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Rieke, Johanna Magdalena ; Zhang, Rong ; Braun, Doreen ; Yilmaz, Öznur ; Japp, Anna S. ; Lopes, Filipa M. ; Pleschka, Michael ; Hilger, Alina Christine ; Schneider, Sophia ; Newman, William G. ; Schneider, Sophia ; Newman, William G. ; Beaman, Glenda M. ; Nordenskjöld, Agneta ; Ebert, Anne-Karoline ; Promm, Martin ; Rösch, Wolfgang H. ; Stein, Raimund ; Hirsch, Karin ; Schäfer, Frank-Mattias ; Schmiedeke, Eberhard ; Boemers, Thomas M. ; Lacher, Martin ; Kluth, Dietrich ; Gosemann, Jan-Hendrik ; Anderberg, Magnus ; Barker, Gillian ; Holmdahl, Gundela ; Läckgren, Göran ; Keene, David ; Cervellione, Raimondo M. ; Giorgio, Elisa ; Di Grazia, Massimo ; Feitz, Wouter F. J. ; Marcelis, Carlo L. M. ; Rooij, Iris Antonia Leonarda Martina van ; Bökenkamp, Arend ; Beckers, Goedele M. A. ; Keegan, Catherine E. ; Sharma, Amit ; Dakal, Tikam Chand ; Wittler, Lars ; Grote, Phillip ; Zwink, Nadine ; Jenetzky, Ekkehart ; Brusco, Alfredo ; Thiele, Holger ; Ludwig, Michael ; Schweizer, Ulrich ; Woolf, Adrian S. ; Odermatt, Benjamin ; Reutter, Heiko
Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.
Vascular endothelial growth factors (VEGFs), initially thought to act specifically on the vascular system, exert trophic effects on neural cells during development and adulthood. Therefore, the VEGF system serves as a promising therapeutic target for brain pathologies, but its simultaneous action on vascular cells paves the way for harmful side effects. To circumvent these deleterious effects, many studies have aimed to clarify whether VEGFs directly affect neural cells or if the effects are mediated secondarily via other cell types, like vascular cells. A great number of reports have shown the expression and function of VEGF receptors (VEGFRs), mainly VEGFR-1 and -2, in neural cells, where VEGFR-2 has been described as the major mediator of VEGF-A signals. This review aims to summarize and compare the divergent roles of VEGFR-1 and -2 during CNS development and homeostasis.
Théry, Clotilde ; Witwer, Kenneth W. ; Aikawa, Elena ; Alcaraz, Maria Jose ; Anderson, Johnathon D. ; Andriantsitohaina, Ramaroson ; Antoniou, Anna ; Arab, Tanina ; Archer, Fabienne ; Atkin-Smith, Georgia K. ; Ayre, D. Craig ; Bach, Jean-Marie ; Bachurski, Daniel ; Baharvand, Hossein ; Balaj, Leonora ; Baldacchino, Shawn ; Bauer, Natalie N. ; Baxter, Amy A. ; Bebawy, Mary ; Beckham, Carla ; Zavec, Apolonija Bedina ; Benmoussa, Abderrahim ; Berardi, Anna C. ; Bergese, Paolo ; Bielska, Ewa ; Blenkiron, Cherie ; Bobis-Wozowicz, Sylwia ; Boilard, Eric ; Boireau, Wilfrid ; Bongiovanni, Antonella ; Borràs, Francesc E. ; Bosch, Steffi ; Boulanger, Chantal M. ; Breakefield, Xandra ; Breglio, Andrew M. ; Brennan, Meadhbh Aín ; Brigstock, David R. ; Brisson, Alain ; Broekman, Marike L. D. ; Bromberg, Jacqueline F. ; Bryl-Gorecka, Paulina ; Buch, Shilpa ; Buck, Amy H. ; Burger, Dylan ; Busatto, Sara ; Buschmann, Dominik ; Bussolati, Benedetta ; Buzás, Edit I. ; Byrd, James Bryan ; Camussi, Giovanni ; Carter, David R. F. ; Caruso, Sarah ; Chamley, Lawrence W. ; Chang, Yu-Ting ; Chen, Chihchen ; Chen, Shuai ; Cheng, Lesley ; Chin, Andrew R. ; Clayton, Aled ; Clerici, Stefano P. ; Cocks, Alex ; Cocucci, Emanuele ; Coffey, Robert J. ; Cordeiro-da-Silva, Anabela ; Couch, Yvonne ; Coumans, Frank A. W. ; Coyle, Beth ; Crescitelli, Rossella ; Criado, Miria Ferreira ; D’Souza-Schorey, Crislyn ; Das, Saumya ; Chaudhuri, Amrita Datta ; de-Candia, Paola ; De Santana, Eliezer F. ; De Wever, Olivier ; del Portillo, Hernando A. ; Demaret, Tanguy ; Deville, Sarah ; Devitt, Andrew ; Dhondt, Bert ; Di Vizio, Dolores ; Dieterich, Lothar C. ; Dolo, Vincenza ; Dominguez Rubio, Ana Paula ; Dominici, Massimo ; Dourado, Mauricio R. ; Driedonks, Tom A. P. ; Duarte, Filipe V. ; Duncan, Heather M. ; Eichenberger, Ramon Marc ; Ekström, Karin ; El Andaloussi, Samir ; Elie-Caille, Celine ; Erdbrügger, Uta ; Falcón-Pérez, Juan M. ; Fatima, Farah ; Fish, Jason E. ; Flores-Bellver, Miguel ; Försönits, András ; Frelet-Barrand, Annie ; Fricke, Fabia ; Fuhrmann, Gregor ; Gabrielsson, Susanne ; Gámez-Valero, Ana ; Gardiner, Chris ; Gärtner, Kathrin ; Gaudin, Raphael ; Gho, Yong Song ; Giebel, Bernd ; Gilbert, Caroline ; Gimona, Mario ; Giusti, Ilaria ; Goberdhan, Deborah C. I. ; Görgens, André ; Gorski, Sharon M. ; Greening, David W. ; Groß, Julia Christina ; Gualerzi, Alice ; Gupta, Gopal N. ; Gustafson, Dakota ; Handberg, Aase ; Haraszti, Réka Ágnes ; Harrison, Paul ; Hegyesi, Hargita ; Hendrix, An ; Hill, Andrew F. ; Hochberg, Fred H. ; Hoffmann, Karl F. ; Holder, Beth ; Holthofer, Harry ; Hosseinkhani, Baharak ; Hu, Guoku ; Huang, Yiyao ; Huber, Veronica ; Hunt, Stuart ; Ibrahim, Ahmed Gamal-Eldin ; Ikezu, Tsuneya ; Inal, Jameel M. ; Isin, Mustafa ; Ivanova, Alena ; Jackson, Hannah K. ; Jacobsen, Soren ; Jay, Steven M. ; Jayachandran, Muthuvel ; Jenster, Guido ; Jiang, Lanzhou ; Johnson, Suzanne M. ; Jones, Jennifer C. ; Jong, Ambrose ; Jovanovic-Talisman, Tijana ; Jung, Stephanie ; Kalluri, Raghu ; Kano, Shin-ichi ; Kaur, Sukhbir ; Kawamura, Yumi ; Keller, Evan T. ; Khamari, Delaram ; Khomyakova, Elena ; Khvorova, Anastasia ; Kierulf, Peter ; Kim, Kwang Pyo ; Kislinger, Thomas ; Klingeborn, Mikael ; Klinke, David J. ; Kornek, Miroslaw ; Kosanović, Maja M. ; Kovács, Árpád Ferenc ; Krämer-Albers, Eva-Maria ; Krasemann, Susanne ; Krause, Mirja ; Kurochkin, Igor V. ; Kusuma, Gina D. ; Kuypers, Sören ; Laitinen, Saara ; Langevin, Scott M. ; Languino, Lucia R. ; Lannigan, Joanne ; Lässer, Cecilia ; Laurent, Louise C. ; Lavieu, Gregory ; Lázaro-Ibáñez, Elisa ; Le Lay, Soazig ; Lee, Myung-Shin ; Lee, Yi Xin Fiona ; Lemos, Debora S. ; Lenassi, Metka ; Leszczynska, Aleksandra ; Li, Isaac T. S. ; Liao, Ke ; Libregts, Sten F. ; Ligeti, Erzsebet ; Lim, Rebecca ; Lim, Sai Kiang ; Linē, Aija ; Linnemannstöns, Karen ; Llorente, Alicia ; Lombard, Catherine Ann ; Lorenowicz, Magdalena J. ; Lörincz, Ákos M. ; Lötvall, Jan ; Lovett, Jason ; Lowry, Michelle C. ; Loyer, Xavier ; Lu, Quan ; Lukomska, Barbara ; Lunavat, Taral Rameshchand ; Maas, Sybren L. N. ; Malhi, Harmeet ; Marcilla, Antonio ; Mariani, Jacopo ; Mariscal, Javier ; Martens-Uzunova, Elena S. ; Martin-Jaular, Lorena ; Martinez, M. Carmen ; Martins, Vilma Regina ; Mathieu, Mathilde ; Mathivanan, Suresh ; Maugeri, Marco ; McGinnis, Lynda K. ; McVey, Mark J. ; Meckes, David G. ; Meehan, Katie ; Mertens, Inge ; Minciacchi, Valentina R. ; Möller, Andreas ; Møller Jørgensen, Malene ; Morales-Kastresana, Aizea ; Morhayim, Jess ; Mullier, François ; Muraca, Maurizio ; Musante, Luca ; Mussack, Veronika ; Muth, Dillon C. ; Myburgh, Kathryn H. ; Najrana, Tanbir ; Nawaz, Muhammad ; Nazarenko, Irina ; Nejsum, Peter ; Neri, Christian ; Neri, Tommaso ; Nieuwland, Rienk ; Nimrichter, Leonardo ; Nolan, John P. ; Nolte-’t Hoen, Esther N. M. ; Hooten, Nicole Noren ; O’Driscoll, Lorraine ; O’Grady, Tina ; O’Loghlen, Ana ; Ochiya, Takahiro ; Olivier, Martin ; Ortiz, Alberto ; Ortiz, Luis A. ; Osteikoetxea, Xabier ; Østergaard, Ole ; Ostrowski, Matias ; Park, Jaesung ; Pegtel, Dirk Michiel ; Peinado, Hector ; Perut, Francesca ; Pfaffl, Michael ; Phinney, Donald G. ; Pieters, Bartijn C. H. ; Pink, Ryan Charles ; Pisetsky, David S. ; Pogge von Strandmann, Elke ; Polakovicova, Iva ; Poon, Ivan K. H. ; Powell, Bonita H. ; Prada, Ilaria ; Pulliam, Lynn ; Quesenberry, Peter ; Radeghieri, Annalisa ; Raffai, Robert L. ; Raimondo, Stefania ; Rak, Janusz ; Ramirez, Marcel I. ; Raposo, Graça ; Rayyan, Morsi S. ; Regev-Rudzki, Neta ; Ricklefs, Franz Lennard ; Robbins, Paul D. ; Roberts, David D. ; Rodrigues, Silvia C. ; Rohde, Eva ; Rome, Sophie ; Rouschop, Kasper M. ; Rughetti, Aurelia ; Russell, Ashley E. ; Saá, Paula ; Sahoo, Susmita ; Salas-Huenuleo, Edison ; Sánchez, Catherine ; Saugstad, Julie A. ; Saul, Meike J. ; Schiffelers, Raymond M. ; Schneider, Raphael ; Schøyen, Tine Hiorth ; Scott, Aaron ; Shahaj, Eriomina ; Sharma, Shivani ; Shatnyeva, Olga ; Shekari, Faezeh ; Shelke, Ganesh Vilas ; Shetty, Ashok K. ; Shiba, Kiyotaka ; Siljander, Pia R.-M. ; Silva, Andreia M. ; Skowronek, Agata ; Snyder, Orman L. ; Soares, Rodrigo Pedro ; Sódar, Barbara W. ; Soekmadji, Carolina ; Sotillo, Javier ; Stahl, Philip D. ; Stoorvogel, Willem ; Stott, Shannon L. ; Strasser, Erwin F. ; Swift, Simon ; Tahara, Hidetoshi ; Tewari, Muneesh ; Timms, Kate ; Tiwari, Swasti ; Tixeira, Rochelle ; Tkach, Mercedes ; Toh, Wei Seong ; Tomasini, Richard ; Torrecilhas, Ana Claudia ; Tosar, Juan Pablo ; Toxavidis, Vasilis ; Urbanelli, Lorena ; Vader, Pieter ; Balkom, Bastiaan Wilhelmus Maria van ; Grein, Susanne G. van der ; Van Deun, Jan ; Herwijnen, Martijn J. C. van ; Van Keuren-Jensen, Kendall R. ; Niel, Guillaume van ; Royen, Martin E. van ; Wijnen, Andre J. van ; Vasconcelos, M. Helena ; Vechetti, Ivan J. ; Veit, Tiago D. ; Vella, Laura J. ; Velot, Émilie ; Verweij, Frederik ; Vestad, Beate ; Viñas, Jose Luis ; Visnovitz, Tamás ; Vukman, Krisztina V. ; Wahlgren, Jessica ; Watson, Dionysios C. ; Wauben, Marca H. M. ; Weaver, Alissa ; Webber, Jason P. ; Weber, Viktoria ; Wehman, Ann M. ; Weiss, Daniel J. ; Welsh, Joshua A. ; Wendt, Sebastian ; Wheelock, Åsa M. ; Wiener, Zoltán ; Witte, Leonie ; Wolfram, Joy ; Xagorari, Angeliki ; Xander, Patricia ; Xu, Jing ; Yan, Xiaomei ; Yáñez-Mó, María ; Yin, Hang ; Yuana, Yuana ; Zappulli, Valentina ; Zarubova, Jana ; Žėkas, Vytautas ; Zhang, Jian-ye ; Zhao, Zezhou ; Zheng, Lei ; Zheutlin, Alexander R. ; Zickler, Antje Maria ; Zimmermann, Pascale ; Zivkovic, Angela M. ; Zocco, Davide ; Zuba-Surma, Ewa K.
The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
O’Connell, Kevin S. ; Koromina, Maria ; van der Veen, Tracey ; Boltz, Toni ; David, Friederike S. ; Kay Yang, Jessica Mei ; Lin, Keng-Han ; Wang, Xin ; Coleman, Jonathan R. I. ; Mitchell, Brittany L. ; McGrouther, Caroline C. ; Rangan, Aaditya V. ; Lind, Penelope A. ; Koch, Elise ; Harder, Arvid ; Parker, Nadine ; Bendl, Jaroslav ; Adorjan, Kristina ; Agerbo, Esben ; Albani, Diego ; Alemany, Silvia ; Alliey-Rodriguez, Ney ; Als, Thomas D. ; Andlauer, Till F. M. ; Antoniou, Anastasia ; Ask, Helga ; Bass, Nicholas ; Bauer, Michael ; Beins, Eva C. ; Bigdeli, Tim B. ; Pedersen, Carsten Bøcker ; Boks, Marco P. ; Børte, Sigrid ; Bosch, Rosa ; Brum, Murielle ; Brumpton, Ben M. ; Brunkhorst-Kanaan, Nathalie ; Budde, Monika ; Bybjerg-Grauholm, Jonas ; Byerley, William ; Cabana-Domínguez, Judit ; Cairns, Murray J. ; Carpiniello, Bernardo ; Casas, Miquel ; Cervantes, Pablo ; Chatzinakos, Chris ; Chen, Hsi-Chung ; Clarence, Tereza ; Clarke, Toni-Kim ; Claus, Isabelle ; Coombes, Brandon ; Corfield, Elizabeth C. ; Cruceanu, Cristiana ; Cuellar-Barboza, Alfredo ; Czerski, Piotr M. ; Dafnas, Konstantinos ; Dale, Anders M. ; Dalkner, Nina ; Degenhardt, Franziska ; DePaulo, J. Raymond ; Djurovic, Srdjan ; Drange, Ole Kristian ; Escott-Price, Valentina ; Fanous, Ayman H. ; Fellendorf, Frederike T. ; Ferrier, I. Nicol ; Forty, Liz ; Frank, Josef ; Frei, Oleksandr ; Freimer, Nelson B. ; Fullard, John F. ; Garnham, Julie ; Gizer, Ian R. ; Gordon, Scott D. ; Gordon-Smith, Katherine ; Greenwood, Tiffany A. ; Grove, Jakob ; Guzman-Parra, José ; Ha, Tae Hyon ; Hahn, Tim ; Haraldsson, Magnus ; Hautzinger, Martin ; Havdahl, Alexandra ; Heilbronner, Urs ; Hellgren, Dennis ; Herms, Stefan ; Hickie, Ian B. ; Hoffmann, Per ; Holmans, Peter A. ; Huang, Ming-Chyi ; Ikeda, Masashi ; Jamain, Stéphane ; Johnson, Jessica S. ; Jonsson, Lina ; Kalman, Janos L. ; Kamatani, Yoichiro ; Kennedy, James L. ; Kim, Euitae ; Kim, Jaeyoung ; Kittel-Schneider, Sarah ; Knowles, James A. ; Kogevinas, Manolis ; Kranz, Thorsten M. ; Krebs, Kristi ; Kushner, Steven A. ; Lavebratt, Catharina ; Lawrence, Jacob ; Leber, Markus ; Lee, Heon-Jeong ; Liao, Calwing ; Lucae, Susanne ; Lundberg, Martin ; MacIntyre, Donald J. ; Maier, Wolfgang ; Maihofer, Adam X. ; Malaspina, Dolores ; Manchia, Mirko ; Maratou, Eirini ; Martinsson, Lina ; Mattheisen, Manuel ; McGregor, Nathaniel W. ; McInnis, Melvin G. ; McKay, James D. ; Medeiros, Helena ; Meyer-Lindenberg, Andreas ; Millischer, Vincent ; Morris, Derek W. ; Moutsatsou, Paraskevi ; Mühleisen, Thomas W. ; O’Donovan, Claire ; Olsen, Catherine M. ; Panagiotaropoulou, Georgia ; Papiol, Sergi ; Pardiñas, Antonio F. ; Park, Hye Youn ; Perry, Amy ; Pfennig, Andrea ; Pisanu, Claudia ; Potash, James B. ; Quested, Digby ; Rapaport, Mark H. ; Regeer, Eline J. ; Rice, John P. ; Rivera, Margarita ; Schulte, Eva C. ; Senner, Fanny ; Shadrin, Alexey ; Shilling, Paul D. ; Sigurdsson, Engilbert ; Sindermann, Lisa ; Sirignano, Lea ; Siskind, Dan ; Slaney, Claire ; Sloofman, Laura G. ; Smeland, Olav B. ; Smith, Daniel J. ; Sobell, Janet L. ; Soler Artigas, Maria ; Stein, Dan J. ; Stein, Frederike ; Su, Mei-Hsin ; Sung, Heejong ; Świątkowska, Beata ; Terao, Chikashi ; Tesfaye, Markos ; Tesli, Martin ; Thorgeirsson, Thorgeir E. ; Thorp, Jackson G. ; Toma, Claudio ; Tondo, Leonardo ; Tooney, Paul A. ; Tsai, Shih-Jen ; Tsermpini, Evangelia Eirini ; Vawter, Marquis P. ; Vedder, Helmut ; Vreeker, Annabel ; Walters, James T. R. ; Winsvold, Bendik S. ; Witt, Stephanie H. ; Won, Hong-Hee ; Ye, Robert ; Young, Allan H. ; Zandi, Peter P. ; Zillich, Lea ; Adolfsson, Rolf ; Alda, Martin ; Alfredsson, Lars ; Backlund, Lena ; Baune, Bernhard T. ; Bellivier, Frank ; Bengesser, Susanne ; Berrettini, Wade H. ; Biernacka, Joanna M. ; Boehnke, Michael ; Børglum, Anders D. ; Breen, Gerome ; Carr, Vaughan J. ; Catts, Stanley ; Cichon, Sven ; Corvin, Aiden ; Craddock, Nicholas ; Dannlowski, Udo ; Dikeos, Dimitris ; Etain, Bruno ; Ferentinos, Panagiotis ; Frye, Mark ; Fullerton, Janice M. ; Gawlik, Micha ; Gershon, Elliot S. ; Goes, Fernando S. ; Green, Melissa J. ; Grigoroiu-Serbanescu, Maria ; Hauser, Joanna ; Henskens, Frans A. ; Hjerling-Leffler, Jens ; Hougaard, David M. ; Hveem, Kristian ; Iwata, Nakao ; Jones, Ian ; Jones, Lisa A. ; Kahn, René S. ; Kelsoe, John R. ; Kircher, Tilo ; Kirov, George ; Kuo, Po-Hsiu ; Landén, Mikael ; Leboyer, Marion ; Li, Qingqin S. ; Lissowska, Jolanta ; Lochner, Christine ; Loughland, Carmel ; Luykx, Jurjen J. ; Martin, Nicholas G. ; Mathews, Carol A. ; Mayoral, Fermin ; McElroy, Susan L. ; McIntosh, Andrew M. ; McMahon, Francis J. ; Medland, Sarah E. ; Melle, Ingrid ; Milani, Lili ; Mitchell, Philip B. ; Morken, Gunnar ; Mors, Ole ; Mortensen, Preben Bo ; Müller-Myhsok, Bertram ; Myers, Richard M. ; Myung, Woojae ; Neale, Benjamin M. ; Nievergelt, Caroline M. ; Nordentoft, Merete ; Nöthen, Markus M. ; Nurnberger, John I. ; O’Donovan, Michael C. ; Oedegaard, Ketil J. ; Olsson, Tomas ; Owen, Michael J. ; Paciga, Sara A. ; Pantelis, Christos ; Pato, Carlos N. ; Pato, Michele T. ; Patrinos, George P. ; Pawlak, Joanna M. ; Ramos-Quiroga, Josep Antoni ; Reif, Andreas ; Reininghaus, Eva Z. ; Ribasés, Marta ; Rietschel, Marcella ; Ripke, Stephan ; Rouleau, Guy A. ; Roussos, Panos ; Saito, Takeo ; Schall, Ulrich ; Schalling, Martin ; Schofield, Peter R. ; Schulze, Thomas G. ; Scott, Laura J. ; Scott, Rodney J. ; Serretti, Alessandro ; Smoller, Jordan W. ; Squassina, Alessio ; Stahl, Eli A. ; Stefansson, Hreinn ; Stefansson, Kari ; Stordal, Eystein ; Streit, Fabian ; Sullivan, Patrick F. ; Turecki, Gustavo ; Vaaler, Arne E. ; Vieta, Eduard ; Vincent, John B. ; Waldman, Irwin D. ; Weickert, Cynthia S. ; Weickert, Thomas W. ; Werge, Thomas ; Whiteman, David C. ; Zwart, John-Anker ; Edenberg, Howard J. ; McQuillin, Andrew ; Forstner, Andreas J. ; Mullins, Niamh ; Di Florio, Arianna ; Ophoff, Roel A. ; Andreassen, Ole A.
Koromina, Maria ; Ravi, Ashvin ; Panagiotaropoulou, Georgia ; Schilder, Brian M. ; Humphrey, Jack ; Braun, Alice ; Bidgeli, Tim ; Chatzinakos, Chris ; Coombes, Brandon ; Kim, Jaeyoung ; Liu, Xiaoxi ; Terao, Chikashi ; O'Connell, Kevin S. ; Adams, Mark ; Adolfsson, Rolf ; Alda, Martin ; Alfredsson, Lars ; Andlauer, Till ; Andreassen, Ole A. ; Antoniou, Anastasia ; Baune, Bernhard T. ; Bengesser, Susanne ; Biernacka, Joanna ; Boehnke, Michael ; Bosch, Rosa ; Cairns, Murray ; Carr, Vaughan J. ; Casas Brugué, Miquel ; Catts, Stanley ; Cichon, Sven ; Corvin, Aiden ; Craddock, Nicholas ; Dafnas, Konstantinos ; Dalkner, Nina ; Dannlowski, Udo ; Degenhardt, Franziska ; Di Florio, Arianna ; Dikeos, Dimitris ; Fellendorf, Frederike Tabea ; Ferentinos, Panagiotis ; Forstner, Andreas Josef ; Forty, Liz ; Frye, Mark ; Fullerton, Janice M. ; Gawlik, Micha ; Gizer, Ian R. ; Gordon-Smith, Katherine ; Green, Melissa J. ; Grigoroiu-Serbanescu, Maria ; Guzman-Parra, José ; Hahn, Tim ; Henskens, Frans ; Hillert, Jan ; Jablensky, Assen V. ; Jones, Lisa ; Jones, Ian ; Jonsson, Lina ; Kelsoe, John R. ; Kircher, Tilo ; Kirov, George ; Kittel-Schneider, Sarah ; Kogevinas, Manolis ; Landén, Mikael ; Leboyer, Marion ; Lenger, Melanie ; Lissowska, Jolanta ; Lochner, Christine ; Loughland, Carmel ; MacIntyre, Donald ; Martin, Nicholas G. ; Maratou, Eirini ; Mathews, Carol A. ; Mayoral, Fermı́n ; McElroy, Susan L. ; McGregor, Nathaniel W. ; McIntosh, Andrew M. ; McQuillin, Andrew ; Michie, Patricia ; Milanova, Vihra ; Mitchell, Philip B. ; Moutsatsou, Paraskevi ; Mowry, Bryan ; Müller-Myhsok, Bertram ; Myers, Richard M. ; Nenadić, Igor ; Nöthen, Markus Maria ; O'Donovan, Claire ; O'Donovan, Michael ; Ophoff, Roel André ; Owen, Michael J. ; Pantelis, Christos ; Pato, Carlos ; Pato, Michele T. ; Patrinos, George P. ; Pawlak, Joanna M. ; Perlis, Roy H. ; Porichi, Evgenia ; Posthuma, Danielle ; Ramos-Quiroga, Josep Antoni ; Reif, Andreas ; Reininghaus, Eva Z. ; Ribasés, Marta ; Rietschel, Marcella ; Schall, Ulrich ; Schulze, Thomas Gerd ; Scott, Laura J. ; Scott, Rodney J. ; Serretti, Alessandro ; Shannon Weickert, Cynthia ; Smoller, Jordan W. ; Soler Artigas, Marı́a ; Stein, Dan J. ; Streit, Fabian ; Toma, Claudio ; Tooney, Paul ; Vieta, Eduard ; Vincent, John B. ; Waldman, Irwin D. ; Weickert, Thomas ; Witt, Stephanie H. ; Hong, Kyung Sue ; Ikeda, Masashi ; Iwata, Nakao ; Świątkowska, Beata ; Won, Hong-Hee ; Edenberg, Howard J. ; Ripke, Stephan ; Raj, Towfique ; Coleman, Jonathan R. I. ; Mullins, Niamh
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
Hou, Liping ; Bergen, Sarah E. ; Akula, Nirmala ; Song, Jie ; Hultman, Christina M. ; Landén, Mikael ; Adli, Mazda ; Alda, Martin ; Ardau, Raffaella ; Arias, Bárbara ; Aubry, Jean-Michel ; Backlund, Lena ; Badner, Judith A. ; Barrett, Thomas B. ; Bauer, Michael ; Baune, Bernhard T. ; Bellivier, Frank ; Benabarre Hernandez, Antonio ; Bengesser, Susanne ; Berrettini, Wade H. ; Bhattacharjee, Abesh Kumar ; Biernacka, Joanna ; Birner, Armin ; Bloss, Cinnamon S. ; Brichant-Petitjean, Clara ; Bui, Elise T. ; Byerley, William ; Cervantes, Pablo ; Chillotti, Caterina ; Cichon, Sven ; Colom, Francesc ; Coryell, William ; Craig, David W. ; Cruceanu, Cristiana ; Czerski, Piotr M. ; Davis, Tony ; Dayer, Alexandre ; Degenhardt, Franziska ; Del Zompo, Maria ; DePaulo, J. Raymond ; Edenberg, Howard J. ; Étain, Bruno ; Falkai, Peter ; Foroud, Tatiana ; Forstner, Andreas Josef ; Frisén, Louise ; Frye, Mark A. ; Fullerton, Janice M. ; Gard, Sébastien ; Garnham, Julie S. ; Gershon, Elliot S. ; Goes, Fernando S. ; Greenwood, Tiffany A. ; Grigoroiu-Serbanescu, Maria ; Hauser, Joanna ; Heilbronner, Urs ; Heilmann-Heimbach, Stefanie ; Herms, Stefan ; Hipolito, Maria ; Hitturlingappa, Shashi ; Hoffmann, Per ; Hofmann, Andrea ; Jamain, Stephane ; Jiménez, Esther ; Kahn, Jean-Pierre ; Kassem, Layla ; Kelsoe, John R. ; Kittel-Schneider, Sarah ; Kliwicki, Sebastian ; Koller, Daniel L. ; König, Barbara ; Lackner, Nina ; Laje, Gonzalo ; Lang, Maren ; Lavebratt, Catharina ; Lawson, William B. ; Leboyer, Marion ; Leckband, Susan G. ; Liu, Chunyu ; Maaser, Anna ; Mahon, Pamela B. ; Maier, Wolfgang ; Maj, Mario ; Manchia, Mirko ; Martinsson, Lina ; McCarthy, Michael J. ; McElroy, Susan L. ; McInnis, Melvin G. ; McKinney, Rebecca ; Mitchell, Philip B. ; Mitjans, Marina ; Mondimore, Francis Mark ; Monteleone, Palmiero ; Mühleisen, Thomas W. ; Nievergelt, Caroline M. ; Nöthen, Markus Maria ; Novák, Tomas ; Nurnberger, John I. ; Nwulia, Evaristus A. ; Ösby, Urban ; Pfennig, Andrea ; Potash, James B. ; Propping, Peter ; Reif, Andreas ; Reininghaus, Eva ; Rice, John ; Rietschel, Marcella ; Rouleau, Guy A. ; Rybakowski, Janusz K. ; Schalling, Martin ; Scheftner, William A. ; Schofield, Peter R. ; Schork, Nicholas J. ; Schulze, Thomas Gerd ; Schumacher, Johannes ; Schweizer, Barbara W. ; Severino, Giovanni ; Shekhtman, Tatyana ; Shilling, Paul D. ; Simhandl, Christian ; Slaney, Claire M. ; Smith, Erin N. ; Squassina, Alessio ; Stamm, Thomas ; Stopkova, Pavla ; Streit, Fabian ; Strohmaier, Jana ; Szelinger, Szabolcs ; Tighe, Sarah K. ; Tortorella, Alfonso ; Turecki, Gustavo ; Vieta, Eduard ; Volkert, Julia ; Witt, Stephanie H. ; Wright, Adam ; Zandi, Peter P. ; Zhang, Peng ; Zollner, Sebastian ; McMahon, Francis J.
Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the Xchromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10-9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10-9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
Acharya, Shreyasi ; Adam, Jaroslav ; Adamová, Dagmar ; Adler, Clemens ; Adolfsson, Jonatan ; Aggarwal, Madan Mohan ; Aglieri Rinella, Gianluca ; Agnello, Michelangelo ; Agrawal, Neelima ; Ahammed, Zubayer ; Ahmad, Nazeer ; Ahn, Sang Un ; Aiola, Salvatore ; Akindinov, Alexander ; Al-Turany, Mohammad ; Alam, Sk Noor ; Antonczyk, Dariusz ; Arend, Andreas ; Bazo Alba, José Luis ; Albuquerque, Danilo Silva de ; Aleksandrov, Dmitry ; Alessandro, Bruno ; Alfaro Molina, Jose Ruben ; Alici, Andrea ; Alkin, Anton ; Alme, Johan ; Alt, Torsten ; Altenkämper, Lucas ; Altsybeev, Igor ; Prado, Caio Alves Garcia ; Andrei, Cristian ; Andreou, Dimitra ; Andrews, Harry Arthur ; Andronic, Anton ; Anguelov, Venelin ; Anson, Christopher Daniel ; Antičić, Tome ; Antinori, Federico ; Antonioli, Pietro ; Anwar, Rafay ; Aphecetche, Laurent Bernard ; Appelshäuser, Harald ; Arcelli, Silvia ; Arnaldi, Roberta ; Arnold, Oliver Werner ; Arsene, Ionut Cristian ; Arslandok, Mesut ; Audurier, Benjamin ; Augustinus, Andre ; Averbeck, Ralf Peter ; Azmi, Mohd Danish ; Badalà, Angela ; Baek, Yong Wook ; Bagnasco, Stefano ; Bailhache, Raphaëlle ; Bala, Renu ; Baldisseri, Alberto ; Ball, Markus ; Baral, Rama Chandra ; Barbano, Anastasia Maria ; Barbera, Roberto ; Barile, Francesco ; Barioglio, Luca ; Barnaföldi, Gergely Gábor ; Barnby, Lee Stuart ; Ramillien Barret, Valerie ; Bartalini, Paolo ; Barth, Klaus ; Bartos, D ; Bartsch, Esther ; Basile, Maurizio ; Bastid, Nicole ; Basu, Sumit ; Bathen, Bastian ; Batigne, Guillaume ; Batyunya, Boris ; Bätzing, Paul Christoph ; Baumann, Christoph ; Bearden, Ian Gardner ; Beck, Hans ; Bedda, Cristina ; Behera, Nirbhay Kumar ; Belikov, Iouri ; Bellini, Francesca ; Bello Martinez, Hector ; Bellwied, Rene ; Espinoza Beltran, Lucina Gabriela ; Belyaev, Vladimir ; Bencédi, Gyula ; Beolè, Stefania ; Berceanu, Ionela ; Bercuci, Alexandru ; Berdnikov, Yaroslav ; Berényi, Dániel ; Bertens, Redmer Alexander ; Berzano, Dario ; Betev, Latchezar ; Bhasin, Anju ; Bhat, Inayat Rasool ; Bhati, Ashok Kumar ; Bhattacharjee, Buddhadeb ; Bhom, Jihyun ; Bianchi, Antonio ; Bianchi, Livio ; Bianchi, Nicola ; Bianchin, Chiara ; Bielčík, Jaroslav ; Bielčíková, Jana ; Bilandzic, Ante ; Biro, Gabor ; Biswas, Rathijit ; Biswas, Saikat ; Blair, Justin Thomas ; Blau, Dmitry S. ; Blume, Christoph ; Boca, Gianluigi ; Bock, Friederike ; Bogdanov, Alexey A. ; Boldizsar, Laszlo ; Bombara, Marek ; Bonomi, Germano ; Bonora, Matthias ; Book, Julian ; Borel, Herve ; Borissov, Alexander ; Borri, Marcello ; Botta, Elena ; Bourjau, Christian ; Bratrud, Lars ; Braun-Munzinger, Peter ; Bregant, Marco ; Broker, Theo Alexander ; Broz, Michal ; Brücken, Erik Jens ; Bruna, Elena ; Bruno, Giuseppe Eugenio ; Bucher, Damian ; Budnikov, Dmitry ; Büsching, Henner ; Bufalino, Stefania ; Bühler, Paul ; Bunčić, Predrag ; Busch, Oliver ; Buthelezi, Edith Zinhle ; Bashir Butt, Jamila ; Buxton, Jesse Thomas ; Cabala, Jan ; Caffarri, Davide ; Caines, Helen Louise ; Caliva, Alberto ; Calvo Villar, Ernesto ; Camerini, Paolo ; Capon, Aaron Allan ; Caragheorgheopol, G ; Carena, Francesco ; Carena, Wisla ; Carnesecchi, Francesca ; Castillo Castellanos, Javier Ernesto ; Castro, Andrew John ; Casula, Ester Anna Rita ; Catanescu, V ; Ceballos Sanchez, Cesar ; Cerello, Piergiorgio ; Chandra, Sinjini ; Chang, Beomsu ; Chapeland, Sylvain ; Chartier, Marielle ; Chattopadhyay, Subhasis ; Chattopadhyay, Sukalyan ; Chauvin, Alex Henri Jean ; Chernenko, Sergey P. ; Cherney, Michael Gerard ; Cheshkov, Cvetan Valeriev ; Cheynis, Brigitte ; Chibante Barroso, Vasco Miguel ; Chinellato, David Dobrigkeit ; Cho, Soyeon ; Chochula, Peter ; Chojnacki, Marek ; Choudhury, Subikash ; Chowdhury, Tasnuva ; Christakoglou, Panagiotis ; Christensen, Christian Holm ; Christiansen, Peter L. ; Chujo, Tatsuya ; Chung, Suh-Urk ; Cicalò, Corrado ; Cifarelli, Luisa ; Cindolo, Federico ; Ciobanu, M ; Cleymans, Jean Willy Andre ; Colamaria, Fabio Filippo ; Colella, Domenico ; Collu, Alberto ; Colocci, Manuel ; Concas, Matteo ; Conesa Balbastre, Gustavo ; Conesa Del Valle, Zaida ; Connors, Megan Elizabeth ; Contreras Nuno, Jesus Guillermo ; Cormier, Thomas Michael ; Corrales Morales, Yasser ; Cortes Maldonado, Ismael ; Cortese, Pietro ; Cosentino, Mauro Rogerio ; Costa, Filippo ; Costanza, Susanna ; Crkovská, Jana ; Crochet, Philippe ; Cuautle Flores, Eleazar ; Cunqueiro Mendez, Leticia ; Dahms, Torsten ; Dainese, Andrea ; Danisch, Meike Charlotte ; Danu, Andrea ; Das, Debasish ; Das, Indranil ; Das, Supriya ; Dash, Ajay Kumar ; Dash, Sadhana ; Daues, Heinz ; De, Sudipan ; De Caro, Annalisa ; De Cataldo, Giacinto ; Conti, Camila de ; Cuveland, Jan de ; De Falco, Alessandro ; De Gruttola, Daniele ; De Marco, Nora ; De Pasquale, Salvatore ; Souza, Rafael Derradi de ; Degenhardt, Hermann Franz ; Deisting, Alexander ; Deloff, Andrzej ; Deplano, Caterina ; Devismes, A ; Dhankher, Preeti ; Di Bari, Domenico ; Di Mauro, Antonio ; Di Nezza, Pasquale ; Di Ruzza, Benedetto ; Dietel, Thomas ; Dillenseger, Pascal ; Divià, Roberto ; Djuvsland, Øystein ; Dobrin, Alexandru Florin ; Domenicis Gimenez, Diogenes ; Donigus, Benjamin ; Dordic, Olja ; Doremalen, Lennart Vincent Rogier van ; Dubey, Anand Kumar ; Dubla, Andrea ; Ducroux, Laurent ; Duggal, Ashpreet Kaur ; Dupieux, Pascal ; Duta, V ; Ehlers Iii, Raymond James ; Elia, Domenico ; Emschermann, David ; Endress, Eric ; Engel, Heiko ; Epple, Eliane ; Erazmus, Barbara Ewa ; Erhardt, Filip ; Espagnon, Bruno ; Esumi, ShinIchi ; Eulisse, Giulio ; Eum, Jongsik ; Evans, David ; Evdokimov, Sergey ; Fabbietti, Laura ; Faivre, Julien ; Fantoni, Alessandra ; Fasel, Markus ; Fateev, O ; Feldkamp, Linus ; Feliciello, Alessandro ; Feofilov, Grigori A. ; Ferencei, Jozef ; Fernández Téllez, Arturo ; Ferretti, Alessandro ; Festanti, Andrea ; Feuillard, Victor Jose Gaston ; Figiel, Jan ; Figueredo, Marcel Araujo Silva ; Filchagin, Sergey ; Finogeev, Dmitry ; Fionda, Fiorella Maria Celeste ; Fleck, M ; Floris, Michele ; Foertsch, Siegfried Valentin ; Foka, Panagiota ; Fokin, Sergey ; Fragiacomo, Enrico ; Francescon, Andrea ; Francisco, Audrey ; Frankenfeld, Ulrich ; Freuen, S ; Fronzé, Gabriele Gaetano ; Fuchs, Ulrich ; Furget, Christophe ; Furs, Artur ; Fusco Girard, Mario ; Gaardhoeje, Jens Joergen ; Gagliardi, Martino ; Gago Medina, Alberto Martín ; Gajdosova, Katarina ; Gallio, Mauro ; Duarte Galvan, Carlos ; Ganoti, Paraskevi ; Garabatos Cuadrado, Jose ; Garcia-Solis, Edmundo Javier ; Garg, Kunal ; Gargiulo, Corrado ; Gasik, Piotr ; Gatz, Henriette ; Gauger, Erin Frances ; Ducati, Maria Beatriz de Leone Gay ; Germain, Marie ; Ghosh, Jhuma ; Ghosh, Premomoy ; Ghosh, Sanjay Kumar ; Gianotti, Paola ; Giolu, G ; Giubellino, Paolo ; Giubilato, Piero ; Gładysz-Dziaduś, Ewa ; Glasow, Richard ; Glässel, Peter ; Gremmler, Svenja ; Gómez Coral, Diego Mauricio ; Gómez Ramírez, Andrés ; Sanchez Gonzalez, Andres ; Gorbunov, Sergey ; Görlich, Lidia Maria ; Gotovac, Sven ; Gottschalk, Dirk ; Gottschlag, Holger ; Grabski, Varlen ; Graczykowski, Łukasz Kamil ; Graham, Katie Leanne ; Grajcarek, Robert ; Greiner, Leo Clifford ; Grelli, Alessandro ; Grigoraș, Costin ; Grigoryev, Vladislav ; Grigoryan, Ara ; Grigoryan, Smbat ; Grimm, Helge ; Grion, Nevio ; Gronefeld, Julius Maximilian ; Grosa, Fabrizio ; Große-Oetringhaus, Jan Fiete ; Grosso, Raffaele ; Gruber, Lukas ; Guber, Fedor ; Guernane, Rachid ; Guerzoni, Barbara ; Gulbrandsen, Kristjan Herlache ; Gunji, Taku ; Gupta, Anik ; Gupta, Ramni ; Gutfleisch, M ; Bautista Guzman, Irais ; Haake, Rüdiger ; Hadjidakis, Cynthia Marie ; Hamagaki, Hideki ; Hamar, Gergö ; Hamon, Julien Charles ; Haque, Md Rihan ; Harris, John William ; Hartig, Matthias ; Harton, Austin Vincent ; Hassan, Hadi ; Hatzifotiadou, Despina ; Hayashi, Shinichi ; Heckel, Stefan Thomas ; Hehner, Joerg ; Heide, Markus ; Hellbär, Ernst ; Helstrup, Håvard ; Herghelegiu, Andrei Ionut ; Herrera Corral, Gerardo Antonio ; Herrmann, Florian ; Herrmann, Norbert ; Hess, Benjamin Andreas ; Hetland, Kristin Fanebust ; Hillemanns, Hartmut ; Hills, Christopher ; Hippolyte, Boris ; Hladkỳ, Jan ; Hohlweger, Bernhard ; Horak, David ; Hornung, Sebastian ; Hosokawa, Ritsuya ; Hristov, Peter ; Huber, Sebastian ; Hughes, Charles ; Humanic, Thomas J. ; Hussain, Nur ; Hussain, Tahir ; Hutter, Dirk ; Hwang, Dae Sung ; Iga Buitron, Sergio Arturo ; Ilkaev, Radiy ; Inaba, Motoi ; Ippolitov, Mikhail ; Irfan, Muhammad ; Islam, Md Samsul ; Ivanov, Marian ; Ivanov, Vladimir ; Izucheev, Vladimir ; Jacak, Barbara ; Jacazio, Nicolò ; Jacobs, Peter Martin ; Jadhav, Manoj Bhanudas ; Jadlovsky, Jan ; Jaelani, Syaefudin ; Jahnke, Cristiane ; Jakubowska, Monika Joanna ; Janik, Malgorzata Anna ; Pahula Hewage, Sandun ; Jena, Chitrasen ; Jena, Satyajit ; Jercic, Marko ; Jiménez Bustamante, Raúl Tonatiuh ; Jones, Peter Graham ; Jusko, Anton ; Kalinak, Peter ; Kalweit, Alexander Philipp ; Kang, Ju Hwan ; Kaplin, Vladimir ; Kar, Somnath ; Karasu Uysal, Ayben ; Karavichev, Oleg V. ; Karavicheva, Tatiana L. ; Karayan, Lilit ; Karczmarczyk, Przemyslaw ; Karpechev, Evgeny ; Kebschull, Udo ; Keidel, Ralf ; Keijdener, Darius Laurens D. ; 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Marin, Ana Maria ; Markert, Christina ; Marquard, Marco ; Martin, Nicole Alice ; Martinengo, Paolo ; Lucio Martinez, Jose Antonio ; Martínez Hernández, Mario Iván ; García Martínez, Ginés ; Martinez Pedreira, Miguel ; Masciocchi, Silvia ; Masera, Massimo ; Masoni, Alberto ; Masson, Erwann ; Mastroserio, Annalisa ; Mathis, Andreas Michael ; Matyja, Adam Tomasz ; Mayer, Christoph ; Mazer, Joel Anthony ; Mazzilli, Marianna ; Mazzoni, Alessandra Maria ; Meddi, Franco ; Melikyan, Yuri ; Menchaca-rocha, Arturo Alejandro ; Meninno, Elisa ; Mercado Pérez, Jorge ; Meres, Michal ; Mhlanga, Sibaliso ; Miake, Yasuo ; Mieskolainen, Matti Mikael ; Mihaylov, Dimitar Lubomirov ; Mikhaylov, Konstantin ; Milošević, Jovan ; Mischke, André ; Mishra, Aditya Nath ; Miśkowiec, Dariusz Czesław ; Mitra, Jubin ; Mitu, Ciprian Mihai ; Mohammadi, Naghmeh ; Mohanty, Bedangadas ; Khan, Mohammed Mohisin ; Godoy, Denise Aparecida Moreira de ; Perez Moreno, Luis Alberto ; Moretto, Sandra ; Morino, Yuhei ; Morreale, Astrid ; 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The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p-Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
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Conesa Del Valle, Zaida ; Connors, Megan Elizabeth ; Contreras Nuno, Jesus Guillermo ; Cormier, Thomas Michael ; Corrales Morales, Yasser ; Cortes Maldonado, Ismael ; Cortese, Pietro ; Cosentino, Mauro Rogerio ; Costa, Filippo ; Costanza, Susanna ; Crkovská, Jana ; Crochet, Philippe ; Cuautle Flores, Eleazar ; Cunqueiro Mendez, Leticia ; Dahms, Torsten ; Dainese, Andrea ; Danisch, Meike Charlotte ; Danu, Andrea ; Das, Debasish ; Das, Indranil ; Das, Supriya ; Dash, Ajay Kumar ; Dash, Sadhana ; Daues, Heinz ; De, Sudipan ; De Caro, Annalisa ; De Cataldo, Giacinto ; Conti, Camila de ; Cuveland, Jan de ; De Falco, Alessandro ; De Gruttola, Daniele ; De Marco, Nora ; De Pasquale, Salvatore ; Souza, Rafael Derradi de ; Degenhardt, Hermann Franz ; Deisting, Alexander ; Deloff, Andrzej ; Deplano, Caterina ; Devismes, A ; Dhankher, Preeti ; Di Bari, Domenico ; Di Mauro, Antonio ; Di Nezza, Pasquale ; Di Ruzza, Benedetto ; Dietel, Thomas ; Dillenseger, Pascal ; Divià, Roberto ; Djuvsland, Øystein ; Dobrin, Alexandru Florin ; Domenicis Gimenez, Diogenes ; Donigus, Benjamin ; Dordic, Olja ; Doremalen, Lennart Vincent Rogier van ; Dubey, Anand Kumar ; Dubla, Andrea ; Ducroux, Laurent ; Duggal, Ashpreet Kaur ; Dupieux, Pascal ; Duta, V ; Ehlers Iii, Raymond James ; Elia, Domenico ; Emschermann, David ; Endress, Eric ; Engel, Heiko ; Epple, Eliane ; Erazmus, Barbara Ewa ; Erhardt, Filip ; Espagnon, Bruno ; Esumi, ShinIchi ; Eulisse, Giulio ; Eum, Jongsik ; Evans, David ; Evdokimov, Sergey ; Fabbietti, Laura ; Faivre, Julien ; Fantoni, Alessandra ; Fasel, Markus ; Fateev, O ; Feldkamp, Linus ; Feliciello, Alessandro ; Feofilov, Grigori A. ; Ferencei, Jozef ; Fernández Téllez, Arturo ; Ferretti, Alessandro ; Festanti, Andrea ; Feuillard, Victor Jose Gaston ; Figiel, Jan ; Figueredo, Marcel Araujo Silva ; Filchagin, Sergey ; Finogeev, Dmitry ; Fionda, Fiorella Maria Celeste ; Fleck, M ; Floris, Michele ; Foertsch, Siegfried Valentin ; Foka, Panagiota ; Fokin, Sergey ; Fragiacomo, Enrico ; Francescon, Andrea ; Francisco, Audrey ; Frankenfeld, Ulrich ; Freuen, S ; Fronzé, Gabriele Gaetano ; Fuchs, Ulrich ; Furget, Christophe ; Furs, Artur ; Fusco Girard, Mario ; Gaardhoeje, Jens Joergen ; Gagliardi, Martino ; Gago Medina, Alberto Martín ; Gajdosova, Katarina ; Gallio, Mauro ; Duarte Galvan, Carlos ; Ganoti, Paraskevi ; Garabatos Cuadrado, Jose ; Garcia-Solis, Edmundo Javier ; Garg, Kunal ; Gargiulo, Corrado ; Gasik, Piotr ; Gatz, Henriette ; Gauger, Erin Frances ; Ducati, Maria Beatriz de Leone Gay ; Germain, Marie ; Ghosh, Jhuma ; Ghosh, Premomoy ; Ghosh, Sanjay Kumar ; Gianotti, Paola ; Giolu, G ; Giubellino, Paolo ; Giubilato, Piero ; Gładysz-Dziaduś, Ewa ; Glasow, Richard ; Glässel, Peter ; Gremmler, Svenja ; Gómez Coral, Diego Mauricio ; Gómez Ramírez, Andrés ; Sanchez Gonzalez, Andres ; Gorbunov, Sergey ; Görlich, Lidia Maria ; Gotovac, Sven ; Gottschalk, Dirk ; Gottschlag, Holger ; Grabski, Varlen ; Graczykowski, Łukasz Kamil ; Graham, Katie Leanne ; Grajcarek, Robert ; Greiner, Leo Clifford ; Grelli, Alessandro ; Grigoraș, Costin ; Grigoryev, Vladislav ; Grigoryan, Ara ; Grigoryan, Smbat ; Grimm, Helge ; Grion, Nevio ; Gronefeld, Julius Maximilian ; Grosa, Fabrizio ; Große-Oetringhaus, Jan Fiete ; Grosso, Raffaele ; Gruber, Lukas ; Guber, Fedor ; Guernane, Rachid ; Guerzoni, Barbara ; Gulbrandsen, Kristjan Herlache ; Gunji, Taku ; Gupta, Anik ; Gupta, Ramni ; Gutfleisch, M ; Bautista Guzman, Irais ; Haake, Rüdiger ; Hadjidakis, Cynthia Marie ; Hamagaki, Hideki ; Hamar, Gergö ; Hamon, Julien Charles ; Haque, Md Rihan ; Harris, John William ; Hartig, Matthias ; Harton, Austin Vincent ; Hassan, Hadi ; Hatzifotiadou, Despina ; Hayashi, Shinichi ; Heckel, Stefan Thomas ; Hehner, Joerg ; Heide, Markus ; Hellbär, Ernst ; Helstrup, Håvard ; Herghelegiu, Andrei Ionut ; Herrera Corral, Gerardo Antonio ; Herrmann, Florian ; Herrmann, Norbert ; Hess, Benjamin Andreas ; Hetland, Kristin Fanebust ; Hillemanns, Hartmut ; Hills, Christopher ; Hippolyte, Boris ; Hladkỳ, Jan ; Hohlweger, Bernhard ; Horak, David ; Hornung, Sebastian ; Hosokawa, Ritsuya ; Hristov, Peter ; Huber, Sebastian ; Hughes, Charles ; Humanic, Thomas J. ; Hussain, Nur ; Hussain, Tahir ; Hutter, Dirk ; Hwang, Dae Sung ; Iga Buitron, Sergio Arturo ; Ilkaev, Radiy ; Inaba, Motoi ; Ippolitov, Mikhail ; Irfan, Muhammad ; Islam, Md Samsul ; Ivanov, Marian ; Ivanov, Vladimir ; Izucheev, Vladimir ; Jacak, Barbara ; Jacazio, Nicolò ; Jacobs, Peter Martin ; Jadhav, Manoj Bhanudas ; Jadlovsky, Jan ; Jaelani, Syaefudin ; Jahnke, Cristiane ; Jakubowska, Monika Joanna ; Janik, Malgorzata Anna ; Pahula Hewage, Sandun ; Jena, Chitrasen ; Jena, Satyajit ; Jercic, Marko ; Jiménez Bustamante, Raúl Tonatiuh ; Jones, Peter Graham ; Jusko, Anton ; Kalinak, Peter ; Kalweit, Alexander Philipp ; Kang, Ju Hwan ; Kaplin, Vladimir ; Kar, Somnath ; Karasu Uysal, Ayben ; Karavichev, Oleg V. ; Karavicheva, Tatiana L. ; Karayan, Lilit ; Karczmarczyk, Przemyslaw ; Karpechev, Evgeny ; Kebschull, Udo ; Keidel, Ralf ; Keijdener, Darius Laurens D. ; Keil, Markus ; Ketzer, Bernhard ; Khabanova, Zhanna ; Khan, Palash ; Khan, Shuaib Ahmad ; Khanzadeev, Alexei ; Kharlov, Yury ; Khatun, Anisa ; Khuntia, Arvind ; Kielbowicz, Mirosław Marek ; Kileng, Bjarte ; Kim, Byungchul ; Kim, Daehyeok ; Kim, Dong Jo ; Kim, Hyeonjoong ; Kim, Jinsook ; Kim, Jiyoung ; Kim, Minjung ; Kim, Minwoo ; Kim, Se Yong ; Kim, Taesoo ; Kirsch, Stefan ; Kisel, Ivan ; Kiselev, Sergej N. ; Kisiel, Adam Ryszard ; Kislov, E ; Kiss, Gabor ; Klay, Jennifer Lynn ; Klein, Carsten ; Klein, Jochen ; Klein-Bösing, Christian ; Klein-Bösing, Melanie ; Kliemant, Michael ; Klingenmeyer, Hannah ; Klewin, Sebastian ; Kluge, Alexander ; Knichel, Michael Linus ; Knospe, Anders Garritt ; Kobdaj, Chinorat ; Varga-Kofarago, Monika ; Kohn, Martin ; Kollegger, Thorsten ; Kondratev, Valerii ; Kondratyeva, Natalia ; Kondratyuk, Evgeny ; Konevskikh, Artem ; Konno, Masahiro ; Konyushikhin, Maxim A. ; Kopcik, Michal ; Kour, Mandeep ; Kouzinopoulos, Charalampos ; Kovalenko, Oleksandr ; Kovalenko, Vladimir ; Kowalski, Marek ; Koyithatta Meethaleveedu, Greeshma ; Králik, Ivan ; Kramer, Frederick ; Kravčáková, Adela ; Krawutschke, Tobias ; Kreis, Lukas ; Krivda, Marian ; Krizek, Filip ; Krumbhorn, Dirk ; Kryshen, Evgeny ; Krzewicki, Mikolaj ; Kubera, Andrew Michael ; Kucera, Vit ; Kuhn, Christian Claude ; Kuijer, Paulus Gerardus ; Kumar, Ajay ; Kumar, Jitendra ; Kumar, Lokesh ; Kumar, Shyam ; Kundu, Sourav ; Kurashvili, Podist ; Kurepin, Alexander ; Kurepin, Alexey B. ; Kuryakin, Alexey ; Kushpil, Svetlana ; Kweon, Min Jung ; Kwon, Youngil ; La Pointe, Sarah Louise ; La Rocca, Paola ; Lagana Fernandes, Caio ; Lai, Yue Shi ; Lakomov, Igor ; Langoy, Rune ; Lapidus, Kirill ; Lara Martinez, Camilo Ernesto ; Lardeux, Antoine Xavier ; Lattuca, Alessandra ; Laudi, Elisa ; Lavicka, Roman ; Lea, Ramona ; Leardini, Lucia ; Lee, Seongjoo ; Lehas, Fatiha ; Lehmann, T ; Lehner, Jorg ; Lehner, Sebastian ; Lehrbach, Johannes ; Lemmon, Roy Crawford ; Lenti, Vito ; Leogrande, Emilia ; Leon Monzon, Ildefonso ; Lesser, F ; Lévai, Peter ; Li, Xiaomei ; Lien, Jørgen André ; Lietava, Roman ; Lim, Bong-Hwi ; Lindal, Svein ; Lindenstruth, Volker ; Lindsay, Scott William ; Lippmann, Christian ; Lisa, Michael A. ; Litichevskyi, Vladyslav ; Llope, William ; Lodato, Davide Francesco ; Lohner, Daniel ; Lønne, Per-Ivar ; Loginov, Vitaly ; Loizides, Constantinos ; Lončar, Petra ; Lopez, Xavier Bernard ; López Torres, Ernesto ; Lowe, Andrew John ; Lu, XianGuo ; Ludolphs, W ; Lüttig, Philipp ; Luhder, Jens Robert ; Lunardon, Marcello ; Luparello, Grazia ; Lupi, Matteo ; Lutz, Tyler Harrison ; Maevskaya, Alla ; Mager, Magnus ; Magureanu, C ; Mahajan, Sanjay ; Mahmoud, Tariq ; Mahmood, Sohail Musa ; Maire, Antonin ; Majka, Richard Daniel ; Malaev, Mikhail ; Malinina, Liudmila ; Mal’Kevich, Dmitry ; Malzacher, Peter ; Mamonov, Alexander ; Manko, Vladislav ; Manso, Franck ; Manzari, Vito ; Mao, Yaxian ; Marchisone, Massimiliano ; Mareš, Jiří ; Margagliotti, Giacomo Vito ; Margotti, Anselmo ; Margutti, Jacopo ; Marin, Ana Maria ; Markert, Christina ; Marquard, Marco ; Martin, Nicole Alice ; Martinengo, Paolo ; Lucio Martinez, Jose Antonio ; Martínez Hernández, Mario Iván ; García Martínez, Ginés ; Martinez Pedreira, Miguel ; Masciocchi, Silvia ; Masera, Massimo ; Masoni, Alberto ; Masson, Erwann ; Mastroserio, Annalisa ; Mathis, Andreas Michael ; Matyja, Adam Tomasz ; Mayer, Christoph ; Mazer, Joel Anthony ; Mazzilli, Marianna ; Mazzoni, Alessandra Maria ; Meddi, Franco ; Melikyan, Yuri ; Menchaca-rocha, Arturo Alejandro ; Meninno, Elisa ; Mercado Pérez, Jorge ; Meres, Michal ; Mhlanga, Sibaliso ; Miake, Yasuo ; Mieskolainen, Matti Mikael ; Mihaylov, Dimitar Lubomirov ; Mikhaylov, Konstantin ; Milošević, Jovan ; Mischke, André ; Mishra, Aditya Nath ; Miśkowiec, Dariusz Czesław ; Mitra, Jubin ; Mitu, Ciprian Mihai ; Mohammadi, Naghmeh ; Mohanty, Bedangadas ; Khan, Mohammed Mohisin ; Godoy, Denise Aparecida Moreira de ; Perez Moreno, Luis Alberto ; Moretto, Sandra ; Morino, Yuhei ; Morreale, Astrid ; Morsch, Andreas ; Muccifora, Valeria ; Mudnic, Eugen ; Muhlheim, Daniel ; Muhuri, Sanjib ; Mukherjee, Maitreyee ; Mulligan, James Declan ; Gameiro Munhoz, Marcelo ; Munning, Konstantin ; Munzer, Robert Helmut ; Murakami, Hikari ; Murray, Sean ; Musa, Luciano ; Musinsky, Jan ; Myers, Corey James ; Myrcha, Julian Wojciech ; Mycke, Jan Felix ; Nag, Dipanjan ; Naik, Bharati ; Nair, Rahul Ramachandran ; Nandi, Basanta Kumar ; Nania, Rosario ; Nappi, Eugenio ; Narayan, Amrendra ; Naru, Muhammad Umair ; Luz, Pedro Hugo Ferreira Natal da ; Nattrass, Christine ; Rosado Navarro, Sebastian ; Nayak, Kishora ; Nayak, Ranjit ; Nayak, Tapan Kumar ; Nazarenko, Sergey ; Nedosekin, Alexander ; Oliveira, Renato Aparecido Negrao de ; Neher, Michael ; Nellen, Lukas ; Nesbo, Simon Voigt ; Ng, Fabian ; Nicassio, Maria ; Niculescu, Mihai ; Niedziela, Jeremi ; Nielsen, Borge Svane ; Nikolaev, Sergey ; Nikulin, Sergey ; Nikulin, Vladimir ; Noferini, Francesco ; Nomokonov, Petr V. ; Nooren, Gerardus ; Cabanillas Noris, Juan Carlos ; 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Petris, M ; Petrov, Viacheslav ; Petrovici, Mihai A. ; Petta, Catia ; Pezzi, Rafael Peretti ; Piano, Stefano ; Pikna, Miroslav ; Pillot, Philippe ; Ozelin de Lima Pimentel, Laís ; Pinazza, Ombretta ; Pinsky, Lawrence ; Pitz, Nora ; Piyarathna, Danthasinghe ; Płoskoń, Mateusz ; Planinic, Mirko ; Pliquett, Fabian ; Pluta, Jan Marian ; Pochybova, Sona ; Podesta Lerma, Pedro Luis Manuel ; Poghosyan, Martin G. ; Polishchuk, Boris ; Poljak, Nikola ; Poonsawat, Wanchaloem ; Pop, Amalia ; Poppenborg, Hendrik ; Porteboeuf, Sarah Julie ; Pozdniakov, Valeriy ; Prasad, Sidharth Kumar ; Preghenella, Roberto ; Prino, Francesco ; Pruneau, Claude A. ; Pshenichnov, Igor A. ; Puccio, Maximiliano ; Puddu, Giovanna ; Pujahari, Prabhat Ranjan ; Punin, Valery ; Putschke, Jörn H. ; Radomski, Sylwester ; Rachevski, Alexandre ; Raha, Sibaji ; Rajput, Sonia ; Rak, Jan ; Rakotozafindrabe, Andry Malala ; Ramello, Luciano ; Rami, Fouad ; Rana, Dhan Bahadur ; Raniwala, Rashmi ; Raniwala, Sudhir ; Räsänen, Sami Sakari ; 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Crispin S. ; Willsher, Emily ; Windelband, Bernd Stefan ; Winn, Michael ; Witt, William Edward ; Xu, C ; Yalcin, Serpil ; Yamakawa, Kosei ; Yang, Ping ; Yano, Satoshi ; Yin, Zhongbao ; Yokoyama, Hiroki ; Yoo, In-kwon ; Yoon, Jin Hee ; Yurchenko, Volodymyr ; Yurevich, Vladimir ; Zaccolo, Valentina ; Zaman, Ali ; Zampolli, Chiara ; Correia Zanoli, Henrique Jose ; Zanevski, Yuri ; Zardoshti, Nima ; Zarochentsev, Andrey ; Závada, Petr ; Zavyalov, Nikolay ; Zbroszczyk, Hanna Paulina ; Zhalov, Mikhail ; Zhang, Haitao ; Zhang, Xiaoming ; Zhang, Yonghong ; Chunhui, Zhang ; Zhang, Zuman ; Zhao, Chengxin ; Zhigareva, Natalia ; Zhou, Daicui ; Zhou, You ; Zhou, Zhuo ; Zhu, Hongsheng ; Zhu, Jianhui ; Zichichi, Antonino ; Zimmer, Stefan ; Zimmermann, Alice ; Zimmermann, Markus ; Zinovjev, Gennady M. ; Zmeskal, Johann ; Zou, Shuguang
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p-Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
Acharya, Shreyasi ; Adam, Jaroslav ; Adamová, Dagmar ; Adler, Clemens ; Adolfsson, Jonatan ; Aggarwal, Madan Mohan ; Aglieri Rinella, Gianluca ; Agnello, Michelangelo ; Agrawal, Neelima ; Ahammed, Zubayer ; Ahmad, Nazeer ; Ahn, Sang Un ; Aiola, Salvatore ; Akindinov, Alexander ; Al-Turany, Mohammad ; Alam, Sk Noor ; Antonczyk, Dariusz ; Arend, Andreas ; Bazo Alba, José Luis ; Albuquerque, Danilo Silva de ; Aleksandrov, Dmitry ; Alessandro, Bruno ; Alfaro Molina, Jose Ruben ; Alici, Andrea ; Alkin, Anton ; Alme, Johan ; Alt, Torsten ; Altenkämper, Lucas ; Altsybeev, Igor ; Prado, Caio Alves Garcia ; Andrei, Cristian ; Andreou, Dimitra ; Andrews, Harry Arthur ; Andronic, Anton ; Anguelov, Venelin ; Anson, Christopher Daniel ; Antičić, Tome ; Antinori, Federico ; Antonioli, Pietro ; Anwar, Rafay ; Aphecetche, Laurent Bernard ; Appelshäuser, Harald ; Arcelli, Silvia ; Arnaldi, Roberta ; Arnold, Oliver Werner ; Arsene, Ionut Cristian ; Arslandok, Mesut ; Audurier, Benjamin ; Augustinus, Andre ; 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Bhati, Ashok Kumar ; Bhattacharjee, Buddhadeb ; Bhom, Jihyun ; Bianchi, Antonio ; Bianchi, Livio ; Bianchi, Nicola ; Bianchin, Chiara ; Bielčík, Jaroslav ; Bielčíková, Jana ; Bilandzic, Ante ; Biro, Gabor ; Biswas, Rathijit ; Biswas, Saikat ; Blair, Justin Thomas ; Blau, Dmitry S. ; Blume, Christoph ; Boca, Gianluigi ; Bock, Friederike ; Bogdanov, Alexey A. ; Boldizsar, Laszlo ; Bombara, Marek ; Bonomi, Germano ; Bonora, Matthias ; Book, Julian ; Borel, Herve ; Borissov, Alexander ; Borri, Marcello ; Botta, Elena ; Bourjau, Christian ; Bratrud, Lars ; Braun-Munzinger, Peter ; Bregant, Marco ; Broker, Theo Alexander ; Broz, Michal ; Brücken, Erik Jens ; Bruna, Elena ; Bruno, Giuseppe Eugenio ; Bucher, Damian ; Budnikov, Dmitry ; Büsching, Henner ; Bufalino, Stefania ; Bühler, Paul ; Bunčić, Predrag ; Busch, Oliver ; Buthelezi, Edith Zinhle ; Bashir Butt, Jamila ; Buxton, Jesse Thomas ; Cabala, Jan ; Caffarri, Davide ; Caines, Helen Louise ; Caliva, Alberto ; Calvo Villar, Ernesto ; Camerini, Paolo ; 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Dobrin, Alexandru Florin ; Domenicis Gimenez, Diogenes ; Donigus, Benjamin ; Dordic, Olja ; Doremalen, Lennart Vincent Rogier van ; Dubey, Anand Kumar ; Dubla, Andrea ; Ducroux, Laurent ; Duggal, Ashpreet Kaur ; Dupieux, Pascal ; Duta, V ; Ehlers Iii, Raymond James ; Elia, Domenico ; Emschermann, David ; Endress, Eric ; Engel, Heiko ; Epple, Eliane ; Erazmus, Barbara Ewa ; Erhardt, Filip ; Espagnon, Bruno ; Esumi, ShinIchi ; Eulisse, Giulio ; Eum, Jongsik ; Evans, David ; Evdokimov, Sergey ; Fabbietti, Laura ; Faivre, Julien ; Fantoni, Alessandra ; Fasel, Markus ; Fateev, O ; Feldkamp, Linus ; Feliciello, Alessandro ; Feofilov, Grigori A. ; Ferencei, Jozef ; Fernández Téllez, Arturo ; Ferretti, Alessandro ; Festanti, Andrea ; Feuillard, Victor Jose Gaston ; Figiel, Jan ; Figueredo, Marcel Araujo Silva ; Filchagin, Sergey ; Finogeev, Dmitry ; Fionda, Fiorella Maria Celeste ; Fleck, M ; Floris, Michele ; Foertsch, Siegfried Valentin ; Foka, Panagiota ; Fokin, Sergey ; Fragiacomo, Enrico ; 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The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p–Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
(2021)
Le Clerc, Sigrid ; Lombardi, Laura ; Amare, Azmeraw T. ; Schubert, Klaus Oliver ; Hou, Liping ; Clark, Scott R. ; Papiol, Sergi ; Cearns, Micah ; Heilbronner, Urs ; Degenhardt, Franziska ; Tekola-Ayele, Fasil ; Hsu, Yi-Hsiang ; Shekhtman, Tatyana ; Adli, Mazda ; Akula, Nirmala ; Akiyama, Kazufumi ; Ardau, Raffaella ; Arias, Bárbara ; Aubry, Jean-Michel ; Backlund, Lena ; Bhattacharjee, Abesh Kumar ; Bellivier, Frank ; Benabarre, Antonio ; Bengesser, Susanne ; Biernacka, Joanna ; Birner, Armin ; Brichant-Petitjean, Clara ; Cervantes, Pablo ; Chen, Hsi-Chung ; Chillotti, Caterina ; Cichon, Sven ; Cruceanu, Cristiana ; Czerski, Piotr M. ; Dalkner, Nina ; Dayer, Alexandre ; Baune, Bernhard T. ; Del Zompo, Maria ; DePaulo, J. Raymond ; Étain, Bruno ; Jamain, Stephane ; Falkai, Peter ; Forstner, Andreas Josef ; Frisen, Louise ; Frye, Mark A. ; Fullerton, Janice M. ; Gard, Sébastien ; Garnham, Julie S. ; Goes, Fernando S. ; Grigoroiu-Serbanescu, Maria ; Grof, Paul ; Hashimoto, Ryota ; Hauser, Joanna ; Herms, Stefan ; Hoffmann, Per ; Jiménez, Esther ; Kahn, Jean-Pierre ; Kassem, Layla ; Kuo, Po-Hsiu ; Kato, Tadafumi ; Kelsoe, John R. ; Kittel-Schneider, Sarah ; Ferensztajn-Rochowiak, Ewa ; König, Barbara ; Kusumi, Ichiro ; Laje, Gonzalo ; Landén, Mikael ; Lavebratt, Catharina ; Leckband, Susan G. ; Tortorella, Alfonso ; Manchia, Mirko ; Martinsson, Lina ; McCarthy, Michael J. ; McElroy, Susan ; Colom, Francesc ; Millischer, Vincent ; Mitjans, Marina ; Mondimore, Francis Mark ; Monteleone, Palmiero ; Nievergelt, Caroline M. ; Nöthen, Markus Maria ; Novák, Tomas ; O'Donovan, Claire ; Ozaki, Norio ; Ösby, Urban ; Pfennig, Andrea ; Potash, James B. ; Reif, Andreas ; Reininghaus, Eva ; Rouleau, Guy A. ; Rybakowski, Janusz K. ; Schalling, Martin ; Schofield, Peter R. ; Schweizer, Barbara W. ; Severino, Giovanni ; Shilling, Paul D. ; Shimoda, Katzutaka ; Simhandl, Christian ; Slaney, Claire M. ; Pisanu, Claudia ; Squassina, Alessio ; Stamm, Thomas ; Stopkova, Pavla ; Maj, Mario ; Turecki, Gustavo ; Vieta, Eduard ; Veeh, Julia ; Witt, Stephanie H. ; Wright, Adam ; Zandi, Peter P. ; Mitchell, Philip B. ; Bauer, Michael ; Alda, Martin ; Rietschel, Marcella ; McMahon, Francis J. ; Schulze, Thomas Gerd ; Spadoni, Jean-Louis ; Boukouaci, Wahid ; Richard, Jean-Romain ; Le Corvoisier, Philippe ; Barrau, Caroline ; Zagury, Jean-François ; Leboyer, Marion ; Tamouza, Ryad
Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
Kolvenbach, Caroline ; Dworschak, Gabriel Clemens ; Frese, Sandra ; Japp, Anna Sophia ; Schuster, Peggy ; Wenzlitschke, Nina ; Yilmaz, Öznur ; Lopes, Filipa M. ; Pryalukhin, Alexey ; Schierbaum, Luca ; Zanden, Loes F. M. van der ; Kause, Franziska ; Schneider, Ronen ; Taranta-Janusz, Katarzyna ; Szczepańska, Maria ; Pawlaczyk, Krzysztof ; Newman, William G. ; Beaman, Glenda M. ; Stuart, Helen ; Cervellione, Raimondo M. ; Feitz, Wouter F. J. ; Rooij, Iris Antonia Leonarda Martina van ; Schreuder, Michiel F. ; Steffens, Martijn ; Weber, Stefanie ; Merz, Waltraut Maria ; Feldkötter, Markus ; Hoppe, Bernd ; Thiele, Holger ; Altmüller, Janine ; Berg, Christoph ; Kristiansen, Glen ; Ludwig, Michael ; Reutter, Heiko ; Woolf, Adrian S. ; Hildebrandt, Friedhelm ; Grote, Phillip ; Zaniew, Marcin ; Odermatt, Benjamin ; Hilger, Alina Christine
Congenital lower urinary-tract obstruction (LUTO) is caused by anatomical blockage of the bladder outflow tract or by functional impairment of urinary voiding. About three out of 10,000 pregnancies are affected. Although several monogenic causes of functional obstruction have been defined, it is unknown whether congenital LUTO caused by anatomical blockage has a monogenic cause. Exome sequencing in a family with four affected individuals with anatomical blockage of the urethra identified a rare nonsense variant (c.2557C>T [p.Arg853∗]) in BNC2, encoding basonuclin 2, tracking with LUTO over three generations. Re-sequencing BNC2 in 697 individuals with LUTO revealed three further independent missense variants in three unrelated families. In human and mouse embryogenesis, basonuclin 2 was detected in lower urinary-tract rudiments. In zebrafish embryos, bnc2 was expressed in the pronephric duct and cloaca, analogs of the mammalian lower urinary tract. Experimental knockdown of Bnc2 in zebrafish caused pronephric-outlet obstruction and cloacal dilatation, phenocopying human congenital LUTO. Collectively, these results support the conclusion that variants in BNC2 are strongly implicated in LUTO etiology as a result of anatomical blockage.
Non-standard errors
(2021)
Menkveld, Albert J. ; Dreber, Anna ; Holzmeister, Felix ; Huber, Jürgen ; Johannesson, Magnus ; Kirchler, Michael ; Razen, Michael ; Weitzel, Utz ; Abad Díaz, David ; Abudy, Menachem ; Adrian, Tobias ; Ait-Sahalia, Yacine ; Akmansoy, Olivier ; Alcock, Jamie ; Alexeev, Vitali ; Aloosh, Arash ; Amato, Livia ; Amaya, Diego ; Angel, James ; Bach, Amadeus ; Baidoo, Edwin ; Bakalli, Gaetan ; Barbon, Andrea ; Bashchenko, Oksana ; Bindra, Parampreet Christopher ; Bjonnes, Geir Hoidal ; Black, Jeff ; Black, Bernard S. ; Bohorquez, Santiago ; Bondarenko, Oleg ; Bos, Charles S. ; Bosch-Rosa, Ciril ; Bouri, Elie ; Brownlees, Christian ; Calamia, Anna ; Cao, Viet Nga ; Capelle-Blancard, Gunther ; Capera, Laura ; Caporin, Massimiliano ; Carrion, Allen ; Caskurlu, Tolga ; Chakrabarty, Bidisha ; Chernov, Mikhail ; Cheung, William M. ; Chincarini, Ludwig Boris ; Chordia, Tarun ; Chow, Sheung Chi ; Clapham, Benjamin ; Colliard, Jean-Edouard ; Comerton-Forde, Carole ; Curran, Edward ; Dao, Thong ; Dare, Wale ; Davies, Ryan J. ; De Blasis, Riccardo ; De Nard, Gianluca ; Declerck, Fany ; Deev, Oleg ; Degryse, Hans ; Deku, Solomon ; Desagre, Christophe ; Dijk, Mathijs van ; Dim, Chukwuma ; Dimpfl, Thomas ; Dong, Yun Jiang ; Drummond, Philip ; Dudda, Tom ; Dumitrescu, Ariadna ; Dyakov, Teodor ; Haubo Dyhrberg, Anne ; Dzieliński, Michał ; Eksi, Asli ; El Kalak, Izidin ; Ellen, Saskia ter ; Eugster, Nicolas ; Evans, Martin D. D. ; Farrell, Michael ; Félez-Viñas, Ester ; Ferrara, Gerardo ; Ferrouhi, El Mehdi ; Flori, Andrea ; Fluharty-Jaidee, Jonathan ; Foley, Sean ; Fong, Kingsley Y. L. ; Foucault, Thierry ; Franus, Tatiana ; Franzoni, Francesco ; Frijns, Bart ; Frömmel, Michael ; Fu, Servanna ; Füllbrunn, Sascha ; Gan, Baoqing ; Gehrig, Thomas ; Gerritsen, Dirk ; Gil-Bazo, Javier ; Glosten, Lawrence R. ; Gomez, Thomas ; Gorbenko, Arseny ; Güçbilmez, Ufuk ; Grammig, Joachim ; Gregoire, Vincent ; Hagströmer, Björn ; Hambuckers, Julien ; Hapnes, Erik ; Harris, Jeffrey H. ; Harris, Lawrence ; Hartmann, Simon ; Hasse, Jean-Baptiste ; Hautsch, Nikolaus ; He, Xuezhong ; Heath, Davidson ; Hediger, Simon ; Hendershott, Terrence ; Hibbert, Ann Marie ; Hjalmarsson, Erik ; Hoelscher, Seth A. ; Hoffmann, Peter ; Holden, Craig W. ; Horenstein, Alex R. ; Huang, Wenqian ; Huang, Da ; Hurlin, Christophe ; Ivashchenko, Alexey ; Iyer, Subramanian Rama ; Jahanshahloo, Hossein ; Jalkh, Naji ; Jones, Charles M. ; Jurkatis, Simon ; Jylha, Petri ; Kaeck, Andreas ; Kaiser, Gabriel ; Karam, Arzé ; Karmaziene, Egle ; Kassner, Bernhard ; Kaustia, Markku ; Kazak, Ekaterina ; Kearney, Fearghal ; Kervel, Vincent van ; Khan, Saad ; Khomyn, Marta ; Klein, Tony ; Klein, Olga ; Klos, Alexander ; Koetter, Michael ; Krahnen, Jan Pieter ; Kolokolov, Aleksey ; Korajczyk, Robert A. ; Kozhan, Roman ; Kwan, Amy ; Lajaunie, Quentin ; Lam, FY Eric C ; Lambert, Marie ; Langlois, Hugues ; Lausen, Jens ; Lauter, Tobias ; Leippold, Markus ; Levin, Vladimir ; Li, Yijie ; Li, Hui ; Liew, Chee Yoong ; Lindner, Thomas ; Linton, Oliver B. ; Liu, Jiacheng ; Liu, Anqi ; Llorente, Guillermo ; Lof, Matthijs ; Lohr, Ariel ; Longstaff, Francis A. ; Lopez-Lira, Alejandro ; Mankad, Shawn ; Mano, Nicola ; Marchal, Alexis ; Martineau, Charles ; Mazzola, Francesco ; Meloso, Debrah ; Mihet, Roxana ; Mohan, Vijay ; Moinas, Sophie ; Moore, David ; Mu, Liangyi ; Muravyev, Dmitriy ; Murphy, Dermot ; Neszveda, Gabor ; Neumeier, Christian ; Nielsson, Ulf ; Nimalendran, Mahendrarajah ; Nolte, Sven ; Norden, Lars L. ; O'Neill, Peter ; Obaid, Khaled ; Ødegaard, Bernt Arne ; Östberg, Per ; Painter, Marcus ; Palan, Stefan ; Palit, Imon ; Park, Andreas ; Pascual, Roberto ; Pasquariello, Paolo ; Pastor, Lubos ; Patel, Vinay ; Patton, Andrew J. ; Pearson, Neil D. ; Pelizzon, Loriana ; Rzeźnik, Aleksandra ; Sanford, Anthony ; Sankaran, Harikumar ; Sarkar, Asani ; Sarno, Lucio ; Scaillet, O. ; Scharnowski, Stefan ; Schenk-Hoppé, Klaus Reiner ; Schertler, Andrea ; Schneider, Michael ; Schroeder, Florian ; Schürhoff, Norman ; Schuster, Philipp ; Schwarz, Marco A. ; Seasholes, Mark S. ; Seeger, Norman ; Shachar, Or ; Shkilko, Andriy ; Shui, Jessica ; Sikic, Mario ; Simion, Giorgia ; Smales, Lee A. ; Söderlind, Paul ; Sojli, Elvira ; Sokolov, Konstantin ; Spokeviciute, Laima ; Stefanova, Denitsa ; Subrahmanyam, Marti G. ; Neusüss, Sebastian ; Szaszi, Barnabas ; Talavera, Oleksandr ; Tang, Yuehua ; Taylor, Nicholas ; Tham, Wing Wah ; Theissen, Erik ; Thimme, Julian ; Tonks, Ian ; Tran, Hai ; Trapin, Luca ; Trolle, Anders B. ; Valente, Giorgio ; Van Ness, Robert A. ; Vasquez, Aurelio ; Verousis, Thanos ; Verwijmeren, Patrick ; Vilhelmsson, Anders ; Vilkov, Grigory ; Vladimirov, Vladimir ; Vogel, Sebastian ; Voigt, Stefan ; Wagner, Wolf ; Walther, Thomas ; Weiss, Patrick ; Wel, Michel van der ; Werner, Ingrid M. ; Westerholm, Joakim ; Westheide, Christian ; Wipplinger, Evert ; Wolf, Michael ; Wolff, Christiaan Cornelis Petrus ; Wolk, Leonard ; Wong, Wing Keung ; Wrampelmeyer, Jan ; Xia, Shuo ; Xiu, Dacheng ; Xu, Ke ; Xu, Caihong ; Yadav, Pradeep ; Yagüe, José ; Yan, Cheng ; Yang, Antti ; Yoo, Woongsun ; Yu, Wenjia ; Yu, Shihao ; Yueshen, Bart Zhou ; Yuferova, Darya ; Zamojski, Marcin ; Zareei, Abalfazl ; Zeisberger, Stefan ; Zhang, Sarah ; Zhang, Xiaoyu ; Zhong, Zhuo ; Zhou, Z. Ivy ; Zhou, Chen ; Zhu, Xingyu Sonya ; Zoican, Marius ; Zwinkels, Remco C. J. ; Chen, Jian ; Duevski, Teodor ; Gao, Ge ; Gemayel, Roland ; Gilder, Dudley ; Kuhle, Paul ; Pagnotta, Emiliano ; Pelli, Michele ; Sönksen, Jantje ; Zhang, Lu ; Ilczuk, Konrad ; Bogoev, Dimitar ; Qian, Ya ; Wika, Hans C. ; Yu, Yihe ; Zhao, Lu ; Mi, Michael ; Bao, Li ; Vaduva, Andreea ; Prokopczuk, Marcel ; Avetikian, Alejandro ; Wu, Zhen-Xing
In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in sample estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: non-standard errors. To study them, we let 164 teams test six hypotheses on the same sample. We find that non-standard errors are sizeable, on par with standard errors. Their size (i) co-varies only weakly with team merits, reproducibility, or peer rating, (ii) declines significantly after peer-feedback, and (iii) is underestimated by participants.
Dultz, Georg ; Shimakami, Tetsuro ; Schneider, Markus ; Murai, Kazuhisa ; Yamane, Daisuke ; Marion, Antoine ; Zeitler, Tobias M. ; Stross, Claudia ; Grimm, Christian ; Richter, Rebecca M. ; Bäumer, Katrin ; Yi, MinKyung ; Biondi, Ricardo M. ; Zeuzem, Stefan ; Tampé, Robert ; Antes, Iris ; Lange, Christian ; Welsch, Christoph
Inhibitors against the NS3-4A protease of hepatitis C virus (HCV) have proven to be useful drugs in the treatment of HCV infection. Although variants have been identified with mutations that confer resistance to these inhibitors, the mutations do not restore replicative fitness and no secondary mutations that rescue fitness have been found. To gain insight into the molecular mechanisms underlying the lack of fitness compensation, we screened known resistance mutations in infectious HCV cell culture with different genomic backgrounds. We observed that the Q41R mutation of NS3-4A efficiently rescues the replicative fitness in cell culture for virus variants containing mutations at NS3-Asp168. To understand how the Q41R mutation rescues activity, we performed protease activity assays complemented by molecular dynamics simulations, which showed that protease-peptide interactions far outside the targeted peptide cleavage sites mediate substrate recognition by NS3-4A and support protease cleavage kinetics. These interactions shed new light on the mechanisms by which NS3-4A cleaves its substrates, viral polyproteins and a prime cellular antiviral adaptor protein, the mitochondrial antiviral signaling protein MAVS. Peptide binding is mediated by an extended hydrogen-bond network in NS3-4A that was effectively optimized for protease-MAVS binding in Asp168 variants with rescued replicative fitness from NS3-Q41R. In the protease harboring NS3-Q41R, the N-terminal cleavage products of MAVS retained high affinity to the active site, rendering the protease susceptible for potential product inhibition. Our findings reveal delicately balanced protease-peptide interactions in viral replication and immune escape that likely restrict the protease adaptive capability and narrow the virus evolutionary space.
Kiltz, Uta ; Buschhorn-Milberger, Verena ; Albrecht, K. ; Lakomek, Heinz-Jürgen ; Lorenz, Hanns-Martin ; Rudwaleit, M. ; Schneider, M. ; Schulze-Koops, Hendrik ; Baraliakos, Xenofon ; Behrens, Frank ; Brandt-Jürgens, Jan ; Haibel, H. ; Hammel, L. ; Karberg, K. ; Kellner, H. ; Krause, Daniela Sandra ; Lange, U. ; Märker-Herrmann, E. ; Poddubnyy, Denis ; Sieper, J. ; Syrbe, Uta ; Braun, J.
Qualitätsstandards (QS) sind messbare Konstrukte, die helfen sollen, Versorgungslücken quantitativ zu erfassen, um langfristig die Versorgungsqualität zu verbessern. Die Assessment of SpondyloArthritis International Society (ASAS) hat kürzlich erstmals internationale QS für das Management von Patient*innen mit axialer Spondyloarthritis (axSpA) konsentiert und veröffentlicht. Die Deutsche Gesellschaft für Rheumatologie (DGRh) hat daraufhin beschlossen, diese Standards durch eine Gruppe von Expert*innen aus unterschiedlichen Versorgungsbereichen zu übersetzen, zu prüfen und ggf. zu übernehmen. Vor diesem Hintergrund wurden erstmals nationale QS für das Management von Patient*innen mit axSpA für Deutschland entwickelt. Hierbei wurde v. a. auf Machbarkeit und Praxisrelevanz geachtet. Letztlich wurden 9 QS definiert, mit denen die Qualität der Versorgung in Deutschland gemessen und verbessert werden kann bzw. soll.
El-Helou, Sabine M. ; Biegner, Anika-Kerstin ; Bode, Sebastian ; Ehl, Stephan ; Heeg, Maximilian ; Maccari, Maria E. ; Ritterbusch, Henrike ; Speckmann, Carsten ; Rusch, Stephan ; Scheible, Raphael ; Warnatz, Klaus ; Atschekzei, Faranaz ; Beider, Renata ; Ernst, Diana ; Gerschmann, Stev ; Jablonka, Alexandra ; Mielke, Gudrun ; Schmidt, Reinhold E. ; Schürmann, Gesine ; Sogkas, Georgios ; Baumann, Ulrich ; Klemann, Christian ; Viemann, Dorothee ; Bernuth, Horst von ; Krüger, Renate ; Hanitsch, Leif Gunnar ; Scheibenbogen, Carmen ; Wittke, Kirsten ; Albert, Michael H. ; Eichinger, Anna ; Hauck, Fabian ; Klein, Christoph ; Rack-Hoch, Anita ; Sollinger, Franz ; Avila, Anne ; Borte, Michael ; Borte, Stephan ; Fasshauer, Maria ; Hauenherm, Anja ; Kellner, Nils ; Müller, Anna H. ; Ülzen, Anett ; Bader, Peter ; Bakhtiar, Shahrzad ; Lee, Jae-Yun ; Heß, Ursula ; Schubert, Ralf ; Wölke, Sandra ; Zielen, Stefan ; Ghosh, Sujal ; Laws, Hans-Jürgen ; Neubert, Jennifer ; Oommen, Prasad Thomas ; Hönig, Manfred ; Schulz, Ansgar ; Steinmann, Sandra ; Schwarz, Klaus ; Dückers, Gregor ; Lamers, Beate ; Langemeyer, Vanessa ; Niehues, Tim ; Shai, Sonu ; Graf, Dagmar ; Müglich, Carmen ; Schmalzing, Marc ; Schwaneck, Eva C. ; Tony, Hans-Peter ; Dirks, Johannes ; Haase, Gabriele ; Liese, Johannes G. ; Morbach, Henner ; Föll, Dirk ; Hellige, Antje ; Wittkowski, Helmut ; Masjosthusmann, Katja ; Mohr, Michael ; Geberzahn, Linda ; Hedrich, Christian Michael ; Müller, Christiane ; Rösen-Wolff, Angela ; Roesler, Joachim ; Zimmermann, Antje ; Behrends, Uta ; Rieber, Nikolaus ; Schauer, Uwe ; Handgretinger, Rupert ; Holzer, Ursula ; Henes, Jörg Christoph ; Kanz, Lothar ; Boesecke, Christoph ; Rockstroh, Jürgen ; Schwarze-Zander, Carolynne ; Wasmuth, Jan-Christian ; Dilloo, Dagmar ; Hülsmann, Brigitte ; Schönberger, Stefan ; Schreiber, Stefan ; Zeuner, Rainald ; Ankermann, Tobias ; Bismarck, Philipp von ; Huppertz, Hans-Iko ; Kaiser-Labusch, Petra ; Greil, Johann ; Jakoby, Donate ; Kulozik, Andreas ; Metzler, Markus ; Naumann-Bartsch, Nora ; Sobik, Bettina ; Graf, Norbert ; Heine, Sabine ; Kobbe, Robin ; Lehmberg, Kai ; Müller, Ingo ; Herrmann, Friedrich ; Horneff, Gerd ; Klein, Ariane ; Peitz, Joachim ; Schmidt, Nadine ; Bielack, Stefan S. ; Groß-Wieltsch, Ute ; Classen, Carl Friedrich ; Klasen, Jessica ; Deutz, Peter ; Kamitz, Dirk ; Lassay, Lisa ; Tenbrock, Klaus ; Wagner, Norbert ; Bernbeck, Benedikt ; Brummel, Bastian ; Lara-Villacanas, Eusebia ; Münstermann, Esther ; Schneider, Dominik T. ; Tietsch, Nadine ; Westkemper, Marco ; Weiß, Michael ; Kramm, Christof M. ; Kühnle, Ingrid ; Kullman, Silke ; Girschick, Hermann ; Specker, Christof ; Vinnemeier-Laubenthal, Elisabeth ; Haenicke, Henriette ; Schulz, Claudia ; Schweigerer, Lothar ; Müller, Thomas G. ; Stiefel, Martina ; Belohradsky, Bernd H. ; Soetedjo, Veronika ; Kindle, Gerhard ; Grimbacher, Bodo
Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.
Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.
Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.
Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
Rainger, Joe ; Beusekom, Ellen van ; Ramsay, Jacqueline K. ; McKie, Lisa ; Al-Gazali, Lihadh ; Pallotta, Rosanna ; Saponari, Anita ; Branney, Peter ; Fisher, Malcolm ; Morrison, Harris ; Bicknell, Louise ; Gautier, Philippe ; Perry, Paul ; Sokhi, Kishan ; Sexton, David ; Bardakjian, Tanya M. ; Schneider, Adele S. ; Elcioglu, Nursel ; Ozkinay, Ferda ; Koenig, Rainer ; Mégarbané, Andre ; Semerci, C. Nur ; Khan, Ayesha ; Zafar, Saemah ; Hennekam, Raoul C. ; Sousa, Sérgio B. ; Ramos, Lina ; Garavelli, Livia ; Furga, Andrea Superti ; Wischmeijer, Anita ; Jackson, Ian J. ; Gillessen-Kaesbach, Gabriele Gertrud ; Brunner, Han G. ; Wieczorek, Dagmar ; Bokhoven, Hans van ; FitzPatrick, David R.
Ophthalmo-acromelic syndrome (OAS), also known as Waardenburg Anophthalmia syndrome, is defined by the combination of eye malformations, most commonly bilateral anophthalmia, with post-axial oligosyndactyly. Homozygosity mapping and subsequent targeted mutation analysis of a locus on 14q24.2 identified homozygous mutations in SMOC1 (SPARC-related modular calcium binding 1) in eight unrelated families. Four of these mutations are nonsense, two frame-shift, and two missense. The missense mutations are both in the second Thyroglobulin Type-1 (Tg1) domain of the protein. The orthologous gene in the mouse, Smoc1, shows site- and stage-specific expression during eye, limb, craniofacial, and somite development. We also report a targeted pre-conditional gene-trap mutation of Smoc1 (Smoc1tm1a) that reduces mRNA to ~10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc1tm1a/tm1a). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc1tm1a/tm1a embryos and pups. Thus partial loss of Smoc-1 results in a convincing phenocopy of the human disease. SMOC-1 is one of the two mammalian paralogs of Drosophila Pentagone, an inhibitor of decapentaplegic. The orthologous gene in Xenopus laevis, Smoc-1, also functions as a Bone Morphogenic Protein (BMP) antagonist in early embryogenesis. Loss of BMP antagonism during mammalian development provides a plausible explanation for both the limb and eye phenotype in humans and mice.
In unserer Zeit jagen sich die Hiobsbotschaften über die Verarmung der Umwelt. Ist es möglich, rasch eine ausgewogene Übersicht der wirklichen Lage zu gewinnen? Für die höheren Pflanzen des Kreises Höxter östlich vom 9.Meridian seit 1976 ja! Damals erschien der "Atlas zur Flora von Südniedersachsen" von H. HAEUPLER. Er umfaßt zu 96% auch die Fläche des Kreises Höxter. Im Gegensatz zu den geschriebenen Floren, die nur bei den selteneren Arten Verbreitungsangaben bringen, arbeitet der Atlas bei allen Arten gleichmäßig flächendeckend. Das ganze Gebiet ist in Grundfelder eingeteilt, hier in Viertel der "Topographischen Karte 1: 25.000", die früher "Meßtischblatt" hieß. In jedem dieser "MTB-Quadranten" hakt mindestens ein Bearbeiter alle Pflanzenarten, die er dort findet, in einer vorgedruckten Liste an. Jede solche Feststellung erscheint in der Karte als Punkt, ältere Angaben, die nach 1945 nicht mehr bestätigt werden konnten, als Kreis.
Schüler, Julia ; Klingner, Kerstin ; Bug, Daniel ; Zöller, Caren ; Maier, Armin ; Dong, Meng ; Willecke, Kerstin ; Peille, Anne-Lise ; Steiner, Eva ; Landesfeind, Manuel ; Copland, John A. ; Siegers, Gabrielle M. ; Haferkamp, Axel ; Böhm, Katharina ; Tsaur, Igor ; Schneider, Meike
Systemic treatment is necessary for one third of patients with renal cell carcinoma. No valid biomarker is currently available to tailor personalized therapy. In this study we established a representative panel of patient derived xenograft (PDX) mouse models from patients with renal cell carcinomas and determined serum levels of high mobility group B1 (HMGB1) protein under treatment with sunitinib, pazopanib, sorafenib, axitinib, temsirolimus and bevacizumab. Serum HMGB1 levels were significantly higher in a subset of the PDX collection, which exhibited slower tumor growth during subsequent passages than tumors with low HMGB1 serum levels. Pre-treatment PDX serum HMGB1 levels also correlated with response to systemic treatment: PDX models with high HMGB1 levels predicted response to bevacizumab. Taken together, we provide for the first time evidence that the damage associated molecular pattern biomarker HMGB1 can predict response to systemic treatment with bevacizumab. Our data support the future evaluation of HMGB1 as a predictive biomarker for bevacizumab sensitivity in patients with renal cell carcinoma.
The representation of small molecules as molecular graphs is a common technique in various fields of cheminformatics. This approach employs abstract descriptions of topology and properties for rapid analyses and comparison. Receptor-based methods in contrast mostly depend on more complex representations impeding simplified analysis and limiting the possibilities of property assignment. In this study we demonstrate that ligand-based methods can be applied to receptor-derived binding site analysis. We introduce the new method PocketGraph that translates representations of binding site volumes into linear graphs and enables the application of graph-based methods to the world of protein pockets. The method uses the PocketPicker algorithm for characterization of binding site volumes and employs a Growing Neural Gas procedure to derive graph representations of pocket topologies. Self-organizing map (SOM) projections revealed a limited number of pocket topologies. We argue that there is only a small set of pocket shapes realized in the known ligand-receptor complexes.
Recent phylogenomic studies have failed to conclusively resolve certain branches of the placental mammalian tree, despite the evolutionary analysis of genomic data from 32 species. Previous analyses of single genes and retroposon insertion data yielded support for different phylogenetic scenarios for the most basal divergences. The results indicated that some mammalian divergences were best interpreted not as a single bifurcating tree, but as an evolutionary network. In these studies the relationships among some orders of the super-clade Laurasiatheria were poorly supported, albeit not studied in detail. Therefore, 4775 protein-coding genes (6,196,263 nucleotides) were collected and aligned in order to analyze the evolution of this clade. Additionally, over 200,000 introns were screened in silico, resulting in 32 phylogenetically informative long interspersed nuclear elements (LINE) insertion events.
The present study shows that the genome evolution of Laurasiatheria may best be understood as an evolutionary network. Thus, contrary to the common expectation to resolve major evolutionary events as a bifurcating tree, genome analyses unveil complex speciation processes even in deep mammalian divergences. We exemplify this on a subset of 1159 suitable genes that have individual histories, most likely due to incomplete lineage sorting or introgression, processes that can make the genealogy of mammalian genomes complex.
These unexpected results have major implications for the understanding of evolution in general, because the evolution of even some higher level taxa such as mammalian orders may sometimes not be interpreted as a simple bifurcating pattern.