544 results on '"Hammer, E."'
Search Results
152. A sociological assessment of alternatives to industrial pollution abatement and subsequent implications for policy research
- Author
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Hammer, E. R.
- Published
- 1974
153. Non-intrusive three-component ratio measurement using an impedance sensor.
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Dykesteen, E., Hallanger, A., Hammer, E., Samnoy, E., and Thorn, R.
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- 1985
- Full Text
- View/download PDF
154. Transformation of 2-hydroxydibenzofuran by laccases of the white rotfungi Trametes versicolor and Pycnoporus cinnabarinus and characterization of oligomerization products
- Author
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Schauer, F., Jonas, U., Bollag, J.-M., and Hammer, E.
- Subjects
BIODEGRADATION ,LACCASE ,MICROBIOLOGY - Abstract
Laccase, a ligninolytic enzyme, was secreted by each of the white rot fungi Trametes versicolor and Pycnoporus cinnabarinus during growthin a nitrogen-rich medium under agitated conditions. After addition of 2-hydroxydibenzofuran to cell-free supernatants of the cultures, yellow precipitates were formed. These precipitates were poorly soluble in water and therefore readily separated from the supernatant. The products formed were more hydrophobic than the substrate, as indicated by their longer retention times on a reverse phase high-performanceliquid chromatography column. Mass spectrometric analysis of the purified products indicated the formation of oligomers. Analysis of the mixture of products by gas chromatography and mass spectrometry afterderivatization with diazomethane suggested the formation of at leastthree dimeric and nine trimeric products. Carbon-carbon and carbon-oxygen bonds were identified in the dimers and trimers, respectively. The nuclear magnetic resonance spectrum of the main dimer suggested coupling of the two monomers at the carbon one position. [ABSTRACT FROM AUTHOR]
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- 1998
155. Death in November: America in Vietnam, 1963
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Hammer, E.J.
- Subjects
BOOK REVIEWS - Published
- 1987
156. Compact light source performance in recessed type luminaires
- Author
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Hammer, E
- Published
- 1998
- Full Text
- View/download PDF
157. Minute from E. R. Hammer to A. K. Robertson re: Extending W. Indian Housing Project to Cover Indians & Pakistanis, with Response from P. Rogers, July 17, 1959
- Author
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Hammer, E. R., author and Rogers, Philip, author
158. 40(th) EASD Annual Meeting of the European Association for the Study of Diabetes : Munich, Germany, 5-9 September 2004
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S. Artigas, A V Dreval, Mark I. McCarthy, C Watson, Peter H. Bennett, M Quint, Y Ikeda, E Alpert, F Schiele, H Sekihara, Erik Gylfe, P Lowe, J Kuhlmann, Alain Golay, V Longo, Shahidul Alam Khan Akm., L G Mantovani, M Zawodniak-Szalapska, G Winkler, T Harrity, L Virág, U Johne, Kuo S-W., Linda C Tapsell, J Rodriguez, Michel Komajda, K Kankova, Carole A. Cull, M Sporna, E Estilles, U Ribel, M C Spruce, E Buzzigoli, T Prazak, J K McLaughlin, M K Lingohr, M Lim, F Calara, A Siebenhofer, G Meregalli, Roberto Anichini, A D Baron, R Kurashvili, P C Butler, G I Fantus, T. E. De Gooyer, Park Y-M., R. Walther, S Heinrich, Agnieszka Zawiejska, S Mukherjee, Nikolaos Papanas, G Wong, Ian D. Caterson, David M. Maahs, Shuichi Kaneko, Alexandra E. Butler, Francisco Javier Ampudia-Blasco, O N Kong, Attali J-R., C A Hedman, K Oshinyemi, Nicolle Müller, I C Cranston, N Okumus, M V Vlaiculescu, Balasubramanian Ravikumar, W W Cheatham, K Mukasa, K B Biswas, Annunziata Lapolla, Phil McEwan, G Mader, Gilles Chassot, Dragi Anevski, Werner A. Scherbaum, M Donath, C Hesselmann, R A Gandhi, David E. Moller, Ezio Bonifacio, C Garcia, V Ifandi, P Hornnes, Nieuwenhoven Fav., C Puech, S Pérez-Del-Pulgar, Kim S-R., G Hines, C Rubio Terrés, Michael Gaster, N. Hosszufalusi, A Scholze, Andrew A. Young, Stavros Liatis, F Hariri, S Tan, Paul Valensi, Allan E. Karlsen, J Kim, E. Moberg, J Kaiser, L Berman, G Nelson, A Altkrüger, P Kothare, D B Cook, S Doran, G. van Dijk, Shahnaz Shahinfar, Kim C-S., P Stahl, M Manousaki, S Sigrist, S K Lim, M. P. Stern, A Guberti, C Rezzani, J McKenney, Karl Thomaseth, Sofia Carlsson, M Julia, R Brillante, I Rubesova, T Darkow, E Matsumoto, Wendy M. Macfarlane, M Di Martino, G Bardini, Rossella Menghini, D Duhot, E Farcasiu, Annalisa Natalicchio, I Lindner, J Buvat, Christian L. Brand, Harry Dorchy, Iwona Pietrzak, Z T Luo, P Home, M Ekelund, Jesper Gromada, Kristine Færch, F Piarulli, H Kim, R Mentel, Zsuzsanna K. Zsengellér, Dullaart Rpf., Anton Luger, Thomas A. Pearson, V Manicardi, P Rösen, Feng Y-M., R Morganti, Lars Hansen, Demuth H-U., Haruo Kasai, A Shostak, Rudi Steffensen, G Taylor, Markolf Hanefeld, C Santini, E Hamaguchi, Roberto Miccoli, F Storms, M Cooper, Y Lee, Allison E. Aiello, P Smith, T Suehiro, K Treece, M Waluś, Timothy A Welborn, Simone Baltrusch, E Kontela, S Chai, J Crean, H Yokoyama, Johan G. Eriksson, Rafael Hernández Hernández, J Rodríguez-Saldaña, M P Tornero, G Formoso, D. Lovell, E Bingham, A Mylonakis, M Manteghetti, D Fedele, Antonio Martín-Duce, Ralph A. DeFronzo, D Salcedo, Kurt Højlund, Antonio Petrone, Sheu Whh., C Gutierrez, Flavia Pricci, S Kurita, Z G Abbas, M M Benedetti, Philippe A. Halban, Daniel J. Cox, O Ljungkvist, Justine Davies, J Palsgaard, Lars Sjöström, E Bosi, L Janin-Manificat, W. F. Kelly, M. Fernandez, E Colak, O V Mulyarchik, B Kronshage, F Lang, M Erfurth, Takashi Kadowaki, N Jendrike, U Walter, J Wishart, Y. Neye, D Kim, N Furuhashi, M Barsotti, D Florow, L Ke, L Borgquist, N C Jackson, Ffolliott M. Fisher, V Baskar, K Yoshioka, Bryan A. Wolf, G Chabrier, R Skoumal, Livio Luzi, H Kose, I Pharisien, B. Klein, H Winiarska, M C Johnson, L Griffiths, Nonna Kravchun, C Combe, Baptist Gallwitz, J Zdychova, L Skorda, Jorma Ilonen, W Gao, I N Steen, A Terrinoni, P D Ambery, W Kern, C M Kusminski, Cho M-H., Paolo Pozzilli, Louise G. Grunnet, E Schönle, David R Matthews, Robert W. Taylor, Y Cohen, Kim H-S., M P Eccles, N B Tutuncu, D McDowell, Richard M. Bergenstal, K Takamatsu, T Steiner, Jaan Palgi, Valdemar Grill, N Niculescu, G Federici, S Lehto, P. M. McKeigue, M Barone, Michael E. Trautmann, S Smirnov, J Mannion, M Eto, C Rousseau, M Conti, C S Ernest, Antonio Ceriello, D H Schweitzer, Jung E-D., Andreas Festa, Avijit Lahiri, A Shepelkevich, A Murro, A Kollmann, Jonathan R.S. Arch, R Landgraf, Son H-Y., I Engelsberger, E Agardh, S Rodríguez-Mulero, P J Kraml, K Lee, D. F. Du Toit, E Kim, G Fadini, Williams Ajk., Philip Home, M B Antcieferov, C Perlemoine, D Perrea, Song X-L., D Ruggieri, Krister Bokvist, Heidi Sørensen, Bilbao, G Yoshino, J P Taylor, Shen H-M., S M Furier, R Urquhart, J Wohlgelernter, Jianping Weng, T. Baba, Q Hong, C Silva, Castaigne J-P., M Felaco, X X Zhang, M Jaroň, Milla Rosengård-Bärlund, J G Papp, Toshio Miyata, Lervang H-H., Park M-K., I Kinalska, A Long, Oomen Phn., N Kogawa, Ippolita Patrizia Patera, S. Karadeniz, Dinesh Selvarajah, D S Chung, A Wensaas, Richard Imrich, M Recasens, J Ruxer, O Buchea, E Wilpart, S P Stepanenko, Le Ttd., H Ohgawara, Mariaconsuelo Valentini, A Mondok, M Peltonen, Marianne O. Larsen, K Chatzianagnostou, Agneta Ståhle, A L Ferrari, L Bordier, F Maingrette, A Matsuda, G Vukomanovic, Jakob D. Wikstrom, T Yamakita, E Gorostiaga, J Jin, B Gopalan, Heinz Drexel, S Hewitt, Rury R. Holman, C Dieterle, T L Ruchti, N Asatiani, M Sidira, A Iezzi, A J Sommerfield, D Châtenet, M L Olsen, R Bergemann, C Koehler, T L Kuraeva, B Balas, Christian Berne, E Santos-Mazo, G Smith, A Siejka, R Kožnarová, A Mattina, S Sheikh, A Adomeit, M Rasmussen, J. Fagerudd, N Busciantella Ricci, Nuria Vilarrasa, E Hammar, T L Thoms, L Aydın, Ron G. Rosenfeld, A Nikolajuk, R Gos, C L Morgan, H L Yu, D Dheelchand, S Ramrath, N Boudriga, Jerome I. Rotter, C Jahannault, W M Weston, Folke Lindgärde, M Hertlova, D Knight, A Monroy-Mayorga, E Pardini, A Chamson-Reig, B Franke, Janie McCluskey, Joseph Bryan, C Nikolopoulou, Christie M. Ballantyne, Fausto Santeusanio, L Pegoraro, M Lee, A Klimenko, S Jaiveer, K. Pettersson-Fernholm, Michael A. Nauck, A Ekbom-Schnell, G Deferrari, Riccardo Schiaffini, S. Pampanelli, Khan Aka., David Hopkins, Maija Wessman, M Kamarinos, Noh J-H., O Ebisui, K McCarroll, Jeppe Sturis, Peter Nowotny, N Gorbenko, Åke Sjöholm, David G. Maggs, A E Halseth, B Cresci, A A Ortiz-Gress, A Korakovouni, O Matejkova, C E Mogensen, C J Lin, Ramon Gomis, H Seaman, C Granier, Yang C-H., F Assah, O Sanchez, Fausto Machicao, Peter G. Morris, Alberto Ortiz, A Giardinelli, D Bracaglia, A Gonzalo, S Pavlatos, Andreas Lechner, F Canovic, L Sjolind, Allan Vaag, Birgitte Bruun Nielsen, David A. Ziegler, Vito Lampasona, R Gershoni-Baruch, A. Dei Cas, H Renz, E Mena, Matthew Waltham, Kim D-M., H Levanen, D D Mick, Valentina Alexandrovna Peterkova, E Meskhishvili, Sarah Nutland, R Bustani, John R. Lindsay, M Christoforidou, A Abicht, E Harno, K Cyganek, A Fitchet, S Neelotpol, P Nikishin, P Serradas, J Hinrichsen, M Halvorson, M Chovatia, B Voet, Jinny Willis, E Parretti, M Haslbeck, M Wellard, L Teng, Julio Wainstein, J S Fischer, K. Lalic, D Roggenland, I Gich, R Anwar, Maurizio Cassader, D Serota, X J Li, R J Schotzinger, Vilmundur Gudnason, Björn Zethelius, S A Wootton, W Andrzejewski, R Rezsohazy, R Gao, T Klimentova, T Mazurek, I Bruckner, C Dohrmann, R E James, G daSilva Xavier, Kim S-Y., A Dorca, Stuart J. Pocock, Terri J. Allen, I Giovos, P B Parab, N H Andersen, P Fotinakis, Miriam Cnop, H Lee, Norbert Tennagels, Omorodola I. Abatan, F Ailett, I. Lager, D Manzella, H Hut, Larry A. Distiller, G Lip, Lim S-K., Rong Zhang, T Tsuno, Steen Knudsen, M. Bajardi, Manuel Benito, Dai Sugimoto, Melvin J. Prince, D W Dunstan, D Rankins, K A Majali, G Ozansoy, Isabella Russo, S Uçak, G Annuzzi, R Talar-Wojnarowska, K Lange, S Neugebauer-Baba, Campbell H. Thompson, Eric Renard, P. D. Mountjoy, Z Morrison, Elizabeth A. Davis, Franco Cavallo, C Corvaja, R Antuña, Craig John Currie, H Linnebjerg, He Y-L., A J Palmer, Mariola R. Chacón, H Malinska, M. Jones, R Lichnovská, K Mandes, Paolo Tessari, T Mokhort, A Laina, H. L. Y. Chan, I Schmidt, R Banks, Richard G. IJzerman, L Ksinantova, G Setti, H Vaudry, A Gallo, V Spallone, Chen J-W., Thomas Danne, A Chong, M Hallschmid, S Aczel, S Hulme, N Islam, M Hosoi, P M Ternan, P Di Bartolo, N Bishara, T Shibasaki, Martin A. Osterhoff, Im S-S., M Jecht, T Hamaguchi, S Mattera, K Ways, Elizabeth Northam, U Rajala, Reinhard W. Holl, L Yang, S Panaiotopoulos, K Horvath, R Kluge, Thora B. Bodvarsdottir, Y Dong, Irene Alemanno, C McDougall, Reimar W. Thomsen, M Campbell, W Rabl, John Öhrvik, Yuichiro Yamada, Paola Ungaro, W Benzer, Mike Sampson, Roberto Trevisan, R G Radu, Aas A-M., P E Lobo, Ricardo Scott, S M Son, Josephine M. Forbes, T A Hillier, K L Wyne, Louis L. Nguyen, J Farmer, M H Tan, Kwon H-S., J Yang, L Sandvik, Franco Folli, A K Jenum, M Nguyen, W Pratipanawatr, A L Frederiksen, Rebecca Smith, Lee H-J., A Schäfer, C Manuelli, G S Denver, T Vukovich, B Maceira, K Matsumoto, K. Chokkalingam, Nurcan Üçeyler, P Modi, Timothy M. Morgan, S Mertens, B M Singh, Michaela Riedl, K Iso, C Cucurullo, G. F. Bottazzo, M Calvani, K Hur, J Wetzels, Kazuhiro Takahashi, Y Aso, H Stammer, M G Masding, Fitsum Guebre-Egziabher, J L González-Sánchez, L Armstrong, Alberto Maran, Peter G.F. Swift, S S Popovic, J Starczynski, E Vitacolonna, Luigi Laviola, R W Gelling, Marina Cardellini, D Barilla, Rosa de Diego Martínez, W H Landschulz, Anne Mette Rosenfalck, R K Wong, Kevin E. Schneider, K Peros, Giuseppe Nanni, F Zhang, I Rákóczi, T Iburi, M Nakhjavani, X Q Zhang, S Tournis, Per Lav Madsen, Graham A. Hitman, A. Tura, K Laubner, N D Kostic, Lawrence M. Dolan, R. Sinha Roy, J A Wagner, J. Tuomilehto, J Hauptman, M Abdel-Ghany, D Lacombe, Toralph Ruge, Johannes A Maassen, Triantafyllos Didangelos, K Sasaki, I Argüelles, Klaus Levin, C Popow, Emanuel Christ, R Chetty, L Baillet-Blanco, Jo-Ann Salmon, T Mine, James L. Trevaskis, I Franke, J Gorski, E A Andrianova, A Dayan, A Caballero, Aleksandra Gilis-Januszewska, M Yasujima, Z Kasalová, C.D.A. Stehouwer, F. K. Gorus, G A Nichols, A Glowania, David P. Strachan, P Fredlund, N. F. da Silva, P Reboldi, M Sausbier, K H Groenier, G Stuccio, N Guttman, K R Ahmed, A D Ristic, T Kapellen, J Coutcher, Aldo V. Greco, Oswald Wagner, A Zagayko, Maria Alevizaki, B B Zhang, W F Ferris, Jenny Fredriksson, Lois Jovanovic, J Hänninen, R De Giglio, Kazuo Yagui, O Potterat, P Hamliton, R E Scranton, B Mankovsky, A Stylianou, B Fellström, Abdel-Wahab Yha., M Kitagawa, Katherine L. Baldock, F R Johnson, F Baigts, S D'Addato, F J Sanz, A Mistry, S D Wise, T Pratipanawatr, U R Fölsch, James R.C. Parkinson, Claudia Sommer, C Park, F E Griffiths, M L Martí, R Demirtunc, S Taniguchi, J Lundkvist, T Siegmund, Juan Sztajzel, C Dienesch, F Baumgartner, L Scalone, T M Mckolanis, K Otake, Ullrik Pedersen-Bjergaard, T M Vriesendorp, Michael B. Wheeler, Henry Schmitt, Peter Hovind, S Lange, Stephane Roze, L. Van Gaal, B Klaproth, Anthony E. Civitarese, D Eckland, A Dagar, D F Hopkins, Kari Stefansson, C Gonzalez-Yanes, B Meyboom-de Jong, D. J. Betteridge, K Buhling, M Crepaldi, Ana M. Wägner, L Renna, L Volpe, R McBride, V Corbo, E O Brennesvik, R P Hayes, R Abdollahnia, G Viviani, C F Liew, Francisco Pérez-Bravo, Jeffrey Baron, Brian M. Frier, H H Samira, D Szentendrei, K. J. Schjoedt, W K Waldhäusl, D Gniuli, D Zou, G Tschank, V Urbančič, A L Nolan, Albertini J-P., J Malcomson, M Larbig, C Cheyssac, K Aurich, C M Kesson, S Heller, Maija E. Miettinen, R F Luco, Adrian J. Cameron, Luigi Mattiello, Z. Metelko, X E Zhang, M Parramón, I. G. Obrosova, J Fruchart, M Ilic, Björn Eliasson, Gilles Chatellier, M A Martín, D M Kendall, Holger Luthman, V F Varillas, D Maccubbin, Jang S-A., Amalia Gastaldelli, E Salzsieder, P. de Mol, A Yoshida, H D Lindner, D Gostiljac, M Just, Pan C-Y., J M Fujitaki, G Eiermann, K Bergenheim, A D Frick, A Agacdiken, K Varytimiadis, K Cseh, D A Jackson, S Calderari, Dena G. Hernandez, H M Liebich, K Min, F. de Zegher, Bernd Kulzer, K Han, Ulrich A. Müller, D Marrero, H Hatakeyama, René Koopman, Doo H-K., Petr Wohl, P. Sharp, P Forder, Thor Aspelund, N Meneveau, R M Schmülling, R Aubert, Thom Sam., H Youshikawa, M Ankelo, D Bowden, I Kelly, Frédéric Fumeron, M Sartini, Robert S. Sherwin, L Varadhan, A Criscimanna, John Betteridge, V Jelic, M Bartnik, N Lemke, B Ursø, A Bertoldo, A M Owona, H Okochi, L Pérez-Tamajó, S L Monfre, Daniel Brandhorst, K T Legg, Andries J. Smit, Veronica Sancho, Masashi Hirai, C Klein, Paul J. Thornalley, A Chaidaroglou, K Miura, B Zinman, O M Dvoynishnikova, J Plank, Jan Bolinder, C Lush, B Rubi, R Pozzilli, M Bashir, S A Shtandel, F Mosca, A Naskalska, Josef Vcelak, U Sausbier, P Cavaiani, T U Baehring, Michele Solimena, P Formisano, M Rastaldi, Bernard Thorens, J Ruzzin, E Arbit, M. Hori, Torkel B. Brismar, E Soltes Rak, A Filo, P Heinke, Matthew P. Coghlan, M Masotti, I Perevozskaya, K Ahn, I Moules, K Van Dyck, I Goldstein, Z Mathe, G Z Zhao, S Fajardo, J Taylor, S Chrul, J C Pareja, D Hadjidakis, A J Scheen, N Siddiqua, D C Cavan, R Grella, Krabbe S, H J Rochlitz, A E Hinkkanen, W Wilpshaar, Richard Stevens, M Dreyer, S Hara, X Wang, Melania Manco, D Gillen, Magalie A. Ravier, Olli Simell, John C. Lawrence, Kohnert K-D., Agardh C-D., A Berghold, L Kristensen, Grant Sfa., N Gursoy, Leif Groop, N Freemantle, Anja Schweizer, L Pala, Legros J-J., C. Di Pietro, N. Yamamoto, J Magyar, B Nikolovski, H Ikeda, D Lee, Bruce A. Buckingham, A O Wollitzer, I Kennedy, C Ernest, Neville H. McClenaghan, S Tanaka, Asimina Mitrakou, T Heinze, W Kerner, Moeenaldeen Al-Sayed, Charles Thivolet, L Klaff, A Miconi, Cristina Valeri, J. O. Christensen, K. Ekberg, A Jardine, T Endo, X Zhang, D F Child, A Kienitz, D K Seidel, H. Tada, Sylvie Abouna, Cyrus Cooper, Catherine R Chittleborough, Roberta Assaloni, S Corbi, A K Bose, K Ozawa, C Ahn, K A Deans, G Jackowski, Martin Gibson, Patrick McElduff, O A Mojiminiyi, Manuel Serrano-Ríos, O Dupuy, A L Davydov, Iwar Klimes, Sten-Anders Ivarsson, N Ichino, R Matsutomo, E R Smith, A Stefanovska, B Dehmel, K Koniavitou, E Agascioglu, M Hatazaki, J. M. Gibson, T Yada, P Ribaux, M Rupnik, K Fridell, G Scutaru, L Chugunova, Henrietta Mulnier, A Kendereski, H Lehnert, C Billi, M Sobczak, Francisco M-Mj., L K Archibald, S Sukumvanich, David B. Dunger, I. Benke, G Yillar, N Stingemore, J. M. Boavida, Y Shi, Jimmy D. Bell, L Bozzetto, Andrew J. Ahmann, E Jebens, J Keiding, Elena Henkel, Mark Fineman, J F McRae, Carol Forsblom, S Martemucci, Lourdes Ibáñez, P G Prieto, L Ringholm Nielsen, S Pratas, B von Stritzky, Julio Rosenstock, Lee K-W., J Stocks, L J Strow, I Samarguliani, L Wennekes, R Cheung, Abhishek Nag, Roberto Gambino, Y Suleymanoglu, E Murphy, T T Durck, M F Peyrot, Y Unno, Alexander Mayorov, Eleuterio Ferrannini, D. C. Rao, D Neely, H Karunajeewa, J Palmisano, Julia B. Lewis, M Ravid, G Pons, E Junca, P Vexiau, S Sailesh, D K Miloslavskiy, O N Bondarenko, U Smith, S Torri, Constantine Tsigos, Cesario Bianchi, Mattia Locatelli, D Jaquet, Virpi Lindi, M Moroi, M E Tushuizen, P Pelicci, R Scognamiglio, Pal Pacher, S M Thyssen, A Péterfalvi, Y Ho, S Guntram, L Romics, T Nakagami, Clive S. Cockram, Irina Kowalska, K Brodbeck, Gojka Roglic, J. Dörig, Lise Tarnow, Therese Tillin, A López-Alba, Martin Krššák, Moses Elisaf, S Hata, D P Snoeck, D Schmoll, O V Udovichenko, A Scaramuzza, J Paul, John H. Fuller, Nicholas Katsilambros, Michele Muggeo, Pia Ekbom, Piero Marchetti, V Melki, C Bailleau, H Stavrianos, A D'Errico, Geremia B. Bolli, Amabile Maier, Kelter A-R., Anders Green, Q J Morélis, Steffen Thiel, C Watkins, R C Cheung, A Clark, Elvira Fioriti, N Ari, Nam J-Y., Y Cottin, L G Krinelke, H Al Mohammedi, Simon C. Fleming, C Jones, Z Kerényi, Ahn Y-H., Meile M-J., P Nánási, M Graner, V Canonico, Gangnerau M-N., Hugh R. Taylor, Giovanni Sartore, A. Dejgaard, Carol Kelley, S. Ali, Stéphane Dalle, Jeffrey S. Gonzalez, Elena Šeböková, Alexander Beck, Ingo B. Leibiger, M Rosu, C Pencea, Werner Waldhäusl, Kaltenbacher M-C., R Butzer, S Thore, Adam G. Tabak, Angelo Avogaro, E Standi, Boris Kovatchev, O Bradescu, Patrizia Dentelli, A Fujita, C Verri, R Chlup, Prasad Ydm., S V Hörsten, van der Merwe M-T., D Hilliard, W Klein, D Worthley, M Udvardy, Berit R. Jensen, A D'Avanzo, J Monaghan, K P Yeo, Guivarch P-H., B Bauduceau, D Weghuber, P Tatti, J Ybarra, S Gwozdziewiczová, E Gasparini, B Saltin, Charlotte Granhall, Howard Leventhal, R Marin, M Tumiati, Cicero Afg., L Csémy, B Berger, S Mikros, D Dall'Asta, M Shahmanesh, Y G Vasiljev, F Potthoff, H S Randeva, G De Berardis, J O Logan, K Warncke, P Uitterlinden, E Rehring, K Gilmore, K Shankhdhar, V V Bojko, M Vahatalo, E A Korolyova, D Wiemann, P G Lankisch, D Hendrie, F Galtier, M Rybarczyk, Gisela Dahlquist, N N Rudovich, G Stein, A Liebl, F Tan, A Westerlund, S Gronemann, I Franklin, Jonathan A. Prince, Peter Arner, E Skliros, T. Sparre, M Vigas, Maddalena Trombetta, L. Bjerre Knudsen, A C Sima, I Dubroca, Alastair Gray, I Weets, R Ferraresi, Schauer Ujw., E. Leinonen, S Corazza, Jonathan Levy, P K Prakash, R Guzder, S. Barnhill, John Blangero, J Herreros, G. de Vries, Cheng Ptw., A Macías-Batista, K. Capito, R Thomas, G Thomas, G Boemi, Lotte Pietraszek, Pierre Fontaine, I Holme, J Smedegaard, C A Harrop, U Helwig, B Levy, A P Gribben, Hiroto Furuta, P Beckett, S Giannini, Ruth L. Coleman, Eva Fernqvist-Forbes, N Cugnardey, A Dumas, Jane Pinaire, S E Hofer, D Shimono, Erik H. Serné, Alain D. Baron, C Battista, M Tanen, M Klementova, V Adams, J Komorowski, Antonio Nicolucci, E. C. Burns, H Sydall, M G Fanara, M G Giovannitti, N Okabayashi, Magdalena Szurkowska, I A Eroshkin, M. I. J. Uusitupa, D Ma, C C Dieguez, J Sutcliffe-Goulden, A V Gaddi, Michał Arabski, Serge Halimi, Wendy C. Burns, S Seclén, H Sugano, A Vinterby, K Backx, L F Diaconu, Fernando Gomez-Peralta, O'Harte Fpm., G Lepeniotis, D Laune, H Kvasničková, N H Wallén, G Boner, G Cieślik, Robert Hermann, Paul Q. Thomas, Y Kumon, Maria Maiello, M Atkins, Kenneth A. Earle, Guowang Xu, H Y Bae, I Reynisdottir, D Perez, D E Cannon, P Fabietti, I Geronooz, J Østergaard, K J Jeitler, S Skourtis, A Zambanini, A Saemann, K Kuboki, Helen L. Lutgers, A C Thai, Arne Melander, D Pinkowski, S G Straub, S A Wolfe-Coote, A Totora, Hayley Dickinson, A Lindenmair, A Ginis, I Faturos, F Van Eylen, C Huard, F Fu, N Wang, B M Rasmussen, Angela Napoli, L Granato, Markus M. Lerch, M. Frandsen, A Lyras, Lawrence S. Phillips, J Mabley, R Goldschmeding, B K Kilhovd, W Liu, Greg Poffenberger, P Cipriano, Anna Maria Charlotte K Lindqvist, A Matsuzawa, J Wang, T Yu, M S Pepper, Lena M. Thorn, Y Sakamoto, Blanche Schwappach, Anna L. Gloyn, P Dupraz, A. M. Schmidt, M Psallas, V Tsirimbis, Carl D. Langefeld, D Sass, H E Scholtz, M. Cailleau, Lauren Julia Brown, K Phillips, M. Iezzi, C Jayawarna, Eleni Anastasiou, R Lobmann, R Lundershausen, H Fujiwara, H R Nan, I C Smith, I A Karpova, A Navazio, S Kang, T. 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Liu, H, Jeong, I, Chae, M, Choi, M, Yoo, H, Kim, C, Yun, M, Na, M, Kang, Y, Kong, O, Son, S, Kim, I, Tanaka, N, Hosoi, M, Matsuyama, Y, Fukumoto, M, Yamakita, T, Yoshioka, K, Ishii, T, Sato, T, Fujii, S, Aoki, T, Shibata, T, Mizutani, N, Suzuki, J, Fowelin, J, Samuelsson, P, Brandrup wogsen, G, Okumura, K, Tokmakova, A, Staroverova, D, Antcieferov, M, Shutichina, I, Kuntchevich, G, Vriesendorp, T, Morélis, Q, Legemate, D, Schaper, F, Mainas, E, Gkioulmpasanis, I, Panagiotou, I, Vassilikos, G, Skorda, L, Sidira, M, Christoforidou, M, Alaveras, A, Artikis, V, Evdemon, E, Lechleitner, M, Koch, T, Ebenbichler, C, Sturm, W, Moretti, L, Moruzzo, D, Boldrini, E, Pandolfo, C, Kameyama, M, Iwasa, R, Cho, M, Nam, J, Huh, K, Kaplar, M, Paragh, G, Erdei, A, Csongradi, E, Garai, I, Varga, J, Galuska, L, Udvardy, M, Higa, M, Kaneko, Y, Hiroi, N, Koziarska, D, Nowacki, P, Majkowska, L, Luzniak, P, Wojciechowska luźniak, A, Tushuizen, M, Nieuwland, R, Snoeck, D, Sturk, A, Diamant, M, Aguiar, L, Bahia, L, Villela, N, Laflor, C, Conde, C, Bottino, D, Dorigo, D, Bouskela, E, Pu, S, Luo, Z, Lam, K, Dan, Q, Xu, A, Shen, J, Cheng, K, Xu, J, Thamer, C, Stefan, N, Haap, M, Heller, E, Tschritter, O, De Prado, A, Ortiz, A, Ybarra, J, Gich, I, Pou, J, Ehren, M, Roggenland, D, Reinsen, B, Klein, H, Rittig, K, Stock, J, Kocher, B, Balletshofer, B, Shon, H, Chung, D, Nakatani, Y, Matsuhisa, M, Kaneto, H, Hatazaki, M, Yoshiuchi, K, Katakami, N, Kawamori, D, Ohtoshi, K, Sakamoto, K, Matsuoka, T, Ozawa, K, Ogawa, S, Hori, M, Yamasaki, Y, Zitouni, K, Harry, D, Nourooz zadeh, J, Earle, K, Olesen, P, Franco, L, Corvaja, C, Semplicini, A, Ceylan işık, A, Arı, N, Rösen, P, Lee, I, Park, K, Jung, E, Shin, D, Jo, S, Obuobie, K, Prakash, P, Hanna, F, Lazarus, J, Varadhan, L, Gurushankar, J, James, D, Sheikh, S, Gaede, P, Zou, D, Vilarrasa, N, Perez maraver, M, Mena, E, Perez, D, Setti, G, Buckingham, R, Urbančič, V, Stefanovska, A, Bernjak, A, Ažman juvan, K, Kocijančič, A, Glowania, A, Filters, T, Fosmark, D, Torjesen, P, Kilhovd, B, Berg, T, Sandvik, L, Hanssen, K, Mentink, C, Donchenko, G, Stepanenko, S, Maingrette, F, Deng, H, Lindenmair, A, Freudenthaler, A, Baumgartner parzer, S, Nizheradze, K, Khoruzhenko, A, Tronko, N, Sheu, W, Ou, H, Shen, H, Lin, T, Wu, H, Yang, C, Mogylnytska, L, Schmoelzer, I, Davies, J, Band, M, Struthers, A, Prázný, M, Škrha, J, Kasalová, Z, Neelotpol, S, Jahan, P, Kauschke, S, Harrop, C, Schäfer, A, Widder, J, Eigenthaler, M, Walter, U, Uchimura, I, Ikebukuro, M, Kaibara, M, Hirata, M, Helal, R, Pervin, F, Yang, X, Jansson, P, Nagaev, I, Jack, M, Carvalho, E, Sunnerhagen, K, Cam, M, Cushman, S, Smith, U, Creely, S, Farmer, J, Gustafson, B, Kusminski, C, Krusinova, E, Wohl, P, Klementova, M, Lanska, V, Mcdougall, C, Kelly, I, Abbas, Z, Lutale, J, Archibald, L, Karunajeewa, H, Stingemore, N, Stuccio, G, Mcgechie, D, Muller, L, Hak, E, Goudzwaard, W, Montorsi, F, Homering, M, Sprenger, K, Goldstein, I, Asnaghi, V, Ferrari, G, Rastaldi, M, Gabellini, D, Dell'Antonio, G, Maestroni, A, Ruggieri, D, Luzi, L, Piemonti, L, Zerbini, G, Anafaroglu, I, Tutuncu, N, Sultana, M, Siddiqua, N, Iwasaki, T, Nakajima, A, Yoneda, M, Mukasa, K, Tanaka, S, and Sekihara, H
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0303 health sciences ,medicine.medical_specialty ,business.industry ,EASD ,Endocrinology, Diabetes and Metabolism ,Human physiology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Diabetes mellitus ,Family medicine ,Internal Medicine ,Medicine ,business ,030217 neurology & neurosurgery ,030304 developmental biology - Published
- 2004
159. Effects of ambient temperature on the performance of bent tube fluorescent lamps
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Hammer, E [Lighting Business Group, General Electric Co., Nela Park, Cleveland, OH (US)]
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- 1989
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160. RAPID ANNEALING IN SILICON TRANSISTORS.
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Hammer, E
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- 1968
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161. The association between Guardian Cap use during practices and sport-related concussion risk in high school American football players.
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Hammer E, Mosiman S, Joachim MR, Taylor E, Cordum A, Brooks MA, and McGuine T
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- Humans, Adolescent, Male, Wisconsin epidemiology, Schools, Brain Concussion, Football injuries, Athletic Injuries epidemiology
- Abstract
Objective: Guardian Caps (GCs) have been widely implemented at all levels of American football participation based on laboratory evidence that they may reduce head impact forces. The purpose of this study was to determine if GC use during practice was associated with a lower risk of sport-related concussion (SRC) during practices and games among high school football players., Methods: Data were collected on 2610 athletes from 41 Wisconsin schools that self-selected into GC or Non-GC cohorts. Athletic trainers recorded practice and game exposures and SRCs through the 2023 season. Generalised linear mixed models were built to determine the effect of GC utilisation on SRC rates, accounting for school and player exposures., Results: In the total cohort (Non-GC n=1188 (45.5%); GC n=1422 (54.5%)), 180 athletes (6.9%) sustained SRCs. 64 SRCs occurred during practice (GC n=33 (51.6%); Non-GC n=31 (48.4%)). GC use was not associated with a decreased risk of SRC during practice in the univariable analysis (relative risk (RR)=1.04, 95% CI 0.58 to 1.86, p=0.90) or after accounting for previous SRC within the last year (RR 1.01, 95% CI 0.57 to 1.79, p=0.97). No players of either cohort wore GCs during games. There were 116 SRCs sustained during games (GC n=68 (58.6%); Non-GC n=48 (41.4%)). GC use during practice was not associated with the risk of SRC during games in the univariable analysis (RR 1.13, 95% CI 0.72 to 1.78, p=0.60) or after accounting for previous SRC within the last year (RR 1.13, 95% CI 0.71 to 1.78, p=0.61)., Conclusion: GC use during practice in high school American football players was not associated with a decreased risk of sustaining SRC in practice or games., Competing Interests: Competing interests: Dr. Hammer is principal investigator and team physician for the University of Wisconsin football team. Dr. Brooks is the District VI representative on the AAP National Nominating Committee and a member of the AAP Council on Sports Medicine & Fitness and former Chair of its Executive Committee. No other disclosures were reported., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)
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- 2025
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162. Quantifying Muscle Volume Deficits Among 38 Lower Extremity Muscles in Collegiate Football Athletes After Anterior Cruciate Ligament Reconstruction.
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Ito N, Martin JA, Joachim MR, Blemker SS, Opar DA, Kliethermes SA, Heiderscheit BC, Baer G, Fabian K, Hammer E, Heidt D, Kuehl M, Lee K, Moll M, Peot R, Sanfilippo J, Tanaka C, Sund S, Lin YC, Hickey J, Homer A, Maniar N, Timmins R, Cousins M, DuCharme O, Feng X, Nguyen A, Riem L, Hart J, McCoy N, Allred D, Beutler A, Campbell D, Wayne Johnson A, Wilwand M, Mortensen B, Remington E, Hauenstein J, Metoyer C, Wagle J, Huff J, Port N, and Reyes J
- Abstract
Background: Quadriceps dysfunction is ubiquitous after anterior cruciate ligament (ACL) reconstruction (ACLR). Addressing quadriceps dysfunction is crucial to improve function, reduce the reinjury risk, and maintain long-term knee health. While deficits specific to the quadriceps are well documented, less is known about the effect of an ACL injury on other lower extremity muscle groups., Purpose/hypothesis: The purpose of this exploratory analysis was to quantify and rank lower extremity muscle volume deficits using magnetic resonance imaging in collegiate football athletes after ACLR. It was hypothesized that the quadriceps muscles would present with the greatest deficits and that compensatory hypertrophy of muscles at adjacent joints such as the hip and ankle would be observed., Study Design: Cross-sectional study; Level of evidence, 3., Methods: This study is a secondary analysis from an ongoing multicenter prospective cohort study involving Division I collegiate football athletes. Athletes who underwent primary unilateral ACLR (1 [3%] allograft, 2 [7%] quadriceps tendon autograft, 22 [73%] bone-patellar tendon-bone autograft, 5 [17%] hamstring tendon autograft) and magnetic resonance imaging were included. Muscle volumes (mL·kg
-1 ·m-1 ) were quantified bilaterally from 38 lower extremity muscles using machine learning technology. Paired-samples t tests were performed between limbs for each muscle, which were then ranked and visualized in a forest plot based on standardized mean differences (surgical - nonsurgical limb)., Results: A total of 30 athletes (mean time from surgery, 27.9 ± 19.0 months) were included. The largest muscle volume deficits in the surgical limb were seen in the 3 uniarticular quadriceps muscles, followed by the biarticular triceps surae muscles. The rectus femoris and soleus did not show significant differences between limbs. Conversely, the fibularis muscle group had a greater muscle volume in the surgical limb compared with the nonsurgical limb. Most other muscle groups did not present significant differences between limbs., Conclusion: Persistent quadriceps atrophy in a cohort of high-level athletes over 2 years after ACLR was highlighted in this study. Deficits in the gastrocnemius muscles, but not in the soleus, were also identified. This comprehensive approach examining various lower extremity muscles revealed latent muscle volume deficits present after ACLR., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This study was supported by research funding from the National Football League (NFL). The NFL had no role in the study design, collection, analysis, or interpretation of the data presented and was not involved in the writing of the manuscript or in the decision to submit the manuscript for publication. S.S.B. (cofounder and Chief Science Officer) and B.C.H. (advisory board member) declare potential competing interests related to this work because of their roles with Springbok Analytics. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.- Published
- 2025
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163. Ex vivo comparison of full-thickness biopsy techniques in the equine small intestine.
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Verhaar N, Hammer E, Reineking W, Hewicker-Trautwein M, and Geburek F
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- Animals, Horses, Biopsy veterinary, Biopsy methods, Biopsy instrumentation, Jejunum pathology, Jejunum surgery, Ileum pathology, Ileum surgery, Female, Male, Intestine, Small pathology, Intestine, Small surgery
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Objective: To compare the practicability and tissue sample quality between different intestinal biopsy techniques., Study Design: Experimental, randomized ex vivo study., Sample Population: Small intestine of nine horses., Methods: Four different biopsy techniques were evaluated in the aboral jejunum and the ileum within 1 h after euthanasia. One segment was used as control (C), and the applied techniques included an 8 mm biopsy punch (BP), transverse wedge resection (TW), longitudinal wedge resection with transverse closure (LW) and a longitudinal sample using Eppendorfer biopsy forceps (EF). Defects were closed using a single-layer continuous Lembert pattern. Duration of the procedure, intestinal diameter, contamination, and bursting pressure were determined. The quality of the obtained tissue samples for histological assessment was evaluated using a semiquantitative score. The jejunal and ileal samples were analyzed separately., Results: All biopsy procedures including defect closure were completed within 5 min, with shorter closure times for BP (p = .03). Minimal contamination could be noted in 1/8 TW and 2/8 LW cases, without significant differences between the groups. Longitudinal closure techniques (BP, EF) showed more constriction than transverse closures (TW, LW) (p < .05). Bursting pressure was >75 mmHg in all cases. Technique BP showed significantly lower biopsy quality scores (p = .009)., Conclusion: The tested biopsy techniques could all be applied effectively within a reasonable time frame, yet the biopsy punch was associated with significant artifacts and risk of missing mucosa., Clinical Significance: The findings provide insights into the possible advantages and limitations of the different techniques and alert the surgeon to potential issues with the quality of the tissue sample., (© 2024 The Author(s). Veterinary Surgery published by Wiley Periodicals LLC on behalf of American College of Veterinary Surgeons.)
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- 2025
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164. The role of the tricellular junction protein ILDR2 in glomerulopathies: Expression patterns and functional insights.
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Siegerist F, Kliewe F, Hammer E, Schakau P, Chi Soh JE, Weber C, Lindenmeyer M, Reichelt-Wurm S, Drenic V, Chatziantoniou C, Chadjichristos CE, Zhang Y, Simm S, Banas MC, Nauck M, Völker U, and Endlich N
- Abstract
The tricellular tight junctions are crucial for the regulation of paracellular flux at tricellular junctions, where tricellulin (MARVELD2) and angulins (ILDR1, ILDR2, or LSR) are localized. The role of ILDR2 in podocytes, specialized epithelial cells in the kidney, is still unknown. We investigated the role of ILDR2 in glomeruli and its influence on blood filtration. Western blots, single-cell RNA sequencing (scRNA-seq), and superresolution microscopy showed a strong expression of ILDR2 in podocytes that colocalized with the podocyte-specific claudin CLDN5. Co-immunoprecipitation revealed that ILDR2 interacts with CLDN5. In glomerulopathies, induced by nephrotoxic serum and by desoxycorticosterone acetate (DOCA)-salt heminephrectomy, ILDR2 was strongly up-regulated. Furthermore, Ildr2 knockout mice exhibited glomerular hypertrophy and decreased podocyte density. However, they did not develop effacement of podocyte foot processes or proteinuria. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomic analysis of isolated glomeruli showed an increase in matrix proteins, such as fibronectin and collagens. This suggests a protective role of ILDR2 in glomerulopathies., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)
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- 2024
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165. DDI2 protease controls embryonic development and inflammation via TCF11/NRF1.
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Nedomova M, Haberecht-Müller S, Möller S, Venz S, Prochazkova M, Prochazka J, Sedlak F, Chawengsaksophak K, Hammer E, Kasparek P, Adamek M, Sedlacek R, Konvalinka J, Krüger E, and Grantz Saskova K
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DDI2 is an aspartic protease that cleaves polyubiquitinated substrates. Upon proteotoxic stress, DDI2 activates the transcription factor TCF11/NRF1 (NFE2L1), crucial for maintaining proteostasis in mammalian cells, enabling the expression of rescue factors, including proteasome subunits. Here, we describe the consequences of DDI2 ablation in vivo and in cells. DDI2 knock-out (KO) in mice caused embryonic lethality at E12.5 with severe developmental failure. Molecular characterization of embryos showed insufficient proteasome expression with proteotoxic stress, accumulation of high molecular weight ubiquitin conjugates and induction of the unfolded protein response (UPR) and cell death pathways. In DDI2 surrogate KO cells, proteotoxic stress activated the integrated stress response (ISR) and induced a type I interferon (IFN) signature and IFN-induced proliferative signaling, possibly ensuring survival. These results indicate an important role for DDI2 in the cell-tissue proteostasis network and in maintaining a balanced immune response., Competing Interests: The authors declare that they have no conflict of interest., (© 2024 The Author(s).)
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- 2024
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166. Investigating FSGS-like injury in zebrafish larvae by nifurpirinol: efficacy and molecular insight.
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Klawitter M, Mattias F, Kliewe F, Hammer E, Völker U, Simm S, Siegerist F, Daniel S, Schindler M, and Endlich N
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- Animals, Disease Models, Animal, Proteomics, Prodrugs pharmacology, Nitroreductases metabolism, Nitroreductases genetics, Zebrafish Proteins metabolism, Zebrafish Proteins genetics, Zebrafish, Glomerulosclerosis, Focal Segmental pathology, Glomerulosclerosis, Focal Segmental metabolism, Glomerulosclerosis, Focal Segmental chemically induced, Glomerulosclerosis, Focal Segmental genetics, Larva drug effects, Podocytes drug effects, Podocytes metabolism, Podocytes pathology
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Identifying effective drugs for focal segmental glomerulosclerosis (FSGS) treatment holds significant importance. Our high-content drug screening on zebrafish larvae relies on nitroreductase/metronidazole (NTR/MTZ)-induced podocyte ablation to generate FSGS-like injury. A crucial factor for successful drug screenings is minimizing variability in injury induction. For this, we introduce nifurpirinol (NFP) as a more reliable prodrug for targeted podocyte depletion. NFP showed a 2.3-fold increase in efficiency at concentrations 1,600-fold lower compared with MTZ-mediated injury induction. Integration into the screening workflow validated its suitability for the high-content drug screening. The presence of crucial FSGS hallmarks, such as podocyte foot process effacement, proteinuria, and activation of parietal epithelial cells, was observed. After the isolation of the glomeruli from the larvae, we identified essential pathways by proteomic analysis. This study shows that NFP serves as a highly effective prodrug to induce the FSGS-like disease in zebrafish larvae and is well-suited for a high-content drug screening to identify new candidates for the treatment of FSGS. NEW & NOTEWORTHY This research investigated the use of nifurpirinol in nanomolar amounts as a prodrug to reliably induce focal segmental glomerulosclerosis (FSGS)-like damage in transgenic zebrafish larvae. Through proteomic analysis of isolated zebrafish glomeruli, we were further able to identify proteins that are significantly regulated after the manifestation of FSGS. These results are expected to expand our knowledge of the pathomechanism of FSGS.
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- 2024
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167. Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome.
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Busley AV, Gutiérrez-Gutiérrez Ó, Hammer E, Koitka F, Mirzaiebadizi A, Steinegger M, Pape C, Böhmer L, Schroeder H, Kleinsorge M, Engler M, Cirstea IC, Gremer L, Willbold D, Altmüller J, Marbach F, Hasenfuss G, Zimmermann WH, Ahmadian MR, Wollnik B, and Cyganek L
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- Humans, Transcription Factors metabolism, Transcription Factors genetics, Mutation genetics, Cardiomyopathy, Hypertrophic genetics, Cardiomyopathy, Hypertrophic pathology, Cardiomyopathy, Hypertrophic metabolism, Polymerization, CRISPR-Cas Systems genetics, Proteolysis, Mutation, Missense, Protein Multimerization, Genes, Recessive, Phenotype, Noonan Syndrome genetics, Noonan Syndrome pathology, Noonan Syndrome metabolism, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells pathology, ras Proteins metabolism, ras Proteins genetics
- Abstract
Noonan syndrome patients harboring causative variants in LZTR1 are particularly at risk to develop severe and early-onset hypertrophic cardiomyopathy. In this study, we investigate the mechanistic consequences of a homozygous variant LZTR1
L580P by using patient-specific and CRISPR-Cas9-corrected induced pluripotent stem cell (iPSC) cardiomyocytes. Molecular, cellular, and functional phenotyping in combination with in silico prediction identify an LZTR1L580P -specific disease mechanism provoking cardiac hypertrophy. The variant is predicted to alter the binding affinity of the dimerization domains facilitating the formation of linear LZTR1 polymers. LZTR1 complex dysfunction results in the accumulation of RAS GTPases, thereby provoking global pathological changes of the proteomic landscape ultimately leading to cellular hypertrophy. Furthermore, our data show that cardiomyocyte-specific MRAS degradation is mediated by LZTR1 via non-proteasomal pathways, whereas RIT1 degradation is mediated by both LZTR1-dependent and LZTR1-independent pathways. Uni- or biallelic genetic correction of the LZTR1L580P missense variant rescues the molecular and cellular disease phenotype, providing proof of concept for CRISPR-based therapies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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168. Integrative Analyses of Circulating Proteins and Metabolites Reveal Sex Differences in the Associations with Cardiac Function among DCM Patients.
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Hannemann A, Ameling S, Lehnert K, Dörr M, Felix SB, Nauck M, Al-Noubi MN, Schmidt F, Haas J, Meder B, Völker U, Friedrich N, and Hammer E
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- Humans, Male, Female, Middle Aged, Sex Characteristics, Aged, Ventricular Function, Left, Tandem Mass Spectrometry methods, Blood Proteins metabolism, Adult, Stroke Volume, Biomarkers blood, Sex Factors, Metabolome, Cardiomyopathy, Dilated blood, Cardiomyopathy, Dilated metabolism, Cardiomyopathy, Dilated physiopathology
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Dilated cardiomyopathy (DCM) is characterized by reduced left ventricular ejection fraction (LVEF) and left or biventricular dilatation. We evaluated sex-specific associations of circulating proteins and metabolites with structural and functional heart parameters in DCM. Plasma samples (297 men, 71 women) were analyzed for proteins using Olink assays (targeted analysis) or LC-MS/MS (untargeted analysis), and for metabolites using LC MS/MS (Biocrates AbsoluteIDQ p180 Kit). Associations of proteins (n = 571) or metabolites (n = 163) with LVEF, measured left ventricular end diastolic diameter (LVEDD
measured ), and the dilation percentage of LVEDD from the norm (LVEDDacc. to HENRY ) were examined in combined and sex-specific regression models. To disclose protein-metabolite relations, correlation analyses were performed. Associations between proteins, metabolites and LVEF were restricted to men, while associations with LVEDD were absent in both sexes. Significant metabolites were validated in a second independent DCM cohort (93 men). Integrative analyses demonstrated close relations between altered proteins and metabolites involved in lipid metabolism, inflammation, and endothelial dysfunction with declining LVEF, with kynurenine as the most prominent finding. In DCM, the loss of cardiac function was reflected by circulating proteins and metabolites with sex-specific differences. Our integrative approach demonstrated that concurrently assessing specific proteins and metabolites might help us to gain insights into the alterations associated with DCM.- Published
- 2024
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169. Plasma proteome association with coronary heart disease and carotid intima media thickness: results from the KORA F4 study.
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Elhadad MA, Del C Gómez-Alonso M, Chen CW, Neumeyer S, Delerue T, Rathmann W, Näbauer M, Meisinger C, Kääb S, Seissler J, Graumann J, Koenig W, Suhre K, Gieger C, Völker U, Peters A, Hammer E, and Waldenberger M
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- Humans, Male, Female, Middle Aged, Aged, Case-Control Studies, Carotid Artery Diseases blood, Carotid Artery Diseases diagnostic imaging, Carotid Artery Diseases epidemiology, Proteome, Germany epidemiology, Risk Factors, Risk Assessment, Coronary Artery Disease blood, Coronary Artery Disease diagnostic imaging, Adult, Carotid Intima-Media Thickness, Biomarkers blood, Blood Proteins analysis, Proteomics, Predictive Value of Tests, Coronary Disease blood, Coronary Disease diagnosis, Coronary Disease epidemiology, Coronary Disease diagnostic imaging
- Abstract
Background and Aims: Atherosclerosis is the main cause of stroke and coronary heart disease (CHD), both leading mortality causes worldwide. Proteomics, as a high-throughput method, could provide helpful insights into the pathological mechanisms underlying atherosclerosis. In this study, we characterized the associations of plasma protein levels with CHD and with carotid intima-media thickness (CIMT), as a surrogate measure of atherosclerosis., Methods: The discovery phase included 1000 participants from the KORA F4 study, whose plasma protein levels were quantified using the aptamer-based SOMAscan proteomics platform. We evaluated the associations of plasma protein levels with CHD using logistic regression, and with CIMT using linear regression. For both outcomes we applied two models: an age-sex adjusted model, and a model additionally adjusted for body mass index, smoking status, physical activity, diabetes status, hypertension status, low density lipoprotein, high density lipoprotein, and triglyceride levels (fully-adjusted model). The replication phase included a matched case-control sample from the independent KORA F3 study, using ELISA-based measurements of galectin-4. Pathway analysis was performed with nominally associated proteins (p-value < 0.05) from the fully-adjusted model., Results: In the KORA F4 sample, after Bonferroni correction, we found CHD to be associated with five proteins using the age-sex adjusted model: galectin-4 (LGALS4), renin (REN), cathepsin H (CTSH), and coagulation factors X and Xa (F10). The fully-adjusted model yielded only the positive association of galectin-4 (OR = 1.58, 95% CI = 1.30-1.93), which was successfully replicated in the KORA F3 sample (OR = 1.40, 95% CI = 1.09-1.88). For CIMT, we found four proteins to be associated using the age-sex adjusted model namely: cytoplasmic protein NCK1 (NCK1), insulin-like growth factor-binding protein 2 (IGFBP2), growth hormone receptor (GHR), and GDNF family receptor alpha-1 (GFRA1). After assessing the fully-adjusted model, only NCK1 remained significant (β = 0.017, p-value = 1.39e-06). Upstream regulators of galectin-4 and NCK1 identified from pathway analysis were predicted to be involved in inflammation pathways., Conclusions: Our proteome-wide association study identified galectin-4 to be associated with CHD and NCK1 to be associated with CIMT. Inflammatory pathways underlying the identified associations highlight the importance of inflammation in the development and progression of CHD., (© 2024. The Author(s).)
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- 2024
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170. MassSpecPreppy-An end-to-end solution for automated protein concentration determination and flexible sample digestion for proteomics applications.
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Reder A, Hentschker C, Steil L, Gesell Salazar M, Hammer E, Dhople VM, Sura T, Lissner U, Wolfgramm H, Dittmar D, Harms M, Surmann K, Völker U, and Michalik S
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- Proteins analysis, Workflow, Software, Humans, Animals, Peptides analysis, Peptides chemistry, Proteomics methods
- Abstract
In proteomics, fast, efficient, and highly reproducible sample preparation is of utmost importance, particularly in view of fast scanning mass spectrometers enabling analyses of large sample series. To address this need, we have developed the web application MassSpecPreppy that operates on the open science OT-2 liquid handling robot from Opentrons. This platform can prepare up to 96 samples at once, performing tasks like BCA protein concentration determination, sample digestion with normalization, reduction/alkylation and peptide elution into vials or loading specified peptide amounts onto Evotips in an automated and flexible manner. The performance of the developed workflows using MassSpecPreppy was compared with standard manual sample preparation workflows. The BCA assay experiments revealed an average recovery of 101.3% (SD: ± 7.82%) for the MassSpecPreppy workflow, while the manual workflow had a recovery of 96.3% (SD: ± 9.73%). The species mix used in the evaluation experiments showed that 94.5% of protein groups for OT-2 digestion and 95% for manual digestion passed the significance thresholds with comparable peptide level coefficient of variations. These results demonstrate that MassSpecPreppy is a versatile and scalable platform for automated sample preparation, producing injection-ready samples for proteomics research., (© 2023 The Authors. PROTEOMICS published by Wiley‐VCH GmbH.)
- Published
- 2024
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171. Zyxin is important for the stability and function of podocytes, especially during mechanical stretch.
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Kliewe F, Siegerist F, Hammer E, Al-Hasani J, Amling TRJ, Hollemann JZE, Schindler M, Drenic V, Simm S, Amann K, Daniel C, Lindenmeyer M, Hecker M, Völker U, and Endlich N
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- Humans, Mice, Animals, Zyxin genetics, Zyxin metabolism, Actin Cytoskeleton metabolism, Kidney Glomerulus, Focal Adhesions metabolism, Podocytes metabolism, Hypertension, Renal, Nephritis
- Abstract
Podocyte detachment due to mechanical stress is a common issue in hypertension-induced kidney disease. This study highlights the role of zyxin for podocyte stability and function. We have found that zyxin is significantly up-regulated in podocytes after mechanical stretch and relocalizes from focal adhesions to actin filaments. In zyxin knockout podocytes, we found that the loss of zyxin reduced the expression of vinculin and VASP as well as the expression of matrix proteins, such as fibronectin. This suggests that zyxin is a central player in the translation of mechanical forces in podocytes. In vivo, zyxin is highly up-regulated in patients suffering from diabetic nephropathy and in hypertensive DOCA-salt treated mice. Furthermore, zyxin loss in mice resulted in proteinuria and effacement of podocyte foot processes that was measured by super resolution microscopy. This highlights the essential role of zyxin for podocyte maintenance in vitro and in vivo, especially under mechanical stretch., (© 2024. The Author(s).)
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- 2024
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172. Associations between diet quality, demographics, health conditions and spice and herb intake of adults with chronic kidney disease.
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Hammer E, Acevedo S, and Andrade JM
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- Adult, Humans, Cross-Sectional Studies, Diet, Demography, Spices, Renal Insufficiency, Chronic epidemiology
- Abstract
Scant literature has been able to demonstrate an association between dietary habits and spice and herb consumption, especially for those who have chronic kidney disease. The objectives of this study were to 1) determine the frequency and quantity of spices and herbs consumed and 2) determine the associations between diet quality and its food components, demographics, and health conditions with spice and herb frequency and variety consumption of adults with chronic kidney disease. A cross-sectional online study was conducted with adults with various stages of chronic kidney disease (n = 71). Participants responded to an online demographic, diet and spice and herb questionnaire on RedCap. Diet quality was determined through the diet questionnaire. Descriptives, frequencies and Spearman correlations were conducted using SPSS v28 with a significance of p<0.05. Most participants were in chronic kidney disease stage 3 (42.3%) with a majority (98.6%) self-identifying as non-Hispanic white. On average, participants consumed black pepper more than once daily (47.9%) with the spice quantity at 5 g. The median diet quality score was 38.5 (range 31.5-48.5). Positive associations were identified with overall diet quality scores and certain spices such as basil (r = 0.33; p<0.01) and cinnamon (r = 0.37; p<0.002). Further associations were seen with food groups, self-identifying as white and health conditions with spice frequency and variety of spices and herbs consumed. Overall, positive associations were observed with diet quality and spice and herb intake, in which higher diet quality scores would indicate higher consumption of spices and herbs. Further research should focus on diet quality and spice and herb consumption in reducing progression of this disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hammer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2024
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173. Unveiling the crucial neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies.
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Küry S, Stanton JE, van Woerden G, Hsieh TC, Rosenfelt C, Scott-Boyer MP, Most V, Wang T, Papendorf JJ, de Konink C, Deb W, Vignard V, Studencka-Turski M, Besnard T, Hajdukowicz AM, Thiel F, Möller S, Florenceau L, Cuinat S, Marsac S, Wentzensen I, Tuttle A, Forster C, Striesow J, Golnik R, Ortiz D, Jenkins L, Rosenfeld JA, Ziegler A, Houdayer C, Bonneau D, Torti E, Begtrup A, Monaghan KG, Mullegama SV, Volker-Touw CMLN, van Gassen KLI, Oegema R, de Pagter M, Steindl K, Rauch A, Ivanovski I, McDonald K, Boothe E, Dauber A, Baker J, Fabie NAV, Bernier RA, Turner TN, Srivastava S, Dies KA, Swanson L, Costin C, Jobling RK, Pappas J, Rabin R, Niyazov D, Tsai AC, Kovak K, Beck DB, Malicdan M, Adams DR, Wolfe L, Ganetzky RD, Muraresku C, Babikyan D, Sedláček Z, Hančárová M, Timberlake AT, Al Saif H, Nestler B, King K, Hajianpour MJ, Costain G, Prendergast D, Li C, Geneviève D, Vitobello A, Sorlin A, Philippe C, Harel T, Toker O, Sabir A, Lim D, Hamilton M, Bryson L, Cleary E, Weber S, Hoffman TL, Cueto-González AM, Tizzano EF, Gómez-Andrés D, Codina-Solà M, Ververi A, Pavlidou E, Lambropoulos A, Garganis K, Rio M, Levy J, Jurgensmeyer S, McRae AM, Lessard MK, D'Agostino MD, De Bie I, Wegler M, Jamra RA, Kamphausen SB, Bothe V, Busch LM, Völker U, Hammer E, Wende K, Cogné B, Isidor B, Meiler J, Bosc-Rosati A, Marcoux J, Bousquet MP, Poschmann J, Laumonnier F, Hildebrand PW, Eichler EE, McWalter K, Krawitz PM, Droit A, Elgersma Y, Grabrucker AM, Bolduc FV, Bézieau S, Ebstein F, and Krüger E
- Abstract
Neurodevelopmental proteasomopathies represent a distinctive category of neurodevelopmental disorders (NDD) characterized by genetic variations within the 26S proteasome, a protein complex governing eukaryotic cellular protein homeostasis. In our comprehensive study, we identified 23 unique variants in PSMC5 , which encodes the AAA-ATPase proteasome subunit PSMC5/Rpt6, causing syndromic NDD in 38 unrelated individuals. Overexpression of PSMC5 variants altered human hippocampal neuron morphology, while PSMC5 knockdown led to impaired reversal learning in flies and loss of excitatory synapses in rat hippocampal neurons. PSMC5 loss-of-function resulted in abnormal protein aggregation, profoundly impacting innate immune signaling, mitophagy rates, and lipid metabolism in affected individuals. Importantly, targeting key components of the integrated stress response, such as PKR and GCN2 kinases, ameliorated immune dysregulations in cells from affected individuals. These findings significantly advance our understanding of the molecular mechanisms underlying neurodevelopmental proteasomopathies, provide links to research in neurodegenerative diseases, and open up potential therapeutic avenues.
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- 2024
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174. Metabolic remodeling in cardiac hypertrophy and heart failure with reduced ejection fraction occurs independent of transcription factor EB in mice.
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Dörmann N, Hammer E, Struckmann K, Rüdebusch J, Bartels K, Wenzel K, Schulz J, Gross S, Schwanz S, Martin E, Fielitz B, Pablo Tortola C, Hahn A, Benkner A, Völker U, Felix SB, and Fielitz J
- Abstract
Background: A metabolic shift from fatty acid (FAO) to glucose oxidation (GO) occurs during cardiac hypertrophy (LVH) and heart failure with reduced ejection fraction (HFrEF), which is mediated by PGC-1α and PPARα. While the transcription factor EB (TFEB) regulates the expression of both PPARGC1A /PGC-1α and PPARA /PPARα, its contribution to metabolic remodeling is uncertain., Methods: Luciferase assays were performed to verify that TFEB regulates PPARGC1A expression. Cardiomyocyte-specific Tfeb knockout (cKO) and wildtype (WT) male mice were subjected to 27G transverse aortic constriction or sham surgery for 21 and 56 days, respectively, to induce LVH and HFrEF. Echocardiographic, morphological, and histological analyses were performed. Changes in markers of cardiac stress and remodeling, metabolic shift and oxidative phosphorylation were investigated by Western blot analyses, mass spectrometry, qRT-PCR, and citrate synthase and complex II activity measurements., Results: Luciferase assays revealed that TFEB increases PPARGC1A /PGC-1α expression, which was inhibited by class IIa histone deacetylases and derepressed by protein kinase D. At baseline, cKO mice exhibited a reduced cardiac function, elevated stress markers and a decrease in FAO and GO gene expression compared to WT mice. LVH resulted in increased cardiac remodeling and a decreased expression of FAO and GO genes, but a comparable decline in cardiac function in cKO compared to WT mice. In HFrEF, cKO mice showed an improved cardiac function, lower heart weights, smaller myocytes and a reduction in cardiac remodeling compared to WT mice. Proteomic analysis revealed a comparable decrease in FAO- and increase in GO-related proteins in both genotypes. A significant reduction in mitochondrial quality control genes and a decreased citrate synthase and complex II activities was observed in hearts of WT but not cKO HFrEF mice., Conclusions: TFEB affects the baseline expression of metabolic and mitochondrial quality control genes in the heart, but has only minor effects on the metabolic shift in LVH and HFrEF in mice. Deletion of TFEB plays a protective role in HFrEF but does not affect the course of LVH. Further studies are needed to elucidate if TFEB affects the metabolic flux in stressed cardiomyocytes., 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., (© 2024 Dörmann, Hammer, Struckmann, Rüdebusch, Bartels, Wenzel, Schulz, Gross, Schwanz, Martin, Fielitz, Pablo Tortola, Hahn, Benkner, Völker, Felix and Fielitz.)
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- 2024
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175. Excessive sodium chloride ingestion promotes inflammation and kidney fibrosis in aging mice.
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Bernhardt A, Krause A, Reichardt C, Steffen H, Isermann B, Völker U, Hammer E, Geffers R, Philipsen L, Dhjamandi K, Ahmad S, Brandt S, Lindquist JA, and Mertens PR
- Subjects
- Mice, Animals, Sodium Chloride, Kidney metabolism, Inflammation metabolism, Aging, Sodium Chloride, Dietary adverse effects, Fibrosis, Eating, Kidney Diseases chemically induced, Kidney Diseases genetics, Kidney Diseases pathology, Hypertension metabolism
- Abstract
In aging kidneys, a decline of function resulting from extracellular matrix (ECM) deposition and organ fibrosis is regarded as "physiological." Whether a direct link between high salt intake and fibrosis in aging kidney exists autonomously from arterial hypertension is unclear. This study explores kidney intrinsic changes (inflammation, ECM derangement) induced by a high-salt diet (HSD) in a murine model lacking arterial hypertension. The contribution of cold shock Y-box binding protein (YB-1) as a key orchestrator of organ fibrosis to the observed differences is determined by comparison with a knockout strain ( Ybx1
ΔRosaERT+TX ). Comparisons of tissue from mice fed with normal-salt diet (NSD, standard chow) or high-salt diet (HSD, 4% NaCl in chow; 1% NaCl in water) for up to 16 mo revealed that with HSD tubular cell numbers decrease and tubulointerstitial scarring [periodic acid-Schiff (PAS), Masson's trichrome, Sirius red staining] prevails. In Ybx1ΔRosaERT+TX animals tubular cell damage, a loss of cell contacts with profound tubulointerstitial alterations, and tubular cell senescence was seen. A distinct tubulointerstitial distribution of fibrinogen, collagen type VI, and tenascin-C was detected under HSD, transcriptome analyses determined patterns of matrisome regulation. Temporal increase of immune cell infiltration was seen under HSD of wild type, but not Ybx1ΔRosaERT+TX animals. In vitro Ybx1ΔRosaERT+TX bone marrow-derived macrophages exhibited a defect in polarization (IL-4/IL-13) and abrogated response to sodium chloride. Taken together, HSD promotes progressive kidney fibrosis with premature cell aging, ECM deposition, and immune cell recruitment that is exacerbated in Ybx1ΔRosaERT+TX animals. NEW & NOTEWORTHY Short-term experimental studies link excessive sodium ingestion with extracellular matrix accumulation and inflammatory cell recruitment, yet long-term data are scarce. Our findings with a high-salt diet over 16 mo in aging mice pinpoints to a decisive tipping point after 12 mo with tubular stress response, skewed matrisome transcriptome, and immune cell infiltration. Cell senescence was aggravated in knockout animals for cold shock Y-box binding protein (YB-1), suggesting a novel protective protein function.- Published
- 2023
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176. Global Protein Profiling in Processed Immunohistochemistry Tissue Sections.
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Venz S, von Bohlen Und Halbach V, Hentschker C, Junker H, Kuss AW, Sura T, Krüger E, Völker U, von Bohlen Und Halbach O, Jensen LR, and Hammer E
- Subjects
- Mice, Animals, Immunohistochemistry, Mice, Inbred C57BL, Proteins analysis, Tandem Mass Spectrometry, Paraffin Embedding, Tissue Fixation methods, Proteomics methods, Formaldehyde chemistry
- Abstract
Tissue sections, which are widely used in research and diagnostic laboratories and have already been examined by immunohistochemistry (IHC), may subsequently provide a resource for proteomic studies, even though only small amount of protein is available. Therefore, we established a workflow for tandem mass spectrometry-based protein profiling of IHC specimens and characterized defined brain area sections. We investigated the CA1 region of the hippocampus dissected from brain slices of adult C57BL/6J mice. The workflow contains detailed information on sample preparation from brain slices, including removal of antibodies and cover matrices, dissection of region(s) of interest, protein extraction and digestion, mass spectrometry measurement, and data analysis. The Gene Ontology (GO) knowledge base was used for further annotation. Literature searches and Gene Ontology annotation of the detected proteins verify the applicability of this method for global protein profiling using formalin-fixed and embedded material and previously used IHC slides.
- Published
- 2023
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177. PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production.
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Ebstein F, Küry S, Most V, Rosenfelt C, Scott-Boyer MP, van Woerden GM, Besnard T, Papendorf JJ, Studencka-Turski M, Wang T, Hsieh TC, Golnik R, Baldridge D, Forster C, de Konink C, Teurlings SMW, Vignard V, van Jaarsveld RH, Ades L, Cogné B, Mignot C, Deb W, Jongmans MCJ, Cole FS, van den Boogaard MH, Wambach JA, Wegner DJ, Yang S, Hannig V, Brault JA, Zadeh N, Bennetts B, Keren B, Gélineau AC, Powis Z, Towne M, Bachman K, Seeley A, Beck AE, Morrison J, Westman R, Averill K, Brunet T, Haasters J, Carter MT, Osmond M, Wheeler PG, Forzano F, Mohammed S, Trakadis Y, Accogli A, Harrison R, Guo Y, Hakonarson H, Rondeau S, Baujat G, Barcia G, Feichtinger RG, Mayr JA, Preisel M, Laumonnier F, Kallinich T, Knaus A, Isidor B, Krawitz P, Völker U, Hammer E, Droit A, Eichler EE, Elgersma Y, Hildebrand PW, Bolduc F, Krüger E, and Bézieau S
- Subjects
- Animals, Humans, Mice, Adenosine Triphosphatases genetics, Drosophila melanogaster, Gene Expression, Proteomics, Interferon Type I, Proteasome Endopeptidase Complex metabolism
- Abstract
A critical step in preserving protein homeostasis is the recognition, binding, unfolding, and translocation of protein substrates by six AAA-ATPase proteasome subunits (ATPase-associated with various cellular activities) termed PSMC1-6, which are required for degradation of proteins by 26 S proteasomes. Here, we identified 15 de novo missense variants in the PSMC3 gene encoding the AAA-ATPase proteasome subunit PSMC3/Rpt5 in 23 unrelated heterozygous patients with an autosomal dominant form of neurodevelopmental delay and intellectual disability. Expression of PSMC3 variants in mouse neuronal cultures led to altered dendrite development, and deletion of the PSMC3 fly ortholog Rpt5 impaired reversal learning capabilities in fruit flies. Structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune programs. The proteostatic perturbations in T cells from patients with PSMC3 variants correlated with a dysregulation in type I interferon (IFN) signaling in these T cells, which could be blocked by inhibition of the intracellular stress sensor protein kinase R (PKR). These results suggest that proteotoxic stress activated PKR in patient-derived T cells, resulting in a type I IFN response. The potential relationship among proteosome dysfunction, type I IFN production, and neurodevelopment suggests new directions in our understanding of pathogenesis in some neurodevelopmental disorders.
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- 2023
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178. Proteomic Analysis in Valvular Cardiomyopathy: Aortic Regurgitation vs. Aortic Stenosis.
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Holst T, Petersen J, Ameling S, Müller L, Christ T, Gedeon N, Eschenhagen T, Reichenspurner H, Hammer E, and Girdauskas E
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- Humans, Proteomics, Disease Progression, Aortic Valve Insufficiency surgery, Aortic Valve Insufficiency complications, Aortic Valve Stenosis, Cardiomyopathies complications
- Abstract
Left ventricular (LV) reverse remodeling after aortic valve (AV) surgery is less predictable in chronic aortic regurgitation (AR) than in aortic stenosis (AS). We aimed to disclose specific LV myocardial protein signatures possibly contributing to differential disease progression. Global protein profiling of LV myocardial samples excised from the subaortic interventricular septum in patients with isolated AR or AS undergoing AV surgery was performed using liquid chromatography-electrospray ionization-tandem mass spectrometry. Based on label-free quantitation protein intensities, a logistic regression model was calculated and adjusted for age, sex and protein concentration. Web-based functional enrichment analyses of phenotype-associated proteins were performed utilizing g:Profiler and STRING. Data are available via ProteomeXchange with identifier PXD039662. Lysates from 38 patients, including 25 AR and 13 AS samples, were analyzed. AR patients presented with significantly larger LV diameters and volumes (end-diastolic diameter: 61 (12) vs. 48 (13) mm, p < 0.001; end-diastolic volume: 180.0 (74.6) vs. 92.3 (78.4), p = 0.001). A total of 171 proteins were associated with patient phenotype: 117 were positively associated with AR and the enrichment of intracellular compartment proteins (i.e., assigned to carbohydrate and nucleotide metabolism, protein biosynthesis and the proteasome) was detected. Additionally, 54 were positively associated with AS and the enrichment of extracellular compartment proteins (i.e., assigned to the immune and hematopoietic system) was observed. In summary, functional enrichment analysis revealed specific AR- and AS-associated signatures of LV myocardial proteins.
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- 2023
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179. Association of in-competition injury risk and the degree of rapid weight cutting prior to competition in division I collegiate wrestlers.
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Hammer E, Sanfilippo JL, Johnson G, and Hetzel S
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- Humans, Universities, Athletes, Adipose Tissue, Body Weight, Wrestling injuries
- Abstract
Objectives: Weight cutting is thought to offer a competitive advantage in wrestling. Dehydration has deleterious effects on physical and cognitive function, which may increase the risk of injury. The purpose of the study was to investigate whether the degree of weight cutting was associated with injury risk., Methods: Data were collected prospectively in a cohort of collegiate wrestlers over seven seasons. Changes in weight, body fat and lean mass were measured during the preseason, at midseason and before competition. Cox proportional-hazard ratios were calculated for risk of in-competition injury., Results: Among 67 unique division 1 collegiate wrestlers (163 athlete seasons), there were 53 unique injuries affecting 46 athletes. There was no difference in absolute weight change, per cent weight change, per cent body fat change or per cent lean mass change between injured and non-injured wrestlers from the preseason to midseason measurements. From midseason to competition weight, change in body weight was -7.0%±3.2% (-5.3 kg±2.6) in injured athletes compared with -5.7%±3.3% (-4.3 kg±2.5) in non-injured athletes. For every kilogram of body weight lost, wrestlers had a 14% increased hazard of injury (HR 1.14, 95% CI 1.04 to 1.25, p=0.004). For every 1% of body weight lost, wrestlers had an 11% increased hazard of injury (HR 1.11, 95% CI 1.03 to 1.19, p=0.005)., Conclusion: Rapid weight cutting was associated with a higher risk of in-competition injuries in division 1 collegiate wrestlers. For every per cent in body weight lost, wrestlers had an 11% increased hazard of injury during competition., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
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180. BCL11B depletion induces the development of highly cytotoxic innate T cells out of IL-15 stimulated peripheral blood αβ CD8+ T cells.
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Forkel H, Grabarczyk P, Depke M, Troschke-Meurer S, Simm S, Hammer E, Michalik S, Hentschker C, Corleis B, Loyal L, Zumpe M, Siebert N, Dorhoi A, Thiel A, Lode H, Völker U, and Schmidt CA
- Subjects
- Killer Cells, Natural, CD8-Positive T-Lymphocytes, Transcription Factors metabolism, Interleukin-15 pharmacology, Interleukin-15 metabolism, T-Lymphocytes, Cytotoxic metabolism
- Abstract
BCL11B, an essential transcription factor for thymopoiesis, regulates also vital processes in post-thymic lymphocytes. Increased expression of BCL11B was recently correlated with the maturation of NK cells, whereas reduced BCL11B levels were observed in native and induced T cell subsets displaying NK cell features. We show that BCL11B-depleted CD8+ T cells stimulated with IL-15 acquired remarkable innate characteristics. These induced innate CD8+ (iiT8) cells expressed multiple innate receptors like NKp30, CD161, and CD16 as well as factors regulating migration and tissue homing while maintaining their T cell phenotype. The iiT8 cells effectively killed leukemic cells spontaneously and neuroblastoma spheroids in the presence of a tumor-specific monoclonal antibody mediated by CD16 receptor activation. These iiT8 cells integrate the innate natural killer cell activity with adaptive T cell longevity, promising an interesting therapeutic potential. Our study demonstrates that innate T cells, albeit of limited clinical applicability given their low frequency, can be efficiently generated from peripheral blood and applied for adoptive transfer, CAR therapy, or combined with therapeutic antibodies., Competing Interests: The authors report there are no competing interests to declare., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)
- Published
- 2022
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181. Immunoproteasomes control activation of innate immune signaling and microglial function.
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Çetin G, Studencka-Turski M, Venz S, Schormann E, Junker H, Hammer E, Völker U, Ebstein F, and Krüger E
- Subjects
- Animals, Mice, Humans, Proteasome Endopeptidase Complex metabolism, Proteome metabolism, Proteomics, Phagocytosis, Protein Kinases metabolism, Interferons metabolism, Ubiquitins metabolism, Microglia, NF-kappa B metabolism
- Abstract
Microglia are the resident immune cells of the central nervous system (CNS) and play a major role in the regulation of brain homeostasis. To maintain their cellular protein homeostasis, microglia express standard proteasomes and immunoproteasomes (IP), a proteasome isoform that preserves protein homeostasis also in non-immune cells under challenging conditions. The impact of IP on microglia function in innate immunity of the CNS is however not well described. Here, we establish that IP impairment leads to proteotoxic stress and triggers the unfolded and integrated stress responses in mouse and human microglia models. Using proteomic analysis, we demonstrate that IP deficiency in microglia results in profound alterations of the ubiquitin-modified proteome among which proteins involved in the regulation of stress and immune responses. In line with this, molecular analysis revealed chronic activation of NF-κB signaling in IP-deficient microglia without further stimulus. In addition, we show that IP impairment alters microglial function based on markers for phagocytosis and motility. At the molecular level IP impairment activates interferon signaling promoted by the activation of the cytosolic stress response protein kinase R. The presented data highlight the importance of IP function for the proteostatic potential as well as for precision proteolysis to control stress and immune signaling in microglia function., 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 © 2022 Çetin, Studencka-Turski, Venz, Schormann, Junker, Hammer, Völker, Ebstein and Krüger.)
- Published
- 2022
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182. ACTN2 Mutant Causes Proteopathy in Human iPSC-Derived Cardiomyocytes.
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Zech ATL, Prondzynski M, Singh SR, Pietsch N, Orthey E, Alizoti E, Busch J, Madsen A, Behrens CS, Meyer-Jens M, Mearini G, Lemoine MD, Krämer E, Mosqueira D, Virdi S, Indenbirken D, Depke M, Salazar MG, Völker U, Braren I, Pu WT, Eschenhagen T, Hammer E, Schlossarek S, and Carrier L
- Subjects
- Humans, Induced Pluripotent Stem Cells metabolism, Myocytes, Cardiac metabolism, Sarcomeres metabolism, Actinin genetics, Actinin metabolism, Cardiomyopathy, Hypertrophic genetics, Cardiomyopathy, Hypertrophic metabolism, Protein Aggregation, Pathological genetics, Protein Aggregation, Pathological metabolism
- Abstract
Genetic variants in α-actinin-2 (ACTN2) are associated with several forms of (cardio)myopathy. We previously reported a heterozygous missense (c.740C>T) ACTN2 gene variant, associated with hypertrophic cardiomyopathy, and characterized by an electro-mechanical phenotype in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Here, we created with CRISPR/Cas9 genetic tools two heterozygous functional knock-out hiPSC lines with a second wild-type (ACTN2wt) and missense ACTN2 (ACTN2mut) allele, respectively. We evaluated their impact on cardiomyocyte structure and function, using a combination of different technologies, including immunofluorescence and live cell imaging, RNA-seq, and mass spectrometry. This study showed that ACTN2mut presents a higher percentage of multinucleation, protein aggregation, hypertrophy, myofibrillar disarray, and activation of both the ubiquitin-proteasome system and the autophagy-lysosomal pathway as compared to ACTN2wt in 2D-cultured hiPSC-CMs. Furthermore, the expression of ACTN2mut was associated with a marked reduction of sarcomere-associated protein levels in 2D-cultured hiPSC-CMs and force impairment in engineered heart tissues. In conclusion, our study highlights the activation of proteolytic systems in ACTN2mut hiPSC-CMs likely to cope with ACTN2 aggregation and therefore directs towards proteopathy as an additional cellular pathology caused by this ACTN2 variant, which may contribute to human ACTN2 -associated cardiomyopathies.
- Published
- 2022
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183. Short-term Pregnancy Outcomes After Nirmatrelvir-Ritonavir Treatment for Mild-to-Moderate Coronavirus Disease 2019 (COVID-19).
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Loza A, Farias R, Gavin N, Wagner R, Hammer E, and Shields A
- Subjects
- Female, Infant, Newborn, Pregnancy, Humans, Ritonavir therapeutic use, Ritonavir adverse effects, Lopinavir therapeutic use, SARS-CoV-2, Pregnancy Outcome, Antiviral Agents therapeutic use, Drug Combinations, Pregnancy Complications, Infectious drug therapy, COVID-19 Drug Treatment
- Abstract
This is a descriptive study of pregnant patients who received nirmatrelvir-ritonavir therapy from April 16, 2022, through May 18, 2022. Patients were eligible to receive nirmatrelvir-ritonavir if they were diagnosed with mild-to-moderate coronavirus disease 2019 (COVID-19) with symptom onset within 5 days, did not require oxygen therapy or hospital admission, and had no contraindications to nirmatrelvir-ritonavir. During the study time frame, 11 patients were identified as candidates for nirmatrelvir-ritonavir treatment. All patients agreed to nirmatrelvir-ritonavir treatment after a telehealth consultation; seven patients completed the treatment. All patients who received nirmatrelvir-ritonavir experienced symptom resolution without the need for additional care. All but one patient tolerated nirmatrelvir-ritonavir without immediate adverse effects, and no adverse fetal or neonatal effects were observed., Competing Interests: Financial Disclosure Andrea Shields reports money was paid to her institution from ACOG as a member of the Board of Directors. Money was paid to her institution from the American Board of Obstetrics and Gynecology as a specialty and subspecialty qualifying examiner, and from the Agency for Healthcare Research and Quality (grant) to develop obstetrics life support. The other authors did not report any potential conflicts of interest., (Copyright © 2022 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2022
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184. Riociguat attenuates the changes in left ventricular proteome and microRNA profile after experimental aortic stenosis in mice.
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Benkner A, Rüdebusch J, Nath N, Hammer E, Grube K, Gross S, Dhople VM, Eckstein G, Meitinger T, Kaderali L, Völker U, Fielitz J, and Felix SB
- Subjects
- Animals, Disease Models, Animal, Heart Ventricles, Male, Mice, Mice, Inbred C57BL, Proteome, Pyrazoles, Pyrimidines, Ventricular Remodeling, Aortic Valve Stenosis, Heart Failure drug therapy, MicroRNAs
- Abstract
Background and Purpose: Development and progression of heart failure involve endothelial and myocardial dysfunction as well as a dysregulation of the NO-sGC-cGMP signalling pathway. Recently, we reported that the sGC stimulator riociguat has beneficial effects on cardiac remodelling and progression of heart failure in response to chronic pressure overload. Here, we examined if these beneficial effects of riociguat were also reflected in alterations of the myocardial proteome and microRNA profiles., Experimental Approach: Male C57BL/6N mice underwent transverse aortic constriction (TAC) and sham-operated mice served as controls. TAC and sham animals were randomised and treated with either riociguat or vehicle for 5 weeks, starting 3 weeks after surgery, when cardiac hypertrophy was established. Afterwards, we performed mass spectrometric proteome analyses and microRNA sequencing of proteins and RNAs, respectively, isolated from left ventricles (LVs)., Key Results: TAC-induced changes of the LV proteome were significantly reduced by treatment with riociguat. Bioinformatics analyses revealed that riociguat improved TAC-induced cardiovascular disease-related pathways, metabolism and energy production, for example, reversed alterations in the levels of myosin heavy chain 7, cardiac phospholamban and ankyrin repeat domain-containing protein 1. Riociguat also attenuated TAC-induced changes of microRNA levels in the LV., Conclusion and Implications: The sGC stimulator riociguat exerted beneficial effects on cardiac structure and function during pressure overload, which was accompanied by a reversal of TAC-induced changes of the cardiac proteome and microRNA profile. Our data support the potential of riociguat as a novel therapeutic agent for heart failure., (© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
- Published
- 2022
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185. Tight Complex Formation of the Fumarate Sensing DcuS-DcuR Two-Component System at the Membrane and Target Promoter Search by Free DcuR Diffusion.
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Gencheva S, Dersch S, Surmann K, Wernet M, Antelo L, Hammer E, Graumann PL, Hellmann N, and Unden G
- Subjects
- DNA, Bacterial, Dicarboxylic Acid Transporters genetics, Dicarboxylic Acid Transporters metabolism, Escherichia coli genetics, Fumarates metabolism, Gene Expression Regulation, Bacterial, Promoter Regions, Genetic, DNA-Binding Proteins genetics, Escherichia coli Proteins genetics, Protein Kinases metabolism, Transcription Factors genetics
- Abstract
Signaling of two-component systems by phosphoryl transfer requires interaction of the sensor kinase with the response regulator. Interaction of the C4-dicarboxylate-responsive and membrane-integral sensor kinase DcuS with the response regulator DcuR was studied. In vitro , the cytoplasmic part of DcuS (PAS
C -Kin) was employed. Stable complexes were formed, when either DcuS or DcuR were phosphorylated ( Kd 22 ± 11 and 28 ± 7 nM, respectively). The unphosphorylated proteins produced a more labile complex ( Kd 1380 ± 395 nM). Bacterial two-hybrid studies confirm interaction of DcuR with DcuS (and PASC -Kin) in vivo . The absolute contents of DcuR (197-979 pmol mg-1 protein) in the bacteria exceeded those of DcuS by more than 1 order of magnitude. According to the Kd values, DcuS exists in complex, with phosphorylated but also unphosphorylated DcuR. In live cell imaging, the predominantly freely diffusing DcuR becomes markedly less mobile after phosphorylation and activation of DcuS by fumarate. Portions of the low mobility fraction accumulated at the cell poles, the preferred location of DcuS, and other portions within the cell, representing phosphorylated DcuR bound to promoters. In the model, acitvation of DcuS increases the affinity toward DcuR, leading to DcuS-P × DcuR formation and phosphorylation of DcuR. The complex is stable enough for phosphate-transfer, but labile enough to allow exchange between DcuR from the cytosol and DcuR-P of the complex. Released DcuR-P diffuses to target promoters and binds. Uncomplexed DcuR-P in the cytosol binds to nonactivated DcuS and becomes dephosphorylated. The lower affinity between DcuR and DcuS avoids blocking of DcuS and allows rapid exchange of DcuR. IMPORTANCE Complex formation of membrane-bound sensor kinases with the response regulators represents an inherent step of signaling from the membrane to the promoters on the DNA. In the C4-dicarboxylate-sensing DcuS-DcuR two-component system, complex formation is strengthened by activation (phosphorylation) in vitro and in vivo , with trapping of the response regulator DcuR at the membrane. Single-molecule tracking of DcuR in the bacterial cell demonstrates two populations of DcuR with decreased mobility in the bacteria after activation: one at the membrane, but a second in the cytosol, likely representing DNA-bound DcuR. The data suggest a model with binding of DcuR to DcuS-P for phosphorylation, and of DcuR-P to DcuS for dephosphorylation, allowing rapid adaptation of the DcuR phosphorylation state. DcuR-P is released and transferred to DNA by 3D diffusion.- Published
- 2022
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186. Deficiency in FTSJ1 Affects Neuronal Plasticity in the Hippocampal Formation of Mice.
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von Bohlen Und Halbach V, Venz S, Nwakor S, Hentschker C, Hammer E, Junker H, Kuss AW, von Bohlen Und Halbach O, and Jensen LR
- Abstract
The role of the tRNA methyltransferase FTSJ1 in the brain is largely unknown. We analyzed whether FTSJ1-deficient mice (KO) displayed altered neuronal plasticity. We explored open field behavior (10 KO mice (aged 22-25 weeks)) and 11 age-matched control littermates (WT) and examined mean layer thickness (7 KO; 6 WT) and dendritic spines (5 KO; 5 WT) in the hippocampal area CA1 and the dentate gyrus. Furthermore, long-term potentiation (LTP) within area CA1 was investigated (5 KO; 5 WT), and mass spectrometry (MS) using CA1 tissue (2 each) was performed. Compared to controls, KO mice showed a significant reduction in the mean thickness of apical CA1 layers. Dendritic spine densities were also altered in KO mice. Stable LTP could be induced in the CA1 area of KO mice and remained stable at for at least 1 h, although at a lower level as compared to WTs, while MS data indicated differential abundance of several proteins, which play a role in neuronal plasticity. FTSJ1 has an impact on neuronal plasticity in the murine hippocampal area CA1 at the morphological and physiological levels, which, in conjunction with comparable changes in other cortical areas, might accumulate in disturbed learning and memory functions.
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- 2022
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187. Serum starvation induces sexual dimorphisms in secreted proteins of human umbilical vein endothelial cells (HUVECs) from twin pairs.
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Lorenz M, Witt E, Völker U, Stangl K, Stangl V, and Hammer E
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- Cell Culture Techniques methods, Cells, Cultured, Female, Human Umbilical Vein Endothelial Cells metabolism, Humans, Male, Sex Factors, Proteins metabolism, Sex Characteristics
- Abstract
There is growing evidence for sex and gender differences in the clinical manifestation and outcomes of human diseases. Human primary endothelial cells represent a useful cardiovascular model to study sexual dimorphisms at the cellular level. Here, we analyzed sexual dimorphisms of the secretome after serum starvation using human umbilical vein endothelial cells (HUVECs) from twin pairs of the opposite sex to minimize the impact of varying genetic background. HUVECs were starved for 5 and 16 h, respectively, and proteins of the cell culture supernatants were analyzed by tandem mass spectrometry. Altogether, 960 extracellular proteins were identified of which 683 were amendable to stringent quantification. Significant alterations were observed for 455 proteins between long-term and short-term starvation and the majority were similar in both sexes. Only 5 proteins showed significant sex-specific regulation between long-versus short-term starvation. Furthermore, 19 unique proteins with significant sexual dimorphisms at the same time points of serum starvation were observed. A larger number of proteins, for example tissue factor inhibitor 2 (TFPI2), displayed higher levels in the supernatants of females compared to male cells after long term serum starvation that might point to higher adaptation capacity of female cells. The overall results demonstrate that male and female cells differ in their secretome., (© 2022 The Authors. Proteomics published by Wiley-VCH GmbH.)
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- 2022
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188. Emergence and intensification of dairying in the Caucasus and Eurasian steppes.
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Scott A, Reinhold S, Hermes T, Kalmykov AA, Belinskiy A, Buzhilova A, Berezina N, Kantorovich AR, Maslov VE, Guliyev F, Lyonnet B, Gasimov P, Jalilov B, Eminli J, Iskandarov E, Hammer E, Nugent SE, Hagan R, Majander K, Onkamo P, Nordqvist K, Shishlina N, Kaverzneva E, Korolev AI, Khokhlov AA, Smolyaninov RV, Sharapova SV, Krause R, Karapetian M, Stolarczyk E, Krause J, Hansen S, Haak W, and Warinner C
- Subjects
- Animals, Archaeology, Cattle, Horses, Humans, Livestock, Sheep, White People, Dairying, Grassland
- Abstract
Archaeological and archaeogenetic evidence points to the Pontic-Caspian steppe zone between the Caucasus and the Black Sea as the crucible from which the earliest steppe pastoralist societies arose and spread, ultimately influencing populations from Europe to Inner Asia. However, little is known about their economic foundations and the factors that may have contributed to their extensive mobility. Here, we investigate dietary proteins within the dental calculus proteomes of 45 individuals spanning the Neolithic to Greco-Roman periods in the Pontic-Caspian Steppe and neighbouring South Caucasus, Oka-Volga-Don and East Urals regions. We find that sheep dairying accompanies the earliest forms of Eneolithic pastoralism in the North Caucasus. During the fourth millennium BC, Maykop and early Yamnaya populations also focused dairying exclusively on sheep while reserving cattle for traction and other purposes. We observe a breakdown in livestock specialization and an economic diversification of dairy herds coinciding with aridification during the subsequent late Yamnaya and North Caucasus Culture phases, followed by severe climate deterioration during the Catacomb and Lola periods. The need for additional pastures to support these herds may have driven the heightened mobility of the Middle and Late Bronze Age periods. Following a hiatus of more than 500 years, the North Caucasian steppe was repopulated by Early Iron Age societies with a broad mobile dairy economy, including a new focus on horse milking., (© 2022. The Author(s).)
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- 2022
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189. Fetal Zone Steroids Show Discrete Effects on Hyperoxia-Induced Attenuation of Migration in Cultured Oligodendrocyte Progenitor Cells.
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Sunny DE, Krüger EL, Hammer E, Völker U, and Heckmann M
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- Animals, Dehydroepiandrosterone pharmacology, Estradiol pharmacology, Female, Humans, Infant, Newborn, Infant, Premature metabolism, Placenta metabolism, Pregnancy, Proteomics, Rats, Steroids pharmacology, Hyperoxia metabolism, Oligodendrocyte Precursor Cells metabolism, Premature Birth
- Abstract
Cerebral oxygenation disturbances contribute to the pathogenesis of brain lesions in preterm infants with white matter damage. These children are at risk of developing long-term neurodevelopmental disabilities. Preterm birth is associated with sudden hormonal changes along with an untimely increase in oxygen tissue tension. There is a persistent high postnatal production of fetal zone steroids (FZS), which serve in the fetoplacental unit as precursors for placental estrogen synthesis during pregnancy. The role of FZS in events associated with oxygenation differences and their impact on the developing white matter is not well understood. Therefore, we investigated the effect of hyperoxia (80% O
2 ) and subsequent administration of FZS on the protein composition and migration capabilities of immature oligodendrocytes using the OLN93 (rat-derived OPC) cell line as an experimental model. We tested the effect of the FZS, dehydroepiandrosterone (DHEA), 16 α -OH-DHEA, and adiol (5-androstene-3 β , 17 β -diol). After 24-hour exposure to hyperoxia, we monitored the changes in the proteome profile following treatment and observed significant alterations in pathways regulating cytoskeletal remodelling, cell migration, and cell survival. Additionally, hyperoxia leads to impaired migration of the OLN93 cells in culture. Administration of the FZS showed positive effects on the migration process under normoxic conditions in general. However, under hyperoxic conditions, the trend was less prominent. The observed effects could be related to changes in levels of cofilin/LIMK pathway-associated proteins. Adiol had a negative effect when administered together with estradiol, and the proteomic data reveal the activation of ephrin receptor signalling that might be responsible for the attenuation of migration. The results suggest that FZS can differentially regulate pathways involved in the migration of OLN93 cells. A deeper insight into the precise role of endogenous FZS would be an essential prerequisite for developing new treatment strategies including supplementation of estradiol and other steroids in preterm infants., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2022 Donna E. Sunny et al.)- Published
- 2022
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190. Tissue-specific multi-omics analysis of atrial fibrillation.
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Assum I, Krause J, Scheinhardt MO, Müller C, Hammer E, Börschel CS, Völker U, Conradi L, Geelhoed B, Zeller T, Schnabel RB, and Heinig M
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- Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeobox Protein Nkx-2.5 genetics, Homeobox Protein Nkx-2.5 metabolism, Humans, Polymorphism, Single Nucleotide genetics, Quantitative Trait Loci genetics, Atrial Fibrillation genetics, Genomics, Organ Specificity
- Abstract
Genome-wide association studies (GWAS) for atrial fibrillation (AF) have uncovered numerous disease-associated variants. Their underlying molecular mechanisms, especially consequences for mRNA and protein expression remain largely elusive. Thus, refined multi-omics approaches are needed for deciphering the underlying molecular networks. Here, we integrate genomics, transcriptomics, and proteomics of human atrial tissue in a cross-sectional study to identify widespread effects of genetic variants on both transcript (cis-eQTL) and protein (cis-pQTL) abundance. We further establish a novel targeted trans-QTL approach based on polygenic risk scores to determine candidates for AF core genes. Using this approach, we identify two trans-eQTLs and five trans-pQTLs for AF GWAS hits, and elucidate the role of the transcription factor NKX2-5 as a link between the GWAS SNP rs9481842 and AF. Altogether, we present an integrative multi-omics method to uncover trans-acting networks in small datasets and provide a rich resource of atrial tissue-specific regulatory variants for transcript and protein levels for cardiovascular disease gene prioritization., (© 2022. The Author(s).)
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- 2022
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191. Differences in Cell-Intrinsic Inflammatory Programs of Yolk Sac and Bone Marrow Macrophages.
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Elhag S, Stremmel C, Zehrer A, Plocke J, Hennel R, Keuper M, Knabe C, Winterhalter J, Gölling V, Tomas L, Weinberger T, Fischer M, Liu L, Wagner F, Lorenz M, Stark K, Häcker H, Schmidt-Supprian M, Völker U, Jastroch M, Lauber K, Straub T, Walzog B, Hammer E, and Schulz C
- Subjects
- Animals, Cell Differentiation genetics, Cell Proliferation, Gene Expression Profiling, Gene Expression Regulation, Glycolysis, HEK293 Cells, Hematopoietic Stem Cells pathology, Homeodomain Proteins metabolism, Humans, Inflammasomes metabolism, Mice, Inbred C57BL, Phagocytosis, Proteome metabolism, Proto-Oncogene Proteins c-kit metabolism, Transcriptome genetics, Mice, Bone Marrow pathology, Inflammation pathology, Macrophages pathology, Yolk Sac pathology
- Abstract
Background: Tissue-resident macrophages have mixed developmental origins. They derive in variable extent from yolk sac (YS) hematopoiesis during embryonic development. Bone marrow (BM) hematopoietic progenitors give rise to tissue macrophages in postnatal life, and their contribution increases upon organ injury. Since the phenotype and functions of macrophages are modulated by the tissue of residence, the impact of their origin and developmental paths has remained incompletely understood., Methods: In order to decipher cell-intrinsic macrophage programs, we immortalized hematopoietic progenitors from YS and BM using conditional HoxB8, and carried out an in-depth functional and molecular analysis of differentiated macrophages., Results: While YS and BM macrophages demonstrate close similarities in terms of cellular growth, differentiation, cell death susceptibility and phagocytic properties, they display differences in cell metabolism, expression of inflammatory markers and inflammasome activation. Reduced abundance of PYCARD (ASC) and CASPASE-1 proteins in YS macrophages abrogated interleukin-1β production in response to canonical and non-canonical inflammasome activation., Conclusions: Macrophage ontogeny is associated with distinct cellular programs and immune response. Our findings contribute to the understanding of the regulation and programming of macrophage functions.
- Published
- 2021
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192. Cytokine-Mediated Alterations of Human Cardiac Fibroblast's Secretome.
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Bräuninger H, Thottakara T, Schön J, Voss S, Dhople V, Warnke S, Scherschel K, Schrage B, Kirchhof P, Blankenberg S, Völker U, Westermann D, Hammer E, and Lindner D
- Subjects
- Cardiomyopathy, Dilated genetics, Cardiomyopathy, Dilated metabolism, Cardiomyopathy, Dilated pathology, Cells, Cultured, Collagen genetics, Collagen metabolism, Cytokines genetics, Cytokines metabolism, Fibroblasts cytology, Fibroblasts metabolism, Humans, Microscopy, Fluorescence, Myocardium cytology, Oligonucleotide Array Sequence Analysis, Secretome metabolism, Tandem Mass Spectrometry, Transforming Growth Factor beta genetics, Transforming Growth Factor beta metabolism, Transforming Growth Factor beta pharmacology, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha metabolism, Tumor Necrosis Factor-alpha pharmacology, Cytokines pharmacology, Fibroblasts drug effects, Myocardium metabolism, Secretome drug effects, Transcriptome drug effects
- Abstract
Fibroblasts contribute to approximately 20% of the non-cardiomyocytic cells in the heart. They play important roles in the myocardial adaption to stretch, inflammation, and other pathophysiological conditions. Fibroblasts are a major source of extracellular matrix (ECM) proteins whose production is regulated by cytokines, such as TNF-α or TGF-β. The resulting myocardial fibrosis is a hallmark of pathological remodeling in dilated cardiomyopathy (DCM). Therefore, in the present study, the secretome and corresponding transcriptome of human cardiac fibroblasts from patients with DCM was investigated under normal conditions and after TNF-α or TGF-β stimulation. Secreted proteins were quantified via mass spectrometry and expression of genes coding for secreted proteins was analyzed via Affymetrix Transcriptome Profiling. Thus, we provide comprehensive proteome and transcriptome data on the human cardiac fibroblast's secretome. In the secretome of quiescent fibroblasts, 58% of the protein amount belonged to the ECM fraction. Interestingly, cytokines were responsible for 5% of the total protein amount in the secretome and up to 10% in the corresponding transcriptome. Furthermore, cytokine gene expression and secretion were upregulated upon TNF-α stimulation, while collagen secretion levels were elevated after TGF-β treatment. These results suggest that myocardial fibroblasts contribute to pro-fibrotic and to inflammatory processes in response to extracellular stimuli.
- Published
- 2021
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193. Immunoproteasome impairment via β5i/LMP7-deletion leads to sustained pancreatic injury from experimental pancreatitis.
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de Freitas Chama LL, Ebstein F, Wiesrecker B, Wagh PR, Hammer E, Weiss FU, Junker H, Studencka-Turski M, Lerch MM, Krüger E, and Sendler M
- Subjects
- Animals, Cell Death, Cells, Cultured, Chemokine CXCL10 metabolism, Cysteine Endopeptidases metabolism, Female, Gene Deletion, Interferon-beta metabolism, Interleukin-1beta metabolism, Male, Mice, Mice, Inbred C57BL, Pancreas metabolism, Ubiquitination, Cysteine Endopeptidases genetics, Pancreatitis metabolism, Proteasome Endopeptidase Complex metabolism
- Abstract
Uncovering potential new targets involved in pancreatitis may permit the development of new therapies and improvement of patient's outcome. Acute pancreatitis is a primarily sterile disease characterized by a severe systemic inflammatory response associated with extensive necrosis and a mortality rate of up to 24%. Considering that one of the reported disease mechanisms comprises the endoplasmic reticulum (ER) stress response and that the immunoproteasome is a key regulator to prevent proteotoxic stress in an inflammatory context, we investigated its role in acute pancreatitis. In this study, we demonstrate that immunoproteasome deficiency by deletion of the β5i/LMP7-subunit leads to persistent pancreatic damage. Interestingly, immunoproteasome-deficient mice unveil increased activity of pancreatic enzymes in the acute disease phase as well as higher secretion of Interleukin-6 and transcript expression of the Interleukin IL-1β, IFN-β cytokines and the CXCL-10 chemokine. Cell death was increased in immunoproteasome-deficient mice, which appears to be due to the increased accumulation of ubiquitin-protein conjugates and prolonged unfolded protein response. Accordingly, our findings suggest that the immunoproteasome plays a protective role in acute pancreatitis via its role in the clearance of damaged proteins and the balance of ER stress responses in pancreatic acini and in macrophages cytokine production., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
- Published
- 2021
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194. Are psychiatric disorders associated with thyroid hormone therapy in adolescents and young adults with type 1 diabetes?
- Author
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Eckert A, Galler A, Papsch M, Hess M, Holder M, Döing C, Bierkamp-Christophersen D, Hammer E, Pappa A, and Lanzinger S
- Subjects
- Adolescent, Adult, Case-Control Studies, Child, Diabetes Mellitus, Type 1 psychology, Female, Follow-Up Studies, Germany epidemiology, Humans, Male, Mental Disorders chemically induced, Mental Disorders metabolism, Prognosis, Thyroid Diseases complications, Thyroid Diseases epidemiology, Young Adult, Diabetes Mellitus, Type 1 physiopathology, Mental Disorders pathology, Thyroid Diseases drug therapy, Thyroid Hormones adverse effects
- Abstract
Background: To evaluate the association between thyroid autoimmunity and psychiatric disorders (depression, anxiety, eating disorder, schizophrenia or attention-deficit/hyperactivity disorder) among adolescents and young adults with type 1 diabetes (11-25 years)., Methods: We compared 9368 type 1 diabetes patients with thyroid autoimmunity (3789 of them treated with levothyroxine) with 62 438 type 1 diabetes patients without any thyroid disease from a multicentre diabetes patient follow-up registry (DPV) in terms of psychiatric disorders. Thyroid autoimmunity was defined as documented diagnosis of Hashimoto thyroiditis or positive antibodies against thyroid peroxidase or thyroglobulin. Multivariable logistic regression models were used to calculate odds ratios for the respective psychiatric disorders in type 1 diabetes patients with thyroid autoimmunity (overall and stratified by levothyroxine therapy) compared to type 1 diabetes patients without thyroid diseases (reference)., Results: Of the 9368 patients with thyroid autoimmunity, 62% were female with a median (Q1-Q3) age of 16.3 (14.2-17.6) years. Thyroid autoimmunity (with or without levothyroxine therapy) revealed a slight, but significant higher chance for depression (odds ratio [OR], 1.35, 95% confidence interval [CI], 1.19, 1.52), eating disorder (OR, 1.25, CI, 1.03, 1.51), attention-deficit/hyperactivity disorder (OR, 1.22, CI, 1.07, 1.39) and schizophrenia (OR, 1.63, CI, 1.04, 2.56). In individuals with prescribed levothyroxine therapy because of thyroid dysfunction significantly higher odds for depression (OR, 1.63, CI, 1.34, 1.99), anxiety (OR, 1.60, CI, 1.18, 2.18), and attention-deficit/hyperactivity disorder (OR, 1.71, CI, 1.38, 2.12) were observed compared to reference. Thyroid autoimmunity without required levothyroxine therapy revealed no differences to the reference group., Conclusions: Patients on levothyroxine had significantly higher odds for psychiatric disorders, but thyroid autoimmunity in terms of high antibody levels only did not show higher odds for any psychiatric disorder., (© 2020 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)
- Published
- 2021
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195. Fetal Zone Steroids and Estrogen Show Sex Specific Effects on Oligodendrocyte Precursor Cells in Response to Oxidative Damage.
- Author
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Sunny DE, Hammer E, Ittermann T, Krüger EL, Hübner S, Hartmann MF, Wudy SA, Völker U, and Heckmann M
- Subjects
- Animals, Dehydroepiandrosterone urine, Female, Humans, Infant, Newborn, Male, Mice, Minor Histocompatibility Antigens metabolism, Nuclear Pore Complex Proteins metabolism, Oxidative Stress, Dehydroepiandrosterone analogs & derivatives, Estradiol physiology, Infant, Premature metabolism, Oligodendrocyte Precursor Cells physiology, Pregnanolone physiology, Sex Characteristics
- Abstract
Oxygen causes white matter damage in preterm infants and male sex is a major risk factor for poor neurological outcome, which speculates the role of steroid hormones in sex-based differences. Preterm birth is accompanied by a drop in 17β-estradiol (E2) and progesterone along with increased levels of fetal zone steroids (FZS). We performed a sex-based analysis on the FZS concentration differences in urine samples collected from preterm and term infants. We show that, in preterm urine samples, the total concentration of FZS, and in particular the 16α-OH-DHEA concentration, is significantly higher in ill female infants as compared to males. Since we previously identified Nup133 as a novel target protein affected by hyperoxia, here we studied the effect of FZS, allopregnanolone (Allo) and E2 on differentiation and Nup133 signaling using mouse-derived primary oligodendrocyte progenitor cells (OPCs). We show that the steroids could reverse the effect of hyperoxia-mediated downregulation of Nup133 in cultured male OPCs. The addition of FZS and E2 protected cells from oxidative stress. However, E2, in presence of 16α-OH-DHEA, showed a negative effect on male cells. These results assert the importance of sex-based differences and their potential implications in preterm stress response.
- Published
- 2021
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196. Diabetic nephropathy in pregnancy: Report of two cases progressing to end-stage renal disease within one year postpartum.
- Author
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Attique HB, Phachu D, Loza A, Campbell W, Hammer E, and Elali I
- Abstract
Background: Diabetes mellitus is a leading cause of nephropathy and end-stage renal disease. However, diabetic nephropathy during pregnancy in patients with normal glomerular filtration rate and subsequent progression to end-stage renal disease has not been well studied., Cases: This report presents two patients with poorly controlled type 1 diabetes mellitus who had diabetic nephropathy with preserved estimated glomerular filtration rate (Case 1: 117 mL/min/1.73m
2 ; Case 2: 79 mL/min/1.73m2 ) and shared a similar clinical course, with glomerular filtration rates decreasing by approximately one-half during pregnancy and progression to end-stage renal disease within the first year postpartum. Both women had a long history of type 1 diabetes: 18 years and 24 years for case 1 and case 2 respectively. The first patient's course of pregnancy was complicated by difficult-to-control blood glucose and hypertension with subsequent preeclampsia. The second patient's course of pregnancy was complicated by difficult-to-control blood sugars and preterm labor resulting in classical cesarean delivery at 24 weeks. Both patients had renal biopsies shortly after delivery as their renal function continued to worsen postpartum. Both kidney biopsies demonstrated advanced diabetic nephropathy changes and ultimately required chronic renal replacement therapy within 7-9 months postpartum., Conclusion: Comprehensive family planning discussions with women who have diabetic nephropathy should include the risks of renal disease progression, even in those patients with preserved renal function at the time of conception., (© 2021 Published by Elsevier B.V.)- Published
- 2021
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197. How to help runners steer clear of injury.
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Sidhar K and Hammer E
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Risk Factors, United States, Accidental Injuries prevention & control, Family Practice standards, Practice Guidelines as Topic, Preventive Medicine standards, Running injuries, Running standards, Shoes standards
- Abstract
Assess risk factors, then work to address modifiable ones, such as wearing the right running shoes and building up slowly. Don't let overweight or OA dampen enthusiasm.
- Published
- 2021
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198. Mapping past human land use using archaeological data: A new classification for global land use synthesis and data harmonization.
- Author
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Morrison KD, Hammer E, Boles O, Madella M, Whitehouse N, Gaillard MJ, Bates J, Vander Linden M, Merlo S, Yao A, Popova L, Hill AC, Antolin F, Bauer A, Biagetti S, Bishop RR, Buckland P, Cruz P, Dreslerová D, Dusseldorp G, Ellis E, Filipovic D, Foster T, Hannaford MJ, Harrison SP, Hazarika M, Herold H, Hilpert J, Kaplan JO, Kay A, Klein Goldewijk K, Kolář J, Kyazike E, Laabs J, Lancelotti C, Lane P, Lawrence D, Lewis K, Lombardo U, Lucarini G, Arroyo-Kalin M, Marchant R, Mayle F, McClatchie M, McLeester M, Mooney S, Moskal-Del Hoyo M, Navarrete V, Ndiema E, Góes Neves E, Nowak M, Out WA, Petrie C, Phelps LN, Pinke Z, Rostain S, Russell T, Sluyter A, Styring AK, Tamanaha E, Thomas E, Veerasamy S, Welton L, and Zanon M
- Subjects
- Arabia, Biodiversity, Climate, Conservation of Natural Resources, Data Management, Earth, Planet, Ecosystem, History, Ancient, Humans, Mesopotamia, Archaeology, Natural Resources
- Abstract
In the 12,000 years preceding the Industrial Revolution, human activities led to significant changes in land cover, plant and animal distributions, surface hydrology, and biochemical cycles. Earth system models suggest that this anthropogenic land cover change influenced regional and global climate. However, the representation of past land use in earth system models is currently oversimplified. As a result, there are large uncertainties in the current understanding of the past and current state of the earth system. In order to improve representation of the variety and scale of impacts that past land use had on the earth system, a global effort is underway to aggregate and synthesize archaeological and historical evidence of land use systems. Here we present a simple, hierarchical classification of land use systems designed to be used with archaeological and historical data at a global scale and a schema of codes that identify land use practices common to a range of systems, both implemented in a geospatial database. The classification scheme and database resulted from an extensive process of consultation with researchers worldwide. Our scheme is designed to deliver consistent, empirically robust data for the improvement of land use models, while simultaneously allowing for a comparative, detailed mapping of land use relevant to the needs of historical scholars. To illustrate the benefits of the classification scheme and methods for mapping historical land use, we apply it to Mesopotamia and Arabia at 6 kya (c. 4000 BCE). The scheme will be used to describe land use by the Past Global Changes (PAGES) LandCover6k working group, an international project comprised of archaeologists, historians, geographers, paleoecologists, and modelers. Beyond this, the scheme has a wide utility for creating a common language between research and policy communities, linking archaeologists with climate modelers, biodiversity conservation workers and initiatives., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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199. Specific domain V reduction of beta-2-glycoprotein I induces protein flexibility and alters pathogenic antibody binding.
- Author
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Buchholz I, McDonnell T, Nestler P, Tharad S, Kulke M, Radziszewska A, Ripoll VM, Schmidt F, Hammer E, Toca-Herrera JL, Rahman A, and Delcea M
- Subjects
- Autoantibodies immunology, Cysteine chemistry, Cysteine metabolism, Disulfides chemistry, Immunoglobulin G chemistry, Immunoglobulin G immunology, Microscopy, Atomic Force, Models, Molecular, Protein Binding immunology, Structure-Activity Relationship, beta 2-Glycoprotein I immunology, beta 2-Glycoprotein I metabolism, Autoantibodies chemistry, Protein Conformation, Protein Folding, Protein Interaction Domains and Motifs, beta 2-Glycoprotein I chemistry
- Abstract
Beta-2-glycoprotein I (β2GPI) is a blood protein and the major antigen in the autoimmune disorder antiphospholipid syndrome (APS). β2GPI exists mainly in closed or open conformations and comprises of 11 disulfides distributed across five domains. The terminal Cys288/Cys326 disulfide bond at domain V has been associated with different cysteine redox states. The role of this disulfide bond in conformational dynamics of this protein has not been investigated so far. Here, we report on the enzymatic driven reduction by thioredoxin-1 (recycled by Tris(2-carboxyethyl)phosphine; TCEP) of β2GPI. Specific reduction was demonstrated by Western blot and mass spectrometry analyses confirming majority targeting to the fifth domain of β2GPI. Atomic force microscopy images suggested that reduced β2GPI shows a slightly higher proportion of open conformation and is more flexible compared to the untreated protein as confirmed by modelling studies. We have determined a strong increase in the binding of pathogenic APS autoantibodies to reduced β2GPI as demonstrated by ELISA. Our study is relevant for understanding the effect of β2GPI reduction on the protein structure and its implications for antibody binding in APS patients.
- Published
- 2021
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200. Analysis of DCM associated protein alterations of human right and left ventricles.
- Author
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Ameling S, Bischof J, Dörr M, Könemann S, Empen K, Weitmann K, Klingel K, Beug D, Dhople VM, Völker U, Hammer E, and Felix SB
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- Animals, Heart Ventricles diagnostic imaging, Human Rights, Humans, Mice, Myocardium, Cardiomyopathy, Dilated diagnostic imaging, Ventricular Dysfunction, Left diagnostic imaging
- Abstract
Dilated cardiomyopathy (DCM) is characterized by ventricular chamber enlargement and impaired myocardial function. Endomyocardial biopsies (EMB) enable immunohistochemical and molecular characterization of this disease. However, knowledge about specific molecular patterns and their relation to cardiac function in both ventricles is rare. Therefore, we performed a mass spectrometric analysis of 28 paired EMBs of left (LV) and right ventricles (RV) of patients with DCM or suspected myocarditis allowing quantitative profiling of 743 proteins. We analysed associations between protein abundance of LV and RV as well as the echocardiographic parameters LVEF, TAPSE, LVEDDI, and RVEDDI by linear regression models. Overall, more LV than RV proteins were associated with LV parameters or with RVEDDI. Most LV and RV proteins increasing in level with impairing of LVEF were annotated to structural components of cardiac tissue. Additionally, a high proportion of LV proteins with metabolic functions decreased in level with decreasing LVEF. Results were validated with LV heart sections of a genetic murine heart failure model. The study shows, that remodelling and systolic dysfunction in DCM is mirrored by distinct alterations in protein composition of both ventricles. Loss of LV systolic function is reflected predominantly by alterations in proteins assigned to metabolic functions in the LV whereas structural remodelling was more obvious in the RV. Alterations related to intermediate filaments were seen in both ventricles and highlight such proteins as early indicators of LV loss of function. SIGNIFICANCE: The present study report protein sets in the RV and the LV being associated with ventricular function and remodelling in DCM. Protein abundances in the LV and the RV emphasize and expand current knowledge on pathophysiological changes in heart failure and DCM. While RV and LV EMBs do not differ concerning diagnostic assessment of inflammatory status and virus persistence, additional information reflecting disease severity associated protein alterations can be gained by EMB protein profiling. RV and LV protein data provided complementary information. The protein pattern of the LV reflects metabolic changes and an impaired energy production, which is associated with the degree of LV systolic dysfunction and remodelling and may yield important information about the disease status in DCM. On the other hand, at this disease stage of DCM with still preserved RV function, RV alterations in structural proteins may reflect myocardial compensatory protective mechanisms for maintenance of structure and cellular function. The study highlight particular proteins being of interest as heart failure biomarkers in both ventricles which seem to reflect the severity of the disease. Further comparative studies between different HF aetiologies have to evaluate those proteins as markers specific for DCM., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2021
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