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1.  Plasmid-based Survivin shRNA and GRIM-19 carried by attenuated Salmonella suppresses tumor cell growth 
Asian Journal of Andrology  2012;14(4):536-545.
Persistent activation of Survivin and its overexpression contribute to the formation, progression and metastasis of several different tumor types. Therefore, Survivin is an ideal target for RNA interference mediated-growth inhibition. Blockade of Survivin using specific short hairpin RNAs (shRNA) can significantly reduce prostate tumor growth. RNA interference does not fully ablate target gene expression, owing to the idiosyncrasies associated with shRNAs and their targets. To enhance the therapeutic efficacy of Survivin-specific shRNA, we employed a combinatorial expression of Survivin-specific shRNA and gene associated with retinoid-interferon-induced mortality-19 (GRIM-19). Then, the GRIM-19 coding sequences and Survivin-specific shRNAs were used to create a dual expression plasmid vector and were carried by an attenuated strain of Salmonella enteric serovar typhimurium (S. typhimurium) to treat prostate cancer in vitro and in vivo. We found that the co-expressed Survivin-specific shRNA and GRIM-19 synergistically and more effectively inhibited prostate tumor proliferation and survival, when compared with treatment with either single agent alone in vitro and in vivo. This study has provided a novel cancer gene therapeutic approach for prostate cancer.
doi:10.1038/aja.2011.179
PMCID: PMC3720080  PMID: 22580637
GRIM-19; prostate cancer; RNAi; Salmonella enterica serovar typhimurium; Survivin; tumor cell growth
2.  Strain Prioritization and Genome Mining for Enediyne Natural Products 
mBio  2016;7(6):e02104-16.
ABSTRACT
The enediyne family of natural products has had a profound impact on modern chemistry, biology, and medicine, and yet only 11 enediynes have been structurally characterized to date. Here we report a genome survey of 3,400 actinomycetes, identifying 81 strains that harbor genes encoding the enediyne polyketide synthase cassettes that could be grouped into 28 distinct clades based on phylogenetic analysis. Genome sequencing of 31 representative strains confirmed that each clade harbors a distinct enediyne biosynthetic gene cluster. A genome neighborhood network allows prediction of new structural features and biosynthetic insights that could be exploited for enediyne discovery. We confirmed one clade as new C-1027 producers, with a significantly higher C-1027 titer than the original producer, and discovered a new family of enediyne natural products, the tiancimycins (TNMs), that exhibit potent cytotoxicity against a broad spectrum of cancer cell lines. Our results demonstrate the feasibility of rapid discovery of new enediynes from a large strain collection.
IMPORTANCE
Recent advances in microbial genomics clearly revealed that the biosynthetic potential of soil actinomycetes to produce enediynes is underappreciated. A great challenge is to develop innovative methods to discover new enediynes and produce them in sufficient quantities for chemical, biological, and clinical investigations. This work demonstrated the feasibility of rapid discovery of new enediynes from a large strain collection. The new C-1027 producers, with a significantly higher C-1027 titer than the original producer, will impact the practical supply of this important drug lead. The TNMs, with their extremely potent cytotoxicity against various cancer cells and their rapid and complete cancer cell killing characteristics, in comparison with the payloads used in FDA-approved antibody-drug conjugates (ADCs), are poised to be exploited as payload candidates for the next generation of anticancer ADCs. Follow-up studies on the other identified hits promise the discovery of new enediynes, radically expanding the chemical space for the enediyne family.
doi:10.1128/mBio.02104-16
PMCID: PMC5181780  PMID: 27999165
3.  Evidence for feasibility of fetal trophoblastic cell‐based noninvasive prenatal testing†  
Prenatal Diagnosis  2016;36(11):1009-1019.
Abstract
Objective
The goal was to develop methods for detection of chromosomal and subchromosomal abnormalities in fetal cells in the mother's circulation at 10–16 weeks' gestation using analysis by array comparative genomic hybridization (CGH) and/or next‐generation sequencing (NGS).
Method
Nucleated cells from 30 mL of blood collected at 10–16 weeks' gestation were separated from red cells by density fractionation and then immunostained to identify cytokeratin positive and CD45 negative trophoblasts. Individual cells were picked and subjected to whole genome amplification, genotyping, and analysis by array CGH and NGS.
Results
Fetal cells were recovered from most samples as documented by Y chromosome PCR, short tandem repeat analysis, array CGH, and NGS including over 30 normal male cells, one 47,XXY cell from an affected fetus, one trisomy 18 cell from an affected fetus, nine cells from a trisomy 21 case, three normal cells and one trisomy 13 cell from a case with confined placental mosaicism, and two chromosome 15 deletion cells from a case known by CVS to have a 2.7 Mb de novo deletion.
Conclusion
We believe that this is the first report of using array CGH and NGS whole genome sequencing to detect chromosomal abnormalities in fetal trophoblastic cells from maternal blood. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
What's already known about this topic? Analysis of cell‐free DNA for noninvasive prenatal testing (NIPT) is widely practiced, and the frequency of amniocentesis and CVS has decreased.However, cell‐free NIPT is not adequate for detecting smaller deletions and duplications with high specificity, sensitivity, and positive predictive value.Although fetal nucleated red blood cells and trophoblastic cells are known to be present in the maternal circulation, it has not been possible to develop a reliable cytogenetic cell‐based form of NIPT.
What does this study add? Fetal cytotrophoblasts were successfully recovered from maternal blood.Although a clinical test has not been validated, for the first time, the feasibility of using array comparative genomic hybridization and next generation sequencing to detect chromosomal and subchromosomal abnormalities is demonstrated.The results suggest the possibility of developing a cell‐based form of NIPT with ability to detect abnormalities with a similar accuracy as can currently be obtained with amniocentesis and CVS.
doi:10.1002/pd.4924
PMCID: PMC5129580  PMID: 27616633
4.  Associations of blood lead levels with reproductive hormone levels in men and postmenopausal women: Results from the SPECT-China Study 
Scientific Reports  2016;6:37809.
We examined whether blood lead levels (BLLs) were associated with reproductive hormone levels in a cross-sectional study using data from the SPECT-China study. We selected 2286 men and 1571 postmenopausal women without hormone replacement therapy. BLLs, blood cadmium, total testosterone (TT), oestradiol (E2), luteinizing hormone (LH), follicle stimulating hormone (FSH) and sex hormone binding globulin(SHBG) levels were measured. The results showed that median values (interquartile range) of BLLs were 44.00 μg/L (29.00–62.30) for men and 41.00 μg/L (27.00–59.81) for postmenopausal women. In linear regression, after adjusting for age, current smoking status, body mass index, systolic blood pressure, diabetes and blood cadmium level, TT (P for trend = 0.001) and SHBG (P for trend < 0.001) levels were still positively associated with BLLs in men. Meanwhile, significant positive associations were found for BLLs with SHBG (P for trend = 0.002), FSH (P for trend = 0.001) and LH (P for trend = 0.026) levels in postmenopausal women. Additionally, the association between BLL and SHBG was modified by dysglycaemia (P for interaction = 0.03) in postmenopausal women. In conclusion, BLLs were associated with reproductive hormone levels in the general population of Chinese men and postmenopausal women, which may have important implications for human health. Concerted efforts to reduce adult lead exposure are warranted.
doi:10.1038/srep37809
PMCID: PMC5127181  PMID: 27898110
5.  Gene polymorphisms of pathogenic Helicobacter pylori in patients with different types of gastrointestinal diseases 
World Journal of Gastroenterology  2016;22(44):9718-9726.
Helicobacter pylori (H. pylori) is a kind of chronic infectious pathogen which can cause chronic gastritis, peptic ulcer, gastric cancer and other diseases. The genetic structure of the pathogenic genes of H. pylori varies largely, which contributes to the differences in virulence among various strains, and in clinical symptoms. Virulence genes of H. pylori can be categorized into three main classes: those related to adhesion and colonization, those related to gastric mucosal injury, and others. This review focuses on the relationship between genetic polymorphisms of the three classes of virulence genes of H. pylori and diseases. Most of the genetic polymorphisms of the main virulence factors of H. pylori are summarized in this paper.
doi:10.3748/wjg.v22.i44.9718
PMCID: PMC5124976  PMID: 27956795
Helicobacter pylori; Pathogenic gene; Polymorphism; Gastrointestinal disease
6.  An intrinsic agonist mechanism for activation of glucagon-like peptide-1 receptor by its extracellular domain 
Cell Discovery  2016;2:16042-.
The glucagon-like peptide-1 receptor is a class B G protein coupled receptor (GPCR) that plays key roles in glucose metabolism and is a major therapeutic target for diabetes. The classic two-domain model for class B GPCR activation proposes that the apo-state receptor is auto-inhibited by its extracellular domain, which physically interacts with the transmembrane domain. The binding of the C-terminus of the peptide hormone to the extracellular domain allows the N-terminus of the hormone to insert into the transmembrane domain to induce receptor activation. In contrast to this model, here we demonstrate that glucagon-like peptide-1 receptor can be activated by N-terminally truncated glucagon-like peptide-1 or exendin-4 when fused to the receptor, raising the question regarding the role of N-terminal residues of peptide hormone in glucagon-like peptide-1 receptor activation. Mutations of cysteine 347 to lysine or arginine in intracellular loop 3 transform the receptor into a G protein-biased receptor and allow it to be activated by a nonspecific five-residue linker that is completely devoid of exendin-4 or glucagon-like peptide-1 sequence but still requires the presence of an intact extracellular domain. Moreover, the extracellular domain can activate the receptor in trans in the presence of an intact peptide hormone, and specific mutations in three extracellular loops abolished this extracellular domain trans-activation. Together, our data reveal a dominant role of the extracellular domain in glucagon-like peptide-1 receptor activation and support an intrinsic agonist model of the extracellular domain, in which peptide binding switches the receptor from the auto-inhibited state to the auto-activated state by releasing the intrinsic agonist activity of the extracellular domain.
doi:10.1038/celldisc.2016.42
PMCID: PMC5118412  PMID: 27917297
GLP-1R; class B GPCR; intrinsic agonist; glucagon-like peptide-1; exendin-4; BETP
7.  5th International Symposium on Focused Ultrasound 
Zaaroor, Menashe | Sinai, Alon | Goldsher, Dorit | Eran, Ayelet | Nassar, Maria | Schlesinger, Ilana | Parker, Jonathon | Ravikumar, Vinod | Ghanouni, Pejman | Stein, Sherman | Halpern, Casey | Krishna, Vibhor | Hargrove, Amelia | Agrawal, Punit | Changizi, Barbara | Bourekas, Eric | Knopp, Michael | Rezai, Ali | Mead, Brian | Kim, Namho | Mastorakos, Panagiotis | Suk, Jung Soo | Miller, Wilson | Klibanov, Alexander | Hanes, Justin | Price, Richard | Wang, Shutao | Olumolade, Oluyemi | Kugelman, Tara | Jackson-Lewis, Vernice | Karakatsani, Maria Eleni (Marilena) | Han, Yang | Przedborski, Serge | Konofagou, Elisa | Hynynen, Kullervo | Aubert, Isabelle | Leinenga, Gerhard | Nisbet, Rebecca | Hatch, Robert | Van der Jeugd, Anneke | Evans, Harrison | Götz, Jürgen | Götz, Jürgen | Nisbet, Rebecca | Van der Jeugd, Ann | Evans, Harrison | Leinenga, Gerhard | Fishman, Paul | Yarowsky, Paul | Frenkel, Victor | Wei-Bin, Shen | Nguyen, Ben | Sanchez, Carlos Sierra | Acosta, Camilo | Chen, Cherry | Wu, Shih-Ying | Karakatsani, Maria Eleni (Marilena) | Konofagou, Elisa | Aryal, Muna | Papademetriou, Iason T. | Zhang, Yong-Zhi | Power, Chanikarn | McDannold, Nathan | Porter, Tyrone | Kovacs, Zsofia | Kim, Saejeong | Jikaria, Neekita | Qureshi, Farhan | Bresler, Michele | Frank, Joseph | Odéen, Henrik | Chiou, George | Snell, John | Todd, Nick | Madore, Bruno | Parker, Dennis | Pauly, Kim Butts | Marx, Mike | Ghanouni, Pejman | Jonathan, Sumeeth | Grissom, William | Arvanitis, Costas | McDannold, Nathan | Clement, Gregory | Parker, Dennis | de Bever, Joshua | Odéen, Henrik | Payne, Allison | Christensen, Douglas | Maimbourg, Guillaume | Santin, Mathieu David | Houdouin, Alexandre | Lehericy, Stéphane | Tanter, Mickael | Aubry, Jean Francois | Pauly, Kim Butts | Federau, Christian | Werner, Beat | Halpern, Casey | Ghanouni, Pejman | Paeng, Dong-Guk | Xu, Zhiyuan | Snell, John | Quigg, Anders | Eames, Matt | Jin, Changzhu | Everstine, Ashli | Sheehan, Jason | Lopes, M. Beatriz | Kassell, Neal | Snell, John | Quigg, Anders | Drake, James | Price, Karl | Lustgarten, Lior | Sin, Vivian | Mougenot, Charles | Donner, Elizabeth | Tam, Emily | Hodaie, Mojgan | Waspe, Adam | Looi, Thomas | Pichardo, Samuel | Lee, Wonhye | Chung, Yong An | Jung, Yujin | Song, In-Uk | Yoo, Seung-Schik | Lee, Wonhye | Kim, Hyun-Chul | Jung, Yujin | Chung, Yong An | Song, In-Uk | Lee, Jong-Hwan | Yoo, Seung-Schik | Caskey, Charles | Zinke, Wolf | Cosman, Josh | Shuman, Jillian | Schall, Jeffrey | Aurup, Christian | Wang, Shutao | Chen, Hong | Acosta, Camilo | Konofagou, Elisa | Kamimura, Hermes | Carneiro, Antonio | Todd, Nick | Sun, Tao | Zhang, Yong-Zhi | Power, Chanikarn | Nazai, Navid | Patz, Sam | Livingstone, Margaret | McDannold, Nathan | Mainprize, Todd | Huang, Yuexi | Alkins, Ryan | Chapman, Martin | Perry, James | Lipsman, Nir | Bethune, Allison | Sahgal, Arjun | Trudeau, Maureen | Hynynen, Kullervo | Liu, Hao-Li | Hsu, Po-Hung | Wei, Kuo-Chen | Sun, Tao | Power, Chanikarn | Zhang, Yong-Zhi | Sutton, Jonathan | Alexander, Phillip | Aryal, Muna | Miller, Eric | McDannold, Nathan | Kobus, Thiele | Zhang, Yong-Zhi | McDannold, Nathan | Carpentier, Alexandre | Canney, Michael | Vignot, Alexandre | Beccaria, Kevin | Leclercq, Delphine | Lafon, Cyril | Chapelon, Jean Yves | Hoang-Xuan, Khe | Delattre, Jean-Yves | Idbaih, Ahmed | Xu, Zhiyuan | Moore, David | Xu, Alexis | Schmitt, Paul | Snell, John | Foley, Jessica | Eames, Matt | Sheehan, Jason | Kassell, Neal | Sukovich, Jonathan | Cain, Charles | Xu, Zhiyuan | Pandey, Aditya | Snell, John | Chaudhary, Neeraj | Camelo-Piragua, Sandra | Allen, Steven | Paeng, Dong-Guk | Cannata, Jon | Teofilovic, Dejan | Bertolina, Jim | Kassell, Neal | Hall, Timothy | Xu, Zhen | Wu, Shih-Ying | Karakatsani, Maria Eleni (Marilena) | Grondin, Julien | Sanchez, Carlos Sierra | Ferrera, Vincent | Konofagou, Elisa | ter Haar, Gail | Mouratidis, Petros | Repasky, Elizabeth | Timbie, Kelsie | Badr, Lena | Campbell, Benjamin | McMichael, John | Buckner, Andrew | Prince, Jessica | Stevens, Aaron | Bullock, Timothy | Price, Richard | Skalina, Karin | Guha, Chandan | Orsi, Franco | Bonomo, Guido | Vigna, Paolo Della | Mauri, Giovanni | Varano, Gianluca | Schade, George | Wang, Yak-Nam | Pillarisetty, Venu | Hwang, Joo Ha | Khokhlova, Vera | Bailey, Michael | Khokhlova, Tatiana | Khokhlova, Vera | Sinilshchikov, Ilya | Yuldashev, Petr | Andriyakhina, Yulia | Kreider, Wayne | Maxwell, Adam | Khokhlova, Tatiana | Sapozhnikov, Oleg | Partanen, Ari | Lundt, Jonathan | Allen, Steven | Sukovich, Jonathan | Hall, Timothy | Cain, Charles | Xu, Zhen | Preusser, Tobias | Haase, Sabrina | Bezzi, Mario | Jenne, Jürgen | Langø, Thomas | Midiri, Massimo | Mueller, Michael | Sat, Giora | Tanner, Christine | Zangos, Stephan | Guenther, Matthias | Melzer, Andreas | Menciassi, Arianna | Tognarelli, Selene | Cafarelli, Andrea | Diodato, Alessandro | Ciuti, Gastone | Rothluebbers, Sven | Schwaab, Julia | Strehlow, Jan | Mihcin, Senay | Tanner, Christine | Tretbar, Steffen | Preusser, Tobias | Guenther, Matthias | Jenne, Jürgen | Payen, Thomas | Palermo, Carmine | Sastra, Steve | Chen, Hong | Han, Yang | Olive, Kenneth | Konofagou, Elisa | Adams, Matthew | Salgaonkar, Vasant | Scott, Serena | Sommer, Graham | Diederich, Chris | Vidal-Jove, Joan | Perich, Eloi | Ruiz, Antonio | Velat, Manuela | Melodelima, David | Dupre, Aurelien | Vincenot, Jeremy | Yao, Chen | Perol, David | Rivoire, Michel | Tucci, Samantha | Mahakian, Lisa | Fite, Brett | Ingham, Elizabeth | Tam, Sarah | Hwang, Chang-il | Tuveson, David | Ferrara, Katherine | Scionti, Stephen | Chen, Lili | Cvetkovic, Dusica | Chen, Xiaoming | Gupta, Roohi | Wang, Bin | Ma, Charlie | Bader, Kenneth | Haworth, Kevin | Maxwell, Adam | Holland, Christy | Sanghvi, Narendra | Carlson, Roy | Chen, Wohsing | Chaussy, Christian | Thueroff, Stefan | Cesana, Claudio | Bellorofonte, Carlo | Wang, Qingguo | Wang, Han | Wang, Shengping | Zhang, Junhai | Bazzocchi, Alberto | Napoli, Alessandro | Staruch, Robert | Bing, Chenchen | Shaikh, Sumbul | Nofiele, Joris | Szczepanski, Debra | Staruch, Michelle Wodzak | Williams, Noelle | Laetsch, Theodore | Chopra, Rajiv | Ghanouni, Pejman | Rosenberg, Jarrett | Bitton, Rachelle | Napoli, Alessandro | LeBlang, Suzanne | Meyer, Joshua | Hurwitz, Mark | Pauly, Kim Butts | Partanen, Ari | Yarmolenko, Pavel | Partanen, Ari | Celik, Haydar | Eranki, Avinash | Beskin, Viktoriya | Santos, Domiciano | Patel, Janish | Oetgen, Matthew | Kim, AeRang | Kim, Peter | Sharma, Karun | Chisholm, Alexander | Drake, James | Aleman, Dionne | Waspe, Adam | Looi, Thomas | Pichardo, Samuel | Napoli, Alessandro | Bazzocchi, Alberto | Scipione, Roberto | Temple, Michael | Waspe, Adam | Amaral, Joao Guilherme | Huang, Yuexi | Endre, Ruby | Lamberti-Pasculli, Maria | de Ruiter, Joost | Campbell, Fiona | Stimec, Jennifer | Gupta, Samit | Singh, Manoj | Mougenot, Charles | Hopyan, Sevan | Hynynen, Kullervo | Czarnota, Gregory | Drake, James | Brenin, David | Rochman, Carrie | Kovatcheva, Roussanka | Vlahov, Jordan | Zaletel, Katja | Stoinov, Julian | Han, Yang | Wang, Shutao | Konofagou, Elisa | Bucknor, Matthew | Rieke, Viola | Shim, Jenny | Staruch, Robert | Koral, Korgun | Chopra, Rajiv | Laetsch, Theodore | Lang, Brian | Wong, Carlos | Lam, Heather | Kovatcheva, Roussanka | Vlahov, Jordan | Zaletel, Katja | Stoinov, Julian | Shinkov, Alexander | Hu, Jim | Sharma, Karun | Zhang, Xi | Macoskey, Jonathan | Ives, Kimberly | Owens, Gabe | Gurm, Hitinder | Shi, Jiaqi | Pizzuto, Matthew | Cain, Charles | Xu, Zhen | Payne, Allison | Dillon, Christopher | Christofferson, Ivy | Hilas, Elaine | Shea, Jill | Greillier, Paul | Ankou, Bénédicte | Bessière, Francis | Zorgani, Ali | Pioche, Mathieu | Kwiecinski, Wojciech | Magat, Julie | Melot-Dusseau, Sandrine | Lacoste, Romain | Quesson, Bruno | Pernot, Mathieu | Catheline, Stefan | Chevalier, Philippe | Lafon, Cyril | Marquet, Fabrice | Bour, Pierre | Vaillant, Fanny | Amraoui, Sana | Dubois, Rémi | Ritter, Philippe | Haïssaguerre, Michel | Hocini, Mélèze | Bernus, Olivier | Quesson, Bruno | Tebebi, Pamela | Burks, Scott | Kim, Saejeong | Milo, Blerta | Frank, Joseph | Gertner, Michael | Zhang, Jimin | Wong, Andrew | Fite, Brett | Liu, Yu | Kheirolomoom, Azadeh | Seo, Jai | Watson, Katherine | Mahakian, Lisa | Tam, Sarah | Zhang, Hua | Foiret, Josquin | Borowsky, Alexander | Ferrara, Katherine | Xu, Doudou | Melzer, Andreas | Thanou, Maya | Centelles, Miguell | Wright, Mike | Amrahli, Maral | So, Po-Wah | Gedroyc, Wladyslaw | Centelles, Miguell | Wright, Mike | Gedroyc, Wladyslaw | Thanou, Maya | Kneepkens, Esther | Heijman, Edwin | Keupp, Jochen | Weiss, Steffen | Nicolay, Klaas | Grüll, Holger | Fite, Brett | Wong, Andrew | Liu, Yu | Kheirolomoom, Azadeh | Mahakian, Lisa | Tam, Sarah | Foiret, Josquin | Ferrara, Katherine | Burks, Scott | Nagle, Matthew | Kim, Saejeong | Milo, Blerta | Frank, Joseph | Sapozhnikov, Oleg | Nikolaeva, Anastasia V. | Terzi, Marina E. | Tsysar, Sergey A. | Maxwell, Adam | Cunitz, Bryan | Bailey, Michael | Mourad, Pierre | Downs, Matthew | Yang, Georgiana | Wang, Qi | Konofagou, Elisa | Burks, Scott | Nagle, Matthew | Nguyen, Ben | Bresler, Michele | Kim, Saejeong | Milo, Blerta | Frank, Joseph | Burks, Scott | Nagle, Matthew | Kim, Saejeong | Milo, Blerta | Frank, Joseph | Chen, Johnny | Farry, Justin | Dixon, Adam | Du, Zhongmin | Dhanaliwala, Ali | Hossack, John | Klibanov, Alexander | Ranjan, Ashish | Maples, Danny | Chopra, Rajiv | Bing, Chenchen | Staruch, Robert | Wardlow, Rachel | Staruch, Michelle Wodzak | Malayer, Jerry | Ramachandran, Akhilesh | Nofiele, Joris | Namba, Hirofumi | Kawasaki, Motohiro | Izumi, Masashi | Kiyasu, Katsuhito | Takemasa, Ryuichi | Ikeuchi, Masahiko | Ushida, Takahiro | Crake, Calum | Papademetriou, Iason T. | Zhang, Yong-Zhi | Porter, Tyrone | McDannold, Nathan | Kothapalli, Satya V. V. N. | Leighton, Wan | Wang, Zhaorui | Partanen, Ari | Gach, H. Michael | Straube, William | Altman, Michael | Chen, Hong | Kim, Young-sun | Lim, Hyo Keun | Rhim, Hyunchul | Kim, Young-sun | Lim, Hyo Keun | Rhim, Hyunchul | van Breugel, Johanna | Braat, Manon | Moonen, Chrit | van den Bosch, Maurice | Ries, Mario | Marrocchio, Cristina | Dababou, Susan | Bitton, Rachelle | Pauly, Kim Butts | Ghanouni, Pejman | Lee, Jae Young | Lee, Jae Young | Chung, Hyun Hoon | Kang, Soo Yeon | Kang, Kook Jin | Son, Keon Ho | Zhang, Dandan | Adams, Matthew | Salgaonkar, Vasant | Plata, Juan | Jones, Peter | Pascal-Tenorio, Aurea | Bouley, Donna | Sommer, Graham | Pauly, Kim Butts | Diederich, Chris | Bond, Aaron | Dallapiazza, Robert | Huss, Diane | Warren, Amy | Sperling, Scott | Gwinn, Ryder | Shah, Binit | Elias, W. Jeff | Curley, Colleen | Zhang, Ying | Negron, Karina | Miller, Wilson | Klibanov, Alexander | Abounader, Roger | Suk, Jung Soo | Hanes, Justin | Price, Richard | Karakatsani, Maria Eleni (Marilena) | Samiotaki, Gesthimani | Wang, Shutao | Kugelman, Tara | Acosta, Camilo | Konofagou, Elisa | Kovacs, Zsofia | Tu, Tsang-Wei | Papadakis, Georgios | Hammoud, Dima | Frank, Joseph | Silvestrini, Matthew | Wolfram, Frank | Güllmar, Daniel | Reichenbach, Juergen | Hofmann, Denis | Böttcher, Joachim | Schubert, Harald | Lesser, Thomas G. | Almquist, Scott | Parker, Dennis | Christensen, Douglas | Camarena, Francisco | Jiménez-Gambín, Sergio | Jiménez, Noé | Konofagou, Elisa | Chang, Jin Woo | Chaplin, Vandiver | Griesenauer, Rebekah | Miga, Michael | Caskey, Charles | Ellens, Nicholas | Airan, Raag | Quinones-Hinojosa, Alfredo | Farahani, Keyvan | Partanen, Ari | Feng, Xue | Fielden, Samuel | Zhao, Li | Miller, Wilson | Wintermark, Max | Pauly, Kim Butts | Meyer, Craig | Guo, Sijia | Lu, Xin | Zhuo, Jiachen | Xu, Su | Gullapalli, Rao | Gandhi, Dheeraj | Jin, Changzhu | Brokman, Omer | Eames, Matt | Snell, John | Paeng, Dong-Guk | Baek, Hongchae | Kim, Hyungmin | Leung, Steven | Webb, Taylor | Pauly, Kim Butts | McDannold, Nathan | Zhang, Yong-Zhi | Vykhodtseva, Natalia | Nguyen, Thai-Son | Sukovich, Jonathan | Hall, Timothy | Xu, Zhen | Cain, Charles | Park, Chang Kyu | Park, Sang Man | Jung, Na Young | Kim, Min Soo | Chang, Won Seok | Jung, Hyun Ho | Chang, Jin Woo | Pichardo, Samuel | Hynynen, Kullervo | Plaksin, Michael | Weissler, Yoni | Shoham, Shy | Kimmel, Eitan | Quigg, Anders | Snell, John | Paeng, Dong-Guk | Eames, Matt | Sapozhnikov, Oleg | Rosnitskiy, Pavel B. | Khokhlova, Vera | Shoham, Shy | Krupa, Steve | Hazan, Eilon | Naor, Omer | Levy, Yoav | Maimon, Noam | Brosh, Inbar | Kimmel, Eitan | Kahn, Itamar | Sukovich, Jonathan | Xu, Zhen | Hall, Timothy | Allen, Steven | Cain, Charles | Cahill, Jessica | Sun, Tao | Zhang, Yong-Zhi | Power, Chanikarn | Livingstone, Margaret | McDannold, Nathan | Todd, Nick | Colas, Elodie Constanciel | Wydra, Adrian | Waspe, Adam | Looi, Thomas | Maev, Roman | Pichardo, Samuel | Drake, James | Aly, Amirah | Sun, Tao | Zhang, Yong-Zhi | Sesenoglu-Laird, Ozge | Padegimas, Linas | Cooper, Mark | McDannold, Nathan | Waszczak, Barbara | Tehrani, Seruz | Miller, Wilson | Slingluff, Craig | Larner, James | Andarawewa, Kumari | Bucknor, Matthew | Ozhinsky, Eugene | Shah, Rutwik | Krug, Roland | Rieke, Viola | Deckers, Roel | Linn, Sabine | Suelmann, Britt | Braat, Manon | Witkamp, Arjen | Vaessen, Paul | van Diest, Paul | Bartels, Lambertus W. | Bos, Clemens | van den Bosch, Maurice | Borys, Nicolas | Storm, Gert | Van der Wall, Elsken | Moonen, Chrit | Farr, Navid | Alnazeer, Moez | Yarmolenko, Pavel | Katti, Prateek | Partanen, Ari | Eranki, Avinash | Kim, Peter | Wood, Bradford | Farrer, Alexis | Almquist, Scott | Dillon, Christopher | Parker, Dennis | Christensen, Douglas | Payne, Allison | Ferrer, Cyril | Bartels, Lambertus W. | de Senneville, Baudouin Denis | van Stralen, Marijn | Moonen, Chrit | Bos, Clemens | Liu, Yu | Liu, Jingfei | Fite, Brett | Foiret, Josquin | Leach, J. Kent | Ferrara, Katherine | Gupta, Roohi | Cvetkovic, Dusica | Ma, Charlie | Chen, Lili | Haase, Sabrina | Zidowitz, Stephan | Melzer, Andreas | Preusser, Tobias | Lee, Hsin-Lun | Hsu, Fang-Chi | Kuo, Chia-Chun | Jeng, Shiu-Chen | Chen, Tung-Ho | Yang, Nai-Yi | Chiou, Jeng-Fong | Jeng, Shiu-Chen | Kao, Yi-tzu | Pan, Chia-Hsin | Wu, Jing-Fu | Chen, Tung-Ho | Hsu, Fang-Chi | Lee, Hsin-Lun | Chiou, Jeng-Fong | Hsu, Fang-Chi | Tsai, Yi-Chieh | Lee, Hsin-Lun | Chiou, Jeng-Fong | Johnson, Sara | Parker, Dennis | Payne, Allison | Li, Dawei | He, Ye | Mihcin, Senay | Karakitsios, Ioannis | Strehlow, Jan | Schwenke, Michael | Haase, Sabrina | Demedts, Daniel | Levy, Yoav | Preusser, Tobias | Melzer, Andreas | Mihcin, Senay | Rothluebbers, Sven | Karakitsios, Ioannis | Xiao, Xu | Strehlow, Jan | Demedts, Daniel | Cavin, Ian | Sat, Giora | Preusser, Tobias | Melzer, Andreas | Minalga, Emilee | Payne, Allison | Merrill, Robb | Parker, Dennis | Hadley, Rock | Ramaekers, Pascal | Ries, Mario | Moonen, Chrit | de Greef, Martijn | Shahriari, Kian | Parvizi, Mohammad Hossein | Asadnia, Kiana | Chamanara, Marzieh | Kamrava, Seyed Kamran | Chabok, Hamid Reza | Schwenke, Michael | Strehlow, Jan | Demedts, Daniel | Tanner, Christine | Rothluebbers, Sven | Preusser, Tobias | Strehlow, Jan | Stein, Ruben | Demedts, Daniel | Schwenke, Michael | Rothluebbers, Sven | Preusser, Tobias | Demedts, Daniel | Haase, Sabrina | Muller, Sébastien | Strehlow, Jan | Langø, Thomas | Preusser, Tobias | Tan, Jeremy | Zachiu, Cornel | Ramaekers, Pascal | Moonen, Chrit | Ries, Mario | Wolfram, Frank | Güllmar, Daniel | Schubert, Harald | Lesser, Thomas G. | Erasmus, Hans-Peter | Colas, Elodie Constanciel | Waspe, Adam | Mougenot, Charles | Looi, Thomas | Van Arsdell, Glen | Benson, Lee | Drake, James | Jang, Kee W. | Tu, Tsang-Wei | Jikaria, Neekita | Nagle, Matthew | Angstadt, Mary | Lewis, Bobbi | Qureshi, Farhan | Burks, Scott | Frank, Joseph | McLean, Hailey | Payne, Allison | Hoogenboom, Martijn | Eikelenboom, Dylan | den Brok, Martijn | Wesseling, Pieter | Heerschap, Arend | Fütterer, Jurgen | Adema, Gosse | Wang, Kevin | Zhang, Ying | Zhong, Pei | Xiao, Xu | Joy, Joyce | McLeod, Helen | Melzer, Andreas | Bing, Chenchen | Staruch, Robert | Nofiele, Joris | Szczepanski, Debra | Staruch, Michelle Wodzak | Laetsch, Theodore | Chopra, Rajiv | Bing, Chenchen | Staruch, Robert | Yarmolenko, Pavel | Celik, Haydar | Nofiele, Joris | Szczepanski, Debra | Kim, Peter | Kim, Harry | Lewis, Matthew | Chopra, Rajiv | Shah, Rutwik | Ozhinsky, Eugene | Rieke, Viola | Bucknor, Matthew | Diederich, Chris | Salgaonkar, Vasant | Jones, Peter | Adams, Matthew | Ozilgen, Arda | Zahos, Peter | Coughlin, Dezba | Tang, Xinyan | Lotz, Jeff | Jedruszczuk, Kathleen | Gulati, Amitabh | Solomon, Stephen | Kaye, Elena | Fielden, Samuel | Mugler, John | Miller, Wilson | Pauly, Kim Butts | Meyer, Craig | Barbato, Gaetano | Scoarughi, Gian Luca | Corso, Cristiano | Gorgone, Alessandro | Migliore, Ilaria Giuseppina | Larrabee, Zachary | Hananel, Arik | Eames, Matt | Aubry, Jean-Francois | Eranki, Avinash | Farr, Navid | Partanen, Ari | Sharma, Karun | Yarmolenko, Pavel | Wood, Bradford | Kim, Peter | Farr, Navid | Kothapalli, Satya V. V. N. | Eranki, Avinash | Negussie, Ayele | Wilson, Emmanuel | Seifabadi, Reza | Kim, Peter | Chen, Hong | Wood, Bradford | Partanen, Ari | Moon, Hyungwon | Kang, Jeeun | Sim, Changbeom | Chang, Jin Ho | Kim, Hyuncheol | Lee, Hak Jong | Sasaki, Noboru | Takiguchi, Mitsuyoshi | Sebeke, Lukas | Luo, Xi | de Jager, Bram | Heemels, Maurice | Heijman, Edwin | Grüll, Holger | Strehlow, Jan | Schwenke, Michael | Demedts, Daniel | Preusser, Tobias
Journal of Therapeutic Ultrasound  2016;4(Suppl 1):1-113.
doi:10.1186/s40349-016-0076-5
PMCID: PMC5123388
8.  Induced Pluripotent Stem Cells Inhibit Bleomycin-Induced Pulmonary Fibrosis in Mice through Suppressing TGF-β1/Smad-Mediated Epithelial to Mesenchymal Transition 
Pulmonary fibrosis is a progressive and irreversible fibrotic lung disorder with high mortality and few treatment options. Recently, induced pluripotent stem (iPS) cells have been considered as an ideal resource for stem cell-based therapy. Although, an earlier study demonstrated the therapeutic effect of iPS cells on pulmonary fibrosis, the exact mechanisms remain obscure. The present study investigated the effects of iPS cells on inflammatory responses, transforming growth factor (TGF)-β1 signaling pathway, and epithelial to mesenchymal transition (EMT) during bleomycin (BLM)-induced lung fibrosis. A single intratracheal instillation of BLM (5 mg/kg) was performed to induce pulmonary fibrosis in C57BL/6 mice. Then, iPS cells (c-Myc-free) were administrated intravenously at 24 h following BLM instillation. Three weeks after BLM administration, pulmonary fibrosis was evaluated. As expected, treatment with iPS cells significantly limited the pathological changes, edema, and collagen deposition in lung tissues of BLM-induced mice. Mechanically, treatment with iPS cells obviously repressed the expression ratios of matrix metalloproteinase-2 (MMP-2) to its tissue inhibitor -2 (TIMP-2) and MMP-9/TIMP-1 in BLM-induced pulmonary tissues. In addition, iPS cell administration remarkably suppressed BLM-induced up-regulation of pulmonary inflammatory mediators, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, inducible nitric oxide synthase, nitric oxide, cyclooxygenase-2 and prostaglandin E2. We further demonstrated that transplantation of iPS cells markedly inhibited BLM-mediated activation of TGF-β1/Mothers against decapentaplegic homolog 2/3 (Smad2/3) and EMT in lung tissues through up-regulating epithelial marker E-cadherin and down-regulating mesenchymal markers including fibronectin, vimentin and α-smooth muscle actin. Moreover, in vitro, iPS cell-conditioned medium (iPSC-CM) profoundly inhibited TGF-β1-induced EMT signaling pathway in mouse alveolar epithelial type II cells (AECII). Collectively, our results suggest that transplantation of iPS cells could suppress inflammatory responses, TGF-β1/Smad2/3 pathway and EMT during the progression of BLM-induced pulmonary fibrosis, providing new useful clues regarding the mechanisms of iPS cells in the treatment for this disease.
doi:10.3389/fphar.2016.00430
PMCID: PMC5108931  PMID: 27895584
bleomycin; epithelial to mesenchymal transition (EMT); induced pluripotent stem (iPS) cells; inflammation; pulmonary fibrosis; TGF-β1
9.  Functional Analysis of the Pathogenicity-Related Gene VdPR1 in the Vascular Wilt Fungus Verticillium dahliae 
PLoS ONE  2016;11(11):e0166000.
Verticillium dahliae Kleb., the causal agent of vascular wilt, can seriously diminish the yield and quality of many crops, including cotton. The pathogenic mechanism to cotton is complicated and unclear now. To screen pathogencity related genes and identify their function is the reliable way to explain the mechanism. In this study, we obtained a low-pathogenicity mutant vdpr1 from a T-DNA insertional library of the highly virulent isolate of V. dahliae Vd080, isolated from cotton. The tagged gene was named pathogenicity-related gene (VdPR1). The deletion mutant ΔVdPR1 did not form microsclerotia and showed a drastic reduction in spore yield and mycelial growth, compared to wild type. Also, ΔVdPR1 showed significantly lower protease and cellulase activities than those of wild type. Complementation of the mutant strain with VdPR1 (strain ΔVdPR1-C) almost completely rescued the attributes described above to wild-type levels. The knockout mutant ΔVdPR1 showed delayed infection, caused mild disease symptoms, formed a smaller biomass in roots of the host, and showed compromised systemic invasive growth in the xylem. These results suggest that VdPR1 is a multifaceted gene involved in regulating the growth development, early infection and pathogenicity of V. dahliae.
doi:10.1371/journal.pone.0166000
PMCID: PMC5112940  PMID: 27846253
10.  Rapid 3D Dynamic Arterial Spin Labeling with a Sparse Model-Based Image Reconstruction 
NeuroImage  2015;121:205-216.
Dynamic arterial spin labeling (ASL) MRI measures the perfusion bolus at multiple observation times and yields accurate estimates of cerebral blood flow in the presence of variations in arterial transit time. ASL has intrinsically low signal-to-noise ratio (SNR) and is sensitive to motion, so that extensive signal averaging is typically required, leading to long scan times for dynamic ASL. The goal of this study was to develop an accelerated dynamic ASL method with improved SNR and robustness to motion using a model-based image reconstruction that exploits the inherent sparsity of dynamic ASL data. The first component of this method is a single-shot 3D turbo spin echo spiral pulse sequence accelerated using a combination of parallel imaging and compressed sensing. This pulse sequence was then incorporated into a dynamic pseudo continuous ASL acquisition acquired at multiple observation times, and the resulting images were jointly reconstructed enforcing a model of potential perfusion time courses. Performance of the technique was verified using a numerical phantom and validated on normal volunteers on a 3-Tesla scanner. In simulation, a spatial sparsity constraint improved SNR and reduced estimation errors. Combined with a model-based sparsity constraint, the proposed method further improved SNR, reduced estimation error and suppressed motion artifacts. Experimentally, the proposed method resulted in significant improvements, with scan times as short as 20 seconds per time point. These results suggest that the model-based image reconstruction enables rapid dynamic ASL with improved accuracy and robustness.
doi:10.1016/j.neuroimage.2015.07.018
PMCID: PMC4615585  PMID: 26169322
brain perfusion MRI; arterial spin labeling; dynamic ASL; single-shot spiral ASL; compressed sensing; model-based sparsity
11.  Metformin versus insulin for gestational diabetes mellitus: a meta-analysis 
The aim of the present meta-analysis was to determine the efficacy and safety of metformin for the treatment of women with gestational diabetes mellitus (GDM). We searched databases, including PubMed, Embase and the Cochrane Central Register of Controlled Trials, for randomized controlled trials (RCTs) comparing metformin and insulin treatments in women with GDM. We carried out statistical analyses using RevMan 2011 and used the Grading of Recommendations, Assessment, Development, and Evaluations profiler to rate the quality of evidence of the primary outcomes. We analysed eight studies involving 1592 subjects. Meta-analysis of the RCTs showed that metformin had statistically significant effects on pregnancy-induced hypertension [PIH; risk ratio (RR) 0.54; 95% confidence interval (CI) 0.31, 0.91]. However, its effects on neonatal hypoglycaemia (RR 0.80; 95% CI 0.62, 1.02), rate of large-for-gestational age infants (RR 0.77; 95% CI 0.55, 1.08), respiratory distress syndrome (RR 1.26; 95% CI 0.67, 2.37), phototherapy (RR 0.94; 95% CI 0.67, 1.31) and perinatal death (RR 1.01; 95% CI 0.11, 9.53) were not significant. Our analyses suggest that there is no clinically relevant difference in efficacy or safety between metformin and insulin; however, metformin may be a good choice for GDM because of the lower risk of PIH. The advantages of metformin in terms of glycaemic control, PIH incidence and gestational age at birth are unclear, and should be verified in further trials.
doi:10.1111/bcp.12672
PMCID: PMC4631195  PMID: 25925501
gestational diabetes; insulin; metformin; randomized controlled trial
12.  Destabilization of strigolactone receptor DWARF14 by binding of ligand and E3-ligase signaling effector DWARF3 
Cell Research  2015;25(11):1219-1236.
Strigolactones (SLs) are endogenous hormones and exuded signaling molecules in plant responses to low levels of mineral nutrients. Key mediators of the SL signaling pathway in rice include the α/β-fold hydrolase DWARF 14 (D14) and the F-box component DWARF 3 (D3) of the ubiquitin ligase SCFD3 that mediate ligand-dependent degradation of downstream signaling repressors. One perplexing feature is that D14 not only functions as the SL receptor but is also an active enzyme that slowly hydrolyzes diverse natural and synthetic SLs including GR24, preventing the crystallization of a binary complex of D14 with an intact SL as well as the ternary D14/SL/D3 complex. Here we overcome these barriers to derive a structural model of D14 bound to intact GR24 and identify the interface that is required for GR24-mediated D14-D3 interaction. The mode of GR24-mediated signaling, including ligand recognition, hydrolysis by D14, and ligand-mediated D14-D3 interaction, is conserved in structurally diverse SLs. More importantly, D14 is destabilized upon the binding of ligands and D3, thus revealing an unusual mechanism of SL recognition and signaling, in which the hormone, the receptor, and the downstream effectors are systematically destabilized during the signal transduction process.
doi:10.1038/cr.2015.122
PMCID: PMC4650425  PMID: 26470846
Strigolactones; D14; D3; GR24; receptor/co-receptor
14.  Microfluidic Cell Deformability Assay for Rapid and Efficient Kinase Screening with the CRISPR‐Cas9 System 
Abstract
Herein we report a CRISPR‐Cas9‐mediated loss‐of‐function kinase screen for cancer cell deformability and invasive potential in a high‐throughput microfluidic chip. In this microfluidic cell separation platform, flexible cells with high deformability and metastatic propensity flowed out, while stiff cells remained trapped. Through deep sequencing, we found that loss of certain kinases resulted in cells becoming more deformable and invasive. High‐ranking candidates identified included well‐reported tumor suppressor kinases, such as chk2, IKK‐α, p38 MAPKs, and DAPK2. A high‐ranking candidate STK4 was chosen for functional validation and identified to play an important role in the regulation of cell deformability and tumor suppression. Collectively, we have demonstrated that CRISPR‐based on‐chip mechanical screening is a potentially powerful strategy to facilitate systematic genetic analyses.
doi:10.1002/anie.201601984
PMCID: PMC4945455  PMID: 27258939
analytical methods; biomarkers; cell deformability; CRISPR-Cas9; microfluidics
15.  Neutralizing Antibodies to Severe Fever with Thrombocytopenia Syndrome Virus 4 Years after Hospitalization, China 
Emerging Infectious Diseases  2016;22(11):1985-1987.
Severe fever with thrombocytopenia syndrome is an emerging hemorrhagic fever disease in eastern Asia, caused by a tickborne bunyavirus. Of 25 patients hospitalized with this disease in China, 100% produced and maintained neutralizing antibodies to severe fever with thrombocytopenia syndrome virus for the study period of 4 years.
doi:10.3201/eid2211.160414
PMCID: PMC5088025  PMID: 27767907
severe fever with thrombocytopenia syndrome; SFTS; severe fever with thrombocytopenia syndrome virus; SFTSV; viruses; bunyavirus; hemorrhagic fever; neutralizing antibodies; plaque assay; China
16.  Sedentary Behavior Is Independently Related to Fat Mass among Children and Adolescents in South China 
Nutrients  2016;8(11):667.
We aim to explore the independent associations of sedentary behaviors (SB) with body mass distribution among Chinese children. Data on the screen-based sedentary time (television viewing and computer use) and doing homework, physical activities and dietary intake of 1586 Chinese children (50.3% girls) aged 7–15 years were obtained through validated questionnaires. Skin-fold thickness, body height, and weight were measured to calculate percent body fat (%BF), fat mass index (FMI), and fat-free mass index (FFMI). Parental characteristics were collected by questionnaires. Among girls, time of SB (screen time or doing homework) was positively related to %BF, FMI, and FFMI (p < 0.03) after adjusting for maternal overweight, the average annual income of family, moderate-to-vigorous physical activity energy expenditure, and energy intake: Girls in the highest tertile of screen time/homework had 16.7%/23.3% higher relative FMI and 2.9%/2.9% higher relative FFMI than girls in the lowest tertile. Among boys, screen time was positively associated with FFMI (p < 0.003), but not related to %BF and FMI (p > 0.09), while time of doing homework was positively related to %BF and FMI (p = 0.03). Sedentary behaviors might be positively and independently related to fat mass among Chinese children, and were more pronounced in girls.
doi:10.3390/nu8110667
PMCID: PMC5133055  PMID: 27792134
sedentary time; physical activity; body fat; energy intake
17.  Sex differences in colonization of gut microbiota from a man with short-term vegetarian and inulin-supplemented diet in germ-free mice 
Scientific Reports  2016;6:36137.
Gnotobiotic mouse model is generally used to evaluate the efficacy of gut microbiota. Sex differences of gut microbiota are acknowledged, yet the effect of recipient’s gender on the bacterial colonization remains unclear. Here we inoculated male and female germ-free C57BL/6J mice with fecal bacteria from a man with short-term vegetarian and inulin-supplemented diet. We sequenced bacterial 16S rRNA genes V3-V4 region from donor’s feces and recipient’s colonic content. Shannon diversity index showed female recipients have higher bacteria diversity than males. Weighted UniFrac principal coordinates analysis revealed the overall structures of male recipient’s gut microbiota were significantly separated from those of females, and closer to the donor. Redundancy analysis identified 46 operational taxonomic units (OTUs) differed between the sexes. The relative abundance of 13 OTUs were higher in males, such as Parabacteroides distasonis and Blautia faecis, while 33 OTUs were overrepresented in females, including Clostridium groups and Escherichia fergusonii/Shigella sonnei. Moreover, the interactions of these differential OTUs were sexually distinct. These findings demonstrated that the intestine of male and female mice preferred to accommodate microbiota differently. Therefore, it is necessary to designate the gender of gnotobiotic mice for complete evaluation of modulatory effects of gut microbiota from human feces upon diseases.
doi:10.1038/srep36137
PMCID: PMC5086848  PMID: 27796317
18.  Decreased Integrity, Content, and Increased Transcript Level of Mitochondrial DNA Are Associated with Keratoconus 
PLoS ONE  2016;11(10):e0165580.
Oxidative stress may play an important role in the pathogenesis of keratoconus (KC). Mitochondrial DNA (mtDNA) is involved in mitochondrial function, and the mtDNA content, integrity, and transcript level may affect the generation of reactive oxygen species (ROS) and be involved in the pathogenesis of KC. We designed a case-control study to research the relationship between KC and mtDNA integrity, content and transcription. One-hundred ninety-eight KC corneas and 106 normal corneas from Chinese patients were studied. Quantitative real-time PCR was used to measure the relative mtDNA content, transcript levels of mtDNA and related genes. Long-extension PCR was used to detect mtDNA damage. ROS, mitochondrial membrane potential and ATP were measured by respective assay kit, and Mito-Tracker Green was used to label the mitochondria. The relative mtDNA content of KC corneas was significantly lower than that of normal corneas (P = 9.19×10−24), possibly due to decreased expression of the mitochondrial transcription factor A (TFAM) gene (P = 3.26×10−3). In contrast, the transcript levels of mtDNA genes were significantly increased in KC corneas compared with normal corneas (NADH dehydrogenase subunit 1 [ND1]: P = 1.79×10−3; cytochrome c oxidase subunit 1 [COX1]: P = 1.54×10−3; NADH dehydrogenase subunit 1, [ND6]: P = 4.62×10−3). The latter may be the result of increased expression levels of mtDNA transcription-related genes mitochondrial RNA polymerase (POLRMT) (P = 2.55×10−4) and transcription factor B2 mitochondrial (TFB2M) (P = 7.88×10−5). KC corneas also had increased mtDNA damage (P = 3.63×10−10), higher ROS levels, and lower mitochondrial membrane potential and ATP levels compared with normal corneas. Decreased integrity, content and increased transcript level of mtDNA are associated with KC. These changes may affect the generation of ROS and play a role in the pathogenesis of KC.
doi:10.1371/journal.pone.0165580
PMCID: PMC5081165  PMID: 27783701
19.  The 2nd International Conference on Agricultural and Biological Sciences (ABS 2016) 
BMC Plant Biology  2016;16(Suppl 2):226.
Table of contents
01 The influence of soil salt content on the photosynthetic characteristics of spring wheat with trickle irrigation
Lei Pei, Zhenhua Wang, Jinzhu Zhang, Wenhao Li
02 Comparing growth of fast-growing and slow-growing endophytes in plants via ergosterol quantification
Adeline SY Ting, Yiing Y Chow, Sadequr Rahman
03 Transcriptome and digital gene expression analysis identifies putative triterpene saponin-biosynthetic genes of Panax notoginseng
Rongchang Wei
04 Chitosan-assisted isolation and antioxidant evaluation of flavonoids from Sophora japonica L.
Zhang Hu, Sidong Li, Chuyan Li, Zijuan Li
05 Two kinds of new characteristics of the ektexine ornamentation of ginkgo pollen
Guoxia Wang, Yuzhen Yang, Gang Chen, Qing Luo
06 Analysis of nutrient and medicinal ingredients of Ginkgo pollen in different regions
Guoxia Wang, Ruixia Liu, Yuzhen Yang, Lipei Chen
07 Photosynthetic performance of greening seedlings of seven species to drought stress
Zhiyang Lie, Tongtong Zhou, Weilong Huang, Li Xue
08 Changes of fluorescence parameters of greening seedlings of seven species under drought stress
Jie Li, Zhuomin Wang, Li Xue
09 Mammalian sex hormone affects regeneration capacity and enzymes activity of Triticale L in vitro culture
Ismail Bezirganoglu, Pınar Uysal
10 Fractional Fourier entropy increases the recognition rate of fruit type detection
Shuihua Wang, Zhihai Lu, Jiquan Yang, Yudong Zhang, John Liu, Ling Wei, Shufang Chen, Preetha Phillips, Zhengchao Dong
11 Banana-peanut intercropping reduces Fusarium wilt disease in banana from enhancing soil bacterial microorganisms and leaf nutrition
Hong Li, Xutong Wang, Fengliang Zhao, Guisheng Yang
12 Manganese stress impairs stem ureide nitrogen fixation in yardlong-bean plants in the acidic environment
Hong Li
13 A new pest control method for Rhytidodera bowringii Larvae
Haijie Huang, Li Zhao, Weijian Huang, Jinhui Wang, Zhongrun Zhang
14 Research on the seed-like Fruits of Subg. Sclarea of Salvia of Labiatae in China
Xiaojuan Li, Ning Xu, Guofu Zhou, Ming Wan, Qi Lin, Fanyun Meng, Jianxiu Li
15 Three pulling resistance models of pioneer plant in landslide area
Yichang Chen, Koayung Yu, Chunpin Chang
16 The comparison of physiological and biochemical mechanisms of Reaumuria soongorica and Salsola passerine in different growth pattern
Zijuan Zhou, Peixi Su, Rui Shi, Tingting Xie
17 Resources use efficiency of the cosmopolitan plant Potentilla anserina L. in different alpine habitats in China
Rui Shi, Peixi Su, Zijuan Zhou
18 Cloning of PPDK gene from Red Amaranand transformation of Alfalfa
Xuelan Liu, Yan Zhang, Xiangfa Wei
19 Variation and cluster analysis of morphological characters and nutrient content of Chucrasia tabularis seed
Chong Wu, Yanlei Yin, Lijuan Feng, Xuemei Yang, Fei Wang
20 Effect of the planting density of the areca nut on the growth of intercropped Vanilla
Hua Wang, Huifa Zhuang, Zihui Zhu, Hui Wang
doi:10.1186/s12870-016-0904-3
PMCID: PMC5088514
20.  Angucyclines and Angucyclinones from Streptomyces sp. CB01913 Featuring C-ring Cleavage and Expansion 
Journal of natural products  2015;78(10):2471-2480.
Angucyclines and angucyclinones are aromatic polyketides with a tetracyclic benz[a]anthracene skeleton. The benz[a]anthracene scaffold is biosynthesized by type II polyketide synthases that catalyze the decarboxylative condensation of a short acyl-CoA starter and nine extender units. Angucyclines and angucyclinones, the largest group of polycyclic aromatic polyketides, achieve structural diversity via subsequent oxidation, ring cleavage, amino acid incorporation, and glycosylation. We here report the discovery of 14 angucyclinones and two angucyclines (1–16) from Streptomyces sp. CB01913, identifying 12 new compounds featuring various oxidations on rings A and C (1, 2, and 4), different sugar moieties attached to rings A and B (3 and 6), and C-ring cleavage (5 and 10–14) and expansion (8). These new structural features, highlighted by C-ring cleavage and expansion, enrich the structural diversity of angucyclines and angucyclinones. All compounds were tested for cytotoxicity and antibacterial activities, with 1, 5, 15, and 16 showing moderate activities against selected cancer cell lines or bacterial strains.
Graphical abstract
doi:10.1021/acs.jnatprod.5b00601
PMCID: PMC4845661  PMID: 26335269
21.  Differences in Proinflammatory Property of Six Subtypes of Peroxiredoxins and Anti-Inflammatory Effect of Ligustilide in Macrophages 
PLoS ONE  2016;11(10):e0164586.
Background
Peroxiredoxins (Prxs) are proposed to function as damage-associated molecular patterns (DAMPs) and contribute to post-ischemic neuroinflammation and brain injury by activating Toll-like receptor (TLR) 4 at the acute and subacute phases after ischemic stroke. However, there are few studies concerning the inflammatory profiles of six distinct subtypes of Prxs (Prx1–Prx6). Our previous study demonstrated that the protective effect of ligustilide (LIG) against cerebral ischemia was associated with inhibition of neuroinflammatory response and Prx/TLR4 signaling in rats. Herein, the present study explored the inflammatory members of Prxs and the effect of LIG on their inflammatory responses in macrophages.
Methodology/Principal Findings
The murine RAW264.7 macrophages were treated with each of exogenous recombinant Prxs at a range of 1 to 50 nM for 24 h. The WST-1 test showed that Prx3 exhibited a significant cytotoxicity, whereas the rest five Prxs did not affect cellular viability. The quantitative measurements with spectrometry or ELISA indicated that three subtypes, Prx1, Prx2 and Prx4, increased production of proinflammatory mediators, including nitric oxide (NO) metabolites, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in a concentration-dependent manner. Immunostaining demonstrated that 20 nM Prx1, Prx2 or Prx4 significantly increased expression of TLR4 and iNOS and nuclear translocation of NF-κB p65. However, Prx5 and Prx6 showed no poinflammatory effect in macrophages. Remarkably, LIG treatment effectively inhibited the inflammatory response induced by Prx1, Prx2 and Prx4.
Conclusion
Three members of Prxs, Prx1, Prx2 and Prx4, are inflammatory DAMPs that induce TLR4 activation and inflammatory response in macrophages, which is effectively inhibited by LIG. These results suggest that inflammatory Prxs-activated macrophages may provide a novel cellular model for screening the potential inhibitors of DAMPs-associated inflammatory diseases such as stroke. Moreover, selective blocking strategies targeting the inflammatory subtypes of Prxs probably provide promising therapeutic approaches with a prolonged time window for stroke.
doi:10.1371/journal.pone.0164586
PMCID: PMC5055302  PMID: 27716839
22.  Bone morphogenetic protein-9 promotes the differentiation of mouse spleen macrophages into osteoclasts via the ALK1 receptor and ERK 1/2 pathways in vitro 
Molecular Medicine Reports  2016;14(5):4545-4550.
It has been confirmed that bone morphogenetic protein-9 (BMP-9) promotes the differentiation of osteoblasts. However, the ways in which BMP-9 exerts its effects on the differentiation of osteoclasts and bone resorption remain to be elucidated. The present study was designed to investigate the roles and the molecular mechanism of BMP-9 on the proliferation and differentiation of osteoclast precursors in vitro. Mouse spleen macrophages (RAW 264.7 cells) were cultured in the presence of receptor activator for nuclear factor-κb ligand (RANKL) in vitro. Following treatment with different concentrations of BMP-9, a number of parameters were quantitatively monitored. Cell proliferation was determined using an MTT assay. The expression levels of cell BMP receptor-IA (BMPR-IA), BMPR-IB, BMPR-II and anaplastic lymphoma kinase 1 (ALK1) receptor were detected by ELISA, the small mothers against decapentaplegic pathway, extracellular signal-regulated kinase (ERK)1/2 pathways and markers of osteoclast differentiation were detected by western blotting. The results showed that treatment with BMP-9 alone promoted mouse spleen macrophage proliferation, and the differentiation into osteoclasts occurred only in the presence of RANK. The promoting effect of BMP-9 on cell proliferation and osteoclast differentiation occurred in dose-dependent manner. In addition, BMP-9 significantly upregulated the expression of the ALK1 receptor and inhibited the ERK1/2 pathway. The inhibition of the ERK1/2 pathways was ameliorated by transfection with small interfering (si)RNA ALK1. The effect of BMP-9 on osteoclast differentiation was reduced by transfection with siRNA ALK1, however, the effect was enhanced by the ERK1/2 pathway inhibitor, U0126. The results of the present study demonstrated that BMP-9 promoted the osteoclast differentiation of osteoclast precursors via binding to the ALK1 receptor on the cell surface, and inhibiting the ERK1/2 signaling pathways in the cell.
doi:10.3892/mmr.2016.5803
PMCID: PMC5101994  PMID: 27748860
bone morphogenetic protein-9; mice spleen macrophages; osteoclast formation; anaplastic lymphoma kinase 1 receptor; extracellular signal-regulated kinase 1/2 signaling pathways
23.  Mutations in human IFT140 cause non-syndromic retinal degeneration 
Human genetics  2015;134(10):1069-1078.
Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are two genetically heterogeneous retinal degenerative disorders. Despite the identification of a number of genes involved in LCA and RP, the genetic etiology remains unknown in many patients. In this study, we aimed to identify novel disease-causing genes of LCA and RP. Retinal capture sequencing was initially performed to screen mutations in known disease-causing genes in different cohorts of LCA and RP patients. For patients with negative results, we performed whole exome sequencing and applied a series of variant filtering strategies. Sanger sequencing was done to validate candidate causative IFT140 variants. Exome sequencing data analysis led to the identification of IFT140 variants in multiple unrelated non-syndromic LCA and RP cases. All the variants are extremely rare and predicted to be damaging. All the variants passed Sanger validation and segregation tests provided that the family members’ DNA was available. The results expand the phenotype spectrum of IFT140 mutations to non-syndromic retinal degeneration, thus extending our understanding of intraflagellar transport and primary cilia biology in the retina. This work also improves the molecular diagnosis of retinal degenerative disease.
doi:10.1007/s00439-015-1586-x
PMCID: PMC4565766  PMID: 26216056
24.  TGF-β and NF-κB signaling pathway crosstalk potentiates corneal epithelial senescence through an RNA stress response 
Aging (Albany NY)  2016;8(10):2337-2350.
The corneal epithelium plays important roles in the maintenance of corneal transparency for good vision, and acts as a protective barrier against foreign insults. Structural and functional changes with aging in the corneal epithelium have been documented. Here we found that transforming growth factor-β (TGF-β) is highly expressed in the elderly donor corneal epithelium, as are senescence-associated genes, such as p16 and p21. In human corneal epithelial cell (HCEC) models, TGF-β induces cellular senescence, characterized by increased SA-β-gal positive cells and elevated expression of p16 and p21. Pharmacological inhibition of TGF-β signaling alleviates TGF-β-induced cellular senescence. In addition, we determined that senescence-associated inflammation was significantly aggravated in TGF-β-induced cellular senescence by detecting the expression of interleukin-6 (IL-6), IL-8, and tumor necrosis factor alpha (TNFα). Both genetic and pharmacological approaches revealed that blocking nuclear factor-κB (NF-κB) signaling not only inhibited the production of inflammatory factors, but also rescued the senescent phenotype induced by TGF-β in HCECs. Mechanistically, TGF-β induced an atypical RNA stress responses, leading to accelerated mRNA degradation of IκBα, an inhibitor of NF-κB. Together, our data indicate that TGF-β-driven NF-κB activation contributes to corneal epithelial senescence via RNA metabolism and the inflammation blockade can attenuate TGF-β-induced senescence.
doi:10.18632/aging.101050
PMCID: PMC5115892  PMID: 27713146
corneal epithelium; cellular senescence; transforming growth factor-β; RNA stress granules; nuclear factor-κB
25.  Hypomorphic mutations identified in candidate Leber congenital amaurosis disease gene CLUAP1 
Purpose
Leber congenital amaurosis (LCA) is an early-onset form of retinal degeneration and six of the 22 known LCA disease genes encode photoreceptor ciliary proteins. Despite the identification of 22 LCA disease genes, the genetic basis of approximately 30% of LCA patients remains unknown. We sought to investigate the cause of disease in the remaining 30% by examining cilia-associated genes.
Methods
Whole-exome sequencing was performed on an LCA cohort of 212 unsolved probands previously screened for mutations in known retinal disease genes. Immunohistochemistry using mouse retinas was used to confirm protein localization and zebrafish were used to perform rescue experiments.
Results
A homozygous nonsynonymous mutation was found in a single proband in CLUAP1, a gene required for ciliogenesis and cilia maintenance. Cluap1 knockout zebrafish exhibit photoreceptor cell death as early as five days post fertilization and rescue experiments revealed that our proband’s mutation is significantly hypomorphic.
Conclusion
Consistent with the knowledge that CLUAP1 plays an important role in cilia function and that cilia are critical to photoreceptor function, our results indicate that hypomorphic mutations in CLUAP1 can result in dysfunctional photoreceptors without systemic abnormalities. This represents the first report linking mutations in CLUAP1 to human disease and establishes CLUAP1 as a candidate LCA gene.
doi:10.1038/gim.2015.205
PMCID: PMC4965339  PMID: 26820066
Leber congenital amaurosis (LCA); CLUAP1; early-onset retinal disease; photoreceptor connecting cilium; ciliopathy

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