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10. ESICM LIVES 2016: part one: Milan, Italy. 1-5 October 2016

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Bos, L., Schouten, L., van Vught, L., Wiewel, M., Ong, D., Cremer, O., Artigas, A., Martin-Loeches, I., Hoogendijk, A., van der Poll, T., Horn, J., Juffermans, N., Schultz, M., de Prost, N., Pham, T., Carteaux, G., Dessap, A. Mekontso, Brun-Buisson, C., Fan, E., Bellani, G., Laffey, J., Mercat, A., Brochard, L., Maitre, B., Howells, P. A., Thickett, D. R., Knox, C., Park, D. P., Gao, F., Tucker, O., Whitehouse, T., McAuley, D. F., Perkins, G. D., Pham, T., Laffey, J., Bellani, G., Fan, E., Pisani, L., Roozeman, J. P., Simonis, F. D., Giangregorio, A., Schouten, L. R., Van der Hoeven, S. M., Horn, J., Neto, A. Serpa, Festic, E., Dondorp, A. M., Grasso, S., Bos, L. D., Schultz, M. J., Koster-Brouwer, M., Verboom, D., Scicluna, B., van de Groep, K., Frencken, J., Schultz, M., van der Poll, T., Bonten, M., Cremer, O., Ko, J. I., Kim, K. S., Suh, G. J., Kwon, W. Y., Kim, K., Shin, J. H., Ranzani, O. T., Prina, E., Menendez, R., Ceccato, A., Mendez, R., Cilloniz, C., Gabarrus, A., Ferrer, M., Torres, A., Urbano, A., Zhang, L. A., Swigon, D., Pike, F., Parker, R. S., Clermont, G., Scheer, C., Kuhn, S. O., Modler, A., Vollmer, M., Fuchs, C., Hahnenkamp, K., Rehberg, S., Gründling, M., Taggu, A., Darang, N., Öveges, N., László, I., Tánczos, K., Németh, M., Lebák, G., Tudor, B., Érces, D., Kaszaki, J., Huber, W., Trásy, D., Molnár, Z., Ferrara, G., Edul, V. S. Kanoore, Canales, H. S., Martins, E., Canullán, C., Murias, G., Pozo, M. O., Eguillor, J. F. Caminos, Buscetti, M. G., Ince, C., Dubin, A., Aya, H. D., Rhodes, A., Fletcher, N., Grounds, R. M., Cecconi, M., Jacquet-Lagrèze, M., Riche, M., Schweizer, R., Portran, P., Fornier, W., Lilot, M., Neidecker, J., Fellahi, J. L., Escoresca-Ortega, A., Gutiérrez-Pizarraya, A., Charris-Castro, L., Corcia-Palomo, Y., Fernandez-Delgado, E., Garnacho-Montero, J., Roger, C., Muller, L., Elotmani, L., Lipman, J., Lefrant, J. Y., Roberts, J. A., Muñoz-Bermúdez, R., Samper, M., Climent, C., Vasco, F., Sara, V., Luque, S., Campillo, N., Cerrato, S. Grau, Masclans, J. R., Alvarez-Lerma, F., Brugger, S. Carvalho, Jimenez, G. Jimenez, Torner, M. Miralbés, Cabello, J. Trujillano, Garrido, B. Balsera, Casals, X. Nuvials, Gaite, F. Barcenilla, Vidal, M. Vallverdú, Martínez, M. Palomar, Gusarov, V., Shilkin, D., Dementienko, M., Nesterova, E., Lashenkova, N., Kuzovlev, A., Zamyatin, M., Demoule, A., Carreira, S., Lavault, S., Palancca, O., Morawiec, E., Mayaux, J., Arnulf, I., Similowski, T., Rasmussen, B. S., Maltesen, R. G., Hanifa, M., Pedersen, S., Kristensen, S. R., Wimmer, R., Panigada, M., Bassi, G. Li, Ranzani, O. T., Kolobow, T., Zanella, A., Cressoni, M., Berra, L., Parrini, V., Kandil, H., Salati, G., Livigni, S., Amatu, A., Andreotti, A., Tagliaferri, F., Moise, G., Mercurio, G., Costa, A., Vezzani, A., Lindau, S., Babel, J., Cavana, M., Consonni, D., Pesenti, A., Gattinoni, L., Torres, A., Mansouri, P., Zand, F., Zahed, L., Dehghanrad, F., Bahrani, M., Ghorbani, M., Cambiaghi, B., Moerer, O., Mauri, T., Kunze-Szikszay, N., Ritter, C., Pesenti, A., Quintel, M., Vilander, L. M., Kaunisto, M. A., Vaara, S. T., Pettilä, V., Mulier, J. L. G. Haitsma, Rozemeijer, S., Spoelstra-de Man, A. M. E., Elbers, P. E., Tuinman, P. R., de Waard, M. C., Oudemans-van Straaten, H. M., Liberatore, A. M. A., Souza, R. B., Martins, A. M. C. R. P. F., Vieira, J. C. F., Koh, I. H. J., Martínez, M. Galindo, Sánchez, R. Jiménez, Gascón, L. Martínez, Mulero, M. D. Rodríguez, Freire, A. Ortín, Muñoz, A. Ojados, Acebes, S. Rebollo, Martínez, Á. Fernández, Aliaga, S. Moreno, Para, L. Herrera, Payá, J. Murcia, Mulero, F. Rodríguez, Guerci, P., Ince, Y., Heeman, P., Ergin, B., Ince, C., Uz, Z., Massey, M., Ince, Y., Papatella, R., Bulent, E., Guerci, P., Toraman, F., Ince, C., Longbottom, E. R., Torrance, H. D., Owen, H. C., Hinds, C. J., Pearse, R. M., O’Dywer, M. J., Trogrlic, Z., van der Jagt, M., Lingsma, H., Ponssen, H. H., Schoonderbeek, J. F., Schreiner, F., Verbrugge, S. J., Duran, S., van Achterberg, T., Bakker, J., Gommers, D. A. M. P. J., Ista, E., Krajčová, A., Waldauf, P., Duška, F., Shah, A., Roy, N., McKechnie, S., Doree, C., Fisher, S., Stanworth, S. J., Jensen, J. F., Overgaard, D., Bestle, M. H., Christensen, D. F., Egerod, I., Pivkina, A., Gusarov, V., Zhivotneva, I., Pasko, N., Zamyatin, M., Jensen, J. F., Egerod, I., Bestle, M. H., Christensen, D. F., Alklit, A., Hansen, R. L., Knudsen, H., Grode, L. B., Overgaard, D., Hravnak, M., Chen, L., Dubrawski, A., Clermont, G., Pinsky, M. R., Parry, S. M., Knight, L. D., Connolly, B. C., Baldwin, C. E., Puthucheary, Z. A., Denehy, L., Hart, N., Morris, P. E., Mortimore, J., Granger, C. L., Jensen, H. I., Piers, R., Van den Bulcke, B., Malmgren, J., Metaxa, V., Reyners, A. K., Darmon, M., Rusinova, K., Talmor, D., Meert, A. P., Cancelliere, L., Zubek, L., Maia, P., Michalsen, A., Decruyenaere, J., Kompanje, E., Vanheule, S., Azoulay, E., Vansteelandt, S., Benoit, D., Van den Bulcke, B., Piers, R., Jensen, H. I., Malmgren, J., Metaxa, V., Reyners, A. K., Darmon, M., Rusinova, K., Talmor, D., Meert, A. P., Cancelliere, L., Zubek, L., Maia, P., Michalsen, A., Decruyenaere, J., Kompanje, E., Vanheule, S., Azoulay, E., Vansteelandt, S., Benoit, D., Ryan, C., Dawson, D., Ball, J., Noone, K., Aisling, B., Prudden, S., Ntantana, A., Matamis, D., Savvidou, S., Giannakou, M., Gouva, M., Nakos, G., Koulouras, V., Aron, J., Lumley, G., Milliken, D., Dhadwal, K., McGrath, B. A., Lynch, S. J., Bovento, B., Sharpe, G., Grainger, E., Pieri-Davies, S., Wallace, S., McGrath, B., Lynch, S. J., Bovento, B., Grainger, E., Pieri-Davies, S., Sharpe, G., Wallace, S., Jung, M., Cho, J., Park, H., Suh, G., Kousha, O., Paddle, J., Gripenberg, L. Gamrin, Rehal, M. Sundström, Wernerman, J., Rooyackers, O., de Grooth, H. J., Choo, W. P., Spoelstra-de Man, A. M., Swart, E. L., Oudemans-van Straaten, H. M., Talan, L., Güven, G., Altıntas, N. D., Padar, M., Uusvel, G., Starkopf, L., Starkopf, J., Blaser, A. Reintam, Kalaiselvan, M. S., Arunkumar, A. S., Renuka, M. K., Shivkumar, R. L., Volbeda, M., ten Kate, D., Hoekstra, M., van der Maaten, J. M., Nijsten, M. W., Komaromi, A., Rooyackers, O., Wernerman, J., Norberg, Å., Smedberg, M., Mori, M., Pettersson, L., Norberg, Å., Rooyackers, O., Wernerman, J., Theodorakopoulou, M., Christodoulopoulou, T., Diamantakis, A., Frantzeskaki, F., Kontogiorgi, M., Chrysanthopoulou, E., Lygnos, M., Diakaki, C., Armaganidis, A., Gundogan, K., Dogan, E., Coskun, R., Muhtaroglu, S., Sungur, M., Ziegler, T., Guven, M., Kleyman, A., Khaliq, W., Andreas, D., Singer, M., Meierhans, R., Schuepbach, R., De Brito-Ashurst, I., Zand, F., Sabetian, G., Nikandish, R., Hagar, F., Masjedi, M., Maghsudi, B., Vazin, A., Ghorbani, M., Asadpour, E., Kao, K. C., Chiu, L. C., Hung, C. Y., Chang, C. H., Li, S. H., Hu, H. C., El Maraghi, S., Ali, M., Rageb, D., Helmy, M., Marin-Corral, J., Vilà, C., Masclans, J. R., Vàzquez, A., Martín-Loeches, I., Díaz, E., Yébenes, J. C., Rodriguez, A., Álvarez-Lerma, F., Varga, N., Cortina-Gutiérrez, A., Dono, L., Martínez-Martínez, M., Maldonado, C., Papiol, E., Pérez-Carrasco, M., Ferrer, R., Nweze, K., Morton, B., Welters, I., Houard, M., Voisin, B., Ledoux, G., Six, S., Jaillette, E., Nseir, S., Romdhani, S., Bouneb, R., Loghmari, D., Aicha, N. Ben, Ayachi, J., Meddeb, K., Chouchène, I., Khedher, A., Boussarsar, M., Chan, K. S., Yu, W. L., Marin-Corral, J., Vilà, C., Masclans, J. R., Nolla, J., Vidaur, L., Bonastre, J., Suberbiola, B., Guerrero, J. E., Rodriguez, A., Coll, N. Ramon, Jiménez, G. Jiménez, Brugger, S. Carvalho, Calero, J. Codina, Garrido, B. Balsera, García, M., Martínez, M. Palomar, Vidal, M. Vallverdú, de la Torre, M. C., Vendrell, E., Palomera, E., Güell, E., Yébenes, J. C., Serra-Prat, M., Bermejo-Martín, J. F., Almirall, J., Tomas, E., Escoval, A., Froe, F., Pereira, M. H. Vitoria, Velez, N., Viegas, E., Filipe, E., Groves, C., Reay, M., Chiu, L. C., Hu, H. C., Hung, C. Y., Chang, C. H., Li, S. H., Kao, K. C., Ballin, A., Facchin, F., Sartori, G., Zarantonello, F., Campello, E., Radu, C. M., Rossi, S., Ori, C., Simioni, P., Umei, N., Shingo, I., Santos, A. C., Candeias, C., Moniz, I., Marçal, R., e Silva, Z. Costa, Ribeiro, J. M., Georger, J. F., Ponthus, J. P., Tchir, M., Amilien, V., Ayoub, M., Barsam, E., Martucci, G., Panarello, G., Tuzzolino, F., Capitanio, G., Ferrazza, V., Carollo, T., Giovanni, L., Arcadipane, A., Sánchez, M. López, González-Gay, M. A., Díaz, F. J. Llorca, López, M. I. Rubio, Zogheib, E., Villeret, L., Nader, J., Bernasinski, M., Besserve, P., Caus, T., Dupont, H., Morimont, P., Habran, S., Hubert, R., Desaive, T., Blaffart, F., Janssen, N., Guiot, J., Pironet, A., Dauby, P., Lambermont, B., Zarantonello, F., Ballin, A., Facchin, F., Sartori, G., Campello, E., Pettenuzzo, T., Citton, G., Rossi, S., Simioni, P., Ori, C., Kirakli, C., Ediboglu, O., Ataman, S., Yarici, M., Tuksavul, F., Keating, S., Gibson, A., Gilles, M., Dunn, M., Price, G., Young, N., Remeta, P., Bishop, P., Zamora, M. D. Fernández, Muñoz-Bono, J., Curiel-Balsera, E., Aguilar-Alonso, E., Hinojosa, R., Gordillo-Brenes, A., Arboleda-Sánchez, J. A., Skorniakov, I., Vikulova, D., Whiteley, C., Shaikh, O., Jones, A., Ostermann, M., Forni, L., Scott, M., Sahatjian, J., Linde-Zwirble, W., Hansell, D., Laoveeravat, P., Srisawat, N., Kongwibulwut, M., Peerapornrattana, S., Suwachittanont, N., Wirotwan, T. O., Chatkaew, P., Saeyub, P., Latthaprecha, K., Tiranathanagul, K., Eiam-ong, S., Kellum, J. A., Berthelsen, R. E., Perner, A., Jensen, A. E. K., Jensen, J. U., Bestle, M. H., Gebhard, D. J., Price, J., Kennedy, C. E., Akcan-Arikan, A., Liberatore, A. M. A., Souza, R. B., Martins, A. M. C. R. P. F., Vieira, J. C. F., Kang, Y. R., Nakamae, M. N., Koh, I. H. J., Hamed, K., Khaled, M. M., Soliman, R. Aly, Mokhtar, M. Sherif, Seller-Pérez, G., Arias-Verdú, D., Llopar-Valdor, E., De-Diós-Chacón, I., Quesada-García, G., Herrera-Gutierrez, M. E., Hafes, R., Carroll, G., Doherty, P., Wright, C., Vera, I. G. Guerra, Ralston, M., Gemmell, M. L., MacKay, A., Black, E., Wright, C., Docking, R. I., Appleton, R., Ralston, M. R., Gemmell, L., Appleton, R., Wright, C., Docking, R. I., Black, E., Mackay, A., Rozemeijer, S., Mulier, J. L. G. Haitsma, Röttgering, J. G., Elbers, P. W. G., Spoelstra-de Man, A. M. E., Tuinman, P. R., de Waard, M. C., Oudemans-van Straaten, H. M., Mejeni, N., Nsiala, J., Kilembe, A., Akilimali, P., Thomas, G., Egerod, I., Andersson, A. E., Fagerdahl, A. M., Knudsen, V., Meddeb, K., Cheikh, A. Ben, Hamdaoui, Y., Ayachi, J., Guiga, A., Fraj, N., Romdhani, S., Sma, N., Bouneb, R., Chouchene, I., Khedher, A., Bouafia, N., Boussarsar, M., Amirian, A., Ziaian, B., Masjedi, M., Fleischmann, C., Thomas-Rueddel, D. O., Schettler, A., Schwarzkopf, D., Stacke, A., Reinhart, K., Filipe, E., Escoval, A., Martins, A., Sousa, P., Velez, N., Viegas, E., Tomas, E., Snell, G., Matsa, R., Paary, T. T. S., Kalaiselvan, M. S., Cavalheiro, A. M., Rocha, L. L., Vallone, C. S., Tonilo, A., Lobato, M. D. S., Malheiro, D. T., Sussumo, G., Lucino, N. M., Zand, F., Rosenthal, V. D., Masjedi, M., Sabetian, G., Maghsudi, B., Ghorbani, M., Dashti, A. Sanaei, Yousefipour, A., Goodall, J. R., Williamson, M., Tant, E., Thomas, N., Balci, C., Gonen, C., Haftacı, E., Gurarda, H., Karaca, E., Paldusová, B., Zýková, I., Šímová, D., Houston, S., D’Antona, L., Lloyd, J., Garnelo-Rey, V., Sosic, M., Sotosek-Tokmazic, V., Kuharic, J., Antoncic, I., Dunatov, S., Sustic, A., Chong, C. T., Sim, M., Lyovarin, T., Díaz, F. M. Acosta, Galdó, S. Narbona, Garach, M. Muñoz, Romero, O. Moreno, Bailón, A. M. Pérez, Pinel, A. Carranza, Colmenero, M., Gritsan, A., Gazenkampf, A., Korchagin, E., Dovbish, N., Lee, R. M., Lim, M. P. P., Chong, C. T., Lim, B. C. L., See, J. J., Assis, R., Filipe, F., Lopes, N., Pessoa, L., Pereira, T., Catorze, N., Aydogan, M. S., Aldasoro, C., Marchio, P., Jorda, A., Mauricio, M. D., Guerra-Ojeda, S., Gimeno-Raga, M., Colque-Cano, M., Bertomeu-Artecero, A., Aldasoro, M., Valles, S. L., Tonon, D., Triglia, T., Martin, J. C., Alessi, M. C., Bruder, N., Garrigue, P., Velly, L., Spina, S., Scaravilli, V., Marzorati, C., Colombo, E., Savo, D., Vargiolu, A., Cavenaghi, G., Citerio, G., Andrade, A. H. V., Bulgarelli, P., Araujo, J. A. P., Gonzalez, V., Souza, V. A., Costa, A., Massant, C., Filho, C. A. C. Abreu, Morbeck, R. A., Burgo, L. E., van Groenendael, R., van Eijk, L. T., Leijte, G. P., Koeneman, B., Kox, M., Pickkers, P., García-de la Torre, A., de la Torre-Prados, M., Fernández-Porcel, A., Rueda-Molina, C., Nuevo-Ortega, P., Tsvetanova-Spasova, T., Cámara-Sola, E., García-Alcántara, A., Salido-Díaz, L., Liao, X., Feng, T., Zhang, J., Cao, X., Wu, Q., Xie, Z., Li, H., Kang, Y., Winkler, M. S., Nierhaus, A., Mudersbach, E., Bauer, A., Robbe, L., Zahrte, C., Schwedhelm, E., Kluge, S., Zöllner, C., Morton, B., Mitsi, E., Pennington, S. H., Reine, J., Wright, A. D., Parker, R., Welters, I. D., Blakey, J. D., Rajam, G., Ades, E. W., Ferreira, D. M., Wang, D., Kadioglu, A., Gordon, S. B., Koch, R., Kox, M., Rahamat-Langedoen, J., Schloesser, J., de Jonge, M., Pickkers, P., Bringue, J., Guillamat-Prats, R., Torrents, E., Martinez, M. L., Camprubí-Rimblas, M., Artigas, A., Blanch, L., Park, S. Y., Park, Y. B., Song, D. K., Shrestha, S., Park, S. H., Koh, Y., Park, M. J., Hong, C. W., Lesur, O., Coquerel, D., Sainsily, X., Cote, J., Söllradl, T., Murza, A., Dumont, L., Dumaine, R., Grandbois, M., Sarret, P., Marsault, E., Salvail, D., Auger-Messier, M., Chagnon, F., Lauretta, M. P., Greco, E., Dyson, A., Singer, M., Preau, S., Ambler, M., Sigurta, A., Saeed, S., Singer, M., Sarıca, L. Topcu, Zibandeh, N., Genc, D., Gul, F., Akkoc, T., Kombak, E., Cinel, L., Akkoc, T., Cinel, I., Pollen, S. J., Arulkumaran, N., Singer, M., Torrance, H. D., Longbottom, E. R., Warnes, G., Hinds, C. J., Pennington, D. J., Brohi, K., O’Dwyer, M. J., Kim, H. Y., Na, S., Kim, J., Chang, Y. F., Chao, A., Shih, P. Y., Lee, C. T., Yeh, Y. C., Chen, L. W., Adriaanse, M., Trogrlic, Z., Ista, E., Lingsma, H., Rietdijk, W., Ponssen, H. H., Schoonderbeek, J. F., Schreiner, F., Verbrugge, S. J., Duran, S., Gommers, D. A. M. P. J., van der Jagt, M., Funcke, S., Sauerlaender, S., Saugel, B., Pinnschmidt, H., Reuter, D. A., Nitzschke, R., Perbet, S., Biboulet, C., Lenoire, A., Bourdeaux, D., Pereira, B., Plaud, B., Bazin, J. E., Sautou, V., Mebazaa, A., Constantin, J. M., Legrand, M., Boyko, Y., Jennum, P., Nikolic, M., Oerding, H., Holst, R., Toft, P., Nedergaard, H. K., Haberlandt, T., Jensen, H. I., Toft, P., Park, S., Kim, S., Cho, Y. J., Lim, Y. J., Chan, A., Tang, S., Nunes, S. L., Forsberg, S., Blomqvist, H., Berggren, L., Sörberg, M., Sarapohja, T., Wickerts, C. J., Hofhuis, J. G. M., Rose, L., Blackwood, B., Akerman, E., Mcgaughey, J., Egerod, I., Fossum, M., Foss, H., Georgiou, E., Graff, H. J., Kalafati, M., Sperlinga, R., Schafer, A., Wojnicka, A. G., Spronk, P. E., Zand, F., Khalili, F., Afshari, R., Sabetian, G., Masjedi, M., Maghsudi, B., Khodaei, H. Haddad, Javadpour, S., Petramfar, P., Nasimi, S., Vazin, A., Ziaian, B., Tabei, H., Gunther, A., Hansen, J. O., Sackey, P., Storm, H., Bernhardsson, J., Sundin, Ø., Bjärtå, A., Bienert, A., Smuszkiewicz, P., Wiczling, P., Przybylowski, K., Borsuk, A., Trojanowska, I., Matysiak, J., Kokot, Z., Paterska, M., Grzeskowiak, E., Messina, A., Bonicolini, E., Colombo, D., Moro, G., Romagnoli, S., De Gaudio, A. R., Corte, F. Della, Romano, S. M., Silversides, J. A., Major, E., Mann, E. E., Ferguson, A. J., Mcauley, D. F., Marshall, J. C., Blackwood, B., Fan, E., Diaz-Rodriguez, J. A., Silva-Medina, R., Gomez-Sandoval, E., Gomez-Gonzalez, N., Soriano-Orozco, R., Gonzalez-Carrillo, P. L., Hernández-Flores, M., Pilarczyk, K., Lubarksi, J., Wendt, D., Dusse, F., Günter, J., Huschens, B., Demircioglu, E., Jakob, H., Palmaccio, A., Dell’Anna, A. M., Grieco, D. L., Torrini, F., Iaquaniello, C., Bongiovanni, F., Antonelli, M., Toscani, L., Antonakaki, D., Bastoni, D., Aya, H. D., Rhodes, A., Cecconi, M., Jozwiak, M., Depret, F., Teboul, J. L., Alphonsine, J., Lai, C., Richard, C., Monnet, X., László, I., Demeter, G., Öveges, N., Tánczos, K., Németh, M., Trásy, D., Kertmegi, I., Érces, D., Tudor, B., Kaszaki, J., Molnár, Z., Hasanin, A., Lotfy, A., El-adawy, A., Nassar, H., Mahmoud, S., Abougabal, A., Mukhtar, A., Quinty, F., Habchi, S., Luzi, A., Antok, E., Hernandez, G., Lara, B., Enberg, L., Ortega, M., Leon, P., Kripper, C., Aguilera, P., Kattan, E., Bakker, J., Huber, W., Lehmann, M., Sakka, S., Bein, B., Schmid, R. M., Preti, J., Creteur, J., Herpain, A., Marc, J., Zogheib, E., Trojette, F., Bar, S., Kontar, L., Titeca, D., Richecoeur, J., Gelee, B., Verrier, N., Mercier, R., Lorne, E., Maizel, J., Dupont, H., Slama, M., Abdelfattah, M. E., Eladawy, A., Elsayed, M. A. Ali, Mukhtar, A., Montenegro, A. Pedraza, Zepeda, E. Monares, Granillo, J. Franco, Sánchez, J. S. Aguirre, Alejo, G. Camarena, Cabrera, A. Rugerio, Montoya, A. A. Tanaka, Lee, C., Hatib, F., Cannesson, M., Theerawit, P., Morasert, T., Sutherasan, Y., Zani, G., Mescolini, S., Diamanti, M., Righetti, R., Scaramuzza, A., Papetti, M., Terenzoni, M., Gecele, C., Fusari, M., Hakim, K. A., Chaari, A., Ismail, M., Elsaka, A. H., Mahmoud, T. M., Bousselmi, K., Kauts, V., Casey, W. F., Hutchings, S. D., Naumann, D., Wendon, J., Watts, S., Kirkman, E., Jian, Z., Buddi, S., Lee, C., Settels, J., Hatib, F., Pinsky, M. R., Bertini, P., Guarracino, F., Trepte, C., Richter, P., Haas, S. A., Eichhorn, V., Kubitz, J. C., Reuter, D. A., Soliman, M. S., Hamimy, W. I., Fouad, A. Z., Mukhtar, A. M., Charlton, M., Tonks, L., Mclelland, L., Coats, T. J., Thompson, J. P., Sims, M. R., Williams, D., Roushdy, D. Z., Soliman, R. A., Nahas, R. A., Arafa, M. Y., Hung, W. T., Chiang, C. C., Huang, W. C., Lin, K. C., Lin, S. C., Cheng, C. C., Kang, P. L., Wann, S. 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W., Kaymak, C., Okumus, N., Sari, A., Erdogdu, B., Aksun, S., Basar, H., Ozcan, A., Ozcan, N., Oztuna, D., Malmgren, J. A., Lundin, S., Torén, K., Eckerström, M., Wallin, A., Waldenström, A. C., Riccio, F. C., Pogson, D., Antonio, A. C. P., Leivas, A. F., Kenji, F., James, E., Morgan, P., Carroll, G., Gemmell, L., MacKay, A., Wright, C., Ballantyne, J., Jonnada, S., Gerrard, C. S., Jones, N., Salciccioli, J. D., Marshall, D. C., Komorowski, M., Hartley, A., Sykes, M. C., Goodson, R., Shalhoub, J., Villanueva, J. R. Fernández, Garda, R. Fernández, Lago, A. M. López, Ruiz, E. Rodríguez, Vaquero, R. Hernández, Rodríguez, C. Galbán, Pérez, E. Varo, Hilasque, C., Oliva, I., Sirgo, G., Martin, M. C., Olona, M., Gilavert, M. C., Bodí, M., Ebm, C., Aggarwal, G., Huddart, S., Quiney, N., Cecconi, M., Fernandes, S. M., Silva, J. Santos, Gouveia, J., Silva, D., Marques, R., Bento, H., Alvarez, A., Silva, Z. Costa, Diaz, D. Díaz, Martínez, M. Villanova, Herrejon, E. Palencia, de la Gandara, A. Martinez, Gonzalo, G., Lopez, M. A., de Gopegui Miguelena, P. Ruíz, Matilla, C. I. Bernal, Chueca, P. Sánchez, Longares, M. D. C. Rodríguez, Abril, R. Ramos, Aguilar, A. L. Ruíz, de Murillas, R. Garrido López, Fernández, R. Fernández, Laborías, P. Morales, Castellanos, M. A. Díaz, Laborías, M. E. Morales, Cho, J., Kim, J., Park, J., Woo, S., West, T., Powell, E., Rimmer, A., Orford, C., Jones, N., Williams, J., Matilla, C. I. Bernal, de Gopegui Miguelena, P. Ruiz, Chueca, P. Sánchez, Abril, R. Ramos, Longares, M. D. C. Rodríguez, Aguilar, A. L. Ruíz, de Murillas, R. Garrido López, Bourne, R. S., Shulman, R., Tomlin, M., Mills, G. H., Borthwick, M., Berry, W., Huertas, D. García, Manzano, F., Villagrán-Ramírez, F., Ruiz-Perea, A., Rodríguez-Mejías, C., Santiago-Ruiz, F., Colmenero-Ruiz, M., König, C., Matt, B., Kortgen, A., Hartog, C. S., Wong, A., Balan, C., Barker, G., Srisawat, N., Peerapornratana, S., Laoveeravat, P., Tachaboon, S., Eiam-ong, S., Paratz, J., Kayambu, G., Boots, R., Arzapalo, M. F. Aguilar, Vlasenko, R., Gromova, E., Loginov, S., Kiselevskiy, M., Dolgikova, Y., Tang, K. B., Chau, C. M., Lam, K. N., Gil, E., Suh, G. Y., Park, C. M., Park, J., Chung, C. R., Lee, C. T., Chao, A., Shih, P. Y., Chang, Y. F., Lai, C. H., Hsu, Y. C., Yeh, Y. C., Cheng, Y. J., Colella, V., Zarrillo, N., D’Amico, M., Forfori, F., Pezza, B., Laddomada, T., Beltramelli, V., Pizzaballa, M. L., Doronzio, A., Balicco, B., Kiers, D., van der Heijden, W., Gerretsen, J., de Mast, Q., el Messaoudi, S., Rongen, G., Gomes, M., Kox, M., Pickkers, P., Riksen, N. P., Kashiwagi, Y., Okada, M., Hayashi, K., Inagaki, Y., Fujita, S., Nakamae, M. N., Kang, Y. R., Souza, R. B., Liberatore, A. M. A., Koh, I. H. J., Blet, A., Sadoune, M., Lemarié, J., Bihry, N., Bern, R., Polidano, E., Merval, R., Launay, J. M., Lévy, B., Samuel, J. L., Mebazaa, A., Hartmann, J., Harm, S., and Weber, V.

Published
2016
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14. Modelling the neuropathology of lysosomal storage disorders through disease-specific human induced pluripotent stem cells

Author

Kobolak, J., Molnar, K., Varga, E. (Endre), Bock, I., Jerso, B., Teglasi, A., Zhou, S.L., Lo Giudice, M., Westerveld, M. (Michael), Pijnappel, W., Phanthong, P., Varga, N., Kitiyanant, N., Freude, K., Nakanishi, H., Laszlo, L., Hyttel, P., Dinnyes, A., Kobolak, J., Molnar, K., Varga, E. (Endre), Bock, I., Jerso, B., Teglasi, A., Zhou, S.L., Lo Giudice, M., Westerveld, M. (Michael), Pijnappel, W., Phanthong, P., Varga, N., Kitiyanant, N., Freude, K., Nakanishi, H., Laszlo, L., Hyttel, P., and Dinnyes, A.

Abstract

Mucopolysaccharidosis II (MPS II) is a lysosomal storage disorder (LSD), caused by iduronate 2-sulphatase (IDS) enzyme dysfunction. The neuropathology of the disease is not well understood, although the neural symptoms are currently incurable. MPS II-patient derived iPSC lines were established and differentiated to neuronal lineage. The disease phenotype was confirmed by IDS enzyme and glycosaminoglycan assay. MPS II neuronal precursor cells (NPCs) showed significantly decreased self-renewal capacity, while their cortical neuronal differentiation potential was not affected. Major structural alterations in the ER and Golgi complex, accumulation of storage vacuoles, and increased apoptosis were observed both at protein expression and ultrastructural level in the MPS II neuronal cells, which was more pronounced in GFAP + astrocytes, with increased LAMP2 expression but unchanged in their RAB7 compartment. Based on these finding we hypothesize that lysosomal membrane protein (LMP) carrier vesicles have an initiating role in the formation of storage vacuoles leading to impaired lysosomal function. In conclusion, a novel human MPS II disease model was established for the first time which recapitulates the in vitro neuropathology of the disorder, providing novel information on the disease mechanism which allows better understanding of further lysosomal storage disorders and facilitates drug testing and gene therapy approaches.

Published
2019
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15. Modelling the neuropathology of lysosomal storage disorders through disease-specific human induced pluripotent stem cells

Author

Kobolak, J, Molnar, K, Varga, E, Bock, I, Jerso, B, Teglasi, A, Zhou, SL, Lo Giudice, M, Hoogeveen - Westerveld, Marianne, Pijnappel, Pim, Phanthong, P, Varga, N, Kitiyanant, N, Freude, K, Nakanishi, H, Laszlo, L, Hyttel, P, Dinnyes, A, Kobolak, J, Molnar, K, Varga, E, Bock, I, Jerso, B, Teglasi, A, Zhou, SL, Lo Giudice, M, Hoogeveen - Westerveld, Marianne, Pijnappel, Pim, Phanthong, P, Varga, N, Kitiyanant, N, Freude, K, Nakanishi, H, Laszlo, L, Hyttel, P, and Dinnyes, A

Published
2019

20. Human Papillomavirus DNA and Host Gene mRNA Biomarker Detection in a 'Micro Total Analysis System' (microTAS) Device to Aid Diagnosis of Cervical Intraepithelial Neoplasia

Author

Keegan, H., Pilkington, L., Jordan, R., Mozes, J., Varga, N., Benczik, M., Riegger, L., Koltay, P., Sauer, U., Preininger, C., Koger, B., Brandenburg, A., Müller, W., Faltin, B., Roth, G., Martin, C., Jeney, C., O'Leary, J.J., and Publica

Abstract

Background: Human papillomavirus (HPV) DNA detection has high sensitivity for high-grade cervical intraepithelial neoplasia (CIN), but low specifi city. Cervical cancer research is focused on development of biomarkers (BM) for prediction of disease severity eg. HPV E6/E7mRNA and p16INK4a/Ki67. This study describes a novel set of host mRNA biomarkers, mediator probe PCR (MP-PCR), and microTAS device for HPV DNA and BM detection in LBC. Design: A panel of 21 BM were validated by TaqMan PCR assays on 692 women with known histology and HPV status (Hybrid Capture 2 (HC2) and Linear Array HPV Genotyping (LA-HPV)) recruited from colposcopy clinics through CERVIVA (The Irish Cervical Screening Research Consortium) and Jedlik Anyos HPV Screen Multicentric Clinical Study, Hungary. A novel MP-PCR test was designed for HPV and BM detection, clinically validated on AB7900 thermal cycler and miniaturised for use in a microfluidic chip run on an instrument designed for multichannel thermal cycling and fluorophore detection (microTAS device). Results: Combined BM and HPV testing by TaqMan and hc2 had high specificity (91%), and sensitivity (75%) for CIN1+. HPV16 MP-PCR on AB7900 had high positive predictive value (95%), comparable to HC2 (94%) for CIN2+. On the microTAS device, the HPV16 MP-PCR had a limit of detection of 160 HPV16 copies with high sensitivity (85%) and concordance (82%) to LA-HPV for HPV16 detection. Concordance of TaqMan PCR and the microTAS device for 4 of the mRNA BM ranged from 79% to 83.3%. Conclusions: Combined mRNA BM and HPV DNA detection by PCR methods may be a useful alternative to consecutive BM and HPV, can be readily adapted for microTAS and should be explored further.

Published
2014

21. Designing nanomolar antagonists of DC-SIGN-mediated HIV infection: Ligand presentation using molecular rods

Author

Ordanini, S, Varga, N, Porkolab, V, Thépaut, M, Belvisi, L, Bertaglia, A, Palmioli, A, Berzi, A, Trabattoni, D, Clerici, M, Fieschi, F, Bernardi, A, Ordanini, Stefania, Varga, Norbert, Porkolab, Vanessa, Thépaut, Michel, Belvisi, Laura, Bertaglia, Andrea, Palmioli, Alessandro, Berzi, Angela, Trabattoni, Daria, Clerici, Mario, Fieschi, Franck, Bernardi, Anna, Ordanini, S, Varga, N, Porkolab, V, Thépaut, M, Belvisi, L, Bertaglia, A, Palmioli, A, Berzi, A, Trabattoni, D, Clerici, M, Fieschi, F, Bernardi, A, Ordanini, Stefania, Varga, Norbert, Porkolab, Vanessa, Thépaut, Michel, Belvisi, Laura, Bertaglia, Andrea, Palmioli, Alessandro, Berzi, Angela, Trabattoni, Daria, Clerici, Mario, Fieschi, Franck, and Bernardi, Anna

Abstract

DC-SIGN antagonists were designed combining one selective monovalent glycomimetic ligand with trivalent dendrons separated by a rigid core of controlled length. The design combines multiple multivalency effects to achieve inhibitors of HIV infection, which are active in nanomolar concentration.

Published
2015

26. Mechanisms of Acrylamide Formation.

Author

Back, Nathan, Cohen, Irun R., Kritchevsky, David, Lajtha, Abel, Paoletti, Rodolfo, Friedman, Mendel, Mottram, Don, Blank, I., Robert, F., Goldmann, T., Pollien, P., Varga, N., Devaud, S., Saucy, F., Huynh-Ba, T., and Stadler, R. H.

Abstract

The formation of acrylamide (AA) from L-asparagine was studied in Maillard model systems under pyrolysis conditions. While the early Maillard intermediate N-glucosylasparagine generated ∼2.4 mmol/mol AA, the Amadori compound was a less efficient precursor (0.1 mmol/mol). Reaction with α-dicarbonyls resulted in relatively low AA amounts (0.2–0.5 mmol/mol), suggesting that the Strecker aldehyde pathway is of limited relevance. Similarly, the Strecker alcohol 3-hydroxypropanamide generated low amounts of AA (0.2 mmol/mol). On the other hand, hydroxyacetone afforded more than 4 mmol/mol AA, indicating that α-hydroxycarbonyls are more efficient than α-dicarbonyls in transforming asparagine into AA. The experimental results are consistent with the reaction mechanism proposed, i.e. (i) Streckertype degradation of the Schiff base leading to azomethine ylides, followed by (ii) β-elimination of the decarboxylated Amadori compound to release AA, The functional group in β-position on both sides of the nitrogen atom is crucial. Rearrangement of the azomethine ylide to the decarboxylated Amadori compound is the key step, which is favored if the carbonyl moiety contains a hydroxyl group in β-position to the N-atom. The β-elimination step in the amino acid moiety was demonstrated by reacting under pyrolysis conditions decarboxylated model Amadori compounds obtained by synthesis. [ABSTRACT FROM AUTHOR]

Published
2005
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28. Formation of Vinylogous Compounds in Model Maillard Reaction Systems

Author

Stadler, R. H., Verzegnassi, L., Varga, N., Grigorov, M., Studer, A., Riediker, S., and Schilter, B.

Abstract

The thermal degradation over temperature and time of selected amino acids (Asp, Gln, and Glu) in the presence of reducing sugars was investigated in low moisture model systems. Copyrolysis of glucose−Asp mixtures led to the release of acrylic acid, attaining >5 mmol/mol Asp at 230 °C after 5 min. Spurious amounts of 3-butenamide were detected upon heating Gln together with a carbonyl source. Apparently, intramolecular cyclization is favored to procure 2-pyrrolidinone, reaching levels >3 mmol/mol above 230 °C. 2-Pyrrolidinone was also formed in comparable amounts in pyrolyzed sugar−Glu mixtures, indicating that the Maillard reaction may be an important contributor to the formation of 2-pyrrolidinone in certain cooked foods. The chemical route to acrylic acid and 3-butenamide is probably analogous to that described for acrylamide recently. Evidence is also presented that acrylic acid may be an intermediate in the formation of acrylamide, and yields could be augmented by coincubation of fructose−Asp with certain amino acids such as Gln, reaching approximately 5% of the yield obtained by the Asn route. A computational study to determine the reactivity of the vinylogous products indicated a reduced ability of 3-butenamide as compared to acrylamide to form stable intermediates by Michael nucleophilic addition. Acrylamide and acrylic acid exhibited a similar theoretical reactivity potential toward nucleophiles. No information is as yet available on the occurrence of acrylic acid in cooked foods. Extensive toxicological evaluation indicates that acrylic acid is of no concern at the amounts to be expected in foods.

Published
2003

30. Exploring the effects of light and sleep deprivation on the chromatin structure and transcriptional landscape of specific brain regions

Author

Walsh, SP, Taylor, L, Ashton, A, George, C, Di Pretoro, S, Varga, N, Foster, A, and Jagannath, A

Subjects
Bioinformatics, Circadian rhythms, Genomics, Molecular Biology
Abstract

Disruption to normal circadian rhythms and frequent periods of sleep deprivation (SD), are endemic in today’s 24 hour society; therefore understanding the fundamental biology underlying what happens in the suprachiasmatic nuclei (SCN) during entrainment, and other specific brain regions following SD has never been more important. Current understanding of entrainment and SD within the SCN at the molecular level is still very limited, despite SD already having been shown to have a profound effect on brain function. The published Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) protocol was successfully modified to allow the technique to be effective with small amounts of tissue collected from murine SCN tissue. ATAC-seq was effectively used to investigate chromatin accessibility within cells of the SCN following light pulsing at different times of the day, and following SD in the SCN, dentate gyrus, and cortex. Data from ATAC-seq light pulse experiments was compared to published gene expression data following light pulsing and determined changes in chromatin accessibility also affect the transcriptome. RNA-seq was used to investigate gene expression following SD, and gain insights into how chromatin affects the transcriptome following SD. Results obtained indicate, chromatin accessibility is highly dynamic within all brain regions investigated. ATAC-seq revealed chromatin accessibility changes in the SCN following light pulsing, but only at certain times of the day, and discovered chromatin modification across all brain regions following SD. Several genes identified close to differential chromatin are already known to play an important role within the molecular clock, and are recognized to be important for entrainment and SD. In addition several novel genes with differential chromatin nearby have been identified that also likely have an important role during entrainment and following SD. Several areas of differential chromatin were investigated using a luciferase reporter assay, and results obtained indicate the areas of chromatin are able to strongly drive gene expression, and respond to treatment using forskolin and horse serum, both known to have an effect on the molecular clock.

Published
2022

31. Legal History of the Development of the Process of Forced Execution of Claims in Croatian Law

Author

Kasap, Jelena, Lachner, Višnja, Frenkel, A. D., and Varga, N.

Subjects
process of forced execution of claims, Croatian mediaeval law, the customary law, compulsory settlements, enforcement proceedings
Abstract

Although modern legal science, both Croatian and comparative, recognizes a specially defined legal institute for enforcing claims that is realized in the framework of a special procedure governed by the Enforcement Act, the historical context of the development of the mentioned institute, although undisputable, was not so uniform. It is well known in numerous legal-historical researches that the emergence of the first forms of compulsory setlling of the claims can be found in antique legal systems, but features inherent to that institute suitable for modern legal interpretation begin to be individualized in medieval law. When it comes to Croatian mediaeval law, it should be borne in mind that the determination of the mentioned institution can not be interpreted by means of unique legal sources. For this reason, the subject of analysis in this research will be the provisions of the medieval statutes of our coastal cities and the customary law that was valid in the area of Slavonia and a smaller part of Croatia through the Verbeci's Tripartite. Provided that solutions used to enforce compulsory settlements in some research sources that we are daling with in this research are marked by the common features (along with some variations) in the content of the research we are going to describe and critically analyze the provisions related to the composition and authority of the bodies that have conducted the procedure, the order of settlement and the consequences of not granting a claim in a special proceeding. The purpose of this research is to realize the filling of obvious gaps in Croatian legal-historical science when it comes to the development of enforcement proceedings. This will set the safe foundation for studying the institute in contemporary law.

Published
2019

32. Manifestations of populism in late 5th century Athens

Author

Adamidis, V, Frenkel, DA, and Varga, N

Abstract

In this chapter, by reference to modern research on populism, the manifestations of this phenomenon in fifth century Athens are analysed, while pointing to some legal responses to counter it. Despite the rigorous and comprehensive study of Athenian democracy, surprisingly enough no systematic application of the concept of populism (as defined by modern political theory) to classical Athens has taken place; this chapter aims to fill this gap. My conclusion is that modern political theory on populism can be legitimately applied to contexts other than Western liberal democracies, being particularly suitable for a closer analysis of ancient Athens, while in return, Athenian legal and extralegal responses to populism could provide valuable guidance on how to tame this phenomenon.

Published
2019

34. Designing nanomolar antagonists of DC-SIGN-mediated HIV infection: ligand presentation using molecular rods

Author

Stefania Ordanini, Vanessa Porkolab, Angela Berzi, Alessandro Palmioli, Franck Fieschi, Laura Belvisi, Michel Thépaut, Mario Clerici, Daria Trabattoni, Anna Bernardi, Andrea Bertaglia, Norbert Varga, Università degli Studi di Milano = University of Milan (UNIMI), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fondazione Don Carlo Gnocchi, MP3, SPR, European Project: PITN-GA-2008-213592,ETN-Carmusys, Università degli Studi di Milano [Milano] (UNIMI), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Ordanini, S, Varga, N, Porkolab, V, Thépaut, M, Belvisi, L, Bertaglia, A, Palmioli, A, Berzi, A, Trabattoni, D, Clerici, M, Fieschi, F, and Bernardi, A

Subjects
Materials Chemistry2506 Metals and Alloys, CD4-Positive T-Lymphocytes, Dendrimers, Stereochemistry, Human immunodeficiency virus (HIV), Surfaces, Coatings and Film, Ligand, Ceramics and Composite, HIV Infections, Receptors, Cell Surface, Ligands, medicine.disease_cause, Catalysis, Catalysi, Cell Line, Glycomimetic, Dendrimer, Materials Chemistry, medicine, Humans, HIV Infection, Lectins, C-Type, Cells, Cultured, Serum Albumin, Rigid core, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, Electronic, Optical and Magnetic Material, Chemistry (all), Metals and Alloys, General Chemistry, Combinatorial chemistry, 3. Good health, Surfaces, Coatings and Films, Electronic, Optical and Magnetic Materials, DC-SIGN, CD4-Positive T-Lymphocyte, Cell Adhesion Molecule, HIV-1, Ceramics and Composites, biology.protein, Cell Adhesion Molecules, Mannose, Human
Abstract

International audience; DC-SIGN antagonists were designed combining one selective monovalent glycomimetic ligand with trivalent dendrons separated by a rigid core of controlled length. The design combines multiple multivalency effects to achieve inhibitors of HIV infection, which are active in nanomolar concentration.

Published
2015

35. European Young Pediatricians Association: Laying the Foundations for Collaboration, Integration, and Networking among Pediatricians of the Future

Author

Matthieu Bendavid, Andrea Bon, Sofia Rosenbaum, Vasile Valeriu Lupu, Ömer Faruk Beşer, Manuel Ferreira-Magalhães, Davide Vecchio, Harachuhi Ghazaryan, Mine Ozdil, David H. James, Borbala Zsigmond, Sebastian Gray, Ancuta Ignat, Salvatore Aversa, Maxime Bacquet, Roberto Raschetti, Pinar Urenden Elicin, Norbi Varga, Paola Berlese, Martin Magner, Gizem Pamuk, Gray, S., Raschetti, R., Beşer, Ö., Elicin, P., Aversa, S., Pamuk, G., Ozdil, M., Berlese, P., Ferreira-Magalhães, M., Magner, M., Ignat, A., Lupu, V., Zsigmond, B., Ghazaryan, H., Rosenbaum, S., Bendavid, M., Bacquet, M., Varga, N., James, D., Bon, A., and Vecchio, D.

Subjects
medicine.medical_specialty, Education, Medical, business.industry, International Cooperation, Child Health, Pediatrics, Child health, Europe, 03 medical and health sciences, 0302 clinical medicine, Physicians, 030225 pediatrics, Family medicine, Environmental health, Pediatrics, Perinatology and Child Health, Humans, Medicine, 030212 general & internal medicine, Child, business, Association (psychology), Societies, Medical
Published
2016
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36. Strengthening an Intramolecular Non-Classical Hydrogen Bond to Get in Shape for Binding.

Author

Varga N, Smieško M, Jiang X, Jakob RP, Wagner B, Mühlethaler T, Dätwyler P, Zihlmann P, Rabbani S, Maier T, Schwardt O, and Ernst B

Subjects
Sialyl Lewis X Antigen chemistry, Sialyl Lewis X Antigen metabolism, E-Selectin metabolism, E-Selectin chemistry, Ligands, Models, Molecular, Hydrogen Bonding
Abstract

In this research article, we report on the strengthening of a non-classical hydrogen bond (C-H⋅⋅⋅O) by introducing electron withdrawing groups at the carbon atom. The approach is demonstrated on the example of derivatives of the physiological E-selectin ligand sialyl Lewis x (1, sLe x ). Its affinity is mainly due to a beneficial entropy term, which is predominantly caused by the pre-organization of sLe x in its binding conformation. We have shown, that among the elements responsible for the pre-organization, the stabilization by a non-classical hydrogen bond between the H-C5 of l-fucose and the ring oxygen O5 of the neighboring d-galactose moiety is essential and yields 7.4 kJ mol -1 . This effect could be further strengthened by replacing l-fucose by 6,6,6-trifluoro-l-fucose leading to an improved non-classical H-bond of 14.9 kJ mol -1 , i.e., an improved pre-organization in the bioactive conformation. For a series of glycomimetics of sLe x (1), this outcome could be confirmed by high field NMR-shifts of the H-C5 Fuc , by X-ray diffraction analysis of glycomimetics co-crystallized with E-selectin as well as by isothermal titration calorimetry. Furthermore, the electron-withdrawing character of the CF 3 -group beneficially influences the pharmacokinetic properties of sLe x mimetics. Thus, acid-stability, a prerequisite for gastrointestinal stability, could be substantially improved., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Published
2024
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37. Synthesis and Systematic Investigation of Lepidiline A and Its Gold(I), Silver(I), and Copper(I) Complexes Using In Vitro Cancer Models and Multipotent Stem Cells.

Author

Tóth S, Szlávik MF, Mandel R, Fekecs F, Tusnády G, Vajda F, Varga N, Apáti Á, Bényei A, Paczal A, Kotschy A, and Szakács G

Abstract

The imidazole alkaloid lepidiline A from the root of Lepidium meyenii has a moderate to low in vitro anticancer effect. Our aim was to extend cytotoxicity investigations against a panel of cancer cells, including multidrug-resistant cancer cells, and multipotent stem cells. Lepidiline A is a N-heterocyclic carbene precursor, therefore a suitable ligand source for metal complexes. Thus, we synthesized lepidiline A and its copper(I), gold(I), and silver(I) complexes and tested them against ovarian, gastrointestinal, breast, and uterine cancer cells and bone marrow-derived and adipose-derived mesenchymal stem cells. Lepidiline A and its copper complex demonstrated moderate cytotoxicity, while silver and gold complexes exhibited significantly enhanced and consistent cytotoxicity against both cancer and stem cell lines. ABCB1 in the multidrug-resistant uterine sarcoma line conferred significant resistance against lepidiline A and the copper-lepidiline A complex, but not against the silver and gold complexes. Our results indicate that only the copper complex induced a significant and universal increase in the production of reactive oxygen species within cells. In summary, binding of metal ions to lepidiline A results in enhanced cytotoxicity with the nature of the metal ion playing a critical role in determining its properties., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Published
2024
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38. Determinants of the heart rate variability in type 1 diabetes mellitus.

Author

Hajdu M, Garmpis K, Vértes V, Vorobcsuk-Varga N, Molnár GA, Hejjel L, Wittmann I, and Faludi R

Subjects
Female, Humans, Heart Rate physiology, Heart, Autonomic Nervous System physiology, Diabetes Mellitus, Type 1 complications, Cardiovascular Diseases
Abstract

Background: Evaluation of heart rate variability (HRV) detects the early subclinical alterations of the autonomic nervous system. Thus, impaired HRV is the earliest subclinical marker of cardiac autonomic neuropathy (CAN) in type 1 diabetes mellitus (T1DM)., Objectives: We aimed to explore the HRV parameters in asymptomatic T1DM patients and compare them with the results obtained in healthy subjects. Potential associations between HRV parameters and the established risk factors for CAN and cardiovascular diseases were also investigated., Methods: Seventy T1DM patients (38 ± 12 years, 46 females) and 30 healthy subjects were enrolled into the study. For HRV analysis, beat-to-beat heart rate was recorded for 30 min. The less noisy 5-min segment of the recording was analyzed by Bittium Cardiac Navigator HRV analysis software. Time domain, frequency domain, and nonlinear indices were calculated., Results: Regarding ratio of low to high frequency component (LF/HF), no differences were found between the two populations ( p = 0.227). All the further, time domain, frequency domain, and nonlinear HRV indices were significantly lower in T1DM patients (each p < 0.001). In multiple linear models, disease duration remained the only independent predictor of LF/HF ratio ( p = 0.019). HbA 1c was found to be significant independent predictor of all further time domain (SDNN, p < 0.001; rMSSD, p < 0.001), frequency domain (VLF, p < 0.001; LF, p = 0.002; HF, p = 0.006; Total Power, p = 0.002), and nonlinear indices (SD1, p = 0.006; SD2, p = 0.007), alone, or in combination with other factors, such as age or body mass index., Conclusion: Asymptomatic T1DM patients have significantly reduced overall HRV as compared with healthy subjects, indicating subclinical CAN. Quality of the glycemic control is important determinant of HRV among T1DM patients. This relationship is independent of other risk factors for CAN or cardiovascular diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hajdu, Garmpis, Vértes, Vorobcsuk-Varga, Molnár, Hejjel, Wittmann and Faludi.)

Published
2023
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39. Lipid-Based Nanocarriers for Delivery of Neuroprotective Kynurenic Acid: Preparation, Characterization, and BBB Transport.

Author

Juhász Á, Ungor D, Varga N, Katona G, Balogh GT, and Csapó E

Subjects
Animals, Swine, Liposomes, Neuroprotection, Brain, Blood-Brain Barrier, Kynurenic Acid
Abstract

Encapsulation possibilities of an extensively investigated neuroprotective drug (kynurenic acid, KYNA) are studied via lipid-based nanocarriers to increase the blood-brain barrier (BBB) specific permeability. The outcomes of various preparation conditions such as stirring and sonication time, concentration of the lipid carriers and the drug, and the drug-to-lipid ratio are examined. Considering the experimentally determined encapsulation efficiency, hydrodynamic diameter, and ζ-potential values, the initial lipid and drug concentration as well as the stirring and sonication time of the preparation were optimized. The average hydrodynamic diameter of the prepared asolectin-(LIP) and water-soluble lipopolymer (WSLP)-based liposomes was found to be ca. 25 and 60 nm under physiological conditions. The physicochemical characterization of the colloidal carriers proves that the preparation of the drug-loaded liposomes was a successful process, and secondary interactions were indicated between the drug molecule and the polymer residues around the WSLP membrane. Dissolution profiles of the active molecule under physiological conditions were registered, and the release of the unformulated and encapsulated drug is very similar. In addition to this outcome, the in vitro polar brain lipid extract (porcine)-based permeability test proved the achievement of two- or fourfold higher BBB specific penetration and lipid membrane retention for KYNA in the liposomal carriers relative to the unformatted drug.

Published
2023
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40. The Effect of Concentration, Temperature, and pH on the Formation of Hyaluronic Acid-Surfactant Nanohydrogels.

Author

Seres L, Csapó E, Varga N, and Juhász Á

Abstract

The assembly of colloidal hyaluronic acid (HyA, as a polysaccharide) based hydrogel particles in an aqueous medium is characterized in the present paper, with an emphasis on the particular case of nanohydrogels formed by surfactant-neutralized polysaccharide networks. The structural changes and particle formation process of polysaccharide- and cationic-surfactant-containing systems were induced by the charge neutralization ability and the hydrophobic interactions of cetyltrimethylammonium bromide (CTAB) under different conditions. Based on the rheological, light scattering, ζ-potential, turbidity, and charge titration measurements, it can be concluded that the preparation of the HyA-CTAB particles can be greatly controlled. The results indicate that more available negative charges can be detected on the polymer chain at smaller initial amounts of HyA (c HyA < 0.10 mg/mL), where a molecular solution can be formed. The change in the pH has a negligible effect on the formation process (particle aggregation appears at n CTAB /n HyA,monomer ~1.0 in every case), while the temperature dependence of the critical micelle concentration (c.m.c.) of CTAB determines the complete neutralization of the forming nanohydrogels. The results of our measurements confirm that after the appearance of stable colloidal particles, a structural change and aggregation of the polymer particles take place, and finally the complete charge neutralization of the system occurs.

Published
2023
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41. The Mycoplasma hyorhinis genome displays differential chromatin accessibility.

Author

Taylor L, Walsh S, Ashton A, Varga N, Kapoor S, George C, and Jagannath A

Abstract

Whilst the regulation of chromatin accessibility and its effect on gene expression have been well studied in eukaryotic species, the role of chromatin dynamics and 3D organisation in genome reduced bacteria remains poorly understood [1,2]. In this study we profiled the accessibility of the Mycoplasma hyorhinis genome, these data were collected fortuitously as part of an experiment where ATAC-Seq was conducted on mycoplasma, contaminated mammalian cells. We found a differential and highly reproducible chromatin accessibility landscape, with regions of increased accessibility corresponding to genes important for the bacteria's life cycle and infectivity. Furthermore, accessibility in general correlated with transcriptionally active genes as profiled by RNA-Seq, but peaks of high accessibility were also seen in non-coding and intergenic regions, which could contribute to the topological organisation of the genome. However, changes in transcription induced by starvation or application of the RNA polymerase inhibitor rifampicin did not themselves change the accessibility profile, which confirms that the differential accessibility is inherently a property of the genome, and not a consequence of its function. These results together show that differential chromatin accessibility is a key feature of the regulation of gene expression in bacteria., Competing Interests: 10.13039/501100000769The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

Published
2023
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42. Core-Shell Structured PLGA Particles Having Highly Controllable Ketoprofen Drug Release.

Author

Varga N, Bélteki R, Juhász Á, and Csapó E

Abstract

The non-steroid anti-inflammatory drug ketoprofen (KP) as a model molecule is encapsulated in different poly(lactide-co-glycolide) (PLGA) nanostructured particles, using Tween20 (TWEEN) and Pluronic F127 (PLUR) as stabilizers to demonstrate the design of a biocompatible colloidal carrier particles with highly controllable drug release feature. Based on TEM images the formation of well-defined core-shell structure is highly favorable using nanoprecipitation method. Stabile polymer-based colloids with ~200-210 nm hydrodynamic diameter can be formed by successful optimization of the KP concentration with the right choice of stabilizer. Encapsulation efficiency (EE%) of 14-18% can be achieved. We clearly confirmed that the molecular weight of the stabilizer thus its structure greatly controls the drug release from the PLGA carrier particles. It can be determined that ~20% and ~70% retention is available with the use of PLUR and TWEEN, respectively. This measurable difference can be explained by the fact that the non-ionic PLUR polymer provides a steric stabilization of the carrier particles in the form of a loose shell, while the adsorption of the non-ionic biocompatible TWEEN surfactant results in a more compact and well-ordered shell around the PLGA particles. In addition, the release property can be further tuned by decreasing the hydrophilicity of PLGA by changing the monomer ratio in the range of ~20-60% (PLUR) and 70-90% (TWEEN).

Published
2023
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43. Quality of glycemic control has significant impact on myocardial mechanics in type 1 diabetes mellitus.

Author

Hajdu M, Knutsen MO, Vértes V, Vorobcsuk-Varga N, Molnár G, Wittmann I, and Faludi R

Subjects
Humans, Female, Ventricular Function, Left, Echocardiography methods, Heart Ventricles, Glycemic Control, Diabetes Mellitus, Type 1 complications
Abstract

The potential associations between disease duration, glycemic control, and the echocardiographic markers of the myocardial mechanics were investigated in asymptomatic T1DM patients. Seventy T1DM patients (38.2 ± 11.7 years, 46 female) and 30 healthy volunteers were investigated. Besides the conventional and tissue Doppler measurements, left ventricular global longitudinal (GLS) and circumferential (GCS) strain as well as left and right atrial strain parameters were measured with 2D speckle tracking technique. Median HbA 1c level was 7.4 (1.8)%. Even when added age and hypertension to the model, current HbA1c level remained independent predictor of left ventricular GLS (p = 0.002), GCS (p < 0.001), mitral e' (p = 0.018), tricuspid e' (p = 0.018) and left (p = 0.039) and right atrial conduit strain (p = 0.047) in multiple linear regression models. Correlations between disease duration and the echocardiographic variables lost their significance in multiple models. In patients with a combination of HbA 1c  ≤ 7.4% and no hypertension, echocardiographic findings did not differ from those in healthy volunteers. Patients with HbA 1c  > 7.4% and no hypertension and especially patients with coexisting hypertension and HbA 1c  > 7.4%, exhibited significantly impaired myocardial mechanics. Quality of glycemic control has a significant impact on myocardial mechanics in T1DM patients. Regarding disease duration this relationship was not proved., (© 2022. The Author(s).)

Published
2022
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44. Serum albumin/hyaluronic acid nanoconjugate: Evaluation of concentration-dependent structural changes to form an efficient drug carrier particle.

Author

Varga N, Seres L, Kovács NA, Turcsányi Á, Juhász Á, and Csapó E

Subjects
Cell Line, Tumor, Hyaluronic Acid chemistry, Serum Albumin, Drug Carriers chemistry, Nanoconjugates chemistry
Abstract

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Published
2022
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45. Partial Disturbance of Microprocessor Function in Human Stem Cells Carrying a Heterozygous Mutation in the DGCR8 Gene.

Author

Reé D, Fóthi Á, Varga N, Kolacsek O, Orbán TI, and Apáti Á

Subjects
Humans, RNA Processing, Post-Transcriptional, Stem Cells metabolism, Mutation, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, MicroRNAs genetics, MicroRNAs metabolism
Abstract

Maturation of microRNAs (miRNAs) begins by the "Microprocessor" complex, containing the Drosha endonuclease and its partner protein, "DiGeorge Syndrome Critical Region 8" (DGCR8). Although the main function of the two proteins is to coordinate the first step of precursor miRNAs formation, several studies revealed their miRNA-independent functions in other RNA-related pathways (e.g., in snoRNA decay) or, for the DGCR8, the role in tissue development. To investigate the specific roles of DGCR8 in various cellular pathways, we previously established a human embryonic stem-cell (hESC) line carrying a monoallelic DGCR8 mutation by using the CRISPR-Cas9 system. In this study, we genetically characterized single-cell originated progenies of the cell line and showed that DGCR8 heterozygous mutation results in only a modest effect on the mRNA level but a significant decrease at the protein level. Self-renewal and trilineage differentiation capacity of these hESCs were not affected by the mutation. However, partial disturbance of the Microprocessor function could be revealed in pri-miRNA processing along the human chromosome 19 miRNA cluster in several clones. With all these studies, we can demonstrate that the mutant hESC line is a good model to study not only miRNA-related but also other "noncanonical" functions of the DGCR8 protein.

Published
2022
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46. Functional indications for transposase domestications - Characterization of the human piggyBac transposase derived (PGBD) activities.

Author

Kolacsek O, Wachtl G, Fóthi Á, Schamberger A, Sándor S, Pergel E, Varga N, Raskó T, Izsvák Z, Apáti Á, and Orbán TI

Subjects
DNA Transposable Elements genetics, Genome, Human, Histone-Lysine N-Methyltransferase genetics, Humans, Phylogeny, Domestication, Transposases genetics, Transposases metabolism
Abstract

Transposable elements are widespread in all living organisms. In addition to self-reproduction, they are a major source of genetic variation that drives genome evolution but our knowledge of the functions of human genes derived from transposases is limited. There are examples of transposon-derived, domesticated human genes that lost (SETMAR) or retained (THAP9) their transposase activity, however, several remnants in the human genome have not been thoroughly investigated yet. These include the five human piggyBac-derived sequences (PGBD1-5) which share ancestry with the Trichoplusia ni originated piggyBac (PB) transposase. Since PB is widely used in gene delivery applications, the potential activities of endogenous PGBDs are important to address. However, previous data is controversial, especially with the claimed transposition activity of PGBD5, it awaits further investigations. Here, we aimed to systematically analyze all five human PGBD proteins from several aspects, including phylogenetic conservation, potential transposase activity, expression pattern and their regulation in different stress conditions. Among PGBDs, PGBD5 is under the highest purifying selection, and exhibits the most cell type specific expression pattern. In a two-component vector system, none of the human PGBDs could mobilize either the insect PB transposon or the endogenous human PB-like MER75 and MER85 elements with intact terminal sequences. When cells were exposed to various stress conditions, including hypoxia, oxidative or UV stress, the expression profiles of all PGBDs showed different, often cell type specific responses; however, the pattern of PGBD5 in most cases had the opposite tendency than that of the other piggyBac-derived elements. Taken together, our results indicate that human PGBD elements did not retain their mobilizing activity, but their cell type specific, and cellular stress related expression profiles point toward distinct domesticated functions that require further characterization., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2022
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47. Distribution Types of Lichens in Hungary That Indicate Changing Environmental Conditions.

Author

Farkas E, Varga N, Veres K, Matus G, Sinigla M, and Lőkös L

Abstract

Distribution data originating from earlier herbarium collections and recent biodiversity records form the basis of distribution analyses in lichen species with different ecological requirements, where the records allowed comparisons or showed clear trends. As the occurrences of lichens are strongly correlated to background environmental conditions (e.g., air pollution, global warming), confirmed by Wirth's ecological indicator values, the analysis of distribution types has a great value for bioindication and the establishment of current and future climatic and pollution situations. Five distribution types were introduced-presented by characteristic examples (13)-according to lichen distribution maps prepared in different periods of time (representing changing environmental conditions): (1) species of decreasing occurrences by time (e.g., Lobaria pulmonaria , Menegazzia terebrata , suboceanic, acidic pollution sensitive species), (2) species with no or few former records but with increasing occurrences in recent decades (e.g., Flavoparmelia soredians , Hyperphyscia adglutinata , Solenopsora candicans , sub-Mediterranean species), (3) species with increasing and then (from c. 2000) decreasing occurrences (e.g., Scoliciosporum chlorococcum , Straminella conizaeoides , acidofrequent species), (4) species with widely increasing occurrences in recent decades (e.g., Physcia aipolioides , Piccolia ochrophora , Xanthoria parietina , nitrofrequent species), and (5) species with rapidly increasing occurrences (e.g., Absconditella lignicola , Coenogonium pineti , Evernia divaricata , rapidly spreading species). The proposed distribution types of lichen species may be applied to wider regions (the European or the global level).

Published
2022
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48. Systematic transcriptomic and phenotypic characterization of human and murine cardiac myocyte cell lines and primary cardiomyocytes reveals serious limitations and low resemblances to adult cardiac phenotype.

Author

Onódi Z, Visnovitz T, Kiss B, Hambalkó S, Koncz A, Ágg B, Váradi B, Tóth VÉ, Nagy RN, Gergely TG, Gergő D, Makkos A, Pelyhe C, Varga N, Reé D, Apáti Á, Leszek P, Kovács T, Nagy N, Ferdinandy P, Buzás EI, Görbe A, Giricz Z, and Varga ZV

Subjects
Animals, Biomarkers metabolism, Cell Differentiation genetics, Cell Line, Humans, Mice, Phenotype, Transcriptome, Induced Pluripotent Stem Cells metabolism, Myocytes, Cardiac metabolism
Abstract

Background: Cardiac cell lines and primary cells are widely used in cardiovascular research. Despite increasing number of publications using these models, comparative characterization of these cell lines has not been performed, therefore, their limitations are undetermined. We aimed to compare cardiac cell lines to primary cardiomyocytes and to mature cardiac tissues in a systematic manner., Methods and Results: Cardiac cell lines (H9C2, AC16, HL-1) were differentiated with widely used protocols. Left ventricular tissue, neonatal primary cardiomyocytes, and human induced pluripotent stem cell-derived cardiomyocytes served as reference tissue or cells. RNA expression of cardiac markers (e.g. Tnnt2, Ryr2) was markedly lower in cell lines compared to references. Differentiation induced increase in cardiac- and decrease in embryonic markers however, the overall transcriptomic profile and annotation to relevant biological processes showed consistently less pronounced cardiac phenotype in all cell lines in comparison to the corresponding references. Immunocytochemistry confirmed low expressions of structural protein sarcomeric alpha-actinin, troponin I and caveolin-3 in cell lines. Susceptibility of cell lines to sI/R injury in terms of viability as well as mitochondrial polarization differed from the primary cells irrespective of their degree of differentiation., Conclusion: Expression patterns of cardiomyocyte markers and whole transcriptomic profile, as well as response to sI/R, and to hypertrophic stimuli indicate low-to-moderate similarity of cell lines to primary cells/cardiac tissues regardless their differentiation. Low resemblance of cell lines to mature adult cardiac tissue limits their potential use. Low translational value should be taken into account while choosing a particular cell line to model cardiomyocytes., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2022
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49. Evaluation of noble metal nanostructure-serum albumin interactions in 2D and 3D systems: Thermodynamics and possible mechanisms.

Author

Ungor D, Juhász Á, Varga N, and Csapó E

Subjects
Metals, Serum Albumin, Thermodynamics, Metal Nanoparticles chemistry, Nanostructures
Abstract

In this review, we clearly highlight the importance of the detailed study of the interactions between noble metal colloids (nanoparticles (NPs) and nanoclusters (NCs)) with serum albumins (SAs) due to their rapidly growing presence in biomedical research. Besides the changes in the structure and optical property of SA, we demonstrate that the characteristic localized surface plasmon resonance (LSPR) feature of the colloidal noble metal NPs and the size- and structure-dependent photoluminescence (PL) property of the sub-nanometer sized NCs are also altered differently because of the interactions between them. Namely, for plasmonic NPs - SA interactions the PL quenching of SA (mainly static) is identified, while the SA cause PL enhancement of the ultra-small NCs after complexation. This review summarizes that the thermodynamic nature and the possible mechanisms of the binding processes are dependent partly on the size, morphology, and type of the noble metals, while the chemical structure as well as the charge of the stabilizing ligands have the most dominant effect on the change in optical features. In addition to the thermodynamic data and proposed binding mechanisms provided by three-dimensional spectroscopic techniques, the quantitative and real-time data of "quasi" two-dimensional sensor apparatus should also be considered to provide a comprehensive evaluation on many aspects of the particle/cluster - SA interactions., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2022
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50. Prodrugs of E-selectin Antagonists with Enhanced Pharmacokinetic Properties.

Author

Dätwyler P, Jiang X, Wagner B, Varga N, Mühlethaler T, Hostettler K, Rabbani S, Schwardt O, and Ernst B

Subjects
Administration, Oral, Animals, Biological Availability, Caco-2 Cells, Dose-Response Relationship, Drug, E-Selectin metabolism, Esters administration & dosage, Esters chemistry, Female, Humans, Male, Mice, Mice, Inbred BALB C, Microsomes, Liver chemistry, Microsomes, Liver metabolism, Molecular Structure, Prodrugs administration & dosage, Prodrugs chemistry, Rats, Structure-Activity Relationship, E-Selectin antagonists & inhibitors, Esters pharmacology, Prodrugs pharmacology
Abstract

Because of their large polar surface area, carbohydrates often exhibit insufficient pharmacokinetic properties. Specifically, the carboxylic acid function of the tetrasaccharide sialyl Lewis x , a pharmacophore crucial for the formation of a salt bridge with selectins, prevents oral availability. A common approach is the transfer of carboxylic acid into ester prodrugs. Once the prodrug is either actively or passively absorbed, the active principle is released by hydrolysis. In the present study, ester prodrugs of selectin antagonists with aliphatic promoieties were synthesized and their potential for oral availability was investigated in vitro and in vivo. The addition of lipophilic ester moieties to overcome insufficient lipophilicity improved passive permeation into enterocytes, however at the same time supported efflux back to the small intestines as well as oxidation into non-hydrolysable metabolites. In summary, our examples demonstrate that different modifications of carbohydrates can result in opposing effects and have to be studied in their entirety., (© 2021 Wiley-VCH GmbH.)

Published
2022
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