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

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1.  An eye organoid approach identifies Six3 suppression of R-spondin 2 as a critical step in mouse neuroretina differentiation 
Cell reports  2017;21(6):1534-1549.
Recent advances in self-organizing, 3-dimensional tissue cultures of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) provided an in vitro model that recapitulates many aspects of the in vivo developmental steps. Using Rax-GFP expressing ESCs, newly generated Six3−/− iPSCs and conditional null Six3delta/f;Rax-Cre ESCs we identified Six3 repression of R-spondin 2 (Rspo2) as a required step during optic vesicle morphogenesis and neuroretina differentiation. We validated these results in vivo by showing that transient ectopic expression of Rspo2 in the anterior neural plate of transgenic mouse embryos was sufficient to inhibit neuroretina differentiation. Additionally, using a chimeric eye organoid assay we determined that Six3-null cells exert a non-cell autonomous repressive effect during optic vesicle formation and neuroretina differentiation. Our results further validate the organoid culture system as a reliable and fast alternative to identify and evaluate genes involved in eye morphogenesis and neuroretina differentiation in vivo.
Graphical abstract
PMCID: PMC5728169  PMID: 29117559
eye; optic vesicles; Six3; pluripotent stem cells; organoids; neuroretina; R-spondins; Wnt; mouse
2.  Imprinting alterations in sperm may not significantly influence ART outcomes and imprinting patterns in the cord blood of offspring 
PLoS ONE  2017;12(11):e0187869.
An increase in imprinting disorders in children conceived though assisted reproductive technologies (ARTs) has been the subject of several reports. The transmission of imprinting errors from the sperm of infertile fathers is believed to be a possible reason for the increased occurrence of these disorders. However, whether the imprinting alterations in sperm affect ART outcomes and the imprinting of offspring is unclear. In the current study, we analyzed the methylation of H19, SNRPN and KCNQ1OT1 by pyrosequencing sperm samples from 97 infertile patients and 31 proven fertile males as well as cord blood samples from 13 infantswho were conceived by infertile parents through intracytoplasmic sperm injection (ICSI) and 30 healthy newborns who were conceived naturally. After four cases were excluded owing to the lack of a sequencing signal, the infertile patients were subgrouped into normal (69 cases) and abnormal (24 cases) imprinting groups according to the reference range set by the control group. Between the groups, there were no significant differences in ART outcomes. Significantly different levels of methylation were detected in H19, but none of the imprinted genes were determined to be outside of the methylation reference range set by the values derived from the naturally conceived controls. Three CpG loci were found to be significantly hypomethylated in the maternally imprinted gene KCNQ1OT1 in two patients from the abnormal imprinting group, none of which were caused by sperm imprinting errors. In addition, the paternal H19 gene exhibited discrepant methylation patterns between the sperm controls and the cord blood controls. Our data suggest that increased imprinting errors in the sperm of infertile patients do not have an obvious influence on ART outcomes or the imprinting of offspring.
PMCID: PMC5685618  PMID: 29136648
3.  Geographical Variations in the Environmental Determinants of Physical Inactivity among U.S. Adults 
Physical inactivity is a major modifiable risk factor for morbidity, disability and premature mortality worldwide. This study assessed the geographical variations in the impact of environmental quality on physical inactivity among U.S. adults. Data on county-level prevalence of leisure-time physical inactivity came from the Behavioral Risk Factor Surveillance System. County environment was measured by the Environmental Quality Index (EQI), a comprehensive index of environmental conditions that affect human health. The overall EQI consists of five subdomains—air, water, land, social, and built environment. Geographically weighted regressions (GWRs) were performed to estimate and map county-specific impact of overall EQI and its five subdomains on physical inactivity prevalence. The prevalence of leisure-time physical inactivity among U.S. counties was 25% in 2005. On average, one standard deviation decrease in the overall EQI was associated with an increase in county-level prevalence of leisure-time physical inactivity by nearly 1%. However, substantial geographical variations in the estimated environmental determinants of physical inactivity were present. The estimated changes of county-level prevalence of leisure-time physical inactivity resulted from one standard deviation decrease of the overall EQI ranged from an increase of over 3% to a decrease of nearly 2% across U.S. counties. Analogous, the estimated changes of county-level prevalence of leisure-time physical inactivity resulted from one standard deviation decrease of the EQI air, water, land, social, and built environment subdomains ranged from an increase of 2.6%, 1.5%, 2.9%, 3.3%, and 1.7% to a decrease of 2.9%, 1.4%, 2.4%, 2.4%, and 0.8% across U.S. counties, respectively. Given the substantial heterogeneities in the environmental determinants of physical inactivity, locally customized physical activity interventions are warranted to address the most concerning area-specific environmental issue.
PMCID: PMC5707965  PMID: 29088093
physical inactivity; environmental quality; geographical variation; geographically weighted regression
4.  Endolysin LysEF-P10 shows potential as an alternative treatment strategy for multidrug-resistant Enterococcus faecalis infections 
Scientific Reports  2017;7:10164.
Phage-derived lysins can hydrolyse bacterial cell walls and show great potential for combating Gram-positive pathogens. In this study, the potential of LysEF-P10, a new lysin derived from a isolated Enterococcus faecalis phage EF-P10, as an alternative treatment for multidrug-resistant E. faecalis infections, was studied. LysEF-P10 shares only 61% amino acid identity with its closest homologues. Four proteins were expressed: LysEF-P10, the cysteine, histidine-dependent amidohydrolase/peptidase (CHAP) domain (LysEF-P10C), the putative binding domain (LysEF-P10B), and a fusion recombination protein (LysEF-P10B-green fluorescent protein). Only LysEF-P10 showed highly efficient, broad-spectrum bactericidal activity against E. faecalis. Several key functional residues, including the Cys-His-Asn triplet and the calcium-binding site, were confirmed using 3D structure prediction, BLAST and mutation analys. We also found that calcium can switch LysEF-P10 between its active and inactive states and that LysEF-P10B is responsible for binding E. faecalis cells. A single administration of LysEF-P10 (5 μg) was sufficient to protect mice against lethal vancomycin-resistant Enterococcus faecalis (VREF) infection, and LysEF-P10-specific antibody did not affect its bactericidal activity or treatment effect. Moreover, LysEF-P10 reduced the number of Enterococcus colonies and alleviated the gut microbiota imbalance caused by VREF. These results indicate that LysEF-P10 might be an alternative treatment for multidrug-resistant E. faecalis infections.
PMCID: PMC5579260  PMID: 28860505
5.  From Mechanistic Study to Chiral Catalyst Optimization: Theoretical Insight into Binaphthophosphepine-catalyzed Asymmetric Intramolecular [3 + 2] Cycloaddition 
Scientific Reports  2017;7:7619.
Density functional M11 was used to study the mechanism and enantioselectivity of a binaphthophosphepine-catalyzed intramolecular [3 + 2] cycloaddition reaction. The computational results revealed that this reaction proceeds through nucleophilic addition of the phosphine catalyst to the allene, which yields a zwitterionic phosphonium intermediate. The subsequent stepwise [3 + 2] annulation process, which starts with the intramolecular nucleophilic addition of the allenoate moiety to the electron-deficient olefin group, determines the enantioselectivity of the reaction. This step is followed by a ring-closing reaction and water-assisted proton-transfer process to afford the final product with concomitant regeneration of the phosphine catalyst. Theoretical predictions of the enantioselectivity for various phosphine catalysts were consistent with experimental observations, and 2D contour maps played an important role in explaining the origin of the enantioselectivity. Moreover, on the basis of our theoretical study, new binaphthophosphepine catalysts were designed and that are expecting to afford higher enantioselectivity in this cycloaddition reaction.
PMCID: PMC5548760
6.  World Congress Integrative Medicine & Health 2017: Part one 
Brinkhaus, Benno | Falkenberg, Torkel | Haramati, Aviad | Willich, Stefan N. | Briggs, Josephine P. | Willcox, Merlin | Linde, Klaus | Theorell, Töres | Wong, Lisa M. | Dusek, Jeffrey | Wu, Darong | Eisenberg, David | Haramati, Aviad | Berger, Bettina | Kemper, Kathi | Stock-Schröer, Beate | Sützl-Klein, Hedda | Ferreri, Rosaria | Kaplan, Gary | Matthes, Harald | Rotter, Gabriele | Schiff, Elad | Arnon, Zahi | Hahn, Eckhard | Luberto, Christina M. | Martin, David | Schwarz, Silke | Tauschel, Diethard | Flower, Andrew | Gramminger, Harsha | Gupta, Hedwig H. | Gupta, S. N. | Kerckhoff, Annette | Kessler, Christian S. | Michalsen, Andreas | Kessler, Christian S. | Kim, Eun S. | Jang, Eun H. | Kim, Rana | Jan, Sae B. | Mittwede, Martin | Mohme, Wiebke | Ben-Arye, Eran | Bonucci, Massimo | Saad, Bashar | Breitkreuz, Thomas | Rossi, Elio | Kebudi, Rejin | Daher, Michel | Razaq, Samaher | Gafer, Nahla | Nimri, Omar | Hablas, Mohamed | Kienle, Gunver Sophia | Samuels, Noah | Silbermann, Michael | Bandelin, Lena | Lang, Anna-Lena | Wartner, Eva | Holtermann, Christoph | Binstock, Maxwell | Riebau, Robert | Mujkanovic, Edin | Cramer, Holger | Lauche, Romy | Michalsen, Andres | Ward, Lesley | Cramer, Holger | Irnich, Dominik | Stör, Wolfram | Burnstock, Geoffrey | Schaible, Hans-Georg | Ots, Thomas | Langhorst, Jost | Lauche, Romy | Sundberg, Tobias | Falkenberg, Torkel | Amarell, Catherina | Amarell, Catherina | Anheyer, Melanie | Eckert, Marion | Eckert, Marion | Ogal, Mercedes | Eckert, Marion | Amarell, Catherina | Schönauer, Annette | Reisenberger, Birgit | Brand, Bernhard | Anheyer, Dennis | Dobos, Gustav | Kroez, Matthias | Martin, David | Matthes, Harald | Ammendola, Aldo | Mao, Jun J. | Witt, Claudia | Yang, Yufei | Dobos, Gustav | Oritz, Miriam | Horneber, Markus | Voiß, Petra | Reisenberger, Birgit | von Rosenstiel, Alexandra | Eckert, Marion | Ogal, Mercedes | Amarell, Catharina | Anheyer, Melanie | Schad, Friedemann | Schläppi, Marc | Kröz, Matthias | Büssing, Arndt | Bar-Sela, Gil | Matthes, Harald | Schiff, Elad | Ben-Arye, Eran | Arnon, Zahi | Avshalomov, David | Attias, Samuel | Schönauer, Annette | Haramati, Aviad | Witt, Claudia | Brinkhaus, Benno | Cotton, Sian | Jong, Miek | Jong, Mats | Scheffer, Christian | Haramati, Aviad | Tauschel, Diethard | Edelhäuser, Friedrich | AlBedah, Abdullah | Lee, Myeong Soo | Khalil, Mohamed | Ogawa, Keiko | Motoo, Yoshiharu | Arimitsu, Junsuke | Ogawa, Masao | Shimizu, Genki | Stange, Rainer | Kraft, Karin | Kuchta, Kenny | Watanabe, Kenji | Bonin, D | Büssing, Arndt | Gruber, Harald | Koch, Sabine | Gruber, Harald | Pohlmann, Urs | Caldwell, Christine | Krantz, Barbara | Kortum, Ria | Martin, Lily | Wieland, Lisa S. | Kligler, Ben | Gould-Fogerite, Susan | Zhang, Yuqing | Wieland, Lisa S. | Riva, John J. | Lumpkin, Michael | Ratner, Emily | Ping, Liu | Jian, Pei | Hamme, Gesa-Meyer | Mao, Xiaosong | Chouping, Han | Schröder, Sven | Hummelsberger, Josef | Wullinger, Michael | Brodzky, Marc | Zalpour, Christoff | Langley, Julia | Weber, Wendy | Mudd, Lanay M. | Wayne, Peter | Witt, Clauda | Weidenhammer, Wolfgang | Fønnebø, Vinjar | Boon, Heather | Steel, Amie | Bugarcic, Andrea | Rangitakatu, Melisa | Steel, Amie | Adams, Jon | Sibbritt, David | Wardle, Jon | Leach, Matthew | Schloss, Janet | Dieze, Helene | Boon, Heather | Ijaz, Nadine | Willcox, Merlin | Heinrich, Michael | Lewith, George | Flower, Andrew | Graz, Bertrand | Adam, Daniela | Grabenhenrich, Linus | Ortiz, Miriam | Binting, Sylvia | Reinhold, Thomas | Brinkhaus, Benno | Andermo, Susanne | Sundberg, Tobias | Falkenberg, Torkel | Nordberg, Johanna Hök | Arman, Maria | Bhasin, Manoj | Fan, Xueyi | Libermann, Towia | Fricchione, Gregory | Denninger, John | Benson, Herbert | Berger, Bettina | Stange, Rainer | Michalsen, Andreas | Martin, David D. | Boers, Inge | Vlieger, Arine | Jong, Miek | Brinkhaus, Benno | Teut, Michael | Ullmann, Alexander | Ortiz, Miriam | Rotter, Gabriele | Binting, Sylvia | Lotz, Fabian | Roll, Stephanie | Canella, Claudia | Mikolasek, Michael | Rostock, Matthias | Beyer, Jörg | Guckenberger, Matthias | Jenewein, Josef | Linka, Esther | Six, Claudia | Stoll, Sarah | Stupp, Roger | Witt, Claudia M. | Chuang, Elisabeth | Kligler, Ben | McKee, Melissa D. | Cramer, Holger | Lauche, Romy | Klose, Petra | Lange, Silke | Langhorst, Jost | Dobos, Gustav | Chung, Vincent C. H. | Wong, Hoi L. C. | Wu, Xin Y. | Wen, Grace Y. G. | Ho, Robin S. T. | Ching, Jessica Y. L. | Wu, Justin C. Y. | Coakley, Amanda | Flanagan, Jane | Annese, Christine | Empoliti, Joanne | Gao, Zishan | Liu, Xugang | Yu, Shuguang | Yan, Xianzhong | Liang, Fanrong | Hohmann, Christoph D. | Steckhan, Nico | Ostermann, Thomas | Paetow, Arion | Hoff, Evelyn | Michalsen, Andreas | Hu, Xiao-Yang | Wu, Ruo-Han | Logue, Martin | Blonde, Clara | Lai, Lily Y. | Stuart, Beth | Flower, Andrew | Fei, Yu-Tong | Moore, Michael | Liu, Jian-Ping | Lewith, George | Hu, Xiao-Yang | Wu, Ruo-Han | Logue, Martin | Blonde, Clara | Lai, Lily Y. | Stuart, Beth | Flower, Andrew | Fei, Yu-Tong | Moore, Michael | Liu, Jian-Ping | Lewith, George | Jeitler, Michael | Zillgen, Hannah | Högl, Manuel | Steckhan, Nico | Stöckigt, Barbara | Seifert, Georg | Michalsen, Andreas | Kessler, Christian | Khadivzadeh, Talat | Bashtian, Maryam Hassanzadeh | Aval, Shapour Badiee | Esmaily, Habibollah | Kim, Jihye | Kim, Keun H. | Klocke, Carina | Joos, Stefanie | Koshak, Abdulrahman | Wie, Li | Koshak, Emad | Wali, Siraj | Alamoudi, Omer | Demerdash, Abdulrahman | Qutub, Majdy | Pushparaj, Peter | Heinrich, Michael | Kruse, Sigrid | Fischer, Isabell | Tremel, Nadine | Rosenecker, Joseph | Leung, Brenda | Takeda, Wendy | Liang, Ning | Feng, Xue | Liu, Jian-ping | Cao, Hui-juan | Luberto, Christina M. | Shinday, Nina | Philpotts, Lisa | Park, Elyse | Fricchione, Gregory L. | Yeh, Gloria | Munk, Niki | Zakeresfahani, Arash | Foote, Trevor R. | Ralston, Rick | Boulanger, Karen | Özbe, Dominik | Gräßel, Elmar | Luttenberger, Katharina | Pendergrass, Anna | Pach, Daniel | Bellmann-Strobl, Judit | Chang, Yinhui | Pasura, Laura | Liu, Bin | Jäger, Sven F. | Loerch, Ronny | Jin, Li | Brinkhaus, Benno | Ortiz, Miriam | Reinhold, Thomas | Roll, Stephanie | Binting, Sylvia | Icke, Katja | Shi, Xuemin | Paul, Friedemann | Witt, Claudia M. | Rütz, Michaela | Lynen, Andreas | Schömitz, Meike | Vahle, Maik | Salomon, Nir | Lang, Alon | Lahat, Adi | Kopylov, Uri | Ben-Horin, Shomron | Har-Noi, Ofir | Avidan, Benjamin | Elyakim, Rami | Gamus, Dorit | NG, Siew | Chang, Jessica | Wu, Justin | Kaimiklotis, John | Schumann, Dania | Buttó, Ludovica | Langhorst, Jost | Dobos, Gustav | Haller, Dirk | Cramer, Holger | Smith, Caroline | de Lacey, Sheryl | Chapman, Michael | Ratcliffe, Julie | Johnson, Neil | Lyttleton, Jane | Boothroyd, Clare | Fahey, Paul | Tjaden, Bram | van Vliet, Marja | van Wietmarschen, Herman | Jong, Miek | Tröger, Wilfried | Vuolanto, Pia | Aarva, Paulina | Sorsa, Minna | Helin, Kaija | Wenzel, Claudia | Zoderer, Iris | Pammer, Patricia | Simon, Patrick | Tucek, Gerhard | Wode, Kathrin | Henriksson, Roger | Sharp, Lena | Stoltenberg, Anna | Nordberg, Johanna Hök | Xiao-ying, Yang | Wang, Li-qiong | Li, Jin-gen | Liang, Ning | Wang, Ying | Liu, Jian-ping | Balneaves, Lynda | Capler, Rielle | Bocci, Chiara | Guffi, Marta | Paolini, Marina | Meaglia, Ilaria | Porcu, Patrizia | Ivaldi, Giovanni B. | Dragan, Simona | Bucuras, Petru | Pah, Ana M. | Badalica-Petrescu, Marius | Buleu, Florina | Hogea-Stoichescu, Gheorghe | Christodorescu, Ruxandra | Kao, Lan | Cho, Yumin | Klafke, Nadja | Mahler, Cornelia | von Hagens, Cornelia | Uhlmann, Lorenz | Bentner, Martina | Schneeweiss, Andreas | Mueller, Andreas | Szecsenyi, Joachim | Joos, Stefanie | Neri, Isabella | Ortiz, Miriam | Schnabel, Katharina | Teut, Michael | Rotter, Gabriele | Binting, Sylvia | Cree, Margit | Lotz, Fabian | Suhr, Ralf | Brinkhaus, Benno | Rossi, Elio | Baccetti, Sonia | Firenzuoli, Fabio | Monechi, Maria V. | Di Stefano, Mariella | Amunni, Gianni | Wong, Wendy | Chen, Bingzhong | Wu, Justin | Amri, Hakima | Haramati, Aviad | Kotlyanskaya, Lucy | Anderson, Belinda | Evans, Roni | Kligler, Ben | Marantz, Paul | Bradley, Ryan | Booth-LaForce, Cathryn | Zwickey, Heather | Kligler, Benjamin | Brooks, Audrey | Kreitzer, Mary J. | Lebensohn, Patricia | Goldblatt, Elisabeth | Esmel-Esmel, Neus | Jiménez-Herrera, Maria | Ijaz, Nadine | Boon, Heather | Jocham, Alexandra | Stock-Schröer, Beate | Berberat, Pascal O. | Schneider, Antonius | Linde, Klaus | Masetti, Morgana | Murakozy, Henriette | Van Vliet, Marja | Jong, Mats | Jong, Miek | Agdal, Rita | Atarzadeh, Fatemeh | Jaladat, Amir M. | Hoseini, Leila | Amini, Fatemeh | Bai, Chen | Liu, Tiegang | Zheng, Zian | Wan, Yuxiang | Xu, Jingnan | Wang, Xuan | Yu, He | Gu, Xiaohong | Daneshfard, Babak | Nimrouzi, Majid | Tafazoli, Vahid | Alorizi, Seyed M. Emami | Saghebi, Seyed A. | Fattahi, Mohammad R. | Salehi, Alireza | Rezaeizadeh, Hossein | Zarshenas, Mohammad M. | Nimrouzi, Majid | Fox, Kealoha | Hughes, John | Kostanjsek, Nenad | Espinosa, Stéphane | Lewith, George | Fisher, Peter | Latif, Abdul | Lefeber, Donald | Paske, William | Öztürk, Ali Ö. | Öztürk, Gizemnur | Boers, Inge | Tissing, Wim | Naafs, Marianne | Busch, Martine | Jong, Miek | Daneshfard, Babak | Sanaye, Mohammad R. | Dräger, Kilian | Fisher, Peter | Kreitzer, Mary J. | Evans, Roni | Leininger, Brent | Shafto, Kate | Breen, Jenny | Sanaye, Mohammad R. | Daneshfard, Babak | Simões-Wüst, Ana P. | Moltó-Puigmartí, Carolina | van Dongen, Martien | Dagnelie, Pieter | Thijs, Carel | White, Shelley | Wiesener, Solveig | Salamonsen, Anita | Stub, Trine | Fønnebø, Vinjar | Abanades, Sergio | Blanco, Mar | Masllorens, Laia | Sala, Roser | Al-Ahnoumy, Shafekah | Han, Dongwoon | He, Luzhu | Kim, Ha Yun | In Choi, Da | Alræk, Terje | Stub, Trine | Kristoffersen, Agnete | von Sceidt, Christel | Michalsen, Andreas | Bruset, Stig | Musial, Frauke | Anheyer, Dennis | Cramer, Holger | Lauche, Romy | Saha, Felix J. | Dobos, Gustav | Anheyer, Dennis | Haller, Heidemarie | Lauche, Romy | Dobos, Gustav | Cramer, Holger | Azizi, Hoda | Khadem, Nayereh | Hassanzadeh, Malihe | Estiri, Nazanin | Azizi, Hamideh | Tavassoli, Fatemeh | Lotfalizadeh, Marzieh | Zabihi, Reza | Esmaily, Habibollah | Azizi, Hoda | Shabestari, Mahmoud Mohammadzadeh | Paeizi, Reza | Azari, Masoumeh Alvandi | Bahrami-Taghanaki, Hamidreza | Zabihi, Reza | Azizi, Hamideh | Esmaily, Habibollah | Baars, Erik | De Bruin, Anja | Ponstein, Anne | Baccetti, Sonia | Di Stefano, Mariella | Rossi, Elio | Firenzuoli, Fabio | Segantini, Sergio | Monechi, Maria Valeria | Voller, Fabio | Barth, Jürgen | Kern, Alexandra | Lüthi, Sebastian | Witt, Claudia | Barth, Jürgen | Zieger, Anja | Otto, Fabius | Witt, Claudia | Beccia, Ariel | Dunlap, Corina | Courneene, Brendan | Bedregal, Paula | Passi, Alvaro | Rodríguez, Alfredo | Chang, Mayling | Gutiérrez, Soledad | Beissner, Florian | Beissner, Florian | Preibisch, Christine | Schweizer-Arau, Annemarie | Popovici, Roxana | Meissner, Karin | Beljanski, Sylvie | Belland, Laura | Rivera-Reyes, Laura | Hwang, Ula | Berger, Bettina | Sethe, Dominik | Hilgard, Dörte | Heusser, Peter | Bishop, Felicity | Al-Abbadey, Miznah | Bradbury, Katherine | Carnes, Dawn | Dimitrov, Borislav | Fawkes, Carol | Foster, Jo | MacPherson, Hugh | Roberts, Lisa | Yardley, Lucy | Lewith, George | Bishop, Felicity | Al-Abbadey, Miznah | Bradbury, Katherine | Carnes, Dawn | Dimitrov, Borislav | Fawkes, Carol | Foster, Jo | MacPherson, Hugh | Roberts, Lisa | Yardley, Lucy | Lewith, George | Bishop, Felicity | Holmes, Michelle | Lewith, George | Yardley, Lucy | Little, Paul | Cooper, Cyrus | Bogani, Patrizia | Maggini, Valentina | Gallo, Eugenia | Miceli, Elisangela | Biffi, Sauro | Mengoni, Alessio | Fani, Renato | Firenzuoli, Fabio | Brands-Guendling, Nadine | Guendling, Peter W. | Bronfort, Gert | Evans, Roni | Haas, Mitch | Leininger, Brent | Schulz, Craig | Bu, Xiangwei | Wang, J. | Fang, T. | Shen, Z. | He, Y. | Zhang, X. | Zhang, Zhengju | Wang, Dali | Meng, Fengxian | Büssing, Arndt | Baumann, Klaus | Frick, Eckhard | Jacobs, Christoph | Büssing, Arndt | Grünther, Ralph-Achim | Lötzke, Désirée | Büssing, Arndt | Jung, Sonny | Lötzke, Désirée | Recchia, Daniela R. | Robens, Sibylle | Ostermann, Thomas | Berger, Bettina | Stankewitz, Josephin | Kröz, Matthias | Jeitler, Mika | Kessler, Christian | Michalsen, Andreas | Cheon, Chunhoo | Jang, Bo H. | Ko, Seong G. | Huang, Ching W. | Sasaki, Yui | Ko, Youme | Cheshire, Anna | Ridge, Damien | Hughes, John | Peters, David | Panagioti, Maria | Simon, Chantal | Lewith, George | Cho, Hyun J. | Han, Dongwoon | Choi, Soo J. | Jung, Young S. | Im, Hyea B | Cooley, Kieran | Tummon-Simmons, Laura | Cotton, Sian | Luberto, Christina M. | Wasson, Rachel | Kraemer, Kristen | Sears, Richard | Hueber, Carly | Derk, Gwendolyn | Lill, JR | An, Ruopeng | Steinberg, Lois | Rodriguez, Lourdes Diaz | la Fuente, Francisca García-de | De la Vega, Miguel | Vargas-Román, Keyla | Fernández-Ruiz, Jonatan | Cantarero-Villanueva, Irene | Rodriguez, Lourdes Diaz | García-De la Fuente, Francisca | Jiménez-Guerrero, Fanny | Vargas-Román, Keyla | Fernández-Ruiz, Jonatan | Galiano-Castillo, Noelia | Diaz-Saez, Gualberto | Torres-Jimenez, José I. | Garcia-Gomez, Olga | Hortal-Muñoz, Luis | Diaz-Diez, Camino | Dicen, Demijon | Diezel, Helene | Adams, Jon | Steel, Amie | Wardle, Jon | Diezel, Helene | Steel, Amie | Frawley, Jane | Wardle, Jon | Broom, Alex | Adams, Jon | Dong, Fei | Yu, He | Liu, Tiegang | Ma, Xueyan | Yan, Liyi | Wan, Yuxiang | Zheng, Zian | Gu, Xiaohong | Dong, Fei | Yu, He | Wu, Liqun | Liu, Tiegang | Ma, Xueyan | Ma, Jiaju | Yan, Liyi | Wan, Yuxiang | Zheng, Zian | Zhen, Jianhua | Gu, Xiaohong | Dubois, Julie | Rodondi, Pierre-Yves | Edelhäuser, Friedrich | Schwartze, Sophia | Trapp, Barbara | Cysarz, Dirk
PMCID: PMC5498855
7.  Polarization sensitive optical coherence microscopy for brain imaging 
Optics letters  2016;41(10):2213-2216.
Optical coherence tomography (OCT) and optical coherence microscopy (OCM) have demonstrated the ability to investigate cyto- and myelo-architecture in the brain. Polarization-sensitive OCT provides sensitivity to additional contrast mechanisms, specifically the birefringence of myelination, and therefore is advantageous for investigating white matter fiber tracts. In this study, we developed a polarization-sensitive optical coherence microscope (PS-OCM) with 3.5 μm axial and 1.3 μm transverse resolution to investigate fiber organization and orientation at a finer scale than previously demonstrated with PS-OCT. In a fully reconstructed mouse brain section, we showed that at the focal depths of 20 – 70 μm, the PS-OCM reliably identifies the neuronal fibers and quantifies the in-plane orientation.
PMCID: PMC5357322  PMID: 27176965
8.  The Bacteriophage EF-P29 Efficiently Protects against Lethal Vancomycin-Resistant Enterococcus faecalis and Alleviates Gut Microbiota Imbalance in a Murine Bacteremia Model 
Enterococcus faecalis is becoming an increasingly important opportunistic pathogen worldwide, especially because it can cause life-threatening nosocomial infections. Treating E. faecalis infections has become increasingly difficult because of the prevalence of multidrug-resistant E. faecalis strains. Because bacteriophages show specificity for their bacterial hosts, there has been a growth in interest in using phage therapies to combat the rising incidence of multidrug-resistant bacterial infections. In this study, we isolated a new lytic phage, EF-P29, which showed high efficiency and a broad host range against E. faecalis strains, including vancomycin-resistant strains. The EF-P29 genome contains 58,984 bp (39.97% G+C), including 101 open reading frames, and lacks known putative virulence factors, integration-related proteins or antibiotic resistance determinants. In murine experiments, the administration of a single intraperitoneal injection of EF-P29 (4 × 105 PFU) at 1 h after challenge was sufficient to protect all mice against bacteremia caused by infection with a vancomycin-resistant E. faecalis strain (2 × 109 CFU/mouse). E. faecalis colony counts were more quickly eliminated in the blood of EF-P29-protected mice than in unprotected mice. We also found that exogenous E. faecalis challenge resulted in enrichment of members of the genus Enterococcus (family Enterococcaceae) in the guts of the mice, suggesting that it can enter the gut and colonize there. The phage EF-P29 reduced the number of colonies of genus Enterococcus and alleviated the gut microbiota imbalance that was caused by E. faecalis challenge. These data indicate that the phage EF-P29 shows great potential as a therapeutic treatment for systemic VREF infection. Thus, phage therapies that are aimed at treating opportunistic pathogens are also feasible. The dose of phage should be controlled and used at the appropriate level to avoid causing imbalance in the gut microbiota.
PMCID: PMC5423268
vancomycin-resistant Enterococcus faecalis; phage therapy; bacteremia; gut microbiota; opportunistic pathogens
9.  Community partnerships in healthy eating and lifestyle promotion: A network analysis 
Preventive Medicine Reports  2017;6:294-301.
Promoting healthy eating and lifestyles among populations with limited resources is a complex undertaking that often requires strong partnerships between various agencies. In local communities, these agencies are typically located in different areas, serve diverse subgroups, and operate distinct programs, limiting their communication and interactions with each other. This study assessed the network of agencies in local communities that promote healthy eating and lifestyles among populations with limited resources. Network surveys were administered in 2016 among 89 agencies located in 4 rural counties in Michigan that served limited-resource audiences. The agencies were categorized into 8 types: K-12 schools, early childhood centers, emergency food providers, health-related agencies, social resource centers, low-income/subsidized housing complexes, continuing education organizations, and others. Network analysis was conducted to examine 4 network structures—communication, funding, cooperation, and collaboration networks between agencies within each county. Agencies had a moderate level of cooperation, but were only loosely connected in the other 3 networks, indicated by low network density. Agencies in a network were decentralized rather than centralized around a few influential agencies, indicated by low centralization. There was evidence regarding homophily in a network, indicated by some significant correlations within agencies of the same type. Agencies connected in any one network were considerably more likely to be connected in all the other networks as well. In conclusion, promoting healthy eating and lifestyles among populations with limited resources warrants strong partnership between agencies in communities. Network analysis serves as a useful tool to evaluate community partnerships and facilitate coalition building.
•We assess network of agencies promoting healthy lifestyle in limited-resource people.•Agencies were only loosely connected and largely decentralized.•Agencies of the same type were more closely connected than those of different types.•Agencies connected in one network were more likely to be connected in other networks.•Network analysis is a useful tool to evaluate and facilitate community partnerships.
PMCID: PMC5390690
Community networks; Diet; Life style
10.  Stabilization of Two Radicals with One Metal: A Stepwise Coupling Model for Copper-Catalyzed Radical–Radical Cross-Coupling 
Scientific Reports  2017;7:43579.
Transition metal-catalyzed radical–radical cross-coupling reactions provide innovative methods for C–C and C–heteroatom bond construction. A theoretical study was performed to reveal the mechanism and selectivity of the copper-catalyzed C–N radical–radical cross-coupling reaction. The concerted coupling pathway, in which a C–N bond is formed through the direct nucleophilic addition of a carbon radical to the nitrogen atom of the Cu(II)–N species, is demonstrated to be kinetically unfavorable. The stepwise coupling pathway, which involves the combination of a carbon radical with a Cu(II)–N species before C–N bond formation, is shown to be probable. Both the Mulliken atomic spin density distribution and frontier molecular orbital analysis on the Cu(II)–N intermediate show that the Cu site is more reactive than that of N; thus, the carbon radical preferentially react with the metal center. The chemoselectivity of the cross-coupling is also explained by the differences in electron compatibility of the carbon radical, the nitrogen radical and the Cu(II)–N intermediate. The higher activation free energy for N–N radical–radical homo-coupling is attributed to the mismatch of Cu(II)–N species with the nitrogen radical because the electrophilicity for both is strong.
PMCID: PMC5341085  PMID: 28272407
11.  Length of stay, hospitalization cost, and in-hospital mortality in US adult inpatients with immune thrombocytopenic purpura, 2006–2012 
In this study, we examined the length of stay, hospitalization cost, and risk of in-hospital mortality among US adult inpatients with immune thrombocytopenic purpura (ITP).
We analyzed nationally representative data obtained from Nationwide/National Inpatient Sample database of discharges from 2006 to 2012.
In the US, there were an estimated 296,870 (95% confidence interval [CI]: 284,831–308,909) patient discharges recorded for ITP from 2006 to 2012, during which ITP-related hospitalizations had increased steadily by nearly 30%. The average length of stay for an ITP-related hospitalization was found to be 6.02 days (95% CI: 5.93–6.10), which is 28% higher than that of the overall US discharge population (4.70 days, 95% CI: 4.66–4.74). The average cost of ITP-related hospitalizations was found to be US$16,594 (95% CI: US$16,257–US$16,931), which is 48% higher than that of the overall US discharge population (US$11,200; 95% CI: US$11,033–US$11,368). Gender- and age-adjusted mortality risk in inpatients with ITP was 22% (95% CI: 19%–24%) higher than that of the overall US discharge population. Across diagnosis related groups, length of stay for ITP-related hospitalizations was longest for septicemia (7.97 days, 95% CI: 7.55–8.39) and splenectomy (7.40 days, 95% CI: 6.94–7.86). Splenectomy (US$25,262; 95% CI: US$24,044–US$26,481) and septicemia (US$18,430; 95% CI: US$17,353–US$19,507) were associated with the highest cost of hospitalization. The prevalence of mortality in ITP-related hospitalizations was highest for septicemia (11.11%, 95% CI: 9.60%–12.63%) and intracranial hemorrhage (9.71%, 95% CI: 7.65%–11.77%).
Inpatients with ITP had longer hospital stay, bore higher costs, and faced greater risk of mortality than the overall US discharge population.
PMCID: PMC5268091  PMID: 28176930
hospitalization; inpatient; cost; mortality; length of stay; immune thrombocytopenic purpura; national inpatient sample
12.  Mapping the Prevalence of Physical Inactivity in U.S. States, 1984-2015 
PLoS ONE  2016;11(12):e0168175.
Physical inactivity is a leading cause of morbidity, disability and premature mortality in the U.S. and worldwide. This study aimed to map the prevalence of physical inactivity across U.S. states over the past three decades, and estimate the over-time adjusted changes in the prevalence of physical inactivity in each state.
Individual-level data (N = 6,701,954) were taken from the 1984–2015 Behavioral Risk Factor Surveillance System (BRFSS), an annually repeated cross-sectional survey of state-representative adult population. Prevalence of self-reported leisure-time physical inactivity was estimated by state and survey year, accounting for the BRFSS sampling design. Logistic regressions were performed to estimate the changes in the prevalence of physical inactivity over the study period for each state, adjusting for individual characteristics including sex, age, race/ethnicity, education, marital status, and employment status.
The prevalence of leisure-time physical inactivity varied substantially across states and survey years. In general, the adjusted prevalence of physical inactivity gradually declined over the past three decades in a majority of states. However, a substantial proportion of American adults remain physically inactive. Among the 50 states and District of Columbia, 45 had over a fifth of their adult population without any leisure-time physical activity, and 8 had over 30% without physical activity in 2015. Moreover, the adjusted prevalence of physical inactivity in several states (Arizona, North Carolina, North Dakota, Utah, West Virginia, and Wyoming) remained largely unchanged or even increased (Minnesota and Ohio) over the study period.
Although the prevalence of physical inactivity declined over the past three decades in a majority of states, the rates remain substantially high and vary considerably across states. Closely monitoring and tracking physical activity level using the state physical activity maps can help guide policy and program development to promote physical activity and reduce the burden of chronic disease.
PMCID: PMC5154575  PMID: 27959906
13.  Cost-Effectiveness of Nutrition Intervention in Long-Term Care 
To determine the cost-effectiveness of two nutrition interventions on food, beverage, and supplement intake and body weight.
Randomized, controlled trial.
Five skilled nursing home facilities.
Long-stay residents with orders for nutrition supplementation (N = 154).
Participants were randomized into a usual care control group, an oral liquid nutrition supplement (ONS) intervention group, or a snack intervention group. Research staff provided ONS, according to orders or a variety of snack foods and beverages twice per day between meals, 5 days per week for 24 weeks and assistance to promote consumption.
Research staff independently weighed residents at baseline and monthly during the 24-week intervention. Resident food, beverage and supplement intake and the amount of staff time spent providing assistance were assessed for 2 days at baseline and 2 days per month during the intervention using standardized observation and weighed intake procedures.
The ONS intervention group took in an average of 265 calories more per day and the snack intervention group an average of 303 calories more per day than the control group. Staff time required to provide each intervention averaged 11 and 14 minutes per person per offer for ONS and snacks, respectively, and 3 minutes for usual care. Both interventions were cost-effective in increasing caloric intake, but neither intervention had a significant effect on body weight, despite positive trends.
Oral liquid nutrition supplements and snack offers were efficacious in promoting caloric intake when coupled with assistance to promote consumption and a variety of options, but neither intervention resulted in significant weight gain.
PMCID: PMC5131725  PMID: 26503137
long-term care; nutrition intervention; oral liquid nutrition supplements; unintentional weight loss
14.  Survivin Improves Reprogramming Efficiency of Human Neural Progenitors by Single Molecule OCT4 
Stem Cells International  2016;2016:4729535.
Induced pluripotent stem (iPS) cells have been generated from human somatic cells by ectopic expression of four Yamanaka factors. Here, we report that Survivin, an apoptosis inhibitor, can enhance iPS cells generation from human neural progenitor cells (NPCs) together with one factor OCT4 (1F-OCT4-Survivin). Compared with 1F-OCT4, Survivin accelerates the process of reprogramming from human NPCs. The neurocyte-originated induced pluripotent stem (NiPS) cells generated from 1F-OCT4-Survivin resemble human embryonic stem (hES) cells in morphology, surface markers, global gene expression profiling, and epigenetic status. Survivin keeps high expression in both iPS and ES cells. During the process of NiPS cell to neural cell differentiation, the expression of Survivin is rapidly decreased in protein level. The mechanism of Survivin promotion of reprogramming efficiency from NPCs may be associated with stabilization of β-catenin in WNT signaling pathway. This hypothesis is supported by experiments of RT-PCR, chromatin immune-precipitation, and Western blot in human ES cells. Our results showed overexpression of Survivin could improve the efficiency of reprogramming from NPCs to iPS cells by one factor OCT4 through stabilization of the key molecule, β-catenin.
PMCID: PMC5128714  PMID: 27974895
15.  Optimization of hierarchical structure and nanoscale-enabled plasmonic refraction for window electrodes in photovoltaics 
Nature Communications  2016;7:12825.
An ideal network window electrode for photovoltaic applications should provide an optimal surface coverage, a uniform current density into and/or from a substrate, and a minimum of the overall resistance for a given shading ratio. Here we show that metallic networks with quasi-fractal structure provides a near-perfect practical realization of such an ideal electrode. We find that a leaf venation network, which possesses key characteristics of the optimal structure, indeed outperforms other networks. We further show that elements of hierarchal topology, rather than details of the branching geometry, are of primary importance in optimizing the networks, and demonstrate this experimentally on five model artificial hierarchical networks of varied levels of complexity. In addition to these structural effects, networks containing nanowires are shown to acquire transparency exceeding the geometric constraint due to the plasmonic refraction.
In photovoltaics window electrodes must display uniform current transport, as well as high light transmission from the substrate. Here, Han et al. show that quasi-fractal metallic networks provide a practical realization of an electrode structure with an optimal surface coverage and a uniform current density.
PMCID: PMC5052667  PMID: 27667099
16.  LysGH15 kills Staphylococcus aureus without being affected by the humoral immune response or inducing inflammation 
Scientific Reports  2016;6:29344.
The lysin LysGH15, derived from the staphylococcal phage GH15, exhibits a wide lytic spectrum and highly efficient lytic activity against methicillin-resistant Staphylococcus aureus (MRSA). Here, we found that LysGH15 did not induce resistance in MRSA or methicillin-sensitive S. aureus (MSSA) strains after repeated treatment. Although LysGH15 triggered the generation of LysGH15-specific antibodies in mice, these antibodies did not block lytic activity in vitro (nor the binding capacity of LysGH15). More importantly, when the antibody titre was highest in mice immunized with LysGH15, a single intravenous injection of LysGH15 was sufficient to protect mice against lethal infection with MRSA. These results indicated that LysGH15-specific antibodies did not affect the killing efficiency of LysGH15 against MRSA in vitro or in vivo. LysGH15 also reduced pro-inflammatory cytokines in mice with lethal infections. Furthermore, a high-dose LysGH15 injection did not cause significant adverse effects or pathological changes in the main organs of treated animals. These results provide further evidence for the administration of LysGH15 as an alternative strategy for the treatment of infections caused by MRSA.
PMCID: PMC4935890  PMID: 27385518
17.  Inexpensive transparent nanoelectrode for crystalline silicon solar cells 
We report an easily manufacturable and inexpensive transparent conductive electrode for crystalline silicon (c-Si) solar cells. It is based on a silver nanoparticle network self-forming in the valleys between the pyramids of a textured solar cell surface, transformed into a nanowire network by sintering, and subsequently “buried” under the silicon surface by a metal-assisted chemical etching. We have successfully incorporated these steps into the conventional c-Si solar cell manufacturing process, from which we have eliminated the expensive screen printing and firing steps, typically used to make the macro-electrode of conducting silver fingers. The resulting, preliminary solar cell achieved power conversion efficiency only 14 % less than the conventionally processed c-Si control cell. We expect that a cell with an optimized processing will achieve at least efficiency of the conventional commercial cell, but at significantly reduced manufacturing cost.
Electronic supplementary material
The online version of this article (doi:10.1186/s11671-016-1533-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4927558  PMID: 27356559
Metallic nanowire networks; Metal-assisted chemical etching; Antireflection coating; Photovoltaics; Crystalline silicon solar cells
18.  Plain Water and Sugar-Sweetened Beverage Consumption in Relation to Energy and Nutrient Intake at Full-Service Restaurants 
Nutrients  2016;8(5):263.
Background: Drinking plain water, such as tap or bottled water, provides hydration and satiety without adding calories. We examined plain water and sugar-sweetened beverage (SSB) consumption in relation to energy and nutrient intake at full-service restaurants. Methods: Data came from the 2005–2012 National Health and Nutrition Examination Survey, comprising a nationally-representative sample of 2900 adults who reported full-service restaurant consumption in 24-h dietary recalls. Linear regressions were performed to examine the differences in daily energy and nutrient intake at full-service restaurants by plain water and SSB consumption status, adjusting for individual characteristics and sampling design. Results: Over 18% of U.S. adults had full-service restaurant consumption on any given day. Among full-service restaurant consumers, 16.7% consumed SSBs, 2.6% consumed plain water but no SSBs, and the remaining 80.7% consumed neither beverage at the restaurant. Compared to onsite SSB consumption, plain water but no SSB consumption was associated with reduced daily total energy intake at full-service restaurants by 443.4 kcal, added sugar intake by 58.2 g, saturated fat intake by 4.4 g, and sodium intake by 616.8 mg, respectively. Conclusion: Replacing SSBs with plain water consumption could be an effective strategy to balance energy/nutrient intake and prevent overconsumption at full-service restaurant setting.
PMCID: PMC4882676  PMID: 27153083
plain water; sugar-sweetened beverage; diet quality; 24-h dietary recall; full-service restaurant; energy intake; added sugar; saturated fat; sodium
19.  Cloning and purification of the first termicin-like peptide from the cockroach Eupolyphaga sinensis 
Termicin is an antimicrobial peptide with six cysteines forming three disulfide bridges that was firstly isolated from the salivary glands and hemocytes of the termite Pseudacanthotermes spiniger. In contrast to many broad-spectrum antimicrobial peptides, termicin is most active against filamentous fungi. Although more than one hundred complementary DNAs (cDNAs) encoding termicin-like peptides have been reported to date, all these termicin-like peptides were obtained from Isoptera insects.
The cDNA was cloned by combination of cDNA library construction kit and DNA sequencing. The polypeptide was purified by gel filtration and reversed-phase high performance liquid chromatography (RP-HPLC). Its amino acid sequence was determined by Edman degradation and mass spectrometry. Antimicrobial activity was tested against several bacterial and fungal strains. The minimum inhibitory concentration (MIC) was determined by microdilution tests.
A novel termicin-like peptide with primary structure ACDFQQCWVTCQRQYSINFISARCNGDSCVCTFRT was purified from extracts of the cockroach Eupolyphaga sinensis (Insecta: Blattodea). The cDNA encoding Es-termicin was cloned by cDNA library screening. This cDNA encoded a 60 amino acid precursor which included a 25 amino acid signal peptide. Amino acid sequence deduced from the cDNA matched well with the result of protein Edman degradation. Susceptibility test indicated that Es-termicin showed strong ability to kill fungi with a MIC of 25 μg/mL against Candida albicans ATCC 90028. It only showed limited potency to affect the growth of Gram-positive bacteria with a MIC of 200 μg/mL against Enterococcus faecalis ATCC 29212. It was inactive against gram-negative bacteria at the highest concentration tested (400 μg/mL). Es-termicin showed high sequence similarity with termicins from many species of termites (Insecta: Isoptera).
This is the first report of a termicin-like peptide isolated from E. sinensis that belongs to the insect order Blattodea. Our results demonstrate the diversity of termicin-like peptides, as well as antimicrobial peptides in insects.
PMCID: PMC4730610  PMID: 26823660
Eupolyphaga sinensis; Cockroach; Termicin-like peptide; Es-termicin; Antifungal peptide
20.  Cannabis Liberalization and Adolescent Cannabis Use: A Cross-National Study in 38 Countries 
PLoS ONE  2015;10(11):e0143562.
To assess the associations between types of cannabis control policies at country level and prevalence of adolescent cannabis use.
Setting, Participants and Design
Multilevel logistic regressions were performed on 172,894 adolescents 15 year of age who participated in the 2001/2002, 2005/2006, or 2009/2010 cross-sectional Health Behaviour in School-Aged Children (HBSC) survey in 38 European and North American countries.
Self-reported cannabis use status was classified into ever use in life time, use in past year, and regular use. Country-level cannabis control policies were categorized into a dichotomous measure (whether or not liberalized) as well as 4 detailed types (full prohibition, depenalization, decriminalization, and partial prohibition). Control variables included individual-level sociodemographic characteristics and country-level economic characteristics.
Considerable intra-class correlations (.15-.19) were found at country level. With respect to the dichotomized cannabis control policy, adolescents were more likely to ever use cannabis (odds ratio (OR) = 1.10, p = .001), use in past year (OR = 1.09, p = .007), and use regularly (OR = 1.26, p = .004). Although boys were substantially more likely to use cannabis, the correlation between cannabis liberalization and cannabis use was smaller in boys than in girls. With respect to detailed types of policies, depenalization was associated with higher odds of past-year use (OR = 1.14, p = .013) and regular use (OR = 1.23, p = .038), and partial prohibition was associated with higher odds of regular use (OR = 2.39, p = .016). The correlation between cannabis liberalization and regular use was only significant after the policy had been introduced for more than 5 years.
Cannabis liberalization with depenalization and partial prohibition policies was associated with higher levels of regular cannabis use among adolescents. The correlations were heterogeneous between genders and between short- and long-terms.
PMCID: PMC4659554  PMID: 26605550
21.  PAX6 Downregulates miR-124 Expression to Promote Cell Migration During Embryonic Stem Cell Differentiation 
Stem Cells and Development  2014;23(19):2297-2310.
PAX6-null mice exhibit defects in multiple organs leading to neonatal lethality, but the mechanism by which this occurs has not yet fully elucidated. In this study, we generated induced pluripotent stem cells (iPSCs) from Pax6-mutant mice and investigated the effect of PAX6 on cell fate during embryoid body (EB) formation. We found that PAX6 promotes cell migration by directly downregulating miR-124, which is important for the fate transition of migratory cells during gastrulation of embryonic stem (ES) cells. Although several downstream targets of miR-124 have been reported, little is known regarding the upstream regulation of miR-124. When we observed EB formation of iPSCs from Pax6-mutant mice, we found that higher levels of miR-124 in Pax6 homozygous EBs (Homo-EBs) inhibited cell migration, whereas inhibition of miR-124 in Homo-EBs rescued the migratory phenotypes associated with PAX6 deficiency. Further, we found that PAX6 binds to the promoter regions of the miR-124-3 gene and directly represses its expression. Therefore, we propose a novel PAX6-miR-124 pathway that controls ES cell migration. Our findings may provide important information for studies on ES cell differentiation and embryonic development.
PMCID: PMC4172463  PMID: 24773074
22.  Obesity and Economic Environments 
This review summarizes our understanding of economic factors during the obesity epidemic and dispels some widely held, but incorrect, beliefs: Rising obesity rates coincided with increases in leisure time (rather than increased work hours), increased fruit and vegetable availability (rather than a decline of healthier foods), and increased exercise uptake. As a share of disposable income, Americans now have the cheapest food available in history, which fueled the obesity epidemic. Weight gain was surprisingly similar across sociodemographic groups or geographic areas, rather than specific to some groups (at every point in time, however, there are clear disparities). It suggests that if we want to understand the role of the environment in the obesity epidemic, we need to understand changes over time affecting all groups, not differences between subgroups at a given time.
Although economic and technological changes in the environment drove the obesity epidemic, the evidence for effective economic policies to prevent obesity remains limited. Taxes on foods with low nutritional value could nudge behavior towards healthier diets, as could subsidies/discounts for healthier foods. However, even a large price change for healthy foods could only close a part of the gap between dietary guidelines and actual food consumption. Political support has been lacking for even moderate price interventions in the US and this may continue until the role of environment factors is accepted more widely. As opinion leaders, clinicians play an important role to shape the understanding of the causes of obesity.
PMCID: PMC4159423  PMID: 24853237
Economic environment; Food; Diet; Physical Activity; Obesity; Body weight; Price; Policy
23.  Randomized Clinical Trial of an Emergency Department Observation Syncope Protocol vs. Routine Inpatient Admission 
Annals of emergency medicine  2013;64(2):167-175.
Study Hypothesis
Older adults are frequently hospitalized from the emergency department (ED) after an episode of unexplained syncope. Current admission patterns are costly with little evidence of benefit. We hypothesized that an Emergency Department Observation Syncope Protocol would reduce resource use without adversely affecting patient-oriented outcomes.
This randomized trial at five EDs compared an ED observation syncope protocol to inpatient admission for intermediate-risk adults (≥50 years) presenting with syncope or near-syncope. Primary outcomes included inpatient admission rate and length-of-stay. Secondary outcomes included 30-day and 6-month serious outcomes after hospital discharge, index and 30-day hospital costs, 30-day quality-of-life scores, and 30-day patient satisfaction.
Study staff randomized 124 patients. Observation resulted in a lower inpatient admission rate (15% vs. 92%, 95%CI Difference: −88%, −66%) and shorter hospital length-of-stay (29 vs. 47 hours, 95%CI Difference: −28, −8). Serious outcome rates after hospital discharge were similar for observation vs. admission at 30-days (3% vs. 0%, 95%CI Difference: −1%, 8%) and 6-months (8% vs. 10%, 95%CI Difference: −13%, 9%). Index hospital costs in the observation group were $629 (95%CI Difference: −$1376, −$56) lower than in the admission group. There were no differences in 30-day quality-of-life scores or in patient satisfaction.
An ED observation syncope protocol reduced the primary outcomes of admission rate and hospital length-of-stay. Analyses of secondary outcomes suggest reduction in index hospital costs with no difference in safety events, quality-of-life, or patient satisfaction. Our findings suggest that an ED observation syncope protocol can be replicated and safely reduce resource use.
PMCID: PMC4019722  PMID: 24239341
24.  Overweight and obesity among U.S. adults with and without disability, 1999–2012 
Preventive Medicine Reports  2015;2:419-422.
Examine the relationship between disability and overweight/obesity among U.S. adults.
Study sample (N = 30,363) came from the National Health and Nutrition Examination Survey 1999–2012 waves. Disability was classified into five domains using standardized indices. Any disability was defined as having any difficulty in performing at least one of the activities in any of the five disability domains. Logistic regressions were conducted to estimate the association between disability and overweight/obesity, adjusted by individual characteristics and multiyear complex sampling design.
Over a quarter (25.99%) of U.S. adults 20 years and older reported having any disability. The overweight/obesity rates across all disability domains were substantially higher than their nondisabled counterparts. The rate of overweight and obesity combined (BMI ≥ 25 kg/m2), obesity (BMI ≥ 30 kg/m2), grade 2 and 3 obesity combined (BMI ≥ 35 kg/m2), and grade 3 obesity (BMI ≥ 40 kg/m2) among people with any disability were 1.14 (73.54% versus 64.50%), 1.38 (41.37% versus 29.99%), 1.71 (19.81% versus 11.60%), and 1.94 (8.60% versus 4.43%) times the corresponding rate among people without disability, respectively. Compared with their nondisabled counterparts, the adjusted odds of overweight and obesity combined, obesity, grade 2 and 3 obesity combined, and grade 3 obesity were 24% (95% confidence interval [CI]: 14%–36%), 32% (95% CI: 22%–44%), 49% (95% CI: 35%–64%), and 55% (95% CI: 27%–89%) higher among people with any disability, respectively.
People with disabilities have substantially higher risk of obesity compared to their nondisabled peers.
PMCID: PMC4721340  PMID: 26844099
Obesity; Overweight; Disability
25.  Microstructural Impact of Ischemia and Bone Marrow-Derived Cell Therapy Revealed with Diffusion Tensor MRI Tractography of the Heart In Vivo 
Circulation  2014;129(17):1731-1741.
The arrangement of myofibers in the heart is highly complex and must be replicated by injected cells to produce functional myocardium. A novel approach to characterize the microstructural response of the myocardium to ischemia and cell therapy, using serial diffusion tensor MRI (DTI) tractography of the heart in vivo, is presented.
Methods and Results
Validation of the approach was performed in normal (n=6) and infarcted mice (n=6) as well as healthy human volunteers. Mice (n=12) were then injected with bone marrow mononuclear cells (BMMCs) 3 weeks after coronary ligation. In half the mice the donor and recipient strains were identical and in half the strains were different. A positive response to cell injection was defined by a decrease in mean diffusivity, an increase in fractional anisotropy, and the appearance of new myofiber tracts with the correct orientation. A positive response to BMMC injection was seen in one mouse. The response of the majority of mice to BMMC injection was neutral (9/12) or negative (2/12). The in vivo tractography findings were confirmed with histology.
DTI-tractography was able to directly resolve the ability of injected cells to generate new myofiber tracts and provided a fundamental readout of their regenerative capacity. A highly novel and translatable approach to assess the efficacy of cell therapy in the heart is thus presented.
PMCID: PMC4034455  PMID: 24619466
Tractography; Diffusion Tensor MRI; Myocardium; Ischemia; Cell Therapy

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