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Kastirke, Gregor ; Schöffler, Markus S. ; Weller, Miriam ; Rist, Jonas ; Boll, Rebecca ; Anders, Nils ; Baumann, Thomas M. ; Eckart, Sebastian ; Erk, Benjamin ; De Fanis, Alberto ; Fehre, Kilian ; Gatton, Averell ; Grundmann, Sven Eric ; Grychtol, Patrik ; Hartung, Alexander ; Hofmann, Max ; Ilchen, Markus ; Janke, Christian Sören ; Kircher, Max ; Kunitski, Maksim ; Li, Xiang ; Mazza, Tommaso ; Melzer, Niklas ; Montano, Jacobo ; Music, Valerija ; Nalin, Giammarco ; Ovcharenko, Yevheniy ; Pier, Andreas ; Rennhack, Nils ; Rivas, Daniel E. ; Dörner, Reinhard ; Rolles, Daniel ; Rudenko, Artem ; Schmidt, Philipp ; Siebert, Juliane ; Strenger, Nico ; Trabert, Daniel ; Vela-Perez, Isabel ; Wagner, Rene ; Weber, Thorsten ; Williams, Joshua B. ; Ziolkowski, Pawel ; Schmidt, Lothar ; Czasch, Achim ; Trinter, Florian ; Meyer, Michael ; Ueda, Kiyoshi ; Demekhin, Philipp V. ; Jahnke, Till
A central motivation for the development of x-ray free-electron lasers has been the prospect of time-resolved single-molecule imaging with atomic resolution. Here, we show that x-ray photoelectron diffraction—where a photoelectron emitted after x-ray absorption illuminates the molecular structure from within—can be used to image the increase of the internuclear distance during the x-ray-induced fragmentation of an O2 molecule. By measuring the molecular-frame photoelectron emission patterns for a two-photon sequential K-shell ionization in coincidence with the fragment ions, and by sorting the data as a function of the measured kinetic energy release, we can resolve the elongation of the molecular bond by approximately 1.2 a.u. within the duration of the x-ray pulse. The experiment paves the road toward time-resolved pump-probe photoelectron diffraction imaging at high-repetition-rate x-ray free-electron lasers.
Long-range angular correlations on the near and away side in p–Pb collisions at √sNN=5.02 TeV
(2013)
Abelev, Betty ; Adam, Jaroslav ; Adamová, Dagmar ; Marshall Adare, Andrew ; Aggarwal, Madan Mohan ; Aglieri Rinella, Gianluca ; Agnello, Michelangelo ; Gabor Agocs, Andras ; Agostinelli, Andrea ; Ahammed, Zubayer ; Ahmad, Nazeer ; Ahmad, Arshad ; Ahn, Sul-Ah ; Ahn, Sang Un ; Ajaz, Muhammad ; Akindinov, Alexander ; Aleksandrov, Dmitry ; Alessandro, Bruno ; Alici, Andrea ; Alkin, Anton ; Jonathan Almaraz Avina, Erick ; Alme, Johan ; Alt, Torsten ; Altini, Valerio ; Altinpinar, Sedat ; Altsybeev, Igor ; Andrei, Cristian ; Andronic, Anton ; Anguelov, Venelin ; Anielski, Jonas ; Daniel Anson, Christopher ; Antičić, Tome ; Antinori, Federico ; Antonioli, Pietro ; Aphecetche, Laurent Bernard ; Appelshäuser, Harald ; Arbor, Nicolas ; Arcelli, Silvia ; Arend, Andreas ; Armesto, Nestor ; Arnaldi, Roberta ; Robert Aronsson, Tomas ; Arsene, Ionut Cristian ; Arslandok, Mesut ; Asryan, Andzhey ; Augustinus, Andre ; Averbeck, Ralf Peter ; Awes, Terry ; Heikki Aysto, Juha ; Danish Azmi, Mohd ; Jakob Bach, Matthias ; 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Kowalski, Marek ; Kox, Serge ; Koyithatta Meethaleveedu, Greeshma ; Kral, Jiří ; Králik, Ivan ; Kramer, Frederick ; Kravčáková, Adela ; Krawutschke, Tobias ; Křelina, Michal ; Kretz, Matthias ; Krivda, Marian ; Krizek, Filip ; Krus, Miroslav ; Kryshen, Evgeny ; Krzewicki, Mikolaj ; Kucheriaev, Yury ; Kugathasan, Thanushan ; Claude Kuhn, Christian ; Kuijer, Paul ; Kulakov, Igor ; Kumar, Jitendra ; Kurashvili, Podist ; Kurepin, Alexander ; Kurepin, Alexey B. ; Kuryakin, Alexey ; Kushpil, Svetlana ; Kushpil, Vasily ; Kvaerno, Henning ; Jung Kweon, Min ; Kwon, Youngil ; Ladron de Guevara, Pedro ; Lakomov, Igor ; Langoy, Rune ; Louise La Pointe, Sarah ; Ernesto Lara, Camilo ; Xavier Lardeux, Antoine ; La Rocca, Paola ; Lea, Ramona ; Lechman, Mateusz ; Sang Lee, Ki ; Chul Lee, Sung ; Richard Lee, Graham ; Legrand, Iosif ; Walter Lehnert, Joerg ; Laurent Lenhardt, Matthieu ; Lenti, Vito ; Leon, Hermes ; Leon Monzon, Ildefonso ; Leon Vargas, Hermes ; Lévai, Peter ; Li, Shuang ; Lien, Jaen ; Lietava, Roman ; Lindal, Svein ; Lindenstruth, Volker ; Lippmann, Christian ; Annan Lisa, Michael ; Martin Ljunggren, Hans ; Loenne, Per-Ivar ; Loggins, Vera ; Loginov, Vitaly ; Lohner, Daniel ; Loizides, Constantinos ; Krister Loo, Kai ; Bernard Lopez, Xavier ; López Torres, Ernesto ; Lovhoiden, Gunnar ; Lu, Xianguo ; Luettig, Philipp ; Lunardon, Marcello ; Luo, Jiebin ; Luparello, Grazia ; Luzzi, Cinzia ; Ma, Rongrong ; Ma, Ke ; Minthaka Madagodahettige-Don, Dilan ; Maevskaya, Alla ; Mager, Magnus ; Mahapatra, Durga Prasad ; Maire, Antonin ; Malaev, Mikhail ; Alicia Maldonado Cervantes, Ivonne ; Malinina, Liudmila ; MalʼKevich, Dmitry ; Malzacher, Peter ; Mamonov, Alexander ; Henri Antoine Manceau, Loic ; Kumar Mangotra, Lalit ; Manko, Vladislav ; Manso, Franck ; Manzari, Vito ; Mao, Yaxian ; Marchisone, Massimiliano ; Mareš, Jiří ; Margagliotti, Giacomo Vito ; Margotti, Anselmo ; Maria Marin, Ana ; Markert, Christina ; Marquard, Marco ; Martashvili, Irakli ; Alice Martin, Nicole ; Martinengo, Paolo ; Ivan Martinez, Mario Ivan ; Martinez Davalos, Arnulfo ; Martínez Garcia, Ginés ; Martynov, Yevgen ; Jean-Michel Mas, Alexis ; Masciocchi, Silvia ; Masera, Massimo ; Masoni, Alberto ; Marie Massacrier, Laure ; Mastroserio, Annalisa ; Tomasz Matyja, Adam ; Mayer, Christoph ; Mazer, Joel ; Maria Mazzoni, Alessandra ; Meddi, Franco ; Alejandro Menchaca-Rocha, Arturo ; Mercado Perez, Jae ; Meres, Michal ; Miake, Yasuo ; Milano, Leonardo ; Milošević, Jovan ; Mischke, André ; Nath Mishra, Aditya ; Miśkowiec, Dariusz Czesław ; Mihai Mitu, Ciprian ; Mizuno, Sanshiro ; Mlynarz, Jocelyn ; Mohanty, Bedangadas ; Molnar, Levente ; Manuel Montano Zetina, Luis ; Monteno, Marco ; Montes Prado, Esther ; Moon, Taebong ; Morando, Maurizio ; Aparecida Moreira De Godoy, Denise ; Moretto, Sandra ; Morreale, Astrid ; Morsch, Andreas ; Muccifora, Valeria ; Mudnic, Eugen ; Muhuri, Sanjib ; Mukherjee, Maitreyee ; Muller, Hans ; Munhoz, Marcelo ; Murray, Sean ; Musa, Luciano ; Musinsky, Jan ; Musso, Alfredo ; Kumar Nandi, Basanta ; Nania, Rosario ; Nappi, Eugenio ; Nattrass, Christine ; Kumar Nayak, Tapan ; Nazarenko, Sergey ; Nedosekin, Alexander ; Nicassio, Maria ; Niculescu, Mihai ; Svane Nielsen, Bae ; Niida, Takafumi ; Nikolaev, Sergey ; Nikolic, Vedran ; Nikulin, Sergey ; Nikulin, Vladimir ; Steven Nilsen, Bjorn ; Stormo Nilsson, Mads ; Noferini, Francesco ; Nomokonov, Petr V. ; Nooren, Gerardus ; Novitzky, Norbert ; Nyanin, Alexandre ; Nyatha, Anitha ; Nygaard, Casper ; Nystrand, Joakim Ingemar ; Ochirov, Alexander ; Oskar Oeschler, Helmut ; Oh, Saehanseul ; Kun Oh, Sun ; Oleniacz, Janusz ; Carlos Oliveira Da Silva, Antonio ; Oppedisano, Chiara ; Ortiz Velasquez, Antonio ; Nils Erik Oskarsson, Anders ; Krystian Ostrowski, Piotr ; Tomasz Otwinowski, Jacek ; Oyama, Ken ; Ozawa, Kyoichiro ; Chiara Pachmayer, Yvonne ; Pachr, Milos ; Padilla, Fatima ; Pagano, Paola ; Paic, Guy ; Painke, Florian ; Pajares Vales, Carlos ; Kumar Pal, Susanta ; Singh Palaha, Arvinder ; Palmeri, Armando ; Papikyan, Vardanush ; Pappalardo, Giuseppe Salvatore ; Jin Park, Woo ; Passfeld, Annika ; Pastircak, Blahoslav ; Ivanovich Patalakha, Dmitri ; Paticchio, Vincenzo ; Paul, Biswarup ; Pavlinov, Alexei ; Pawlak, Tomasz Jan ; Peitzmann, Thomas ; Denis Antonio Pereira Da Costa, Hugo ; Pereira De Oliveira Filho, Elienos ; Peresunko, Dmitri ; Eugenio Perez Lara, Carlos ; Perini, Diego ; Perrino, Davide ; Stanislaw Peryt, Wiktor ; Pesci, Alessandro ; Peskov, Vladimir ; Pestov, Yury N. ; Petráček, Vojtech ; Petran, Michal ; Petris, Mariana ; Rumenov Petrov, Plamen ; Petrovici, Mihai A. ; Petta, Catia ; Piano, Stefano ; Pikna, Miroslav ; Pillot, Philippe ; Pinazza, Ombretta ; Pinsky, Lawrence ; Pitz, Nora ; Piyarathna, Danthasinghe ; Planinic, Mirko ; Ploskon, Mateusz Andrzej ; Marian Pluta, Jan ; Pocheptsov, Timur ; Pochybova, Sona ; Luis Manuel Podesta Lerma, Pedro ; Poghosyan, Martin G. ; Polak, Karel ; Polichtchouk, Boris ; Pop, Amalia ; Porteboeuf-Houssais, Sarah Julie ; Pospisil, Vladimir ; Potukuchi, Baba ; Prasad, Sidharth Kumar ; Preghenella, Roberto ; Prino, Francesco ; Andre Pruneau, Claude ; Pshenichnov, Igor A. ; Puddu, Giovanna ; Punin, Valery ; Putis, Marian ; Putschke, Jörn H. ; Quercigh, Emanuele ; Qvigstad, Henrik ; Rachevski, Alexandre ; Rademakers, Alphonse ; Samuli Raiha, Tomi ; Rak, Jan ; Malala Rakotozafindrabe, Andry ; Ramello, Luciano ; Ramirez Reyes, Abdiel ; Raniwala, Rashmi ; Raniwala, Sudhir ; Sakari Rasanen, Sami ; Theodor Rascanu, Bogdan ; Rathee, Deepika ; Francis Read, Kenneth ; Real, Jean-Sébastien ; Redlich, Krzysztof ; Jan Reed, Rosi ; Ur Rehman, Attiq ; Reichelt, Patrick ; Reicher, Martijn ; Arno Ernst Renfordt, Rainer ; Rita Reolon, Anna ; Reshetin, Andrey ; Vincenz Rettig, Felix ; Revol, Jean-Pierre ; Johannes Reygers, Klaus ; Riccati, Lodovico ; Angelo Ricci, Renato ; Richert, Tuva ; Richter, Matthias ; Riedler, Petra ; Riegler, Werner ; Riggi, Francesco ; Rodrı́guez Cahuantzi, Mario ; Rodriguez Manso, Alis ; Roed, Ketil ; Rohr, David ; Röhrich, Dieter ; Romita, Rosa ; Ronchetti, Federico ; Rosnet, Philippe ; Rossegger, Stefan ; Rossi, Andrea ; Sophie Roy, Christelle ; Kumar Roy, Pradip ; Juan Rubio Montero, Antonio ; Rui, Rinaldo ; Russo, Riccardo ; Ryabinkin, Evgeny ; Rybicki, Andrzej ; Sadovskiy, Sergey ; Šafařík, Karel ; Sahoo, Raghunath ; Kumar Sahu, Pradip ; Saini, Jogender ; Sakaguchi, Hiroaki ; Sakai, Shingo ; Sakata, Dosatsu ; Albert Salgado, Carlos ; Salzwedel, Jai ; Singh Sambyal, Sanjeev ; Samsonov, Vladimir ; Sanchez Castro, Xitzel ; Šándor, Ladislav ; Sandoval, Andres ; Sano, Masato ; Santagati, Gianluca ; Santoro, Romualdo ; Jaako Sarkamo, Juho ; Scapparone, Eugenio ; Scarlassara, Fernando ; Paul Scharenberg, Rolf ; Schiaua, Claudiu Cornel ; Schicker, Rainer ; Joachim Schmidt, Christian ; Rudolf Schmidt, Hans ; Schuchmann, Simone ; Schukraft, Jürgen ; Schuster, Tim ; Roland Schutz, Yves ; Eberhard Schwarz, Kilian ; Schweda, Kai ; Scioli, Gilda ; Scomparin, Enrico ; Aaron Scott, Patrick ; Scott, Rebecca ; Segato, Gianfranco ; Selyuzhenkov, Ilya ; Senyukov, Serhiy ; Seo, Jeewon ; Serci, Sergio ; Serradilla, Eulogio ; Sevcenco, Adrian ; Shabetai, Alexandre ; Shabratova, Galina ; Shahoyan, Ruben ; Sharma, Natasha ; Sharma, Satish ; Sharma, Rohini ; Shigaki, Kenta ; Shtejer, Katherin ; Sibiriak, Yury ; Sicking, Eva ; Siddhanta, Sabyasachi ; Siemiarczuk, Teodor ; Olle Rickard Silvermyr, David ; Silvestre, Catherine ; Simatovic, Goran ; Simonetti, Giuseppe ; Narayana Singaraju, Rama ; Singh, Ranbir ; Singha, Subhash ; Singhal, Vikas ; Sinha, Bikash ; Sinha, Tinku ; Sitar, Branislav ; Sitta, Mario ; Skaali, Toralf Bernhard ; Skjerdal, Kyrre ; Smakal, Radek ; Smirnov, Nikolai ; Snellings, Raimond ; Sogaard, Carsten ; Ariel Soltz, Ron ; Son, Hyungsuk ; Song, Jihye ; Song, Myunggeun ; Soos, Csaba ; Soramel, Francesca ; Sputowska, Iwona ; Spyropoulou-Stassinaki, Martha ; Srivastava, Brijesh Kumar ; Stachel, Johanna ; Stan, Ionel ; Stefanek, Grzegorz ; Steinpreis, Matthew ; Anders Stenlund, Evert ; Francois Steyn, Gideon ; Hendrik Stiller, Johannes ; Stocco, Diego ; Stolpovskiy, Mikhail ; Strmen, Peter ; Suaide, Alexandre Alarcon do Passo ; Subieta Vasquez, Martin Alfonso ; Sugitate, Toru ; Suire, Christophe Pierre ; Sultanov, Rishat ; Šumbera, Michal ; Šuša, Tatjana ; Symons, Timothy ; Toledo, Alejandro Szanto de ; Szarka, Imrich ; Szczepankiewicz, Adam ; Krzysztof Szostak, Artur ; Szymanski, Maciej ; Takahashi, Jun ; Tapia Takaki, Jesus Daniel ; Tarantola Peloni, Attilio ; Tarazona Martinez, Alfonso ; Tauro, Arturo ; Tejeda Muñoz, Guillermo ; Telesca, Adriana ; Terrevoli, Cristina ; Mathias Thader, Jochen ; Thomas, Deepa ; Noel Tieulent, Raphael ; Timmins, Anthony Robert ; Tlusty, David ; Toia, Alberica ; Torii, Hisayuki ; Toscano, Luca ; Trubnikov, Victor ; Truesdale, David Christopher ; Trzaska, Wladyslaw Henryk ; Tsuji, Tomoya ; Tumkin, Alexandr ; Turrisi, Rosario ; Spedstad Tveter, Trine ; Glyndwr Ulery, Jason ; Ullaland, Kjetil ; Ulrich, Jochen ; Uras, Antonio ; Urban, Jozef ; Marie Urciuoli, Guido ; Usai, Gianluca ; Vajzer, Michal ; Vala, Martin ; Valencia Palomo, Lizardo ; Vallero, Sara ; Vyvre, Pierre vande ; Leeuwen, Marco van ; Vannucci, Luigi ; Diozcora Vargas, Aurora ; Varma, Raghava ; Vasileiou, Maria ; Vasiliev, Andrey ; Vechernin, Vladimir ; Veldhoen, Misha ; Venaruzzo, Massimo ; Vercellin, Ermanno ; Vergara, Sergio ; Vernet, Renaud ; Verweij, Marta ; Vicković, Linda ; Viesti, Giuseppe ; Viinikainen, Jussi ; Vilakazi, Zabulon ; Villalobos Baillie, Orlando ; Vinogradov, Yury I. ; Vinogradov, Alexander ; Vinogradov, Leonid ; Virgili, Tiziano ; Viyogi, Yogendra P. ; Vodopianov, Alexander ; Voloshin, Sergei ; Voloshin, Kirill ; Volpe, Giacomo ; Haller, Barthélémy von ; Vorobyev, Ivan ; Vranić, Danilo ; Vrláková, Janka ; Vulpescu, Bogdan ; Vyushin, Alexey ; Wagner, Boris ; Wagner, Vladimir ; Wan, Renzhuo ; Wang, Yaping ; Wang, Yifei ; Wang, Mengliang ; Wang, Dong ; Watanabe, Kengo ; Weber, Michael ; Wessels, Johannes ; Westerhoff, Uwe ; Wiechula, Jens ; Wikne, Jon ; Rudolf Wilde, Martin ; Andrzej Wilk, Grzegorz ; Wilk, Alexander ; Williams, M. Crispin S. ; Windelband, Bernd ; Xaplanteris Karampatsos, Leonidas ; Yaldo, Chris G. ; Yamaguchi, Yorito ; Yang, Hongyan ; Yang, Shiming ; Yasnopolsky, Stanislav ; Yi, JunGyu ; Yin, Zhongbao ; Yoo, In-Kwon ; Yoon, Jongik ; Yu, Weilin ; Yuan, Xianbao ; Yushmanov, Igor ; Zaccolo, Valentina ; Zach, Cenek ; Zampolli, Chiara ; Zaporozhets, Sergey ; Zarochentsev, Andrey ; Závada, Petr ; Zaviyalov, Nikolai ; Zbroszczyk, Hanna Paulina ; Zelnicek, Pierre ; Ion Zgura, Sorin ; Zhalov, Mikhail ; Zhang, Haitao ; Zhang, Xiaoming ; Zhou, Fengchu ; Zhou, You ; Zhou, Daicui ; Zhu, Hongsheng ; Zhu, Jianhui ; Zhu, Jianlin ; Zhu, Xiangrong ; Zichichi, Antonino ; Zimmermann, Alice ; Zinovjev, Gennady M. ; Denis Zoccarato, Yannick ; Zynovyev, Mykhaylo ; Zyzak, Maksym
Angular correlations between charged trigger and associated particles are measured by the ALICE detector in p–Pb collisions at a nucleon–nucleon centre-of-mass energy of 5.02 TeV for transverse momentum ranges within 0.5<pT,assoc<pT,trig<4 GeV/c. The correlations are measured over two units of pseudorapidity and full azimuthal angle in different intervals of event multiplicity, and expressed as associated yield per trigger particle. Two long-range ridge-like structures, one on the near side and one on the away side, are observed when the per-trigger yield obtained in low-multiplicity events is subtracted from the one in high-multiplicity events. The excess on the near-side is qualitatively similar to that recently reported by the CMS Collaboration, while the excess on the away-side is reported for the first time. The two-ridge structure projected onto azimuthal angle is quantified with the second and third Fourier coefficients as well as by near-side and away-side yields and widths. The yields on the near side and on the away side are equal within the uncertainties for all studied event multiplicity and pT bins, and the widths show no significant evolution with event multiplicity or pT. These findings suggest that the near-side ridge is accompanied by an essentially identical away-side ridge.
Um die kontinuierlich auf uns einströmende Menge an Reizen zu verarbeiten, ist es wichtig, die Informationen genau zu selektieren. Ein hilfreicher Mechanismus ist hierbei die Aufmerksamkeit gezielt nur auf eine Informationsquelle zu richten und zu verarbeiten.
So ist es möglich, selbst in komplexen Situationen, wie zum Beispiel einer Feier mit vielen verschiedenen Gesprächen, ganz gezielt ein einzelnes herauszufiltern.
Der Effekt von Aufmerksamkeit auf auditory steady-state Responses (aSSR) wurde in der Vergangenheit schon in verschiedenen Studien mit unterschiedlichen Messverfahren und Stimuli untersucht. Dabei wurden teils widersprüchliche Ergebnisse gefunden, die entweder gar keine oder auf sehr kleine Frequenzbereiche beschränkte Aufmerksamkeitseffekte fanden.
Das Ziel dieser Studie war es, die Auswirkungen von Aufmerksamkeit auf die aSSR innerhalb eines größeren Frequenzspektrums (11 Hz, 23 Hz, 41 Hz, 73 Hz und 97 Hz) zu analysieren. Für diesen Zweck wurden den Probanden nach Instruktion der zu beachtenden Seite jeweils zwei benachbarte Modulationsfrequenzen während vier aufeinander folgenden Blöcken dichotisch präsentiert. Die Probanden wurden angewiesen, Trägerfrequenzänderungen auf der zu beachtenden Seite durch Betätigen einer Maustaste anzugeben. Die Registrierung der aSSR-Antworten geschah mittels Elektroenzephalogramm (EEG). Auch die durch die Stimulation hervorgerufene P300 wurde dargestellt.
Bezüglich des Effekts von Aufmerksamkeit auf die aSSRs zeigte sich nach Analyse der gewonnenen Daten im Frequenzbereich von 23 Hz eine Auswirkung. Diese stellte sich in Form einer Amplitudensteigerung auf der jeweils durch den Probanden beachteten Präsentationsseite dar. Bei einer Modulationsfrequenz von 41 Hz kam es bei Präsentation auf der rechten Seite zu höheren Amplituden als bei Präsentation auf der linken Seite. Bei 73 Hz und 97 Hz konnte keinerlei Auswirkung weder der Aufmerksamkeit noch der Präsentationsseite registriert werden. Auffällig war bei den präsentierten Tönen im 20 Hz und 70 Hz Bereich auch eine im Vergleich zu den anderen Frequenzbereichen (11 Hz, 41 Hz und 97 Hz) verlängerte Reaktionszeit der Probanden. In Kombination mit der Modulation der aSSR-Amplitude durch Aufmerksamkeit bei 23 Hz könnte dies ein Hinweis auf einen förderlichen Einfluss der Aufgabenschwierigkeit auf die Detektierbarkeit von Aufmerksamkeitseffekten sein.
Im Gegensatz hierzu zeigte die dargestellte P300 in allen präsentierten Blöcken einen deutlichen Effekt der Aufmerksamkeit. Dieser äußerte sich ebenfalls in einer Steigerung der Amplitude.
Es scheint also zumindest ein moderater Einfluss von Aufmerksamkeit auf die aSSRs zu existieren. Gleichzeitig wirkt dieser allerdings stark abhängig von gewähltem Stimulus und Messmethode. Der Effekt von Aufmerksamkeit auf die P300 konnte dagegen gut repliziert werden und scheint daher bei dichotischer Stimulation ein deutlicher Marker für Aufmerksamkeit zu sein.
We show that market discipline, defined as the extent to which firm specific risk characteristics are reflected in market prices, eroded during the recent financial crisis in 2008. We design a novel test of changes in market discipline based on the relation between firm specific risk characteristics and debt-to-equity hedge ratios. We find that market discipline already weakened after the rescue of Bear Stearns before disappearing almost entirely after the failure of Lehman Brothers. The effect is stronger for investment banks and large financial institutions, while there is no comparable effect for non-financial firms.
Background: Understanding the location and cell-type specific binding of Transcription Factors (TFs) is important in the study of gene regulation. Computational prediction of TF binding sites is challenging, because TFs often bind only to short DNA motifs and cell-type specific co-factors may work together with the same TF to determine binding. Here, we consider the problem of learning a general model for the prediction of TF binding using DNase1-seq data and TF motif description in form of position specific energy matrices (PSEMs).
Methods: We use TF ChIP-seq data as a gold-standard for model training and evaluation. Our contribution is a novel ensemble learning approach using random forest classifiers. In the context of the ENCODE-DREAM in vivo TF binding site prediction challenge we consider different learning setups.
Results: Our results indicate that the ensemble learning approach is able to better generalize across tissues and cell-types compared to individual tissue-specific classifiers or a classifier built based upon data aggregated across tissues. Furthermore, we show that incorporating DNase1-seq peaks is essential to reduce the false positive rate of TF binding predictions compared to considering the raw DNase1 signal.
Conclusions: Analysis of important features reveals that the models preferentially select motifs of other TFs that are close interaction partners in existing protein protein-interaction networks. Code generated in the scope of this project is available on GitHub: https://github.com/SchulzLab/TFAnalysis (DOI: 10.5281/zenodo.1409697).
Background: Enhancers play a fundamental role in orchestrating cell state and development. Although several methods have been developed to identify enhancers, linking them to their target genes is still an open problem. Several theories have been proposed on the functional mechanisms of enhancers, which triggered the development of various methods to infer promoter–enhancer interactions (PEIs). The advancement of high-throughput techniques describing the three-dimensional organization of the chromatin, paved the way to pinpoint long-range PEIs. Here we investigated whether including PEIs in computational models for the prediction of gene expression improves performance and interpretability.
Results: We have extended our TEPIC framework to include DNA contacts deduced from chromatin conformation capture experiments and compared various methods to determine PEIs using predictive modelling of gene expression from chromatin accessibility data and predicted transcription factor (TF) motif data. We designed a novel machine learning approach that allows the prioritization of TFs binding to distal loop and promoter regions with respect to their importance for gene expression regulation. Our analysis revealed a set of core TFs that are part of enhancer–promoter loops involving YY1 in different cell lines.
Conclusion: We present a novel approach that can be used to prioritize TFs involved in distal and promoter-proximal regulatory events by integrating chromatin accessibility, conformation, and gene expression data. We show that the integration of chromatin conformation data can improve gene expression prediction and aids model interpretability.
his paper studies heterogeneity in the reaction to rank feedback. In a laboratory experiment, individuals take part in a series of dynamic real-effort contests with intermediate feedback. To solve the identification problem in estimating the causal effect of rank feedback on subsequent effort provision we implement a random multiplier in the first round of each contest. The realization of this multiplier then serves as a valid instrument for rank feedback. While rank feedback has a robust effect on subsequent effort provision on average, an explicit analysis of between-subject heterogeneity reveals that a substantial fraction of participants in fact react entirely opposite than the aggregated results indicate. We further show that this heterogeneity has consequences for overall outcomes, thereby arguing that heterogeneous sensitivities to rank feedback could have implications for the design of various policies in education and organizations.
Halwe, Sandro ; Kupke, Alexandra ; Vanshylla, Kanika ; Liberta, Falk ; Grüll, Henning ; Zehner, Matthias ; Rohde, Cornelius ; Krähling, Verena ; Gellhorn Serra, Michelle ; Kreer, Christoph ; Klüver, Michael ; Sauerhering, Lucie ; Schmidt, Jörg ; Cai, Zheng ; Han, Fei ; Young, David ; Yang, Guangwei ; Widera, Marek ; Koch, Manuel ; Werner, Anke ; Kämper, Lennart ; Becker, Nico ; Marlow, Michael S. ; Eickmann, Markus ; Ciesek, Sandra ; Schiele, Felix ; Klein, Florian ; Becker, Stephan
Despite the recent availability of vaccines against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there is an urgent need for specific anti-SARS-CoV-2 drugs. Monoclonal neutralizing antibodies are an important drug class in the global fight against the SARS-CoV-2 pandemic due to their ability to convey immediate protection and their potential to be used as both prophylactic and therapeutic drugs. Clinically used neutralizing antibodies against respiratory viruses are currently injected intravenously, which can lead to suboptimal pulmonary bioavailability and thus to a lower effectiveness. Here we describe DZIF-10c, a fully human monoclonal neutralizing antibody that binds the receptor-binding domain of the SARS-CoV-2 spike protein. DZIF-10c displays an exceptionally high neutralizing potency against SARS-CoV-2, retains full activity against the variant of concern (VOC) B.1.1.7 and still neutralizes the VOC B.1.351, although with reduced potency. Importantly, not only systemic but also intranasal application of DZIF-10c abolished the presence of infectious particles in the lungs of SARS-CoV-2 infected mice and mitigated lung pathology when administered prophylactically. Along with a favorable pharmacokinetic profile, these results highlight DZIF-10c as a novel human SARS-CoV-2 neutralizing antibody with high in vitro and in vivo antiviral potency. The successful intranasal application of DZIF-10c paves the way for clinical trials investigating topical delivery of anti-SARS-CoV-2 antibodies.
Background: Understanding the location and cell-type specific binding of Transcription Factors (TFs) is important in the study of gene regulation. Computational prediction of TF binding sites is challenging, because TFs often bind only to short DNA motifs and cell-type specific co-factors may work together with the same TF to determine binding. Here, we consider the problem of learning a general model for the prediction of TF binding using DNase1-seq data and TF motif description in form of position specific energy matrices (PSEMs).
Methods: We use TF ChIP-seq data as a gold-standard for model training and evaluation. Our contribution is a novel ensemble learning approach using random forest classifiers. In the context of the ENCODE-DREAM in vivo TF binding site prediction challenge we consider different learning setups.
Results: Our results indicate that the ensemble learning approach is able to better generalize across tissues and cell-types compared to individual tissue-specific classifiers or a classifier applied to the data aggregated across tissues. Furthermore, we show that incorporating DNase1-seq peaks is essential to reduce the false positive rate of TF binding predictions compared to considering the raw DNase1 signal.
Conclusions: Analysis of important features reveals that the models preferentially select motifs of other TFs that are close interaction partners in existing protein protein-interaction networks. Code generated in the scope of this project is available on GitHub: https://github.com/SchulzLab/TFAnalysis (DOI: 10.5281/zenodo.1409697)
Hartke, Juliane ; Schell, Tilman ; Jongepier, Evelien ; Schmidt, Hanno ; Sprenger, Philipp P. ; Paule, Juraj ; Bornberg-Bauer, Erich ; Schmitt, Thomas ; Menzel, Florian ; Pfenninger, Markus ; Feldmeyer, Barbara
The success of social insects is largely intertwined with their highly advanced chemical communication system that facilitates recognition and discrimination of species and nest-mates, recruitment, and division of labor. Hydrocarbons, which cover the cuticle of insects, not only serve as waterproofing agents but also constitute a major component of this communication system. Two cryptic Crematogaster species, which share their nest with Camponotus ants, show striking diversity in their cuticular hydrocarbon (CHC) profile. This mutualistic system therefore offers a great opportunity to study the genetic basis of CHC divergence between sister species. As a basis for further genome-wide studies high-quality genomes are needed. Here, we present the annotated draft genome for Crematogaster levior A. By combining the three most commonly used sequencing techniques—Illumina, PacBio, and Oxford Nanopore—we constructed a high-quality de novo ant genome. We show that even low coverage of long reads can add significantly to overall genome contiguity. Annotation of desaturase and elongase genes, which play a role in CHC biosynthesis revealed one of the largest repertoires in ants and a higher number of desaturases in general than in other Hymenoptera. This may provide a mechanistic explanation for the high diversity observed in C. levior CHC profiles.
Dreis, Caroline ; Ottenlinger, Florian ; Putyrski, Mateusz ; Ernst, Andreas ; Huhn, Meik ; Schmidt, Katrin G. ; Pfeilschifter, Josef ; Radeke, Heinfried H.
IL-1 family member IL-33 exerts a variety of immune activating and regulating properties and has recently been proposed as a prognostic biomarker for cancer diseases, although its precise role in tumor immunity is unclear. Here we analyzed in vitro conditions influencing the function of IL-33 as an alarmin and a co-factor for the activity of cytotoxic CD8+ T cells in order to explain the widely discussed promiscuous behavior of IL-33 in vivo. Circulating IL-33 detected in the serum of healthy human volunteers was biologically inactive. Additionally, bioactivity of exogenous recombinant IL-33 was significantly reduced in plasma, suggesting local effects of IL-33, and inactivation in blood. Limited availability of nutrients in tissue causes necrosis and thus favors release of IL-33, which—as described before—leads to a locally high expression of the cytokine. The harsh conditions however influence T cell fitness and their responsiveness to stimuli. Nutrient deprivation and pharmacological inhibition of mTOR mediated a distinctive phenotype characterized by expression of IL-33 receptor ST2L on isolated CD8+ T cells, downregulation of CD8, a transitional CD45RAlowROlow phenotype and high expression of secondary lymphoid organ chemokine receptor CCR7. Under nutrient deprivation, IL-33 inhibited an IL-12 induced increase in granzyme B protein expression and increased expression of GATA3 and FOXP3 mRNA. IL-33 enhanced the TCR-dependent activation of CD8+ T cells and co-stimulated the IL-12/TCR-dependent expression of IFNγ. Respectively, GATA3 and FOXP3 mRNA were not regulated during TCR-dependent activation. TCR-dependent stimulation of PBMC, but not LPS, initiated mRNA expression of soluble IL-33 decoy receptor sST2, a control mechanism limiting IL-33 bioactivity to avoid uncontrolled inflammation. Our findings contribute to the understanding of the compartment-specific activity of IL-33. Furthermore, we newly describe conditions, which promote an IL-33-dependent induction of pro- or anti-inflammatory activity in CD8+ T cells during nutrient deprivation.
Hoffmann, Markus ; Trummer, Nico ; Schwartz, Leon ; Jankowski, Jakub ; Kyung Lee, Hye ; Willruth, Lina-Liv ; Lazareva, Olga ; Yuan, Kevin ; Baumgarten, Nina ; Schmidt, Florian ; Baumbach, Jan ; Schulz, Marcel Holger ; Blumenthal, David B. ; Hennighausen, Lothar ; List, Markus
Background: Eukaryotic gene expression is controlled by cis-regulatory elements (CREs), including promoters and enhancers, which are bound by transcription factors (TFs). Differential expression of TFs and their binding affinity at putative CREs determine tissue- and developmental-specific transcriptional activity. Consolidating genomic data sets can offer further insights into the accessibility of CREs, TF activity, and, thus, gene regulation. However, the integration and analysis of multi-modal data sets are hampered by considerable technical challenges. While methods for highlighting differential TF activity from combined chromatin state data (e.g., ChIP-seq, ATAC-seq, or DNase-seq) and RNA-seq data exist, they do not offer convenient usability, have limited support for large-scale data processing, and provide only minimal functionality for visually interpreting results.
Results: We developed TF-Prioritizer, an automated pipeline that prioritizes condition-specific TFs from multi-modal data and generates an interactive web report. We demonstrated its potential by identifying known TFs along with their target genes, as well as previously unreported TFs active in lactating mouse mammary glands. Additionally, we studied a variety of ENCODE data sets for cell lines K562 and MCF-7, including twelve histone modification ChIP-seq as well as ATAC-seq and DNase-seq datasets, where we observe and discuss assay-specific differences.
Conclusion: TF-Prioritizer accepts ATAC-seq, DNase-seq, or ChIP-seq and RNA-seq data as input and identifies TFs with differential activity, thus offering an understanding of genome-wide gene regulation, potential pathogenesis, and therapeutic targets in biomedical research.
Hoffmann, Markus ; Trummer, Nico ; Jankowski, Jakub ; Kyung Lee, Hye ; Willruth, Lina-Liv ; Lazareva, Olga ; Yuan, Kevin ; Baumgarten, Nina ; Schmidt, Florian ; Baumbach, Jan ; Schulz, Marcel Holger ; Blumenthal, David B. ; Hennighausen, Lothar ; List, Markus
Background Eukaryotic gene expression is controlled by cis-regulatory elements (CREs) including promoters and enhancers which are bound by transcription factors (TFs). Differential expression of TFs and their putative binding sites on CREs cause tissue and developmental-specific transcriptional activity. Consolidating genomic data sets can offer further insights into the accessibility of CREs, TF activity, and thus gene regulation. However, the integration and analysis of multi-modal data sets are hampered by considerable technical challenges. While methods for highlighting differential TF activity from combined ChIP-seq and RNA-seq data exist, they do not offer good usability, have limited support for large-scale data processing, and provide only minimal functionality for visual result interpretation.
Results We developed TF-Prioritizer, an automated java pipeline to prioritize condition-specific TFs derived from multi-modal data. TF-Prioritizer creates an interactive, feature-rich, and user-friendly web report of its results. To showcase the potential of TF-Prioritizer, we identified known active TFs (e.g., Stat5, Elf5, Nfib, Esr1), their target genes (e.g., milk proteins and cell-cycle genes), and newly classified lactating mammary gland TFs (e.g., Creb1, Arnt).
Conclusion TF-Prioritizer accepts ChIP-seq and RNA-seq data, as input and suggests TFs with differential activity, thus offering an understanding of genome-wide gene regulation, potential pathogenesis, and therapeutic targets in biomedical research.
Baumgarten, Nina ; Schmidt, Florian ; Wegner, Martin ; Hebel, Marie ; Kaulich, Manuel ; Schulz, Marcel Holger
Genome-wide CRISPR screens are becoming more widespread and allow the simultaneous interrogation of thousands of genomic regions. Although recent progress has been made in the analysis of CRISPR screens, it is still an open problem how to interpret CRISPR mutations in non-coding regions of the genome. Most of the tools concentrate on the interpretation of mutations introduced in gene coding regions. We introduce a computational pipeline that uses epigenomic information about regulatory elements for the interpretation of CRISPR mutations in non-coding regions. We illustrate our approach on the analysis of a genome-wide CRISPR screen in hTERT-RPE-1 cells and reveal novel regulatory elements that mediate chemoresistance against doxorubicin in these cells. We infer links to established and to novel chemoresistance genes. Our approach is general and can be applied on any cell type and with different CRISPR enzymes.
Wöckel, Achim ; Festl, Jasmin ; Stüber, Tanja ; Brust, Katharina ; Stangl, Stephanie ; Heuschmann, Peter Ulrich ; Albert, Ute Susann ; Budach, Wilfried ; Follmann, Markus ; Janni, Wolfgang ; Kopp, Ina ; Kreienberg, Rolf ; Kühn, Thorsten ; Langer, Thomas ; Nothacker, Monika ; Scharl, Anton ; Schreer, Ingrid ; Link, Hartmut ; Engel, Jutta ; Fehm, Tanja ; Weis, Joachim ; Welt, Anja ; Steckelberg, Anke ; Feyer, Petra ; König, Klaus ; Hahne, Andrea ; Kreipe, Hans H. ; Knoefel, Wolfram Trudo ; Denkinger, Michael ; Brucker, Sara ; Lüftner, Diana ; Kubisch, Christian ; Gerlach, Christina ; Lebeau, Annette ; Siedentopf, Friederike ; Petersen, Cordula ; Bartsch, Hans Helge ; Schulz-Wendtland, Rüdiger ; Hahn, Markus ; Hanf, Volker ; Müller-Schimpfle, Markus ; Henscher, Ulla ; Roncarati, Renza ; Katalinic, Alexander ; Heitmann, Christoph ; Honegger, Christoph ; Paradies, Kerstin ; Bjelic-Radisic, Vesna ; Degenhardt, Friedrich ; Wenz, Frederik ; Rick, Oliver ; Hölzel, Dieter ; Zaiss, Matthias ; Kemper, Gudrun ; Budach, Volker ; Denkert, Carsten Michael ; Gerber, Bernd ; Tesch, Hans ; Hirsmüller, Susanne ; Sinn, Hans-Peter ; Dunst, Jürgen ; Münstedt, Karsten ; Bick, Ulrich ; Fallenberg, Eva ; Tholen, Reina ; Hung, Roswita ; Baumann, Freerk T. ; Beckmann, Matthias Wilhelm ; Blohmer, Jens-Uwe ; Fasching, Peter Andreas ; Lux, Michael Patrick ; Harbeck, Nadia ; Hadji, Peyman ; Hauner, Hans ; Heywang-Köbrunner, Sylvia H. ; Huober, Jens ; Hübner, Jutta ; Jackisch, Christian ; Loibl, Sibylle ; Lück, Hans-Jürgen ; Minckwitz, Gunter von ; Möbus, Volker ; Müller, Volkmar ; Nöthlings, Ute ; Schmidt, Marcus ; Schmutzler, Rita Katharina ; Schneeweiss, Andreas ; Schütz, Florian ; Stickeler, Elmar ; Thomssen, Christoph ; Untch, Michael ; Wesselmann, Simone ; Bücker, Arno ; Krockenberger, Mathias Heinric
Ziele: Das Ziel dieser offiziellen Leitlinie, die von der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG) und der Deutschen Krebsgesellschaft (DKG) publiziert und koordiniert wurde, ist es, die Früherkennung, Diagnostik, Therapie und Nachsorge des Mammakarzinoms zu optimieren.
Methoden: Der Aktualisierungsprozess der S3-Leitlinie aus 2012 basierte zum einen auf der Adaptation identifizierter Quellleitlinien und zum anderen auf Evidenzübersichten, die nach Entwicklung von PICO-(Patients/Interventions/Control/Outcome-)Fragen, systematischer Recherche in Literaturdatenbanken sowie Selektion und Bewertung der gefundenen Literatur angefertigt wurden. In den interdisziplinären Arbeitsgruppen wurden auf dieser Grundlage Vorschläge für Empfehlungen und Statements erarbeitet, die im Rahmen von strukturierten Konsensusverfahren modifiziert und graduiert wurden.
Empfehlungen: Der Teil 1 dieser Kurzversion der Leitlinie zeigt Empfehlungen zur Früherkennung, Diagnostik und Nachsorge des Mammakarzinoms: Der Stellenwert des Mammografie-Screenings wird in der aktualisierten Leitlinienversion bestätigt und bildet damit die Grundlage der Früherkennung. Neben den konventionellen Methoden der Karzinomdiagnostik wird die Computertomografie (CT) zum Staging bei höherem Rückfallrisiko empfohlen. Die Nachsorgekonzepte beinhalten Untersuchungsintervalle für die körperliche Untersuchung, Ultraschall und Mammografie, während weiterführende Gerätediagnostik und Tumormarkerbestimmungen bei der metastasierten Erkrankung Anwendung finden.
Wöckel, Achim ; Festl, Jasmin ; Stüber, Tanja ; Brust, Katharina ; Stangl, Stephanie ; Heuschmann, Peter Ulrich ; Albert, Ute Susann ; Budach, Wilfried ; Follmann, Markus ; Janni, Wolfgang ; Kopp, Ina ; Kreienberg, Rolf ; Kühn, Thorsten ; Langer, Thomas ; Nothacker, Monika ; Scharl, Anton ; Schreer, Ingrid ; Link, Hartmut ; Engel, Jutta ; Fehm, Tanja ; Weis, Joachim ; Welt, Anja ; Steckelberg, Anke ; Feyer, Petra ; König, Klaus ; Hahne, Andrea ; Kreipe, Hans H. ; Knoefel, Wolfram Trudo ; Denkinger, Michael ; Brucker, Sara ; Lüftner, Diana ; Kubisch, Christian ; Gerlach, Christina ; Lebeau, Annette ; Siedentopf, Friederike ; Petersen, Cordula ; Bartsch, Hans Helge ; Schulz-Wendtland, Rüdiger ; Hahn, Markus ; Hanf, Volker ; Müller-Schimpfle, Markus ; Henscher, Ulla ; Roncarati, Renza ; Katalinic, Alexander ; Heitmann, Christoph ; Honegger, Christoph ; Paradies, Kerstin ; Bjelic-Radisic, Vesna ; Degenhardt, Friedrich ; Wenz, Frederik ; Rick, Oliver ; Hölzel, Dieter ; Zaiss, Matthias ; Kemper, Gudrun ; Budach, Volker ; Denkert, Carsten Michael ; Gerber, Bernd ; Tesch, Hans ; Hirsmüller, Susanne ; Sinn, Hans-Peter ; Dunst, Jürgen ; Münstedt, Karsten ; Bick, Ulrich ; Fallenberg, Eva ; Tholen, Reina ; Hung, Roswita ; Baumann, Freerk T. ; Beckmann, Matthias Wilhelm ; Blohmer, Jens-Uwe ; Fasching, Peter Andreas ; Lux, Michael Patrick ; Harbeck, Nadia ; Hadji, Peyman ; Hauner, Hans ; Heywang-Köbrunner, Sylvia H. ; Huober, Jens ; Hübner, Jutta ; Jackisch, Christian ; Loibl, Sibylle ; Lück, Hans-Jürgen ; Minckwitz, Gunter von ; Möbus, Volker ; Müller, Volkmar ; Nöthlings, Ute ; Schmidt, Marcus ; Schmutzler, Rita Katharina ; Schneeweiss, Andreas ; Schütz, Florian ; Stickeler, Elmar ; Thomssen, Christoph ; Untch, Michael ; Wesselmann, Simone ; Bücker, Arno ; Krockenberger, Mathias Heinric
Purpose: The aim of this official guideline coordinated and published by the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG) was to optimize the screening, diagnosis, therapy and follow-up care of breast cancer.
Methods: The process of updating the S3 guideline dating from 2012 was based on the adaptation of identified source guidelines which were combined with reviews of evidence compiled using PICO (Patients/Interventions/Control/Outcome) questions and the results of a systematic search of literature databases and the selection and evaluation of the identified literature. The interdisciplinary working groups took the identified materials as their starting point to develop recommendations and statements which were modified and graded in a structured consensus procedure.
Recommendations: Part 1 of this short version of the guideline presents recommendations for the screening, diagnosis and follow-up care of breast cancer. The importance of mammography for screening is confirmed in this updated version of the guideline and forms the basis for all screening. In addition to the conventional methods used to diagnose breast cancer, computed tomography (CT) is recommended for staging in women with a higher risk of recurrence. The follow-up concept includes suggested intervals between physical, ultrasound and mammography examinations, additional high-tech diagnostic procedures, and the determination of tumor markers for the evaluation of metastatic disease.
Activation of TRPC6 channels is essential for lung ischaemia–reperfusion induced oedema in mice
(2012)
Weißmann, Norbert ; Sydykov, Akylbek ; Kalwa, Hermann ; Storch, Ursula ; Fuchs, Beate ; Mederos y Schnitzler, Michael ; Brandes, Ralf ; Grimminger, Friedrich ; Meissner, Marcel ; Freichel, Marc ; Offermanns, Stefan ; Veit, Florian ; Pak, Oleg ; Krause, Karl-Heinz ; Schermuly, Ralph T. ; Brewer, Alison C. ; Schmidt, Harald H. H. W. ; Seeger, Werner ; Shah, Ajay M. ; Gudermann, Thomas ; Ghofrani, Hossein A. ; Dietrich, Alexander
Lung ischaemia–reperfusion-induced oedema (LIRE) is a life-threatening condition that causes pulmonary oedema induced by endothelial dysfunction. Here we show that lungs from mice lacking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2y/−) or the classical transient receptor potential channel 6 (TRPC6−/−) are protected from LIR-induced oedema (LIRE). Generation of chimeric mice by bone marrow cell transplantation and endothelial-specific Nox2 deletion showed that endothelial Nox2, but not leukocytic Nox2 or TRPC6, are responsible for LIRE. Lung endothelial cells from Nox2- or TRPC6-deficient mice showed attenuated ischaemia-induced Ca2+ influx, cellular shape changes and impaired barrier function. Production of reactive oxygen species was completely abolished in Nox2y/− cells. A novel mechanistic model comprising endothelial Nox2-derived production of superoxide, activation of phospholipase C-γ, inhibition of diacylglycerol (DAG) kinase, DAG-mediated activation of TRPC6 and ensuing LIRE is supported by pharmacological and molecular evidence. This mechanism highlights novel pharmacological targets for the treatment of LIRE.
Background Enhancers play a fundamental role in orchestrating cell state and development. Although several methods have been developed to identify enhancers, linking them to their target genes is still an open problem. Several theories have been proposed on the functional mechanisms of enhancers, which triggered the development of various methods to infer promoter enhancer interactions (PEIs). The advancement of high-throughput techniques describing the three-dimensional organisation of the chromatin, paved the way to pinpoint long-range PEIs. Here we investigated whether including PEIs in computational models for the prediction of gene expression improves performance and interpretability.
Results We have extended our Tepic framework to include DNA contacts deduced from chromatin conformation capture experiments and compared various methods to determine PEIs using predictive modelling of gene expression from chromatin accessibility data and predicted transcription factor (TF) motif data. We found that including long-range PEIs deduced from both HiC and HiChIP data indeed improves model performance. We designed a novel machine learning approach that allows to prioritize TFs in distal loop and promoter regions with respect to their importance for gene expression regulation. Our analysis revealed a set of core TFs that are part of enhancer-promoter loops involving YY1 in different cell lines.
Conclusion: We show that the integration of chromatin conformation data improves gene expression prediction, underlining the importance of enhancer looping for gene expression regulation. Our general approach can be used to prioritize TFs that are involved in distal and promoter-proximal regulation using accessibility, conformation and expression data.
Mosalaganti, Shyamal Narayan ; Obarska-Kosinska, Agnieszka ; Siggel, Marc ; Turoňová, Beata ; Zimmerli, Christian Eugen ; Buczak, Katarzyna ; Schmidt, Florian H. ; Margiotta, Erica ; Mackmull, Marie-Therese ; Hagen, Wim ; Hummer, Gerhard ; Beck, Martin ; Kosinski, Jan
Nuclear pore complexes (NPCs) mediate nucleocytoplasmic transport. Their intricate 120 MDa architecture remains incompletely understood. Here, we report a near-complete structural model of the human NPC scaffold with explicit membrane and in multiple conformational states. We combined AI-based structure prediction with in situ and in cellulo cryo-electron tomography and integrative modeling. We show that linker Nups spatially organize the scaffold within and across subcomplexes to establish the higher-order structure. Microsecond-long molecular dynamics simulations suggest that the scaffold is not required to stabilize the inner and outer nuclear membrane fusion, but rather widens the central pore. Our work exemplifies how AI-based modeling can be integrated with in situ structural biology to understand subcellular architecture across spatial organization levels.
An ontology-based method for assessing batch effect adjustment approaches in heterogeneous datasets
(2018)
Schmidt, Florian ; List, Markus ; Cukuroglu, Engin ; Köhler, Sebastian ; Göke, Jonathan ; Schulz, Marcel Holger
Motivation: International consortia such as the Genotype-Tissue Expression (GTEx) project, The Cancer Genome Atlas (TCGA) or the International Human Epigenetics Consortium (IHEC) have produced a wealth of genomic datasets with the goal of advancing our understanding of cell differentiation and disease mechanisms. However, utilizing all of these data effectively through integrative analysis is hampered by batch effects, large cell type heterogeneity and low replicate numbers. To study if batch effects across datasets can be observed and adjusted for, we analyze RNA-seq data of 215 samples from ENCODE, Roadmap, BLUEPRINT and DEEP as well as 1336 samples from GTEx and TCGA. While batch effects are a considerable issue, it is non-trivial to determine if batch adjustment leads to an improvement in data quality, especially in cases of low replicate numbers.
Results: We present a novel method for assessing the performance of batch effect adjustment methods on heterogeneous data. Our method borrows information from the Cell Ontology to establish if batch adjustment leads to a better agreement between observed pairwise similarity and similarity of cell types inferred from the ontology. A comparison of state-of-the art batch effect adjustment methods suggests that batch effects in heterogeneous datasets with low replicate numbers cannot be adequately adjusted. Better methods need to be developed, which can be assessed objectively in the framework presented here.
Several studies suggested that transcription factor (TF) binding to DNA may be impaired or enhanced by DNA methylation. We present MeDeMo, a toolbox for TF motif analysis that combines information about DNA methylation with models capturing intra-motif dependencies. In a large-scale study using ChIP-seq data for 335 TFs, we identify novel TFs that are affected by DNA methylation. Overall, we find that CpG methylation decreases the likelihood of binding for the majority of TFs. For a considerable subset of TFs, we show that intra-motif dependencies are pivotal for accurately modelling the impact of DNA methylation on TF binding.
Waitz, Markus ; Bello, Roger Y. ; Metz, Daniel ; Lower, Julian ; Trinter, Florian ; Schober, Carl ; Keiling, Marco ; Lenz, Ute ; Pitzer, Martin ; Mertens, Karolin ; Martins, Michael ; Viefhaus, Jens ; Klumpp, Stephan ; Weber, Thorsten ; Schmidt, Lothar ; Williams, Joshua B. ; Schöffler, Markus S. ; Serov, Vladislav V. ; Kheifets, Anatoli ; Argenti, Luca ; Palacios, Alicia ; Martín, Fernando ; Jahnke, Till ; Dörner, Reinhard
The toolbox for imaging molecules is well-equipped today. Some techniques visualize the geometrical structure, others the electron density or electron orbitals. Molecules are many-body systems for which the correlation between the constituents is decisive and the spatial and the momentum distribution of one electron depends on those of the other electrons and the nuclei. Such correlations have escaped direct observation by imaging techniques so far. Here, we implement an imaging scheme which visualizes correlations between electrons by coincident detection of the reaction fragments after high energy photofragmentation. With this technique, we examine the H2 two-electron wave function in which electron–electron correlation beyond the mean-field level is prominent. We visualize the dependence of the wave function on the internuclear distance. High energy photoelectrons are shown to be a powerful tool for molecular imaging. Our study paves the way for future time resolved correlation imaging at FELs and laser based X-ray sources.
Waitz, Markus ; Bello, Roger Y. ; Metz, Daniel ; Lower, Julian ; Trinter, Florian ; Schober, Carl ; Keiling, Marco ; Lenz, Ute ; Pitzer, Martin ; Mertens, Karolin ; Martins, Michael ; Viefhaus, Jens ; Klumpp, Stephan ; Weber, Thorsten ; Schmidt, Lothar ; Williams, Joshua B. ; Schöffler, Markus S. ; Serov, Vladislav V. ; Kheifets, Anatoli ; Argenti, Luca ; Palacios, Alicia ; Martín, Fernando ; Jahnke, Till ; Dörner, Reinhard
Rist, Jonas ; Klyssek, Kim ; Novikovskiy, Nikolay M. ; Kircher, Max ; Vela-Pérez, Isabel ; Trabert, Daniel ; Grundmann, Sven Eric ; Tsitsonis, Dimitrios ; Siebert, Juliane ; Geyer, Angelina ; Melzer, Niklas ; Schwarz, Christian ; Anders, Nils ; Kaiser, Leon ; Fehre, Kilian ; Hartung, Alexander ; Eckart, Sebastian Gereon ; Schmidt, Lothar ; Schöffler, Markus S. ; Davis, Vernon T. ; Williams, Joshua B. ; Trinter, Florian ; Dörner, Reinhard ; Demekhin, Philipp V. ; Jahnke, Till
How long does it take to emit an electron from an atom? This question has intrigued scientists for decades. As such emission times are in the attosecond regime, the advent of attosecond metrology using ultrashort and intense lasers has re-triggered strong interest on the topic from an experimental standpoint. Here, we present an approach to measure such emission delays, which does not require attosecond light pulses, and works without the presence of superimposed infrared laser fields. We instead extract the emission delay from the interference pattern generated as the emitted photoelectron is diffracted by the parent ion’s potential. Targeting core electrons in CO, we measured a 2d map of photoelectron emission delays in the molecular frame over a wide range of electron energies. The emission times depend drastically on the photoelectrons’ emission directions in the molecular frame and exhibit characteristic changes along the shape resonance of the molecule.
Schmidt, Florian ; Marx, Alexander ; Hebel, Marie ; Wegner, Martin ; Baumgarten, Nina ; Kaulich, Manuel ; Göke, Jonathan ; Vreeken, Jilles ; Schulz, Marcel Holger
Understanding the complexity of transcriptional regulation is a major goal of computational biology. Because experimental linkage of regulatory sites to genes is challenging, computational methods considering epigenomics data have been proposed to create tissue-specific regulatory maps. However, we showed that these approaches are not well suited to account for the variations of the regulatory landscape between cell-types. To overcome these drawbacks, we developed a new method called STITCHIT, that identifies and links putative regulatory sites to genes. Within STITCHIT, we consider the chromatin accessibility signal of all samples jointly to identify regions exhibiting a signal variation related to the expression of a distinct gene. STITCHIT outperforms previous approaches in various validation experiments and was used with a genome-wide CRISPR-Cas9 screen to prioritize novel doxorubicin-resistance genes and their associated non-coding regulatory regions. We believe that our work paves the way for a more refined understanding of transcriptional regulation at the gene-level.
Kennedy, Eamonn ; Vadlamani, Shashank ; Lindsey, Hannah M. ; Lei, Pui-Wa ; Jo-Pugh, Mary ; Adamson, Maheen ; Alda, Martin ; Alonso-Lana, Silvia ; Ambrogi, Sonia ; Anderson, Tim J. ; Arango, Celso ; Asarnow, Robert F. ; Avram, Mihai ; Ayesa-Arriola, Rosa ; Babikian, Talin ; Banaj, Nerisa ; Bird, Laura J. ; Borgwardt, Stefan ; Brodtmann, Amy ; Brosch, Katharina ; Caeyenberghs, Karen ; Calhoun, Vince D. ; Chiaravalloti, Nancy D. ; Cifu, David X. ; Crespo-Facorro, Benedicto ; Dalrymple-Alford, John C. ; Dams-O’Connor, Kristen ; Dannlowski, Udo ; Darby, David ; Davenport, Nicholas ; DeLuca, John ; Díaz-Caneja, Covadonga M. ; Disner, Seth G. ; Dobryakova, Ekaterina ; Ehrlich, Stefan ; Esopenko, Carrie ; Ferrarelli, Fabio ; Frank, Lea E. ; Franz, Carol ; Fuentes-Claramonte, Paola ; Genova, Helen ; Giza, Christopher C. ; Goltermann, Janik ; Grotegerd, Dominik ; Gruber, Marius ; Gutiérrez-Zotes, Alfonso ; Ha, Minji ; Haavik, Jan ; Hinkin, Charles ; Hoskinson, Kristen R. ; Hubl, Daniela ; Irimia, Andrei ; Jansen, Andreas ; Kaess, Michael ; Kang, Xiaojian ; Kenney, Kimbra ; Keřková, Barbora ; Khlif, Mohamed Salah ; Kim, Minah ; Kindler, Jochen ; Kircher, Tilo ; Knı́žková, Karolina ; Kolskår, Knut K. ; Krch, Denise ; Kremen, William S. ; Kuhn, Taylor ; Kumari, Veena ; Kwon, Jun Soo ; Langella, Roberto ; Laskowitz, Sarah ; Lee, Jungha ; Lengenfelder, Jean ; Liebel, Spencer W. ; Liou-Johnson, Victoria ; Lippa, Sara M. ; Løvstad, Marianne ; Lundervold, Astri ; Marotta, Cassandra ; Marquardt, Craig A. ; Mattos, Paulo ; Mayeli, Ahmad ; McDonald, Carrie R. ; Meinert, Susanne ; Melzer, Tracy R. ; Merchán Naranjo, Jessica ; Michel, Chantal ; Morey, Rajendra A. ; Mwangi, Benson ; Myall, Daniel J. ; Nenadić, Igor ; Newsome, Mary R. ; Nunes, Abraham ; O’Brien, Terence J. ; Oertel, Viola ; Ollinger, John ; Olsen, Alexander ; Ortiz Garcı́a de la Foz, Victor ; Ozmen, Mustafa ; Pardoe, Heath ; Parent, Marise ; Piras, Fabrizio ; Piras, Federica ; Pomarol-Clotet, Edith ; Repple, Jonathan ; Richard, Geneviève ; Rodriguez, Jonathan ; Rodriguez, Mabel ; Rootes-Murdy, Kelly ; Rowland, Jared ; Ryan, Nicholas P. ; Salvador, Raymond ; Sanders, Anne-Marthe ; Schmidt, André ; Soares, Jair C. ; Spalleta, Gianfranco ; Španiel, Filip ; Stasenko, Alena ; Stein, Frederike ; Straube, Benjamin ; Thames, April ; Thomas-Odenthal, Florian ; Thomopoulos, Sophia I. ; Tone, Erin ; Torres, Ivan ; Troyanskaya, Maya ; Turner, Jessica A. ; Ulrichsen, Kristine M. ; Umpierrez, Guillermo ; Vilella, Elisabet ; Vivash, Lucy ; Walker, William C. ; Werden, Emilio ; Westlye, Lars T. ; Wild, Krista ; Wroblewski, Adrian ; Wu, Mon-Ju ; Wylie, Glenn R. ; Yatham, Lakshmi N. ; Zunta-Soares, Giovana B. ; Thompson, Paul M. ; Tate, David F. ; Hillary, Frank G. ; Dennis, Emily L. ; Wilde, Elisabeth A.
Investigators in the cognitive neurosciences have turned to Big Data to address persistent replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. While there is tremendous potential to advance science through open data sharing, these efforts unveil a host of new questions about how to integrate data arising from distinct sources and instruments. We focus on the most frequently assessed area of cognition - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated raw data from 53 studies from around the world which measured at least one of three distinct verbal learning tasks, totaling N = 10,505 healthy and brain-injured individuals. A mega analysis was conducted using empirical bayes harmonization to isolate and remove site effects, followed by linear models which adjusted for common covariates. After corrections, a continuous item response theory (IRT) model estimated each individual subject’s latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance by 37% while preserving covariate effects. The effects of age, sex, and education on scores were found to be highly consistent across memory tests. IRT methods for equating scores across AVLTs agreed with held-out data of dually-administered tests, and these tools are made available for free online. This work demonstrates that large-scale data sharing and harmonization initiatives can offer opportunities to address reproducibility and integration challenges across the behavioral sciences.
Slik, J. W. Ferry ; Franklin, Janet ; Arroyo-Rodríguez, Víctor ; Field, Richard ; Aguilar, Salomon ; Aguirre, Nikolay ; Ahumada, Jorge ; Aiba, Shin-Ichiro ; Alves, Luciana F. ; Anitha, Kamalakumari ; Avella, Andres ; Mora, Francisco ; Aymard, Gerardo A. ; Báez, Selene ; Balvanera, Patricia ; Bastian, Meredith L. ; Bastin, Jean-François ; Bellingham, Peter ; van den Berg, Eduardo ; da Conceição Bispo, Polyanna ; Boeckx, Pascal ; Böhning-Gaese, Katrin ; Bongers, Frans ; Boyle, Brad ; Brambach, Fabian ; Brearley, Francis Q. ; Brown, Sandra ; Chai, Shauna-Lee ; Chazdon, Robin L. ; Chen, Shengbin ; Chhang, Phourin ; Chuyong, George ; Ewangog, Corneille ; Coronado, Indiana ; Cristóbal-Azkarate, Jurgi ; Culmsee, Heike ; Damas, Kipiro ; Dattaraja, Handanakere Shivaramaiah ; Davidar, Priya ; DeWalt, Saara J. ; Din, Hazimah ; Drake, Donald R. ; Duque, Alvaro ; Durigan, Giselda ; Eichhorn, Karl ; Schmidt Eler, Eduardo ; Enoki, Tsutomu ; Ensslin, Andreas ; Fandohan, Adandé Belarmain ; Farwig, Nina ; Feeley, Kenneth J. ; Fischer, Markus ; Forshed, Olle ; Garcia, Queila Souza ; Garkoti, Satish Chandra ; Gillespie, Thomas William ; Gillet, Jean-Francois ; Gonmadje, Christelle ; Granzow-de la Cerda, Iñigo ; Griffith, Daniel M. ; Grogan, James ; Hakeem, Khalid Rehman ; Harris, David J. ; Harrison, Rhett D. ; Hector, Andy ; Hemp, Andreas ; Homeier, Jürgen ; Hussain, M. Shah ; Ibarra Manríquez, Guillermo ; Hanum, I. Faridah ; Imai, Nobuo ; Jansen, Patrick A. ; Joly, Carlos Alfredo ; Joseph, Shijo ; Kartawinata, Kuswata ; Kearsley, Elizabeth ; Kelly, Daniel L. ; Kessler, Michael ; Killeen, Timothy J. ; Kooyman, Robert ; Laumonier, Yves ; Laurance, Susan G. ; Laurance, William F. ; Lawes, Michael J. ; Letcher, Susan G. ; Lindsell, Jeremy ; Lovett, Jon ; Lozada, Jose ; Lu, Xinghui ; Lykke, Anne Mette ; Bin Mahmud, Khairil ; Mahayani, Ni Putu Diana ; Mansor, Asyraf ; Marshall, Andrew R. ; Martin, Emanuel H. ; Leal Matos, Darley Calderado ; Meave, Jorge A. ; Melo, Felipe P. L. ; Aguirre Mendoza, Zhofre ; Metali, Faizah ; Medjibe, Vincent P. ; Metzger, Jean Paul ; Metzker, Thiago ; Mohandass, Dharmalingam ; Munguía-Rosas, Miguel A. ; Muñoz, Rodrigo ; Nurtjahy, Eddy ; Lenza de Oliveira, Eddie ; Onrizal, Onrizal ; Parolin, Pia ; Parren, Marc ; Parthasarathy, Narayanaswamy ; Paudel, Ekananda ; Perez, Rolando ; Pérez-García, Eduardo A. ; Pommer, Ulf ; Poorter, Lourens ; Qi, Lan ; F. Piedade, Maria Teresa ; Rodrigues Pinto, José Roberto ; Dalberg Poulsen, Axel ; Poulsen, John R. ; Powers, Jennifer S. ; Prasad, Rama Chandra ; Puyravaud, Jean-Philippe ; Rangel, Orlando ; Reitsma, Jan ; S. B. Rocha, Diogo ; Rolim, Samir ; Rovero, Francesco ; Rozak, Andes ; Ruokolainen, Kalle ; Rutishauser, Ervan ; Rutten, Gemma ; Mohd. Said, Mohd. Nizam ; Saiter, Felipe Z. ; Saner, Philippe ; Santos, Braulio ; dos Santos, João Roberto ; Sarker, Swapan Kumar ; Schmitt, Christine B. ; Schöngart, Jochen ; Schulze, Mark ; Sheil, Douglas ; Sist, Plinio ; Souza, Alexandre F. ; Spironello, Wilson Roberto ; Sposito, Tereza ; Steinmetz, Robert ; Stevart, Tariq ; Suganuma, Marcio Seiji ; Sukri, Rahayu ; Sultana, Aisha ; Sukumar, Raman ; Sunderland, Terry ; Supriyadi, Agus ; Suresh, Hebbalalu S. ; Suzuki, Eizi ; Tabarelli, Marcelo ; Tang, Jianwei ; Tanner, Edmund V. J. ; Targhetta, Natalia ; Theilade, Ida ; Thomas, Duncan ; Timberlake, Jonathan ; de Morisson Valeriano, Márcio ; Valkenburg, Johan van ; Do, Tran Van ; Sam, Hoang Van ; Vandermeer, John H. ; Verbeeck, Hans ; Vetaas, Ole Reidar ; Adekunle, Victor ; Vieira, Simone A. ; Webb, Campbell O. ; Webb, Edward L. ; Whitfeld, Timothy ; Wich, Serge ; Williams, John ; Wiser, Susan ; Wittmann, Florian ; Yang, Xiaobo ; Adou Yao, C. Yves ; Yap, Sandra L. ; Zahawie, Rakan A. ; Zakaria, Rahmad ; Zang, Runguo
Knowledge about the biogeographic affinities of the world’s tropical forests helps to better understand regional differences in forest structure, diversity, composition, and dynamics. Such understanding will enable anticipation of region-specific responses to global environmental change. Modern phylogenies, in combination with broad coverage of species inventory data, now allow for global biogeographic analyses that take species evolutionary distance into account. Here we present a classification of the world’s tropical forests based on their phylogenetic similarity. We identify five principal floristic regions and their floristic relationships: (i) Indo-Pacific, (ii) Subtropical, (iii) African, (iv) American, and (v) Dry forests. Our results do not support the traditional neo- versus paleotropical forest division but instead separate the combined American and African forests from their Indo-Pacific counterparts. We also find indications for the existence of a global dry forest region, with representatives in America, Africa, Madagascar, and India. Additionally, a northern-hemisphere Subtropical forest region was identified with representatives in Asia and America, providing support for a link between Asian and American northern-hemisphere forests.
Bocklitz, Thomas W. ; Salah, Firas Subhi ; Vogler, Nadine ; Heuke, Sandro ; Chernavskaia, Olga ; Schmidt, Carsten ; Waldner, Maximilian J. ; Greten, Florian ; Bräuer, Rolf ; Schmitt, Michael ; Stallmach, Andreas ; Petersen, Iver ; Popp, Jürgen
Background: Due to the steadily increasing number of cancer patients worldwide the early diagnosis and treatment of cancer is a major field of research. The diagnosis of cancer is mostly performed by an experienced pathologist via the visual inspection of histo-pathological stained tissue sections. To save valuable time, low quality cryosections are frequently analyzed with diagnostic accuracies that are below those of high quality embedded tissue sections. Thus, alternative means have to be found that enable for fast and accurate diagnosis as the basis of following clinical decision making.
Methods: In this contribution we will show that the combination of the three label-free non-linear imaging modalities CARS (coherent anti-Stokes Raman-scattering), TPEF (two-photon excited autofluorescence) and SHG (second harmonic generation) yields information that can be translated into computational hematoxylin and eosin (HE) images by multivariate statistics. Thereby, a computational HE stain is generated resulting in pseudo-HE overview images that allow for identification of suspicious regions. The latter are analyzed further by Raman-spectroscopy retrieving the tissue’s molecular fingerprint.
Results: The results suggest that the combination of non-linear multimodal imaging and Raman-spectroscopy possesses the potential as a precise and fast tool in routine histopathology.
Conclusions: As the key advantage, both optical methods are non-invasive enabling for further pathological investigations of the same tissue section, e.g. a direct comparison with the current pathological gold-standard.
Schmidt, Katrin G. ; Herrero San Juan, Martina ; Trautmann, Sandra ; Berninger, Lucija ; Schwiebs, Anja ; Ottenlinger, Florian ; Thomas, Dominique Jeanette ; Zaucke, Frank ; Pfeilschifter, Josef ; Radeke, Heinfried H.
Systemic sclerosis (SSc) is a rare multi-organ autoimmune disease characterized by progressive skin fibrosis. Inflammation, type 2 immunity, and fibrogenic processes are involved in disease development and may be affected by sphingolipids. However, details about early-stage pathophysiological mechanisms and implicated mediators remain elusive. The sphingolipid sphingosine-1-phosphate (S1P) is elevated in the sera of SSc patients, and its receptor S1P5 is expressed in skin tissue. Nevertheless, almost nothing is known about the dermatological contribution of S1P5 to inflammatory and pro-fibrotic processes leading to the pathological changes seen in SSc. In this study, we observed a novel effect of S1P5 on the inflammatory processes during low-dose bleomycin (BLM)-induced fibrogenesis in murine skin. By comparing 2-week-treated skin areas of wild-type (WT) and S1P5-deficient mice, we found that S1P5 is important for the transcriptional upregulation of the Th2 characteristic transcription factor GATA-3 under treatment-induced inflammatory conditions, while T-bet (Th1) and FoxP3 (Treg) mRNA expression was regulated independently of S1P5. Additionally, treatment caused a regulation of S1P receptor 1 and S1P receptor 3 mRNA as well as a regulation of long-chain ceramide profiles, which both differ significantly between the genotypes. Despite S1P5-dependent differences regarding inflammatory processes, similar macroscopic evidence of fibrosis was detected in the skin histology of WT and S1P5-deficient mice after 4 weeks of subcutaneous BLM treatment. However, at the earlier 2-week point in time, the mRNA data of pro-collagen type 1 and SMAD7 indicate a pro-fibrotic S1P5 contribution in the applied SSc mouse model. In conclusion, we propose that S1P5 plays a role as a novel modulator during the early phase of BLM-caused fibrogenesis in murine skin. An immediate relationship between dermal S1P5 expression and fibrotic processes leading to skin alterations, such as formative for SSc pathogenesis, is indicated but should be studied more profound in further investigations. Therefore, this study is an initial step in understanding the role of S1P5-mediated effects during early stages of fibrogenesis, which may encourage the ongoing search for new therapeutic options for SSc patients.
Schmidt, Florian ; Marx, Alexander ; Baumgarten, Nina ; Hebel, Marie ; Wegner, Martin ; Kaulich, Manuel ; Leisegang, Matthias ; Brandes, Ralf ; Göke, Jonathan ; Vreeken, Jilles ; Schulz, Marcel Holger
Understanding how epigenetic variation in non-coding regions is involved in distal gene-expression regulation is an important problem. Regulatory regions can be associated to genes using large-scale datasets of epigenetic and expression data. However, for regions of complex epigenomic signals and enhancers that regulate many genes, it is difficult to understand these associations. We present StitchIt, an approach to dissect epigenetic variation in a gene-specific manner for the detection of regulatory elements (REMs) without relying on peak calls in individual samples. StitchIt segments epigenetic signal tracks over many samples to generate the location and the target genes of a REM simultaneously. We show that this approach leads to a more accurate and refined REM detection compared to standard methods even on heterogeneous datasets, which are challenging to model. Also, StitchIt REMs are highly enriched in experimentally determined chromatin interactions and expression quantitative trait loci. We validated several newly predicted REMs using CRISPR-Cas9 experiments, thereby demonstrating the reliability of StitchIt. StitchIt is able to dissect regulation in superenhancers and predicts thousands of putative REMs that go unnoticed using peak-based approaches suggesting that a large part of the regulome might be uncharted water.
Pati, Sarthak ; Baid, Ujjwal ; Edwards, Brandon ; Sheller, Micah ; Wang, Shih-Han ; Reina, G. Anthony ; Foley, Patrick ; Gruzdev, Alexey ; Karkada, Deepthi ; Davatzikos, Christos ; Sako, Chiharu ; Ghodasara, Satyam ; Bilello, Michel ; Mohan, Suyash ; Vollmuth, Philipp ; Brugnara, Gianluca ; Jayachandran Preetha, Chandrakanth ; Sahm, Felix ; Maier-Hein, Klaus ; Zenk, Maximilian ; Bendszus, Martin ; Wick, Wolfgang ; Calabrese, Evan ; Rudie, Jeffrey ; Villanueva-Meyer, Javier ; Cha, Soonmee ; Ingalhalikar, Madhura ; Jadhav, Manali ; Pandey, Umang ; Saini, Jitender ; Garrett, John ; Larson, Matthew ; Jeraj, Robert ; Currie, Stuart ; Frood, Russell ; Fatania, Kavi ; Huang, Raymond Y. ; Chang, Ken ; Balaña, Carmen ; Capellades, Jaume ; Puig, Josep ; Trenkler, Johannes ; Pichler, Josef ; Necker, Georg ; Haunschmidt, Andreas ; Meckel, Stephan ; Shukla, Gaurav ; Liem, Spencer ; Alexander, Gregory S. ; Lombardo, Joseph ; Palmer, Joshua D. ; Flanders, Adam E. ; Dicker, Adam P. ; Sair, Haris I. ; Jones, Craig K. ; Venkataraman, Archana ; Jiang, Meirui ; So, Tiffany Y. ; Chen, Cheng ; Heng, Pheng Ann ; Dou, Qi ; Kozubek, Michal ; Lux, Filip ; Michálek, Jan ; Matula, Petr ; Keřkovský, Miloš ; Kopřivová, Tereza ; Dostál, Marek ; Vybíhal, Václav ; Vogelbaum, Michael A. ; Mitchell, J. Ross ; Farinhas, Joaquim ; Maldjian, Joseph A. ; Bangalore Yogananda, Chandan Ganesh ; Pinho, Marco C. ; Reddy, Divya ; Holcomb, James ; Wagner, Benjamin C. ; Ellingson, Benjamin M. ; Cloughesy, Timothy F. ; Raymond, Catalina ; Oughourlian, Talia ; Hagiwara, Akifumi ; Wang, Chencai ; To, Minh-Son ; Bhardwaj, Sargam ; Chong, Chee ; Agzarian, Marc ; Falcão, Alexandre Xavier ; Martins, Samuel B. ; Teixeira, Bernardo Corrêa de Almeida ; Sprenger, Flávia ; Menotti, David ; Lucio, Diego R. ; LaMontagne, Pamela ; Marcus, Daniel ; Wiestler, Benedikt ; Kofler, Florian ; Ezhov, Ivan ; Metz, Marie ; Jain, Rajan ; Lee, Matthew ; Lui, Yvonne W. ; McKinley, Richard ; Slotboom, Johannes ; Radojewski, Piotr ; Meier, Raphael ; Wiest, Roland Gerhard Rudi ; Murcia, Derrick ; Fu, Eric ; Haas, Rourke ; Thompson, John ; Ormond, David Ryan ; Badve, Chaitra ; Sloan, Andrew E. ; Vadmal, Vachan ; Waite, Kristin ; Colen, Rivka R. ; Pei, Linmin ; Ak, Murat ; Srinivasan, Ashok ; Bapuraj, Jayapalli Rajiv ; Rao, Arvind ; Wang, Nicholas ; Yoshiaki, Ota ; Moritani, Toshio ; Turk, Sevcan ; Lee, Joonsang ; Prabhudesai, Snehal ; Morón, Fanny ; Mandel, Jacob ; Kamnitsas, Konstantinos ; Glocker, Ben ; Dixon, Luke V. M. ; Williams, Matthew ; Zampakis, Peter ; Panagiotopoulos, Vasileios ; Tsiganos, Panagiotis ; Alexiou, Sotiris ; Haliassos, Ilias ; Zacharaki, Evangelia I. ; Moustakas, Konstantinos ; Kalogeropoulou, Christina ; Kardamakis, Dimitrios M. ; Choi, Yoon Seong ; Lee, Seung-Koo ; Chang, Jong Hee ; Ahn, Sung Soo ; Luo, Bing ; Poisson, Laila ; Wen, Ning ; Tiwari, Pallavi ; Verma, Ruchika ; Bareja, Rohan ; Yadav, Ipsa ; Chen, Jonathan ; Kumar, Neeraj ; Smits, Marion ; Voort, Sebastian R. van der ; Alafandi, Ahmed ; Incekara, Fatih ; Wijnenga, Maarten M. J. ; Kapsas, Georgios ; Gahrmann, Renske ; Schouten, Joost W. ; Dubbink, Hendrikus J. ; Vincent, Arnaud J. P. E. ; Van den Bent, Martin J. ; French, Pim J. ; Klein, Stefan ; Yuan, Yading ; Sharma, Sonam ; Tseng, Tzu-Chi ; Adabi, Saba ; Niclou, Simone P. ; Keunen, Olivier ; Hau, Ann-Christin ; Vallières, Martin ; Fortin, David ; Lepage, Martin ; Landman, Bennett ; Ramadass, Karthik ; Xu, Kaiwen ; Chotai, Silky ; Chambless, Lola B. ; Mistry, Akshitkumar ; Thompson, Reid C. ; Gusev, Yuriy ; Bhuvaneshwar, Krithika ; Sayah, Anousheh ; Bencheqroun, Camelia ; Belouali, Anas ; Madhavan, Subha ; Booth, Thomas C. ; Chelliah, Alysha ; Modat, Marc ; Shuaib, Haris ; Dragos, Carmen ; Abayazeed, Aly ; Kolodziej, Kenneth ; Hill, Michael ; Abbassy, Ahmed ; Gamal, Shady ; Mekhaimar, Mahmoud ; Qayati, Mohamed ; Reyes, Mauricio ; Park, Ji Eun ; Yun, Jihye ; Kim, Ho Sung ; Mahajan, Abhishek ; Muzi, Mark ; Benson, Sean ; Beets-Tan, Regina G. H. ; Teuwen, Jonas ; Herrera-Trujillo, Alejandro ; Trujillo, Maria ; Escobar, William ; Abello, Ana Lorena ; Bernal, Jose ; Gómez, Jhon ; Choi, Joseph ; Baek, Stephen ; Kim, Yusung ; Ismael, Heba ; Allen, Bryan ; Buatti, John M. ; Kotrotsou, Aikaterini ; Li, Hongwei ; Weiss, Tobias ; Weller, Michael ; Bink, Andrea ; Pouymayou, Bertrand ; Shaykh, Hassan F. ; Saltz, Joel ; Prasanna, Prateek ; Shrestha, Sampurna ; Mani, Kartik M. ; Payne, David ; Kurc, Tahsin ; Pelaez, Enrique ; Franco-Maldonado, Heydy ; Loayza, Francis ; Quevedo Sacoto, Andrés Sebastián ; Guevara, Pamela ; Torche, Esteban ; Mendoza, Cristobal ; Vera, Franco ; Ríos, Elvis ; López, Eduardo ; Velastin, Sergio Alejandro ; Ogbole, Godwin ; Soneye, Mayowa ; Oyekunle, Dotun ; Odafe-Oyibotha, Olubunmi ; Osobu, Babatunde ; Shu’aibu, Mustapha ; Dorcas, Adeleye ; Dako, Farouk ; Simpson, Amber L. ; Hamghalam, Mohammad ; Peoples, Jacob J. ; Hu, Ricky ; Tran, Anh ; Cutler, Danielle ; Moraes, Fabio Y. ; Boss, Michael A. ; Gimpel, James ; Kattil Veettil, Deepak ; Schmidt, Kendall ; Bialecki, Brian ; Marella, Sailaja ; Price, Cynthia ; Cimino, Lisa ; Apgar, Charles ; Shah, Prashant ; Menze, Bjoern Holger ; Barnholtz-Sloan, Jill S. ; Martin, Jason ; Bakas, Spyridon
Pati, Sarthak ; Baid, Ujjwal ; Edwards, Brandon ; Sheller, Micah ; Wang, Shih-Han ; Reina, G. Anthony ; Foley, Patrick ; Gruzdev, Alexey ; Karkada, Deepthi ; Davatzikos, Christos ; Sako, Chiharu ; Ghodasara, Satyam ; Bilello, Michel ; Mohan, Suyash ; Vollmuth, Philipp ; Brugnara, Gianluca ; Jayachandran Preetha, Chandrakanth ; Sahm, Felix ; Maier-Hein, Klaus ; Zenk, Maximilian ; Bendszus, Martin ; Wick, Wolfgang ; Calabrese, Evan ; Rudie, Jeffrey ; Villanueva-Meyer, Javier ; Cha, Soonmee ; Ingalhalikar, Madhura ; Jadhav, Manali ; Pandey, Umang ; Saini, Jitender ; Garrett, John ; Larson, Matthew ; Jeraj, Robert ; Currie, Stuart ; Frood, Russell ; Fatania, Kavi ; Huang, Raymond Y. ; Chang, Ken ; Balaña, Carmen ; Capellades, Jaume ; Puig, Josep ; Trenkler, Johannes ; Pichler, Josef ; Necker, Georg ; Haunschmidt, Andreas ; Meckel, Stephan ; Shukla, Gaurav ; Liem, Spencer ; Alexander, Gregory S. ; Lombardo, Joseph ; Palmer, Joshua D. ; Flanders, Adam E. ; Dicker, Adam P. ; Sair, Haris I. ; Jones, Craig K. ; Venkataraman, Archana ; Jiang, Meirui ; So, Tiffany Y. ; Chen, Cheng ; Heng, Pheng Ann ; Dou, Qi ; Kozubek, Michal ; Lux, Filip ; Michálek, Jan ; Matula, Petr ; Keřkovský, Miloš ; Kopřivová, Tereza ; Dostál, Marek ; Vybíhal, Václav ; Vogelbaum, Michael A. ; Mitchell, J. Ross ; Farinhas, Joaquim ; Maldjian, Joseph A. ; Bangalore Yogananda, Chandan Ganesh ; Pinho, Marco C. ; Reddy, Divya ; Holcomb, James ; Wagner, Benjamin C. ; Ellingson, Benjamin M. ; Cloughesy, Timothy F. ; Raymond, Catalina ; Oughourlian, Talia ; Hagiwara, Akifumi ; Wang, Chencai ; To, Minh-Son ; Bhardwaj, Sargam ; Chong, Chee ; Agzarian, Marc ; Falcão, Alexandre Xavier ; Martins, Samuel B. ; Teixeira, Bernardo Corrêa de Almeida ; Sprenger, Flávia ; Menotti, David ; Lucio, Diego R. ; LaMontagne, Pamela ; Marcus, Daniel ; Wiestler, Benedikt ; Kofler, Florian ; Ezhov, Ivan ; Metz, Marie ; Jain, Rajan ; Lee, Matthew ; Lui, Yvonne W. ; McKinley, Richard ; Slotboom, Johannes ; Radojewski, Piotr ; Meier, Raphael ; Wiest, Roland Gerhard Rudi ; Murcia, Derrick ; Fu, Eric ; Haas, Rourke ; Thompson, John ; Ormond, David Ryan ; Badve, Chaitra ; Sloan, Andrew E. ; Vadmal, Vachan ; Waite, Kristin ; Colen, Rivka R. ; Pei, Linmin ; Ak, Murat ; Srinivasan, Ashok ; Bapuraj, Jayapalli Rajiv ; Rao, Arvind ; Wang, Nicholas ; Yoshiaki, Ota ; Moritani, Toshio ; Turk, Sevcan ; Lee, Joonsang ; Prabhudesai, Snehal ; Morón, Fanny ; Mandel, Jacob ; Kamnitsas, Konstantinos ; Glocker, Ben ; Dixon, Luke V. M. ; Williams, Matthew ; Zampakis, Peter ; Panagiotopoulos, Vasileios ; Tsiganos, Panagiotis ; Alexiou, Sotiris ; Haliassos, Ilias ; Zacharaki, Evangelia I. ; Moustakas, Konstantinos ; Kalogeropoulou, Christina ; Kardamakis, Dimitrios M. ; Choi, Yoon Seong ; Lee, Seung-Koo ; Chang, Jong Hee ; Ahn, Sung Soo ; Luo, Bing ; Poisson, Laila ; Wen, Ning ; Tiwari, Pallavi ; Verma, Ruchika ; Bareja, Rohan ; Yadav, Ipsa ; Chen, Jonathan ; Kumar, Neeraj ; Smits, Marion ; Voort, Sebastian R. van der ; Alafandi, Ahmed ; Incekara, Fatih ; Wijnenga, Maarten M. J. ; Kapsas, Georgios ; Gahrmann, Renske ; Schouten, Joost W. ; Dubbink, Hendrikus J. ; Vincent, Arnaud J. P. E. ; Van den Bent, Martin J. ; French, Pim J. ; Klein, Stefan ; Yuan, Yading ; Sharma, Sonam ; Tseng, Tzu-Chi ; Adabi, Saba ; Niclou, Simone P. ; Keunen, Olivier ; Hau, Ann-Christin ; Vallières, Martin ; Fortin, David ; Lepage, Martin ; Landman, Bennett ; Ramadass, Karthik ; Xu, Kaiwen ; Chotai, Silky ; Chambless, Lola B. ; Mistry, Akshitkumar ; Thompson, Reid C. ; Gusev, Yuriy ; Bhuvaneshwar, Krithika ; Sayah, Anousheh ; Bencheqroun, Camelia ; Belouali, Anas ; Madhavan, Subha ; Booth, Thomas C. ; Chelliah, Alysha ; Modat, Marc ; Shuaib, Haris ; Dragos, Carmen ; Abayazeed, Aly ; Kolodziej, Kenneth ; Hill, Michael ; Abbassy, Ahmed ; Gamal, Shady ; Mekhaimar, Mahmoud ; Qayati, Mohamed ; Reyes, Mauricio ; Park, Ji Eun ; Yun, Jihye ; Kim, Ho Sung ; Mahajan, Abhishek ; Muzi, Mark ; Benson, Sean ; Beets-Tan, Regina G. H. ; Teuwen, Jonas ; Herrera-Trujillo, Alejandro ; Trujillo, Maria ; Escobar, William ; Abello, Ana Lorena ; Bernal, Jose ; Gómez, Jhon ; Choi, Joseph ; Baek, Stephen ; Kim, Yusung ; Ismael, Heba ; Allen, Bryan ; Buatti, John M. ; Kotrotsou, Aikaterini ; Li, Hongwei ; Weiss, Tobias ; Weller, Michael ; Bink, Andrea ; Pouymayou, Bertrand ; Shaykh, Hassan F. ; Saltz, Joel ; Prasanna, Prateek ; Shrestha, Sampurna ; Mani, Kartik M. ; Payne, David ; Kurc, Tahsin ; Pelaez, Enrique ; Franco-Maldonado, Heydy ; Loayza, Francis ; Quevedo Sacoto, Andrés Sebastián ; Guevara, Pamela ; Torche, Esteban ; Mendoza, Cristobal ; Vera, Franco ; Ríos, Elvis ; López, Eduardo ; Velastin, Sergio Alejandro ; Ogbole, Godwin ; Soneye, Mayowa ; Oyekunle, Dotun ; Odafe-Oyibotha, Olubunmi ; Osobu, Babatunde ; Shu’aibu, Mustapha ; Dorcas, Adeleye ; Dako, Farouk ; Simpson, Amber L. ; Hamghalam, Mohammad ; Peoples, Jacob J. ; Hu, Ricky ; Tran, Anh ; Cutler, Danielle ; Moraes, Fabio Y. ; Boss, Michael A. ; Gimpel, James ; Kattil Veettil, Deepak ; Schmidt, Kendall ; Bialecki, Brian ; Marella, Sailaja ; Price, Cynthia ; Cimino, Lisa ; Apgar, Charles ; Shah, Prashant ; Menze, Bjoern Holger ; Barnholtz-Sloan, Jill S. ; Martin, Jason ; Bakas, Spyridon