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1.  The diploid genome sequence of an Asian individual 
Nature  2008;456(7218):60-65.
Here we present the first diploid genome sequence of an Asian individual. The genome was sequenced to 36-fold average coverage using massively parallel sequencing technology. We aligned the short reads onto the NCBI human reference genome to 99.97% coverage, and guided by the reference genome, we used uniquely mapped reads to assemble a high-quality consensus sequence for 92% of the Asian individual's genome. We identified approximately 3 million single-nucleotide polymorphisms (SNPs) inside this region, of which 13.6% were not in the dbSNP database. Genotyping analysis showed that SNP identification had high accuracy and consistency, indicating the high sequence quality of this assembly. We also carried out heterozygote phasing and haplotype prediction against HapMap CHB and JPT haplotypes (Chinese and Japanese, respectively), sequence comparison with the two available individual genomes (J. D. Watson and J. C. Venter), and structural variation identification. These variations were considered for their potential biological impact. Our sequence data and analyses demonstrate the potential usefulness of next-generation sequencing technologies for personal genomics.
doi:10.1038/nature07484
PMCID: PMC2716080  PMID: 18987735
2.  Guidelines for the use and interpretation of assays for monitoring autophagy 
Klionsky, Daniel J. | Abdalla, Fabio C. | Abeliovich, Hagai | Abraham, Robert T. | Acevedo-Arozena, Abraham | Adeli, Khosrow | Agholme, Lotta | Agnello, Maria | Agostinis, Patrizia | Aguirre-Ghiso, Julio A. | Ahn, Hyung Jun | Ait-Mohamed, Ouardia | Ait-Si-Ali, Slimane | Akematsu, Takahiko | Akira, Shizuo | Al-Younes, Hesham M. | Al-Zeer, Munir A. | Albert, Matthew L. | Albin, Roger L. | Alegre-Abarrategui, Javier | Aleo, Maria Francesca | Alirezaei, Mehrdad | Almasan, Alexandru | Almonte-Becerril, Maylin | Amano, Atsuo | Amaravadi, Ravi K. | Amarnath, Shoba | Amer, Amal O. | Andrieu-Abadie, Nathalie | Anantharam, Vellareddy | Ann, David K. | Anoopkumar-Dukie, Shailendra | Aoki, Hiroshi | Apostolova, Nadezda | Arancia, Giuseppe | Aris, John P. | Asanuma, Katsuhiko | Asare, Nana Y.O. | Ashida, Hisashi | Askanas, Valerie | Askew, David S. | Auberger, Patrick | Baba, Misuzu | Backues, Steven K. | Baehrecke, Eric H. | Bahr, Ben A. | Bai, Xue-Yuan | Bailly, Yannick | Baiocchi, Robert | Baldini, Giulia | Balduini, Walter | Ballabio, Andrea | Bamber, Bruce A. | Bampton, Edward T.W. | Juhász, Gábor | Bartholomew, Clinton R. | Bassham, Diane C. | Bast, Robert C. | Batoko, Henri | Bay, Boon-Huat | Beau, Isabelle | Béchet, Daniel M. | Begley, Thomas J. | Behl, Christian | Behrends, Christian | Bekri, Soumeya | Bellaire, Bryan | Bendall, Linda J. | Benetti, Luca | Berliocchi, Laura | Bernardi, Henri | Bernassola, Francesca | Besteiro, Sébastien | Bhatia-Kissova, Ingrid | Bi, Xiaoning | Biard-Piechaczyk, Martine | Blum, Janice S. | Boise, Lawrence H. | Bonaldo, Paolo | Boone, David L. | Bornhauser, Beat C. | Bortoluci, Karina R. | Bossis, Ioannis | Bost, Frédéric | Bourquin, Jean-Pierre | Boya, Patricia | Boyer-Guittaut, Michaël | Bozhkov, Peter V. | Brady, Nathan R | Brancolini, Claudio | Brech, Andreas | Brenman, Jay E. | Brennand, Ana | Bresnick, Emery H. | Brest, Patrick | Bridges, Dave | Bristol, Molly L. | Brookes, Paul S. | Brown, Eric J. | Brumell, John H. | Brunetti-Pierri, Nicola | Brunk, Ulf T. | Bulman, Dennis E. | Bultman, Scott J. | Bultynck, Geert | Burbulla, Lena F. | Bursch, Wilfried | Butchar, Jonathan P. | Buzgariu, Wanda | Bydlowski, Sergio P. | Cadwell, Ken | Cahová, Monika | Cai, Dongsheng | Cai, Jiyang | Cai, Qian | Calabretta, Bruno | Calvo-Garrido, Javier | Camougrand, Nadine | Campanella, Michelangelo | Campos-Salinas, Jenny | Candi, Eleonora | Cao, Lizhi | Caplan, Allan B. | Carding, Simon R. | Cardoso, Sandra M. | Carew, Jennifer S. | Carlin, Cathleen R. | Carmignac, Virginie | Carneiro, Leticia A.M. | Carra, Serena | Caruso, Rosario A. | Casari, Giorgio | Casas, Caty | Castino, Roberta | Cebollero, Eduardo | Cecconi, Francesco | Celli, Jean | Chaachouay, Hassan | Chae, Han-Jung | Chai, Chee-Yin | Chan, David C. | Chan, Edmond Y. | Chang, Raymond Chuen-Chung | Che, Chi-Ming | Chen, Ching-Chow | Chen, Guang-Chao | Chen, Guo-Qiang | Chen, Min | Chen, Quan | Chen, Steve S.-L. | Chen, WenLi | Chen, Xi | Chen, Xiangmei | Chen, Xiequn | Chen, Ye-Guang | Chen, Yingyu | Chen, Yongqiang | Chen, Yu-Jen | Chen, Zhixiang | Cheng, Alan | Cheng, Christopher H.K. | Cheng, Yan | Cheong, Heesun | Cheong, Jae-Ho | Cherry, Sara | Chess-Williams, Russ | Cheung, Zelda H. | Chevet, Eric | Chiang, Hui-Ling | Chiarelli, Roberto | Chiba, Tomoki | Chin, Lih-Shen | Chiou, Shih-Hwa | Chisari, Francis V. | Cho, Chi Hin | Cho, Dong-Hyung | Choi, Augustine M.K. | Choi, DooSeok | Choi, Kyeong Sook | Choi, Mary E. | Chouaib, Salem | Choubey, Divaker | Choubey, Vinay | Chu, Charleen T. | Chuang, Tsung-Hsien | Chueh, Sheau-Huei | Chun, Taehoon | Chwae, Yong-Joon | Chye, Mee-Len | Ciarcia, Roberto | Ciriolo, Maria R. | Clague, Michael J. | Clark, Robert S.B. | Clarke, Peter G.H. | Clarke, Robert | Codogno, Patrice | Coller, Hilary A. | Colombo, María I. | Comincini, Sergio | Condello, Maria | Condorelli, Fabrizio | Cookson, Mark R. | Coombs, Graham H. | Coppens, Isabelle | Corbalan, Ramon | Cossart, Pascale | Costelli, Paola | Costes, Safia | Coto-Montes, Ana | Couve, Eduardo | Coxon, Fraser P. | Cregg, James M. | Crespo, José L. | Cronjé, Marianne J. | Cuervo, Ana Maria | Cullen, Joseph J. | Czaja, Mark J. | D'Amelio, Marcello | Darfeuille-Michaud, Arlette | Davids, Lester M. | Davies, Faith E. | De Felici, Massimo | de Groot, John F. | de Haan, Cornelis A.M. | De Martino, Luisa | De Milito, Angelo | De Tata, Vincenzo | Debnath, Jayanta | Degterev, Alexei | Dehay, Benjamin | Delbridge, Lea M.D. | Demarchi, Francesca | Deng, Yi Zhen | Dengjel, Jörn | Dent, Paul | Denton, Donna | Deretic, Vojo | Desai, Shyamal D. | Devenish, Rodney J. | Di Gioacchino, Mario | Di Paolo, Gilbert | Di Pietro, Chiara | Díaz-Araya, Guillermo | Díaz-Laviada, Inés | Diaz-Meco, Maria T. | Diaz-Nido, Javier | Dikic, Ivan | Dinesh-Kumar, Savithramma P. | Ding, Wen-Xing | Distelhorst, Clark W. | Diwan, Abhinav | Djavaheri-Mergny, Mojgan | Dokudovskaya, Svetlana | Dong, Zheng | Dorsey, Frank C. | Dosenko, Victor | Dowling, James J. | Doxsey, Stephen | Dreux, Marlène | Drew, Mark E. | Duan, Qiuhong | Duchosal, Michel A. | Duff, Karen E. | Dugail, Isabelle | Durbeej, Madeleine | Duszenko, Michael | Edelstein, Charles L. | Edinger, Aimee L. | Egea, Gustavo | Eichinger, Ludwig | Eissa, N. Tony | Ekmekcioglu, Suhendan | El-Deiry, Wafik S. | Elazar, Zvulun | Elgendy, Mohamed | Ellerby, Lisa M. | Eng, Kai Er | Engelbrecht, Anna-Mart | Engelender, Simone | Erenpreisa, Jekaterina | Escalante, Ricardo | Esclatine, Audrey | Eskelinen, Eeva-Liisa | Espert, Lucile | Espina, Virginia | Fan, Huizhou | Fan, Jia | Fan, Qi-Wen | Fan, Zhen | Fang, Shengyun | Fang, Yongqi | Fanto, Manolis | Fanzani, Alessandro | Farkas, Thomas | Farre, Jean-Claude | Faure, Mathias | Fechheimer, Marcus | Feng, Carl G. | Feng, Jian | Feng, Qili | Feng, Youji | Fésüs, László | Feuer, Ralph | Figueiredo-Pereira, Maria E. | Fimia, Gian Maria | Fingar, Diane C. | Finkbeiner, Steven | Finkel, Toren | Finley, Kim D. | Fiorito, Filomena | Fisher, Edward A. | Fisher, Paul B. | Flajolet, Marc | Florez-McClure, Maria L. | Florio, Salvatore | Fon, Edward A. | Fornai, Francesco | Fortunato, Franco | Fotedar, Rati | Fowler, Daniel H. | Fox, Howard S. | Franco, Rodrigo | Frankel, Lisa B. | Fransen, Marc | Fuentes, José M. | Fueyo, Juan | Fujii, Jun | Fujisaki, Kozo | Fujita, Eriko | Fukuda, Mitsunori | Furukawa, Ruth H. | Gaestel, Matthias | Gailly, Philippe | Gajewska, Malgorzata | Galliot, Brigitte | Galy, Vincent | Ganesh, Subramaniam | Ganetzky, Barry | Ganley, Ian G. | Gao, Fen-Biao | Gao, George F. | Gao, Jinming | Garcia, Lorena | Garcia-Manero, Guillermo | Garcia-Marcos, Mikel | Garmyn, Marjan | Gartel, Andrei L. | Gatti, Evelina | Gautel, Mathias | Gawriluk, Thomas R. | Gegg, Matthew E. | Geng, Jiefei | Germain, Marc | Gestwicki, Jason E. | Gewirtz, David A. | Ghavami, Saeid | Ghosh, Pradipta | Giammarioli, Anna M. | Giatromanolaki, Alexandra N. | Gibson, Spencer B. | Gilkerson, Robert W. | Ginger, Michael L. | Ginsberg, Henry N. | Golab, Jakub | Goligorsky, Michael S. | Golstein, Pierre | Gomez-Manzano, Candelaria | Goncu, Ebru | Gongora, Céline | Gonzalez, Claudio D. | Gonzalez, Ramon | González-Estévez, Cristina | González-Polo, Rosa Ana | Gonzalez-Rey, Elena | Gorbunov, Nikolai V. | Gorski, Sharon | Goruppi, Sandro | Gottlieb, Roberta A. | Gozuacik, Devrim | Granato, Giovanna Elvira | Grant, Gary D. | Green, Kim N. | Gregorc, Ales | Gros, Frédéric | Grose, Charles | Grunt, Thomas W. | Gual, Philippe | Guan, Jun-Lin | Guan, Kun-Liang | Guichard, Sylvie M. | Gukovskaya, Anna S. | Gukovsky, Ilya | Gunst, Jan | Gustafsson, Åsa B. | Halayko, Andrew J. | Hale, Amber N. | Halonen, Sandra K. | Hamasaki, Maho | Han, Feng | Han, Ting | Hancock, Michael K. | Hansen, Malene | Harada, Hisashi | Harada, Masaru | Hardt, Stefan E. | Harper, J. Wade | Harris, Adrian L. | Harris, James | Harris, Steven D. | Hashimoto, Makoto | Haspel, Jeffrey A. | Hayashi, Shin-ichiro | Hazelhurst, Lori A. | He, Congcong | He, You-Wen | Hébert, Marie-Josée | Heidenreich, Kim A. | Helfrich, Miep H. | Helgason, Gudmundur V. | Henske, Elizabeth P. | Herman, Brian | Herman, Paul K. | Hetz, Claudio | Hilfiker, Sabine | Hill, Joseph A. | Hocking, Lynne J. | Hofman, Paul | Hofmann, Thomas G. | Höhfeld, Jörg | Holyoake, Tessa L. | Hong, Ming-Huang | Hood, David A. | Hotamisligil, Gökhan S. | Houwerzijl, Ewout J. | Høyer-Hansen, Maria | Hu, Bingren | Hu, Chien-an A. | Hu, Hong-Ming | Hua, Ya | Huang, Canhua | Huang, Ju | Huang, Shengbing | Huang, Wei-Pang | Huber, Tobias B. | Huh, Won-Ki | Hung, Tai-Ho | Hupp, Ted R. | Hur, Gang Min | Hurley, James B. | Hussain, Sabah N.A. | Hussey, Patrick J. | Hwang, Jung Jin | Hwang, Seungmin | Ichihara, Atsuhiro | Ilkhanizadeh, Shirin | Inoki, Ken | Into, Takeshi | Iovane, Valentina | Iovanna, Juan L. | Ip, Nancy Y. | Isaka, Yoshitaka | Ishida, Hiroyuki | Isidoro, Ciro | Isobe, Ken-ichi | Iwasaki, Akiko | Izquierdo, Marta | Izumi, Yotaro | Jaakkola, Panu M. | Jäättelä, Marja | Jackson, George R. | Jackson, William T. | Janji, Bassam | Jendrach, Marina | Jeon, Ju-Hong | Jeung, Eui-Bae | Jiang, Hong | Jiang, Hongchi | Jiang, Jean X. | Jiang, Ming | Jiang, Qing | Jiang, Xuejun | Jiang, Xuejun | Jiménez, Alberto | Jin, Meiyan | Jin, Shengkan V. | Joe, Cheol O. | Johansen, Terje | Johnson, Daniel E. | Johnson, Gail V.W. | Jones, Nicola L. | Joseph, Bertrand | Joseph, Suresh K. | Joubert, Annie M. | Juhász, Gábor | Juillerat-Jeanneret, Lucienne | Jung, Chang Hwa | Jung, Yong-Keun | Kaarniranta, Kai | Kaasik, Allen | Kabuta, Tomohiro | Kadowaki, Motoni | Kågedal, Katarina | Kamada, Yoshiaki | Kaminskyy, Vitaliy O. | Kampinga, Harm H. | Kanamori, Hiromitsu | Kang, Chanhee | Kang, Khong Bee | Kang, Kwang Il | Kang, Rui | Kang, Yoon-A | Kanki, Tomotake | Kanneganti, Thirumala-Devi | Kanno, Haruo | Kanthasamy, Anumantha G. | Kanthasamy, Arthi | Karantza, Vassiliki | Kaushal, Gur P. | Kaushik, Susmita | Kawazoe, Yoshinori | Ke, Po-Yuan | Kehrl, John H. | Kelekar, Ameeta | Kerkhoff, Claus | Kessel, David H. | Khalil, Hany | Kiel, Jan A.K.W. | Kiger, Amy A. | Kihara, Akio | Kim, Deok Ryong | Kim, Do-Hyung | Kim, Dong-Hou | Kim, Eun-Kyoung | Kim, Hyung-Ryong | Kim, Jae-Sung | Kim, Jeong Hun | Kim, Jin Cheon | Kim, John K. | Kim, Peter K. | Kim, Seong Who | Kim, Yong-Sun | Kim, Yonghyun | Kimchi, Adi | Kimmelman, Alec C. | King, Jason S. | Kinsella, Timothy J. | Kirkin, Vladimir | Kirshenbaum, Lorrie A. | Kitamoto, Katsuhiko | Kitazato, Kaio | Klein, Ludger | Klimecki, Walter T. | Klucken, Jochen | Knecht, Erwin | Ko, Ben C.B. | Koch, Jan C. | Koga, Hiroshi | Koh, Jae-Young | Koh, Young Ho | Koike, Masato | Komatsu, Masaaki | Kominami, Eiki | Kong, Hee Jeong | Kong, Wei-Jia | Korolchuk, Viktor I. | Kotake, Yaichiro | Koukourakis, Michael I. | Flores, Juan B. Kouri | Kovács, Attila L. | Kraft, Claudine | Krainc, Dimitri | Krämer, Helmut | Kretz-Remy, Carole | Krichevsky, Anna M. | Kroemer, Guido | Krüger, Rejko | Krut, Oleg | Ktistakis, Nicholas T. | Kuan, Chia-Yi | Kucharczyk, Roza | Kumar, Ashok | Kumar, Raj | Kumar, Sharad | Kundu, Mondira | Kung, Hsing-Jien | Kurz, Tino | Kwon, Ho Jeong | La Spada, Albert R. | Lafont, Frank | Lamark, Trond | Landry, Jacques | Lane, Jon D. | Lapaquette, Pierre | Laporte, Jocelyn F. | László, Lajos | Lavandero, Sergio | Lavoie, Josée N. | Layfield, Robert | Lazo, Pedro A. | Le, Weidong | Le Cam, Laurent | Ledbetter, Daniel J. | Lee, Alvin J.X. | Lee, Byung-Wan | Lee, Gyun Min | Lee, Jongdae | lee, Ju-hyun | Lee, Michael | Lee, Myung-Shik | Lee, Sug Hyung | Leeuwenburgh, Christiaan | Legembre, Patrick | Legouis, Renaud | Lehmann, Michael | Lei, Huan-Yao | Lei, Qun-Ying | Leib, David A. | Leiro, José | Lemasters, John J. | Lemoine, Antoinette | Lesniak, Maciej S. | Lev, Dina | Levenson, Victor V. | Levine, Beth | Levy, Efrat | Li, Faqiang | Li, Jun-Lin | Li, Lian | Li, Sheng | Li, Weijie | Li, Xue-Jun | Li, Yan-Bo | Li, Yi-Ping | Liang, Chengyu | Liang, Qiangrong | Liao, Yung-Feng | Liberski, Pawel P. | Lieberman, Andrew | Lim, Hyunjung J. | Lim, Kah-Leong | Lim, Kyu | Lin, Chiou-Feng | Lin, Fu-Cheng | Lin, Jian | Lin, Jiandie D. | Lin, Kui | Lin, Wan-Wan | Lin, Weei-Chin | Lin, Yi-Ling | Linden, Rafael | Lingor, Paul | Lippincott-Schwartz, Jennifer | Lisanti, Michael P. | Liton, Paloma B. | Liu, Bo | Liu, Chun-Feng | Liu, Kaiyu | Liu, Leyuan | Liu, Qiong A. | Liu, Wei | Liu, Young-Chau | Liu, Yule | Lockshin, Richard A. | Lok, Chun-Nam | Lonial, Sagar | Loos, Benjamin | Lopez-Berestein, Gabriel | López-Otín, Carlos | Lossi, Laura | Lotze, Michael T. | Low, Peter | Lu, Binfeng | Lu, Bingwei | Lu, Bo | Lu, Zhen | Luciano, Fréderic | Lukacs, Nicholas W. | Lund, Anders H. | Lynch-Day, Melinda A. | Ma, Yong | Macian, Fernando | MacKeigan, Jeff P. | Macleod, Kay F. | Madeo, Frank | Maiuri, Luigi | Maiuri, Maria Chiara | Malagoli, Davide | Malicdan, May Christine V. | Malorni, Walter | Man, Na | Mandelkow, Eva-Maria | Manon, Stephen | Manov, Irena | Mao, Kai | Mao, Xiang | Mao, Zixu | Marambaud, Philippe | Marazziti, Daniela | Marcel, Yves L. | Marchbank, Katie | Marchetti, Piero | Marciniak, Stefan J. | Marcondes, Mateus | Mardi, Mohsen | Marfe, Gabriella | Mariño, Guillermo | Markaki, Maria | Marten, Mark R. | Martin, Seamus J. | Martinand-Mari, Camille | Martinet, Wim | Martinez-Vicente, Marta | Masini, Matilde | Matarrese, Paola | Matsuo, Saburo | Matteoni, Raffaele | Mayer, Andreas | Mazure, Nathalie M. | McConkey, David J. | McConnell, Melanie J. | McDermott, Catherine | McDonald, Christine | McInerney, Gerald M. | McKenna, Sharon L. | McLaughlin, BethAnn | McLean, Pamela J. | McMaster, Christopher R. | McQuibban, G. Angus | Meijer, Alfred J. | Meisler, Miriam H. | Meléndez, Alicia | Melia, Thomas J. | Melino, Gerry | Mena, Maria A. | Menendez, Javier A. | Menna-Barreto, Rubem F. S. | Menon, Manoj B. | Menzies, Fiona M. | Mercer, Carol A. | Merighi, Adalberto | Merry, Diane E. | Meschini, Stefania | Meyer, Christian G. | Meyer, Thomas F. | Miao, Chao-Yu | Miao, Jun-Ying | Michels, Paul A.M. | Michiels, Carine | Mijaljica, Dalibor | Milojkovic, Ana | Minucci, Saverio | Miracco, Clelia | Miranti, Cindy K. | Mitroulis, Ioannis | Miyazawa, Keisuke | Mizushima, Noboru | Mograbi, Baharia | Mohseni, Simin | Molero, Xavier | Mollereau, Bertrand | Mollinedo, Faustino | Momoi, Takashi | Monastyrska, Iryna | Monick, Martha M. | Monteiro, Mervyn J. | Moore, Michael N. | Mora, Rodrigo | Moreau, Kevin | Moreira, Paula I. | Moriyasu, Yuji | Moscat, Jorge | Mostowy, Serge | Mottram, Jeremy C. | Motyl, Tomasz | Moussa, Charbel E.-H. | Müller, Sylke | Muller, Sylviane | Münger, Karl | Münz, Christian | Murphy, Leon O. | Murphy, Maureen E. | Musarò, Antonio | Mysorekar, Indira | Nagata, Eiichiro | Nagata, Kazuhiro | Nahimana, Aimable | Nair, Usha | Nakagawa, Toshiyuki | Nakahira, Kiichi | Nakano, Hiroyasu | Nakatogawa, Hitoshi | Nanjundan, Meera | Naqvi, Naweed I. | Narendra, Derek P. | Narita, Masashi | Navarro, Miguel | Nawrocki, Steffan T. | Nazarko, Taras Y. | Nemchenko, Andriy | Netea, Mihai G. | Neufeld, Thomas P. | Ney, Paul A. | Nezis, Ioannis P. | Nguyen, Huu Phuc | Nie, Daotai | Nishino, Ichizo | Nislow, Corey | Nixon, Ralph A. | Noda, Takeshi | Noegel, Angelika A. | Nogalska, Anna | Noguchi, Satoru | Notterpek, Lucia | Novak, Ivana | Nozaki, Tomoyoshi | Nukina, Nobuyuki | Nürnberger, Thorsten | Nyfeler, Beat | Obara, Keisuke | Oberley, Terry D. | Oddo, Salvatore | Ogawa, Michinaga | Ohashi, Toya | Okamoto, Koji | Oleinick, Nancy L. | Oliver, F. Javier | Olsen, Laura J. | Olsson, Stefan | Opota, Onya | Osborne, Timothy F. | Ostrander, Gary K. | Otsu, Kinya | Ou, Jing-hsiung James | Ouimet, Mireille | Overholtzer, Michael | Ozpolat, Bulent | Paganetti, Paolo | Pagnini, Ugo | Pallet, Nicolas | Palmer, Glen E. | Palumbo, Camilla | Pan, Tianhong | Panaretakis, Theocharis | Pandey, Udai Bhan | Papackova, Zuzana | Papassideri, Issidora | Paris, Irmgard | Park, Junsoo | Park, Ohkmae K. | Parys, Jan B. | Parzych, Katherine R. | Patschan, Susann | Patterson, Cam | Pattingre, Sophie | Pawelek, John M. | Peng, Jianxin | Perlmutter, David H. | Perrotta, Ida | Perry, George | Pervaiz, Shazib | Peter, Matthias | Peters, Godefridus J. | Petersen, Morten | Petrovski, Goran | Phang, James M. | Piacentini, Mauro | Pierre, Philippe | Pierrefite-Carle, Valérie | Pierron, Gérard | Pinkas-Kramarski, Ronit | Piras, Antonio | Piri, Natik | Platanias, Leonidas C. | Pöggeler, Stefanie | Poirot, Marc | Poletti, Angelo | Poüs, Christian | Pozuelo-Rubio, Mercedes | Prætorius-Ibba, Mette | Prasad, Anil | Prescott, Mark | Priault, Muriel | Produit-Zengaffinen, Nathalie | Progulske-Fox, Ann | Proikas-Cezanne, Tassula | Przedborski, Serge | Przyklenk, Karin | Puertollano, Rosa | Puyal, Julien | Qian, Shu-Bing | Qin, Liang | Qin, Zheng-Hong | Quaggin, Susan E. | Raben, Nina | Rabinowich, Hannah | Rabkin, Simon W. | Rahman, Irfan | Rami, Abdelhaq | Ramm, Georg | Randall, Glenn | Randow, Felix | Rao, V. Ashutosh | Rathmell, Jeffrey C. | Ravikumar, Brinda | Ray, Swapan K. | Reed, Bruce H. | Reed, John C. | Reggiori, Fulvio | Régnier-Vigouroux, Anne | Reichert, Andreas S. | Reiners, John J. | Reiter, Russel J. | Ren, Jun | Revuelta, José L. | Rhodes, Christopher J. | Ritis, Konstantinos | Rizzo, Elizete | Robbins, Jeffrey | Roberge, Michel | Roca, Hernan | Roccheri, Maria C. | Rocchi, Stephane | Rodemann, H. Peter | Rodríguez de Córdoba, Santiago | Rohrer, Bärbel | Roninson, Igor B. | Rosen, Kirill | Rost-Roszkowska, Magdalena M. | Rouis, Mustapha | Rouschop, Kasper M.A. | Rovetta, Francesca | Rubin, Brian P. | Rubinsztein, David C. | Ruckdeschel, Klaus | Rucker, Edmund B. | Rudich, Assaf | Rudolf, Emil | Ruiz-Opazo, Nelson | Russo, Rossella | Rusten, Tor Erik | Ryan, Kevin M. | Ryter, Stefan W. | Sabatini, David M. | Sadoshima, Junichi | Saha, Tapas | Saitoh, Tatsuya | Sakagami, Hiroshi | Sakai, Yasuyoshi | Salekdeh, Ghasem Hoseini | Salomoni, Paolo | Salvaterra, Paul M. | Salvesen, Guy | Salvioli, Rosa | Sanchez, Anthony M.J. | Sánchez-Alcázar, José A. | Sánchez-Prieto, Ricardo | Sandri, Marco | Sankar, Uma | Sansanwal, Poonam | Santambrogio, Laura | Saran, Shweta | Sarkar, Sovan | Sarwal, Minnie | Sasakawa, Chihiro | Sasnauskiene, Ausra | Sass, Miklós | Sato, Ken | Sato, Miyuki | Schapira, Anthony H.V. | Scharl, Michael | Schätzl, Hermann M. | Scheper, Wiep | Schiaffino, Stefano | Schneider, Claudio | Schneider, Marion E. | Schneider-Stock, Regine | Schoenlein, Patricia V. | Schorderet, Daniel F. | Schüller, Christoph | Schwartz, Gary K. | Scorrano, Luca | Sealy, Linda | Seglen, Per O. | Segura-Aguilar, Juan | Seiliez, Iban | Seleverstov, Oleksandr | Sell, Christian | Seo, Jong Bok | Separovic, Duska | Setaluri, Vijayasaradhi | Setoguchi, Takao | Settembre, Carmine | Shacka, John J. | Shanmugam, Mala | Shapiro, Irving M. | Shaulian, Eitan | Shaw, Reuben J. | Shelhamer, James H. | Shen, Han-Ming | Shen, Wei-Chiang
Autophagy  2012;8(4):445-544.
In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
doi:10.4161/auto.19496
PMCID: PMC3404883  PMID: 22966490
LC3; autolysosome; autophagosome; flux; lysosome; phagophore; stress; vacuole
3.  Genome-wide association study in Han Chinese identifies four new susceptibility loci for coronary artery disease 
Nature genetics  2012;44(8):890-894.
We performed a meta-analysis of 2 genome-wide association studies of coronary artery disease comprising 1,515 cases with coronary artery disease and 5,019 controls, followed by de novo replication studies in 15,460 cases and 11,472 controls, all of Chinese Han descent. We successfully identified four new loci for coronary artery disease reaching genome-wide significance (P < 5 × 10−8), which mapped in or near TTC32-WDR35, GUCY1A3, C6orf10-BTNL2 and ATP2B1. We also replicated four loci previously identified in European populations (PHACTR1, TCF21, CDKN2A/B and C12orf51). These findings provide new insights into biological pathways for the susceptibility of coronary artery disease in Chinese Han population.
doi:10.1038/ng.2337
PMCID: PMC3927410  PMID: 22751097
4.  Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies 
Abnet, Christian C. | Wang, Zhaoming | Song, Xin | Hu, Nan | Zhou, Fu-You | Freedman, Neal D. | Li, Xue-Min | Yu, Kai | Shu, Xiao-Ou | Yuan, Jian-Min | Zheng, Wei | Dawsey, Sanford M. | Liao, Linda M. | Lee, Maxwell P. | Ding, Ti | Qiao, You-Lin | Gao, Yu-Tang | Koh, Woon-Puay | Xiang, Yong-Bing | Tang, Ze-Zhong | Fan, Jin-Hu | Chung, Charles C. | Wang, Chaoyu | Wheeler, William | Yeager, Meredith | Yuenger, Jeff | Hutchinson, Amy | Jacobs, Kevin B. | Giffen, Carol A. | Burdett, Laurie | Fraumeni, Joseph F. | Tucker, Margaret A. | Chow, Wong-Ho | Zhao, Xue-Ke | Li, Jiang-Man | Li, Ai-Li | Sun, Liang-Dan | Wei, Wu | Li, Ji-Lin | Zhang, Peng | Li, Hong-Lei | Cui, Wen-Yan | Wang, Wei-Peng | Liu, Zhi-Cai | Yang, Xia | Fu, Wen-Jing | Cui, Ji-Li | Lin, Hong-Li | Zhu, Wen-Liang | Liu, Min | Chen, Xi | Chen, Jie | Guo, Li | Han, Jing-Jing | Zhou, Sheng-Li | Huang, Jia | Wu, Yue | Yuan, Chao | Huang, Jing | Ji, Ai-Fang | Kul, Jian-Wei | Fan, Zhong-Min | Wang, Jian-Po | Zhang, Dong-Yun | Zhang, Lian-Qun | Zhang, Wei | Chen, Yuan-Fang | Ren, Jing-Li | Li, Xiu-Min | Dong, Jin-Cheng | Xing, Guo-Lan | Guo, Zhi-Gang | Yang, Jian-Xue | Mao, Yi-Ming | Yuan, Yuan | Guo, Er-Tao | Zhang, Wei | Hou, Zhi-Chao | Liu, Jing | Li, Yan | Tang, Sa | Chang, Jia | Peng, Xiu-Qin | Han, Min | Yin, Wan-Li | Liu, Ya-Li | Hu, Yan-Long | Liu, Yu | Yang, Liu-Qin | Zhu, Fu-Guo | Yang, Xiu-Feng | Feng, Xiao-Shan | Wang, Zhou | Li, Yin | Gao, She-Gan | Liu, Hai-Lin | Yuan, Ling | Jin, Yan | Zhang, Yan-Rui | Sheyhidin, Ilyar | Li, Feng | Chen, Bao-Ping | Ren, Shu-Wei | Liu, Bin | Li, Dan | Zhang, Gao-Fu | Yue, Wen-Bin | Feng, Chang-Wei | Qige, Qirenwang | Zhao, Jian-Ting | Yang, Wen-Jun | Lei, Guang-Yan | Chen, Long-Qi | Li, En-Min | Xu, Li-Yan | Wu, Zhi-Yong | Bao, Zhi-Qin | Chen, Ji-Li | Li, Xian-Chang | Zhuang, Xiang | Zhou, Ying-Fa | Zuo, Xian-Bo | Dong, Zi-Ming | Wang, Lu-Wen | Fan, Xue-Pin | Wang, Jin | Zhou, Qi | Ma, Guo-Shun | Zhang, Qin-Xian | Liu, Hai | Jian, Xin-Ying | Lian, Sin-Yong | Wang, Jin-Sheng | Chang, Fu-Bao | Lu, Chang-Dong | Miao, Jian-Jun | Chen, Zhi-Guo | Wang, Ran | Guo, Ming | Fan, Zeng-Lin | Tao, Ping | Liu, Tai-Jing | Wei, Jin-Chang | Kong, Qing-Peng | Fan, Lei | Wang, Xian-Zeng | Gao, Fu-Sheng | Wang, Tian-Yun | Xie, Dong | Wang, Li | Chen, Shu-Qing | Yang, Wan-Cai | Hong, Jun-Yan | Wang, Liang | Qiu, Song-Liang | Goldstein, Alisa M. | Yuan, Zhi-Qing | Chanock, Stephen J. | Zhang, Xue-Jun | Taylor, Philip R. | Wang, Li-Dong
Human Molecular Genetics  2012;21(9):2132-2141.
Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10−8, and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19–1.40) and P= 7.63 × 10−10. An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.
doi:10.1093/hmg/dds029
PMCID: PMC3315211  PMID: 22323360
5.  Association study of genetic variants in eight genes/loci with type 2 diabetes in a Han Chinese population 
BMC Medical Genetics  2010;11:97.
Background
At least twenty genes/loci were shown to be associated with type 2diabetes in European original populations. Five of these genes were shown to be associated with type 2 diabetes (T2D) in Chinese populations. The purpose of this study was to replicate the association of genetic vairants in the eight diabetes-related genes/loci with type 2 diabetes in a Han Chinese cohort from western part of China. Nineteen single nucleotide polymorphisms (SNPs) from the eight genes/loci including TCF7L2, HHEX, CDKAL1, SLC30A8, PPARG, IGF2BP2, KCNJ11, and CDKN2A/CDKN2B were genotyped in 1,529 cases and 1,439 controls in a Han Chinese population using the ABI SNaPshot method. The meta-analysis of the association between rs7903146 in TCF7L2 gene and T2D in the Han Chinese was performed.
Results
Among the eight genes/loci examined, we found that four were significantly associated with T2D. Although previous studies showed that the association between the SNP rs7903146 in the TCF7L2 gene and T2D was controversial within the Han Chinese population, we have confirmed the significant association between the SNP rs7903146 in the TCF7L2 gene and T2D in both this study and the meta-analysis in the population. In addition, we also confirmed that three SNPs (rs1111875, rs7923837 and rs5015480) in HHEX , one SNP (rs10946398) in CDKAL1, and three SNPs (rs13266634, rs3802177 and rs11558471) in SLC30A8 were significantly associated with T2D in the population being studied.
Conclusions
We demonstrated that the variants in TCF7L2, CDKAL1, HHEX, and SLC30A8 genes are associated with T2D in a Han Chinese population.
doi:10.1186/1471-2350-11-97
PMCID: PMC2894791  PMID: 20550665
6.  Identification of Susceptibility Variants in ADIPOR1 Gene Associated with Type 2 Diabetes, Coronary Artery Disease and the Comorbidity of Type 2 Diabetes and Coronary Artery Disease 
PLoS ONE  2014;9(6):e100339.
Objective
Adiponectin receptor 1 (encoded by ADIPOR1) is one of the major adiponectin receptors, and plays an important role in glucose and lipid metabolism. However, few studies have reported simultaneous associations between ADIPOR1 variants and type 2 diabetes (T2D), coronary artery disease (CAD) and T2D with CAD. Based on the “common soil” hypothesis, we investigated whether ADIPOR1 polymorphisms contributed to the etiology of T2D, CAD, or T2D with CAD in a Northern Han Chinese population.
Methods
Our multi-disease comparison study enrolled 657 subjects, including 165 with T2D, 173 with CAD, 174 with both T2D and CAD (T2D+CAD), and 145 local healthy controls. Six ADIPOR1 single nucleotide polymorphisms (SNPs) were genotyped and their association with disease risk was analyzed.
Results
Multi-case-control comparison identified two ADIPOR1 variants: rs3737884-G, which was simultaneously associated with an increased risk of T2D, CAD, and T2D+CAD (P-value range, 9.80×10−5−6.30×10−4; odds ratio (OR) range: 1.96–2.42) and 16850797-C, which was separately associated with T2D and T2D+CAD (P-value range: 0.007–0.014; OR range: 1.71–1.77). The risk genotypes of both rs3737884 and 16850797 were consistently associated with common metabolic phenotypes in all three diseases (P-value range: 4.81×10−42−0.001). We observed an increase in the genetic dose-dependent cumulative risk with increasing risk allele numbers in T2D, CAD and T2D+CAD (P trend from 1.35×10−5−0.002).
Conclusions
Our results suggest that ADIPOR1 risk polymorphisms are a strong candidate for the “common soil” hypothesis and could partially contribute to disease susceptibility to T2D, CAD, and T2D with CAD in the Northern Han Chinese population.
doi:10.1371/journal.pone.0100339
PMCID: PMC4072681  PMID: 24967709
8.  Obligate mutualism within a host drives the extreme specialization of a fig wasp genome 
Genome Biology  2013;14(12):R141.
Background
Fig pollinating wasps form obligate symbioses with their fig hosts. This mutualism arose approximately 75 million years ago. Unlike many other intimate symbioses, which involve vertical transmission of symbionts to host offspring, female fig wasps fly great distances to transfer horizontally between hosts. In contrast, male wasps are wingless and cannot disperse. Symbionts that keep intimate contact with their hosts often show genome reduction, but it is not clear if the wide dispersal of female fig wasps will counteract this general tendency. We sequenced the genome of the fig wasp Ceratosolen solmsi to address this question.
Results
The genome size of the fig wasp C. solmsi is typical of insects, but has undergone dramatic reductions of gene families involved in environmental sensing and detoxification. The streamlined chemosensory ability reflects the overwhelming importance of females finding trees of their only host species, Ficus hispida, during their fleeting adult lives. Despite long-distance dispersal, little need exists for detoxification or environmental protection because fig wasps spend nearly all of their lives inside a largely benign host. Analyses of transcriptomes in females and males at four key life stages reveal that the extreme anatomical sexual dimorphism of fig wasps may result from a strong bias in sex-differential gene expression.
Conclusions
Our comparison of the C. solmsi genome with other insects provides new insights into the evolution of obligate mutualism. The draft genome of the fig wasp, and transcriptomic comparisons between both sexes at four different life stages, provide insights into the molecular basis for the extreme anatomical sexual dimorphism of this species.
doi:10.1186/gb-2013-14-12-r141
PMCID: PMC4053974  PMID: 24359812
9.  Acquisition of Maternal Antibodies both from the Placenta and by Lactation Protects Mouse Offspring from Yersinia pestis Challenge 
Clinical and Vaccine Immunology : CVI  2012;19(11):1746-1750.
Artificially passive immunization has been demonstrated to be effective against Yersinia pestis infection in animals. However, maternal antibodies' protective efficacy against plague has not yet been demonstrated. Here, we evaluated the kinetics, protective efficacy, and transmission modes of maternal antibodies, using mice immunized with plague subunit vaccine SV1 (20 μg of F1 and 10 μg of rV270). The results showed that the rV270- and F1-specific antibodies could be detected in the sera of newborn mice (NM) until 10 and 14 weeks of age, respectively. There was no antibody titer difference between the parturient mice immunized with SV1 (PM-S) and the caesarean-section newborns (CSN) from the PM-S or between the lactating mice immunized by SV1 (LM-S) and the cross-fostered mice (CFM) during 3 weeks of lactation. The NM had a 72% protection against 4,800 CFU Y. pestis strain 141 challenge at 6 weeks of age, whereas at 14 weeks of age, NM all succumbed to 5,700 CFU of Y. pestis challenge. After 7 weeks of age, CFM had an 84% protection against 5,000 CFU of Y. pestis challenge. These results indicated that maternal antibodies induced by the plague subunit vaccine in mother mice can be transferred to NM by both placenta and lactation. Passive antibodies from the immunized mothers could persist for 3 months and provide early protection for NM. The degree of early protection is dependent on levels of the passively acquired antibody. The results indicate that passive immunization should be an effective countermeasure against plague during its epidemics.
doi:10.1128/CVI.00455-12
PMCID: PMC3491559  PMID: 22933398
10.  Targeted next-generation sequencing as a comprehensive test for patients with and female carriers of DMD/BMD: a multi-population diagnostic study 
Duchenne and Becker muscular dystrophies (DMD/BMD) are the most commonly inherited neuromuscular disease. However, accurate and convenient molecular diagnosis cannot be achieved easily because of the enormous size of the dystrophin gene and complex causative mutation spectrum. Such traditional methods as multiplex ligation-dependent probe amplification plus Sanger sequencing require multiple steps to fulfill the diagnosis of DMD/BMD. Here, we introduce a new single-step method for the genetic analysis of DMD patients and female carriers in real clinical settings and demonstrate the validation of its accuracy. A total of 89 patients, 18 female carriers and 245 non-DMD patients were evaluated using our targeted NGS approaches. Compared with traditional methods, our new method yielded 99.99% specificity and 98.96% sensitivity for copy number variations detection and 100% accuracy for the identification of single-nucleotide variation mutations. Additionally, this method is able to detect partial deletions/duplications, thus offering precise personal DMD gene information for gene therapy. We detected novel partial deletions of exons in nine samples for which the breakpoints were located within exonic regions. The results proved that our new method is suitable for routine clinical practice, with shorter turnaround time, higher accuracy, and better insight into comprehensive genetic information (detailed breakpoints) for ensuing gene therapy.
doi:10.1038/ejhg.2013.82
PMCID: PMC3865410  PMID: 23756440
targeted NGS; genetic diagnosis; Duchenne and Becker muscular dystrophies; statistical analysis for CNVs; breakpoints
11.  Effect of titanium dioxide nanoparticles on zebrafish embryos and developing retina 
AIM
To investigate the impact of titanium dioxide nanoparticles (TiO2 NPs) on embryonic development and retinal neurogenesis.
METHODS
The agglomeration and sedimentation of TiO2 NPs solutions at different dilutions were observed, and the ultraviolet-visible spectra of their supernatants were measured. Zebrafish embryos were experimentally exposed to TiO2 NPs until 72h postfertilization (hpf). The retinal neurogenesis and distribution of the microglia were analyzed by immunohistochemistry and whole mount in situ hybridization.
RESULTS
The 1 mg/L was determined to be an appropriate exposure dose. Embryos exposed to TiO2 NPs had a normal phenotype. The neurogenesis was initiated on time, and ganglion cells, cones and rods were well differentiated at 72 hpf. The expression of fms mRNA and the 4C4 antibody, which were specific to microglia in the central nervous system (CNS), closely resembled their endogenous profile.
CONCLUSION
These data demonstrate that short-term exposure to TiO2 NPs at a low dose does not lead to delayed embryonic development or retinal neurotoxicity.
doi:10.3980/j.issn.2222-3959.2014.06.01
PMCID: PMC4270981  PMID: 25540739
titanium dioxide nanoparticles; retina; microglia; zebrafish
12.  Developing discriminate model and comparative analysis of differentially expressed genes and pathways for bloodstream samples of diabetes mellitus type 2 
BMC Bioinformatics  2014;15(Suppl 17):S5.
Background
Diabetes mellitus of type 2 (T2D), also known as noninsulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes, is a common disease. It is estimated that more than 300 million people worldwide suffer from T2D. In this study, we investigated the T2D, pre-diabetic and healthy human (no diabetes) bloodstream samples using genomic, genealogical, and phonemic information. We identified differentially expressed genes and pathways. The study has provided deeper insights into the development of T2D, and provided useful information for further effective prevention and treatment of the disease.
Results
A total of 142 bloodstream samples were collected, including 47 healthy humans, 22 pre-diabetic and 73 T2D patients. Whole genome scale gene expression profiles were obtained using the Agilent Oligo chips that contain over 20,000 human genes. We identified 79 significantly differentially expressed genes that have fold change ≥ 2. We mapped those genes and pinpointed locations of those genes on human chromosomes. Amongst them, 3 genes were not mapped well on the human genome, but the rest of 76 differentially expressed genes were well mapped on the human genome. We found that most abundant differentially expressed genes are on chromosome one, which contains 9 of those genes, followed by chromosome two that contains 7 of the 76 differentially expressed genes. We performed gene ontology (GO) functional analysis of those 79 differentially expressed genes and found that genes involve in the regulation of cell proliferation were among most common pathways related to T2D. The expression of the 79 genes was combined with clinical information that includes age, sex, and race to construct an optimal discriminant model. The overall performance of the model reached 95.1% accuracy, with 91.5% accuracy on identifying healthy humans, 100% accuracy on pre-diabetic patients and 95.9% accuract on T2D patients. The higher performance on identifying pre-diabetic patients was resulted from more significant changes of gene expressions among this particular group of humans, which implicated that patients were having profound genetic changes towards disease development.
Conclusion
Differentially expressed genes were distributed across chromosomes, and are more abundant on chromosomes 1 and 2 than the rest of the human genome. We found that regulation of cell proliferation actually plays an important role in the T2D disease development. The predictive model developed in this study has utilized the 79 significant genes in combination with age, sex, and racial information to distinguish pre-diabetic, T2D, and healthy humans. The study not only has provided deeper understanding of the disease molecular mechanisms but also useful information for pathway analysis and effective drug target identification.
doi:10.1186/1471-2105-15-S17-S5
PMCID: PMC4304197  PMID: 25559614
T2D; pre-diabetic; differential gene expression; Gene Ontology (GO) analysis; Discriminant model
13.  Serum Amyloid A and Clusterin as Potential Predictive Biomarkers for Severe Hand, Foot and Mouth Disease by 2D-DIGE Proteomics Analysis 
PLoS ONE  2014;9(9):e108816.
Hand, foot, and mouth disease (HFMD) affects more than one million children, is responsible for several hundred child deaths every year in China and is the cause of widespread concerns in society. Only a small fraction of HFMD cases will develop further into severe HFMD with neurologic complications. A timely and accurate diagnosis of severe HFMD is essential for assessing the risk of progression and planning the appropriate treatment. Human serum can reflect the physiological or pathological states, which is expected to be an excellent source of disease-specific biomarkers. In the present study, a comparative serological proteome analysis between severe HFMD patients and healthy controls was performed via a two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) strategy. Fifteen proteins were identified as differentially expressed in the sera of the severe HFMD patients compared with the controls. The identified proteins were classified into different groups according to their molecular functions, biological processes, protein classes and physiological pathways by bioinformatics analysis. The up-regulations of two identified proteins, serum amyloid A (SAA) and clusterin (CLU), were confirmed in the sera of the HFMD patients by ELISA assay. This study not only increases our background knowledge about and scientific insight into the mechanisms of HFMD, but also reveals novel potential biomarkers for the clinical diagnosis of severe HFMD.
doi:10.1371/journal.pone.0108816
PMCID: PMC4182520  PMID: 25268271
14.  Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4 
Nature genetics  2012;44(11):1231-1235.
Prostate cancer risk–associated variants have been reported in populations of European descent, African-Americans and Japanese using genome-wide association studies (GWAS). To systematically investigate prostate cancer risk–associated variants in Chinese men, we performed the first GWAS in Han Chinese. In addition to confirming several associations reported in other ancestry groups, this study identified two new risk-associated loci for prostate cancer on chromosomes 9q31.2 (rs817826, P = 5.45 × 10−14) and 19q13.4 (rs103294, P = 5.34 × 10−16) in 4,484 prostate cancer cases and 8,934 controls. The rs103294 marker at 19q13.4 is in strong linkage equilibrium with a 6.7-kb germline deletion that removes the first six of seven exons in LILRA3, a gene regulating inflammatory response, and was significantly associated with the mRNA expression of LILRA3 in T cells (P < 1 × 10−4). These findings may advance the understanding of genetic susceptibility to prostate cancer.
doi:10.1038/ng.2424
PMCID: PMC4116636  PMID: 23023329
15.  Pre-existing type 2 diabetes and risk of lung cancer: a report from two prospective cohort studies of 133 024 Chinese adults in urban Shanghai 
BMJ Open  2014;4(7):e004875.
Objectives
Observational studies of type 2 diabetes (T2D) and lung cancer risk are limited and controversial. We thus examined the association between T2D and risk of incident lung cancer using a cohort design.
Setting
Data from two ongoing population-based cohorts (the Shanghai Men's Health Study, SMHS, 2002–2006 and the Shanghai Women's Health Study, SWHS, 1996–2000) were used. Cox proportional-hazards regression models with T2D as a time-varying exposure were modelled to estimate HRs and 95% CIs.
Participants
The study population included 61 491 male participants aged 40–74 years from SMHS and 74 941 female participants aged 40–70 years from SWHS.
Outcome measure
Lung cancer cases were identified through annual record linkage to the Shanghai Cancer Registry and Shanghai Municipal Registry of Vital Statistics, and were further verified through home visits and a review of medical charts by clinical and/or pathological experts. Outcome data until 31 December 2010 for men and women were used for the present analysis.
Results
After a median follow-up of 6.3 years for SMHS and 12.2 years for SWHS, incident lung cancer cases were detected in 492 men and 525 women. A null association between T2D and lung cancer risk was observed in men (HR=0.87, 95% CI 0.62 to 1.21) and women (HR=0.92, 95% CI 0.69 to 1.24) after adjustments for potential confounders. Similar results were observed among never smokers.
Conclusions
There is little evidence that pre-existing T2D may influence the incidence of lung cancer.
doi:10.1136/bmjopen-2014-004875
PMCID: PMC4091264  PMID: 24993754
EPIDEMIOLOGY; ONCOLOGY; PUBLIC HEALTH
16.  Inherent Dynamics of Head Domain Correlates with ATP-Recognition of P2X4 Receptors: Insights Gained from Molecular Simulations 
PLoS ONE  2014;9(5):e97528.
P2X receptors are ATP-gated ion channels involved in many physiological functions, and determination of ATP-recognition (AR) of P2X receptors will promote the development of new therapeutic agents for pain, inflammation, bladder dysfunction and osteoporosis. Recent crystal structures of the zebrafish P2X4 (zfP2X4) receptor reveal a large ATP-binding pocket (ABP) located at the subunit interface of zfP2X4 receptors, which is occupied by a conspicuous cluster of basic residues to recognize triphosphate moiety of ATP. Using the engineered affinity labeling and molecular modeling, at least three sites (S1, S2 and S3) within ABP have been identified that are able to recognize the adenine ring of ATP, implying the existence of at least three distinct AR modes in ABP. The open crystal structure of zfP2X4 confirms one of three AR modes (named AR1), in which the adenine ring of ATP is buried into site S1 while the triphosphate moiety interacts with clustered basic residues. Why architecture of ABP favors AR1 not the other two AR modes still remains unexplored. Here, we examine the potential role of inherent dynamics of head domain, a domain involved in ABP formation, in AR determinant of P2X4 receptors. In silico docking and binding free energy calculation revealed comparable characters of three distinct AR modes. Inherent dynamics of head domain, especially the downward motion favors the preference of ABP for AR1 rather than AR2 and AR3. Along with the downward motion of head domain, the closing movement of loop139–146 and loop169–183, and structural rearrangements of K70, K72, R298 and R143 enabled ABP to discriminate AR1 from other AR modes. Our observations suggest the essential role of head domain dynamics in determining AR of P2X4 receptors, allowing evaluation of new strategies aimed at developing specific blockers/allosteric modulators by preventing the dynamics of head domain associated with both AR and channel activation of P2X4 receptors.
doi:10.1371/journal.pone.0097528
PMCID: PMC4039465  PMID: 24878662
17.  Adenosine A2B receptor modulates intestinal barrier function under hypoxic and ischemia/reperfusion conditions 
Background: Intestinal barrier function failure from ischemia/reperfusion (I/R) and acute hypoxia has been implicated as a critical determinant in the predisposition to intestinal inflammation and a number of inflammatory disorders. Here, we identified the role of Adenosine A2B receptor (A2BAR) in the regulation of intestinal barrier function under I/R and acute hypoxic conditions. Methods: C57BL/6J mice were used, and were randomized into three groups: Sham, I/R, IR+PSB1115 (a specific A2BAR antagonist) groups. After surgery, the small bowel was harvested for immunohistochemical staining, RNA and protein content, and intestinal permeability analyses. Using an epithelial cell culture model, we investigated the influence of hypoxia on the epithelial function, and the role of A2BAR in the expressions of tight junction and epithelial permeability. The expressions of Claudin-1, occludin and ZO-1 were detected by RT-PCR and Western-Blot. Epithelial barrier function was assessed with transepithelial resistance (TER). Results and conclusions: The A2BAR antagonist, PSB1115, significantly increased tight junction protein expression after intestinal I/R or acute hypoxia conditions. PSB1115 also attenuated the disrupted distribution of TJ proteins. Furthermore, inhibition of A2BAR attenuated the decrease in TER induced by I/R or acute hypoxic conditions, and maintained intestinal barrier function. Antagonism of A2BAR activity improves intestinal epithelial structure and barrier function in a mouse model of intestinal I/R and a cell model of acute hypoxia. These findings support a potentially destructive role for A2BAR under intestinal I/R and acute hypoxic conditions.
PMCID: PMC4069946  PMID: 24966910
Ischemia/reperfusion; hypoxia; adenosine A2B receptor; tight junction; claudin-1; occludin; ZO-1; TER
18.  HIV-, HCV-, and Co-Infections and Associated Risk Factors among Drug Users in Southwestern China: A Township-Level Ecological Study Incorporating Spatial Regression 
PLoS ONE  2014;9(3):e93157.
Background
The human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are major public health problems. Many studies have been performed to investigate the association between demographic and behavioral factors and HIV or HCV infection. However, some of the results of these studies have been in conflict.
Methodology/Principal Findings
The data of all entrants in the 11 national methadone clinics in the Yi Autonomous Prefecture from March 2004 to December 2012 were collected from the national database. Several spatial regression models were used to analyze specific community characteristics associated with the prevalence of HIV and HCV infection at the township level. The study enrolled 6,417 adult patients. The prevalence of HIV infection, HCV infection and co-infection was 25.4%, 30.9%, and 11.0%, respectively. Prevalence exhibited stark geographical variations in the area studied. The four regression models showed Yi ethnicity to be associated with both the prevalence of HIV and of HIV/HCV co-infection. The male drug users in some northwestern counties had greater odds of being infected with HIV than female drug users, but the opposite was observed in some eastern counties. The ‘being in drug rehabilitation variable was found to be positively associated with prevalence of HCV infection in some southern townships, however, it was found to be negatively associated with it in some northern townships.
Conclusions/Significance
The spatial modeling creates better representations of data such that public health interventions must focus on areas with high frequency of HIV/HCV to prevent further transmission of both HIV and HCV.
doi:10.1371/journal.pone.0093157
PMCID: PMC3970964  PMID: 24687006
19.  The sequence and de novo assembly of the giant panda genome 
Li, Ruiqiang | Fan, Wei | Tian, Geng | Zhu, Hongmei | He, Lin | Cai, Jing | Huang, Quanfei | Cai, Qingle | Li, Bo | Bai, Yinqi | Zhang, Zhihe | Zhang, Yaping | Wang, Wen | Li, Jun | Wei, Fuwen | Li, Heng | Jian, Min | Li, Jianwen | Zhang, Zhaolei | Nielsen, Rasmus | Li, Dawei | Gu, Wanjun | Yang, Zhentao | Xuan, Zhaoling | Ryder, Oliver A. | Leung, Frederick Chi-Ching | Zhou, Yan | Cao, Jianjun | Sun, Xiao | Fu, Yonggui | Fang, Xiaodong | Guo, Xiaosen | Wang, Bo | Hou, Rong | Shen, Fujun | Mu, Bo | Ni, Peixiang | Lin, Runmao | Qian, Wubin | Wang, Guodong | Yu, Chang | Nie, Wenhui | Wang, Jinhuan | Wu, Zhigang | Liang, Huiqing | Min, Jiumeng | Wu, Qi | Cheng, Shifeng | Ruan, Jue | Wang, Mingwei | Shi, Zhongbin | Wen, Ming | Liu, Binghang | Ren, Xiaoli | Zheng, Huisong | Dong, Dong | Cook, Kathleen | Shan, Gao | Zhang, Hao | Kosiol, Carolin | Xie, Xueying | Lu, Zuhong | Zheng, Hancheng | Li, Yingrui | Steiner, Cynthia C. | Lam, Tommy Tsan-Yuk | Lin, Siyuan | Zhang, Qinghui | Li, Guoqing | Tian, Jing | Gong, Timing | Liu, Hongde | Zhang, Dejin | Fang, Lin | Ye, Chen | Zhang, Juanbin | Hu, Wenbo | Xu, Anlong | Ren, Yuanyuan | Zhang, Guojie | Bruford, Michael W. | Li, Qibin | Ma, Lijia | Guo, Yiran | An, Na | Hu, Yujie | Zheng, Yang | Shi, Yongyong | Li, Zhiqiang | Liu, Qing | Chen, Yanling | Zhao, Jing | Qu, Ning | Zhao, Shancen | Tian, Feng | Wang, Xiaoling | Wang, Haiyin | Xu, Lizhi | Liu, Xiao | Vinar, Tomas | Wang, Yajun | Lam, Tak-Wah | Yiu, Siu-Ming | Liu, Shiping | Zhang, Hemin | Li, Desheng | Huang, Yan | Wang, Xia | Yang, Guohua | Jiang, Zhi | Wang, Junyi | Qin, Nan | Li, Li | Li, Jingxiang | Bolund, Lars | Kristiansen, Karsten | Wong, Gane Ka-Shu | Olson, Maynard | Zhang, Xiuqing | Li, Songgang | Yang, Huanming | Wang, Jian | Wang, Jun
Nature  2009;463(7279):311-317.
Using next-generation sequencing technology alone, we have successfully generated and assembled a draft sequence of the giant panda genome. The assembled contigs (2.25 gigabases (Gb)) cover approximately 94% of the whole genome, and the remaining gaps (0.05 Gb) seem to contain carnivore-specific repeats and tandem repeats. Comparisons with the dog and human showed that the panda genome has a lower divergence rate. The assessment of panda genes potentially underlying some of its unique traits indicated that its bamboo diet might be more dependent on its gut microbiome than its own genetic composition. We also identified more than 2.7 million heterozygous single nucleotide polymorphisms in the diploid genome. Our data and analyses provide a foundation for promoting mammalian genetic research, and demonstrate the feasibility for using next-generation sequencing technologies for accurate, cost-effective and rapid de novo assembly of large eukaryotic genomes.
doi:10.1038/nature08696
PMCID: PMC3951497  PMID: 20010809
20.  Risk Factors for Major Adverse Events of Video-Assisted Thoracic Surgery Lobectomy for Lung Cancer 
Aims: The purpose of this study was to identify the risk factors for major adverse events of VATS (Video-Assisted Thoracic Surgery) lobectomy for primary lung cancer.
Methods: 1806 Patients (1032 males, 57.1%) planned to undergo VATS lobectomy for stage IA-IIIA lung cancer from July 2007 to June 2012. The Thoracic Morbidity and Mortality Classification TM&M system was used to evaluate the presence and severity of complications. Postoperative complications were observed during a 30-day follow up. Univariate and multivariate analysis were used to analyze the independent risk factors for major adverse events.
Results: Successful rate of VATS lobectomy was 97.6% (1763/1806). Major complications occurred in 129 patients (7.3%), with a mortality of 0.3% (5/1763). Pulmonary complications contribute up to 90.7% of the major complications and 80% of mortality. Logistic regression indicated that comorbidities, elder age ≥70y, operative time ≥240min and hybrid VATS were predictors for major adverse events (P<0.05). Hybrid and converted VATS lobectomy result in higher major adverse events compared with complete VATS, 15.1%, 20.9% and 7.4% respectively (P=0.013).
Conclusions: The overall complication rate and mortality of VATS lobectomy are low, while major complications sometimes occur. Pulmonary complications are the most common major complications and cause of mortality. Age ≥70y, comorbidities, operative time ≥240min and Hybrid VATS are predictors of major adverse events.
doi:10.7150/ijms.8912
PMCID: PMC4081307  PMID: 25013365
Non-small cell lung cancer; VATS; Lobectomy; Major Adverse Events; Risk factor
21.  Impact of polysomy 17 on HER2 testing of invasive breast cancer patients 
Background: Current American Society of Clinical Oncology/College of American Pathologists guidelines define HER2-positive tumors as those with > 6 HER2 genes per nucleus or those with HER2/CEP17 (chromosome 17) ratio > 2.2. These guidelines are potentially contradictory in tumors with polysomy of chromosome 17. The current study was performed to determine the impact of polysomy 17 on the interpretation of HER2 testing of invasive breast carcinomas. Methods: Chromosome 17 copies and HER2 gene status were identified by fluorescent in situ hybridization in 384 cases with invasive breast cancer, and the corresponding HER2 expression was obtained by immunohistochemistry stain. Results: The average CEP17 copy number for the group was 2.1 (range, 1.0-12.4). Forty-eight cases (13.8%, 48/348) were identified as chromosome 17 polysomy with CEP 17 copy number ≥ 3. Ninety-two (26.4%) cases had > 6 copies of HER2 per nucleus, and 92 cases (26.4%) qualified as HER2 gene amplified using the HER2/CEP17 ratio (> 2.2) guideline. Polysomy 17 showed poorly positive correlations with both HER2 gene copy number and HER2 overexpression (P < 0.01, r = 0.338 and 0.271, respectively). The distribution of clinicopathologic parameters of Polysomy 17 tumors was more similar to HER2 negative than HER2 positive tumors. Conclusions: Polysomy 17 is a crucial cause of equivocal HER2 testing results by FISH, depending on which criterion (ratio vs. absolute number) is used for interpretation. Polysomy 17 cannot be an independent predictive factor for HER2 gene amplification or protein overexpression.
PMCID: PMC3885470  PMID: 24427336
Chromosome 17; polysomy; breast cancer; human epidermal growth factor receptor (HER2); fluorescence in situ hybridization (FISH); immunohistochemistry (IHC)
22.  Solution-processed small-molecule solar cells: breaking the 10% power conversion efficiency 
Scientific Reports  2013;3:3356.
A two-dimensional conjugated small molecule (SMPV1) was designed and synthesized for high performance solution-processed organic solar cells. This study explores the photovoltaic properties of this molecule as a donor, with a fullerene derivative as an acceptor, using solution processing in single junction and double junction tandem solar cells. The single junction solar cells based on SMPV1 exhibited a certified power conversion efficiency of 8.02% under AM 1.5 G irradiation (100 mW cm−2). A homo-tandem solar cell based on SMPV1 was constructed with a novel interlayer (or tunnel junction) consisting of bilayer conjugated polyelectrolyte, demonstrating an unprecedented PCE of 10.1%. These results strongly suggest solution-processed small molecular materials are excellent candidates for organic solar cells.
doi:10.1038/srep03356
PMCID: PMC3842540  PMID: 24285006
23.  Akt-p53-miR-365-cyclin D1/cdc25A axis contributes to gastric tumorigenesis induced by PTEN deficiency 
Nature Communications  2013;4:2544.
Although PTEN/Akt signaling is frequently deregulated in human gastric cancers, the in vivo causal link between its dysregulation and gastric tumorigenesis has not been established. Here we show that inactivation of PTEN in mouse gastric epithelium initiates spontaneous carcinogenesis with complete penetrance by 2 months of age. Mechanistically, activation of Akt suppresses the abundance of p53, leading to decreased transcription of miR-365, thus causing upregulation of cyclin D1 and cdc25A, which promotes gastric cell proliferation. Importantly, genetic ablation of Akt1 restores miR-365 expression and effectively rescues gastric tumorigenesis in PTEN-mutant mice. Moreover, orthotopic restoration of miR-365 represses PTEN-deficient-induced hyperplasia. In human gastric cancer tissues, miR-365 reduction correlates with poorly differentiated histology, deep invasion and advanced stage, as well as the deregulation of PTEN, phosphorylated Akt, p53, cyclin D1 and cdc25A. These data demonstrate that the PTEN-Akt-p53-miR-365-cyclin D1/cdc25A axis serves as a new mechanism underlying gastric tumorigenesis, providing potential new therapeutic targets.
The PTEN/Akt signalling pathway has been implicated in the pathogenesis of gastric cancer. Here, Guo et al. show that activation of Akt signalling results in the dysregulation of miR-365, which promotes tumorigenesis and that miR-365 reduction correlates with advance-stage tumours in gastric cancer patients.
doi:10.1038/ncomms3544
PMCID: PMC3826643  PMID: 24149576
24.  Identification of Five Serum Protein Markers for Detection of Ovarian Cancer by Antibody Arrays 
PLoS ONE  2013;8(10):e76795.
Background
Protein and antibody arrays have emerged as a promising technology to study protein expression and protein function in a high-throughput manner. These arrays also represent a new opportunity to profile protein expression levels in cancer patients’ samples and to identify useful biosignatures for clinical diagnosis, disease classification, prediction, drug development and patient care. We applied antibody arrays to discover a panel of proteins which may serve as biomarkers to distinguish between patients with ovarian cancer and normal controls.
Methodology/Principal Findings
Using a case-control study design of 34 ovarian cancer patients and 53 age-matched healthy controls, we profiled the expression levels of 174 proteins using antibody array technology and determined the CA125 level using ELISA. The expression levels of those proteins were analyzed using 3 discriminant methods, including artificial neural network, classification tree and split-point score analysis. A panel of 5 serum protein markers (MSP-alpha, TIMP-4, PDGF-R alpha, and OPG and CA125) was identified, which could effectively detect ovarian cancer with high specificity (95%) and high sensitivity (100%), with AUC =0.98, while CA125 alone had an AUC of 0.87.
Conclusions/Significance
Our pilot study has shown the promising set of 5 serum markers for ovarian cancer detection.
doi:10.1371/journal.pone.0076795
PMCID: PMC3792870  PMID: 24116163
25.  The Jagged-2/Notch-1/Hes-1 Pathway Is Involved in Intestinal Epithelium Regeneration after Intestinal Ischemia-Reperfusion Injury 
PLoS ONE  2013;8(10):e76274.
Background
Notch signaling plays a critical role in the maintenance of intestinal crypt epithelial cell proliferation. The aim of this study was to investigate the role of Notch signaling in the proliferation and regeneration of intestinal epithelium after intestinal ischemia reperfusion (I/R) injury.
Methods
Male Sprague-Dawley rats were subjected to sham operation or I/R by occlusion of the superior mesenteric artery (SMA) for 20 min. Intestinal tissue samples were collected at 0, 1, 2, 4, and 6 h after reperfusion. Proliferation of the intestinal epithelium was evaluated by immunohistochemical staining of proliferating nuclear antigen (PCNA). The mRNA and protein expression levels of Notch signaling components were examined using Real-time PCR and Western blot analyses. Immunofluorescence was also performed to detect the expression and location of Jagged-2, cleaved Notch-1, and Hes-1 in the intestine. Finally, the γ-secretase inhibitor DAPT and the siRNA for Jagged-2 and Hes-1 were applied to investigate the functional role of Notch signaling in the proliferation of intestinal epithelial cells in an in vitro IEC-6 culture system.
Results
I/R injury caused increased intestinal crypt epithelial cell proliferation and increased mRNA and protein expression of Jagged-2, Notch-1, and Hes-1. The immunofluorescence results further confirmed increased protein expression of Jagged-2, cleaved Notch-1, and Hes-1 in the intestinal crypts. The inhibition of Notch signaling with DAPT and the suppression of Jagged-2 and Hes-1 expression using siRNA both significantly inhibited the proliferation of IEC-6 cells.
Conclusion
The Jagged-2/Notch-1/Hes-1 signaling pathway is involved in intestinal epithelium regeneration early after I/R injury by increasing crypt epithelial cell proliferation.
doi:10.1371/journal.pone.0076274
PMCID: PMC3789708  PMID: 24098462

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