproteinase-3 (MMP-3) increased in cholesterol-fed coronary arteries, predominantly in the neointima. This study demonstrates experimental hypercholesterolemia induced ultrastructural changes of the IEL in the coronary circulation. The IEL may play an important role in the development of structural changes which characterize the early phase of coronary atherosclerosis.
PMCID: PMC3054544  PMID: 9886168

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