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1. Structural basis for sequestration and autoinhibition of cGAS by chromatin

Author

Michalski, Sebastian, de Oliveira Mann, Carina C., Stafford, Che A., Witte, Gregor, Bartho, Joseph, Lammens, Katja, Hornung, Veit, and Hopfner, Karl-Peter

Subjects
Chromatin -- Physiological aspects -- Structure, Transferases -- Physiological aspects -- Structure, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Cyclic GMP-AMP synthase (cGAS) is an innate immune sensor for cytosolic microbial DNA.sup.1. After binding DNA, cGAS synthesizes the messenger 2'3'-cyclic GMP-AMP (cGAMP).sup.2-4, which triggers cell-autonomous defence and the production of type I interferons and pro-inflammatory cytokines via the activation of STING.sup.5. In addition to responding to cytosolic microbial DNA, cGAS also recognizes mislocalized cytosolic self-DNA and has been implicated in autoimmunity and sterile inflammation.sup.6,7. Specificity towards pathogen- or damage-associated DNA was thought to be caused by cytosolic confinement. However, recent findings place cGAS robustly in the nucleus.sup.8-10, where tight tethering of chromatin is important to prevent autoreactivity to self-DNA.sup.8. Here we show how cGAS is sequestered and inhibited by chromatin. We provide a cryo-electron microscopy structure of the cGAS catalytic domain bound to a nucleosome, which shows that cGAS does not interact with the nucleosomal DNA, but instead interacts with histone 2A-histone 2B, and is tightly anchored to the 'acidic patch'. The interaction buries the cGAS DNA-binding site B, and blocks the formation of active cGAS dimers. The acidic patch robustly outcompetes agonistic DNA for binding to cGAS, which suggests that nucleosome sequestration can efficiently inhibit cGAS, even when accessible DNA is nearby, such as in actively transcribed genomic regions. Our results show how nuclear cGAS is sequestered by chromatin and provides a mechanism for preventing autoreactivity to nuclear self-DNA. Biochemical and structural analyses show how tethering of the nucleotidyltransferase cGAS to chromatin prevents autoimmune recognition of nuclear DNA., Author(s): Sebastian Michalski [sup.1] [sup.2] , Carina C. de Oliveira Mann [sup.1] [sup.2] , Che A. Stafford [sup.1] [sup.2] , Gregor Witte [sup.1] [sup.2] , Joseph Bartho [sup.1] [sup.2] , [...]

Published
2020
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2. DNA-sensing inflammasomes cause recurrent atherosclerotic stroke

Author

Cao, Jiayu, Roth, Stefan, Zhang, Sijia, Kopczak, Anna, Mami, Samira, Asare, Yaw, Georgakis, Marios K., Messerer, Denise, Horn, Amit, Shemer, Ruth, Jacqmarcq, Charlene, Picot, Audrey, Green, Jack P., Schlegl, Christina, Li, Xinghai, Tomas, Lukas, Dutsch, Alexander, Liman, Thomas G., Endres, Matthias, Wernsdorf, Saskia R., Fürle, Christina, Carofiglio, Olga, Zhu, Jie, Brough, David, Hornung, Veit, Dichgans, Martin, Vivien, Denis, Schulz, Christian, Dor, Yuval, Tiedt, Steffen, Sager, Hendrik B., Grosse, Gerrit M., and Liesz, Arthur

Abstract

The risk of early recurrent events after stroke remains high despite currently established secondary prevention strategies1. Risk is particularly high in patients with atherosclerosis, with more than 10% of patients experiencing early recurrent events1,2. However, despite the enormous medical burden of this clinical phenomenon, the underlying mechanisms leading to increased vascular risk and recurrent stroke are largely unknown. Here, using a novel mouse model of stroke-induced recurrent ischaemia, we show that stroke leads to activation of the AIM2 inflammasome in vulnerable atherosclerotic plaques via an increase of circulating cell-free DNA. Enhanced plaque inflammation post-stroke results in plaque destabilization and atherothrombosis, finally leading to arterioarterial embolism and recurrent stroke within days after the index stroke. We confirm key steps of plaque destabilization also after experimental myocardial infarction and in carotid artery plaque samples from patients with acute stroke. Rapid neutrophil NETosis was identified as the main source of cell-free DNA after stroke and NET–DNA as the causative agent leading to AIM2 inflammasome activation. Neutralization of cell-free DNA by DNase treatment or inhibition of inflammasome activation reduced the rate of stroke recurrence after experimental stroke. Our findings present an explanation for the high recurrence rate after incident ischaemic events in patients with atherosclerosis. The detailed mechanisms uncovered here provide clinically uncharted therapeutic targets for which we show high efficacy to prevent recurrent events. Targeting DNA-mediated inflammasome activation after remote tissue injury represents a promising avenue for further clinical development in the prevention of early recurrent events.

Published
2024
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3. Unveiling the strong interaction among hadrons at the LHC

Author

Acharya, Shreyasi, Adamova, Dagmar, Ahn, Sang Un, Bhattacharjee, Buddhadeb, Yurchenko, Volodymyr, Zaccolo, Valentina, Zaman, Ali, Zampolli, Chiara, Correia Zanoli, Henrique Jose, Zardoshti, Nima, Zarochentsev, Andrey, Zavada, Petr, Zavyalov, Nikolay, Zbroszczyk, Hanna Paulina, Bianchi, Antonio, Zhalov, Mikhail, Zhang, Song, Zhang, Xiaoming, Zhang, Zuman, Zherebchevskii, Vladimir, Yu, Zhi, Zhou, Daicui, Zhou, You, Zhou, Zhuo, Zhu, Jianhui, Bianchi, Livio, Zhu, Ya, Zichichi, Antonino, Zinovjev, Gennady, Zurlo, Nicola, ALICE Collaboration, Bianchi, Nicola, Bielcik, Jaroslav, Bielcikova, Jana, Bilandzic, Ante, Biro, Gabor, Biswas, Rathijit, Biswas, Saikat, Akbar, Zaenal, Blair, Justin Thomas, Blau, Dmitry, Blume, Christoph, Boca, Gianluigi, Bock, Friederike, Bogdanov, Alexey, Boi, Stefano, Bok, Jeongsu, Boldizsar, Laszlo, Bolozdynya, Alexander, Akindinov, Alexander, Bombara, Marek, Bonomi, Germano, Borel, Herve, Borissov, Alexander, Bossi, Hannah, Botta, Elena, Bratrud, Lars, Braun-munzinger, Peter, Bregant, Marco, Broz, Michal, Al-turany, Mohammad, Bruna, Elena, Bruno, Giuseppe Eugenio, Buckland, Matthew Daniel, Budnikov, Dmitry, Buesching, Henner, Bufalino, Stefania, Bugnon, Ophelie, Buhler, Paul Alois, Buncic, Predrag, Buthelezi, Edith Zinhle, Alam, Sk Noor, Bashir Butt, Jamila, Bysiak, Sebastian Adam, Caffarri, Davide, Caliva, Alberto, Calvo Villar, Ernesto, Mejia Camacho, Juan Manuel, Soto Camacho, Rabi, Camerini, Paolo, De Moraes Canedo, Fabio, Capon, Aaron Allan, Silva De Albuquerque, Danilo, Carnesecchi, Francesca, Caron, Robin Albert Andre, Castillo Castellanos, Javier Ernesto, Castro, Andrew John, Casula, Ester Anna Rita, Catalano, Fabio, Ceballos Sanchez, Cesar, Chakraborty, Pritam, Chandra, Sinjini, Chang, Wan, Aleksandrov, Dmitry, Chapeland, Sylvain, Chartier, Marielle, Chattopadhyay, Subhasis, Chattopadhyay, Sukalyan, Chauvin, Alex Henri Jean, Cheshkov, Cvetan Valeriev, Cheynis, Brigitte, Chibante Barroso, Vasco Miguel, Dobrigkeit Chinellato, David, Cho, Soyeon, Alessandro, Bruno, Chochula, Peter, Chowdhury, Tasnuva, Christakoglou, Panagiotis, Christensen, Christian Holm, Christiansen, Peter, Chujo, Tatsuya, Cicalo, Corrado, Cifarelli, Luisa, De Cilladi, Lorenzo, Cindolo, Federico, Alfanda, Haidar Mas'ud, Ciupek, Michael Rudolf, Clai, Giulia, Cleymans, Jean Willy Andre, Colamaria, Fabio Filippo, Colella, Domenico, Collu, Alberto, Colocci, Manuel, Concas, Matteo, Conesa Balbastre, Gustavo, Conesa Del Valle, Zaida, Alfaro Molina, Jose Ruben, Contin, Giacomo, Contreras Nuno, Jesus Guillermo, Cormier, Thomas Michael, Corrales Morales, Yasser, Cortese, Pietro, Cosentino, Mauro Rogerio, Costa, Filippo, Costanza, Susanna, Crochet, Philippe, Cuautle Flores, Eleazar, Adler, Alexander, Ali, Bushra, Cui, Pengyao, Cunqueiro Mendez, Leticia, Dabrowski, Daniel, Dahms, Torsten, Dainese, Andrea, Damas, Florian Paul Andre, Danisch, Meike Charlotte, Danu, Andrea, Das, Debasish, Das, Indranil, Ali, Yasir, Das, Prottay, Das, Prottoy, Das, Supriya, Dash, Ajay Kumar, Dash, Sadhana, De, Sudipan, De Caro, Annalisa, De Cataldo, Giacinto, De Cuveland, Jan, De Falco, Alessandro, Alici, Andrea, De Gruttola, Daniele, De Marco, Nora, De Pasquale, Salvatore, Deb, Suman, Franz Degenhardt, Hermann, Deja, Kamil Rafal, Deloff, Andrzej, Delsanto, Silvia, Deng, Wenjing, Dhankher, Preeti, Alizadehvandchali, Negin, Di Bari, Domenico, Di Mauro, Antonio, Arteche Diaz, Raul, Dietel, Thomas, Raisig, Pascal, Ding, Yanchun, Divia, Roberto, Dixit, Dhruv Utpalkumar, Djuvsland, Oeystein, Dmitrieva, Uliana, Alkin, Anton, Dobrin, Alexandru Florin, Donigus, Benjamin, Dordic, Olja, Dubey, Anand Kumar, Dubla, Andrea, Dudi, Sandeep, Mallick, Dukhishyam, Dupieux, Pascal, Ehlers Iii, Raymond James, Eikeland, Viljar Nilsen, Alme, Johan, Elia, Domenico, Erazmus, Barbara Ewa, Erhardt, Filip, Erokhin, Andrey, Ersdal, Magnus Rentsch, Espagnon, Bruno, Eulisse, Giulio, Evans, David, Evdokimov, Sergey, Fabbietti, Laura, Alt, Torsten, Faggin, Mattia, Faivre, Julien, Fan, Feng, Fantoni, Alessandra, Fasel, Markus, Fecchio, Pietro, Feliciello, Alessandro, Feofilov, Grigorii, Fernandez Tellez, Arturo, Ferrero, Andrea, Altenkamper, Lucas, Ferretti, Alessandro, Festanti, Andrea, Feuillard, Victor Jose Gaston, Figiel, Jan, Filchagin, Sergey, Finogeev, Dmitry, Fionda, Fiorella, Fiorenza, Gabriele, Flor, Fernando Antonio, Flores, Amanda Nicole, Altsybeev, Igor, Foertsch, Siegfried Valentin, Foka, Panagiota, Fokin, Sergey, Fragiacomo, Enrico, Frankenfeld, Ulrich Michael, Fuchs, Ulrich, Furget, Christophe, Furs, Artur, Fusco Girard, Mario, Gaardhoeje, Jens Joergen, Anaam, Mustafa, Gagliardi, Martino, Gago Medina, Alberto Martin, Gal, Arthur Willem Jean, Duarte Galvan, Carlos, Ganoti, Paraskevi, Garabatos Cuadrado, Jose, Alvarado Garcia, Jesus Ricardo, Garcia-solis, Edmundo Javier, Garg, Kunal, Gargiulo, Corrado, Adolfsson, Jonatan, Andrei, Cristian, Garibli, Aydan, Garner, Katharina, Gasik, Piotr Jan, Gauger, Erin Frances, De Leone Gay, Maria Beatriz, Germain, Marie, Ghosh, Jhuma, Ghosh, Premomoy, Ghosh, Sanjay Kumar, Giacalone, Marco, Andreou, Dimitra, Gianotti, Paola, Giubellino, Paolo, Giubilato, Piero, Glaenzer, Aude Marie Camille, Glassel, Peter, Gomez Ramirez, Andres, Gonzalez, Victor, Gonzalez Trueba, Laura Helena, Gorbunov, Sergey, Gorlich, Lidia Maria, Andronic, Anton, Goswami, Ankita, Gotovac, Sven, Grabski, Varlen, Graczykowski, Lukasz Kamil, Graham, Katie Leanne, Greiner, Leo Clifford, Grelli, Alessandro, Grigoras, Costin, Grigoryev, Vladislav, Grigoryan, Ara, Angeletti, Massimo, Grigoryan, Smbat, Groettvik, Ola Slettevoll, Grosa, Fabrizio, Grosse-oetringhaus, Jan Fiete, Grosso, Raffaele, Guernane, Rachid, Guittiere, Manuel, Gulbrandsen, Kristjan Herlache, Gunji, Taku, Gupta, Anik, Anguelov, Venelin, Gupta, Ramni, Bautista Guzman, Irais, Haake, Rudiger, Habib, Michael Karim, Hadjidakis, Cynthia Marie, Hamagaki, Hideki, Hamar, Gergoe, Hamid, Mohammed, Hannigan, Ryan Patrick, Haque, Md Rihan, Anson, Christopher Daniel, Harlenderova, Alena, Harris, John William, Harton, Austin Vincent, Hasenbichler, Jan Anton, Hassan, Hadi, Hassan, Qamar Ul, Hatzifotiadou, Despina, Hauer, Philip, Havener, Laura Brittany, Hayashi, Shinichi, Anticic, Tome, Heckel, Stefan Thomas, Hellbar, Ernst, Helstrup, Haavard, Herghelegiu, Andrei Ionut, Herman, Tomas, Gonzalez Hernandez, Emma, Herrera Corral, Gerardo Antonio, Herrmann, Florian, Hetland, Kristin Fanebust, Hillemanns, Hartmut, Antinori, Federico, Hills, Christopher, Hippolyte, Boris, Hohlweger, Bernhard, Honermann, Jan, Horak, David, Hornung, Andrea, Hornung, Sebastian, Hosokawa, Ritsuya, Hristov, Peter Zahariev, Huang, Chun-lu, Antonioli, Pietro, Hughes, Charles, Huhn, Patrick, Humanic, Thomas, Hushnud, Hushnud, Husova, Lucia Anna, Hussain, Nur, Hussain, Syed Asad, Hutter, Dirk, Iddon, James Philip, Ilkaev, Radiy, Apadula, Nicole, Ilyas, Hira, Inaba, Motoi, Innocenti, Gian Michele, Ippolitov, Mikhail, Isakov, Artem, Islam, Md Samsul, Ivanov, Marian, Ivanov, Vladimir, Izucheev, Vladimir, Jacak, Barbara, Aggarwal, Madan Mohan, Aphecetche, Laurent Bernard, Jacazio, Nicolo, Jacobs, Peter Martin, Jadlovska, Slavka, Jadlovsky, Jan, Jaelani, Syaefudin, Jahnke, Cristiane, Jakubowska, Monika Joanna, Janik, Malgorzata Anna, Janson, Thomas, Jercic, Marko, Appelshaeuser, Harald, Jevons, Oliver Thomas, Jin, Muqing, Jonas, Florian, Jones, Peter Graham, Jung, Jerome, Jung, Michael, Jusko, Anton, Kalinak, Peter, Kalweit, Alexander Philipp, Kaplin, Vladimir, Arcelli, Silvia, Kar, Somnath, Karasu Uysal, Ayben, Karatovic, David, Karavichev, Oleg, Karavicheva, Tatiana, Karczmarczyk, Przemyslaw, Karpechev, Evgeny, Kazantsev, Andrey, Kebschull, Udo Wolfgang, Keidel, Ralf, Arnaldi, Roberta, Keil, Markus, Ketzer, Bernhard Franz, Khabanova, Zhanna, Khan, Ahsan Mehmood, Khan, Shaista, Khanzadeev, Alexei, Kharlov, Yury, Khatun, Anisa, Khuntia, Arvind, Kileng, Bjarte, Arratia Munoz, Miguel Ignacio, Kim, Beomkyu, Kim, Byungchul, Kim, Daehyeok, Kim, Dong Jo, Kim, Eun Joo, Kim, Hyeonjoong, Kim, Jaehyun, Kim, Jinsook, Kim, Jiyoung, Kim, Jungeol, Arsene, Ionut Cristian, Kim, Junlee, Kim, Minjung, Kim, Se Yong, Kim, Taejun, Kim, Taesoo, Kirsch, Stefan, Kisel, Ivan, Kiselev, Sergey, Kisiel, Adam Ryszard, Klay, Jennifer Lynn, Arslandok, Mesut, Klein, Carsten, Klein, Jochen, Klein, Spencer Robert, Klein-boesing, Christian, Kleiner, Matthias, Kluge, Alexander, Knichel, Michael Linus, Knospe, Anders Garritt, Kobdaj, Chinorat, Kohler, Markus Konrad, Augustinus, Andre, Kollegger, Thorsten Sven, Kondratyev, Andrey, Kondratyeva, Natalia, Kondratyuk, Evgeny, Konig, Joshua Leon, Konigstorfer, Stephan Alexander, Konopka, Piotr Jan, Kornakov, Georgui, Koska, Lukas, Kovalenko, Oleksandr, Averbeck, Ralf Peter, Kovalenko, Vladimir, Kowalski, Marek, Kralik, Ivan, Kravcakova, Adela, Kreis, Lukas, Krivda, Marian, Krizek, Filip, Krizkova Gajdosova, Katarina, Kruger, Mario, Kryshen, Evgeny, Aziz, Sizar, Krzewicki, Mikolaj, Kubera, Andrew Michael, Kucera, Vit, Kuhn, Christian Claude, Kuijer, Paulus Gerardus, Kumar, Lokesh, Kundu, Sourav, Kurashvili, Podist, Kurepin, Alexander, Kurepin, Alexey, Aglieri Rinella, Gianluca, Azmi, Mohd Danish, Kuryakin, Alexey, Kushpil, Svetlana, Kvapil, Jakub, Kweon, Min Jung, Kwon, Jiyeon, Kwon, Youngil, La Pointe, Sarah Louise, La Rocca, Paola, Lai, Yue Shi, Lamanna, Massimo, Badala, Angela, Langoy, Rune, Lapidus, Kirill, Lardeux, Antoine Xavier, Larionov, Pavel, Laudi, Elisa, Lavicka, Roman, Lazareva, Tatiana, Lea, Ramona, Leardini, Lucia, Lee, Joonil, Baek, Yongwook, Lee, Seongjoo, Lehner, Sebastian, Lehrbach, Johannes, Lemmon, Roy Crawford, Leon Monzon, Ildefonso, Lesser, Ezra Douglas, Lettrich, Michael, Levai, Peter, Li, Xiaomei, Li, Xing Long, Bagnasco, Stefano, Lien, Jorgen Andre, Lietava, Roman, Lim, Bong-hwi, Lindenstruth, Volker, Lindner, Amelia, Lippmann, Christian, Lisa, Michael Annan, Liu, Alwina Ruixin, Liu, Jian, Liu, Suyuan, Bai, Xiaozhi, Llope, William Joseph, Lofnes, Ingrid Mckibben, Loginov, Vitaly, Loizides, Constantinos, Loncar, Petra, Lopez Lopez, Jorge Andres, Lopez, Xavier Bernard, Lopez Torres, Ernesto, Luhder, Jens Robert, Lunardon, Marcello, Bailhache, Raphaelle Marie, Luparello, Grazia, Ma, Yugang, Maevskaya, Alla, Mager, Magnus, Mahmood, Sohail Musa, Mahmoud, Tariq, Maire, Antonin, Majka, Richard Daniel, Malaev, Mikhail, Malik, Qasim Waheed, Bala, Renu, Malinina, Liudmila, Mal Kevich, Dmitry, Malzacher, Peter, Mandaglio, Giuseppe, Manko, Vladislav, Manso, Franck, Manzari, Vito, Mao, Yaxian, Marchisone, Massimiliano, Mares, Jiri, Balbino, Alessandro, Margagliotti, Giacomo Vito, Margotti, Anselmo, Marin, Ana Maria, Markert, Christina, Marquard, Marco, De Martin, Chiara, Martin, Nicole Alice, Martinengo, Paolo, Martinez, Jacobb Lee, Martinez Hernandez, Mario Ivan, Baldisseri, Alberto, Martinez-garcia, Gines, Masciocchi, Silvia, Masera, Massimo, Masoni, Alberto, Massacrier, Laure Marie, Masson, Erwann, Mastroserio, Annalisa, Mathis, Andreas Michael, Matonoha, Oliver, Toledo Matuoka, Paula Fernanda, Ball, Markus, Matyja, Adam Tomasz, Mayer, Christoph, Mazzaschi, Francesco, Mazzilli, Marianna, Mazzoni, Alessandra Maria, Mechler, Adrian Florin, Meddi, Franco, Melikyan, Yury, Menchaca-rocha, Arturo Alejandro, Cai, Mengke, Agnello, Michelangelo, Balouza, Samah, Meninno, Elisa, Sasikumar Menon, Anjaly, Meres, Michal, Mhlanga, Sibaliso, Miake, Yasuo, Micheletti, Luca, Migliorin, Lucrezia Camilla, Mihaylov, Dimitar Lubomirov, Mikhaylov, Konstantin, Mishra, Aditya Nath, Banerjee, Debjani, Miskowiec, Dariusz Czeslaw, Modak, Abhi, Mohammadi, Naghmeh, Mohanty, Auro Prasad, Mohanty, Bedangadas, Khan, Mohammed Mohisin, Moravcova, Zuzana, Mordasini, Cindy, Moreira De Godoy, Denise Aparecida, Perez Moreno, Luis Alberto, Barbera, Roberto, Morozov, Igor, Morsch, Andreas, Mrnjavac, Teo, Muccifora, Valeria, Mudnic, Eugen, Muhlheim, Daniel Michael, Muhuri, Sanjib, Mulligan, James Declan, Mulliri, Alice, Gameiro Munhoz, Marcelo, Barioglio, Luca, Munzer, Robert Helmut, Murakami, Hikari, Murray, Sean, Musa, Luciano, Musinsky, Jan, Myers, Corey James, Myrcha, Julian Wojciech, Naik, Bharati, Nair, Rahul Ramachandran, Nandi, Basanta Kumar, Barnafoldi, Gergely Gabor, Nania, Rosario, Nappi, Eugenio, Naru, Muhammad Umair, Nassirpour, Adrian Fereydon, Nattrass, Christine, Nayak, Ranjit, Nayak, Tapan Kumar, Nazarenko, Sergey, Neagu, Alexandra, Negrao De Oliveira, Renato Aparecido, Barnby, Lee Stuart, Nellen, Lukas, Nesbo, Simon Voigt, Neskovic, Gvozden, Nesterov, Dmitrii, Neumann, Lukasz Tomasz, Nielsen, Borge Svane, Nikolaev, Sergey, Nikulin, Sergey, Nikulin, Vladimir, Noferini, Francesco, Ramillien Barret, Valerie, Nomokonov, Petr, Norman, Jaime, Novitzky, Norbert, Nowakowski, Piotr, Nyanin, Alexander, Nystrand, Joakim Ingemar, Ogino, Masanori, Ohlson, Alice Elisabeth, Oleniacz, Janusz, Oliveira Da Silva, Antonio Carlos, Bartalini, Paolo, Oliver, Michael Henry, Oppedisano, Chiara, Ortiz Velasquez, Antonio, Oskarsson, Anders Nils Erik, Otwinowski, Jacek Tomasz, Oyama, Ken, Pachmayer, Yvonne Chiara, Pacik, Vojtech, Padhan, Sonali, Pagano, Davide, Bartels, Clara, Paic, Guy, Pan, Jinjin, Panebianco, Stefano, Pareek, Pooja, Park, Jonghan, Parkkila, Jasper Elias, Parmar, Sonia, Pathak, Surya Prakash, Paul, Biswarup, Pazzini, Jacopo, Barth, Klaus, Pei, Hua, Peitzmann, Thomas, Peng, Xinye, Pereira, Luis Gustavo, Pereira Da Costa, Hugo Denis Antonio, Peresunko, Dmitry Yurevich, Mesa Perez, Guillermo, Perrin, Sebastien, Pestov, Yury, Petracek, Vojtech, Agrawal, Neelima, Bartsch, Esther, Petrovici, Mihai, Peretti Pezzi, Rafael, Piano, Stefano, Pikna, Miroslav, Pillot, Philippe, Pinazza, Ombretta, Pinsky, Lawrence, Pinto, Chiara, Pisano, Silvia, Pistone, Daniele, Baruffaldi, Filippo, Ploskon, Mateusz Andrzej, Planinic, Mirko, Pliquett, Fabian, Poghosyan, Martin, Polishchuk, Boris, Poljak, Nikola, Pop, Amalia, Porteboeuf, Sarah Julie, Pozdniakov, Valeriy, Prasad, Sidharth Kumar, Bastid, Nicole, Preghenella, Roberto, Prino, Francesco, Pruneau, Claude Andre, Pshenichnov, Igor, Puccio, Maximiliano, Putschke, Jorn Henning, Qiu, Shi, Quaglia, Luca, Quishpe Quishpe, Raquel Estefania, Ragoni, Simone, Basu, Sumit, Raha, Sibaji, Rajput, Sonia, Rak, Jan, Rakotozafindrabe, Andry Malala, Ramello, Luciano, Rami, Fouad, Rodriguez Ramirez, Saul Anibal, Raniwala, Rashmi, Raniwala, Sudhir, Rasanen, Sami Sakari, Batigne, Guillaume, Rath, Rutuparna, Ratza, Viktor, Ravasenga, Ivan, Read, Kenneth Francis, Redelbach, Andreas Ralph, Redlich, Krzysztof, Rehman, Attiq Ur, Reichelt, Patrick Simon, Reidt, Felix, Ren, Xiaowen, Batyunya, Boris, Renfordt, Rainer Arno Ernst, Jakubcinova, Zuzana, Reygers, Klaus Johannes, Riabov, Andrei, Riabov, Viktor, Richert, Tuva Ora Herenui, Richter, Matthias Rudolph, Riedler, Petra, Riegler, Werner, Riggi, Francesco, Bauri, Dibakar, Ristea, Catalin-lucian, Rode, Sudhir Pandurang, Rodriguez Cahuantzi, Mario, Roeed, Ketil, Rogalev, Roman, Rogochaya, Elena, Rohr, David Michael, Roehrich, Dieter, Fierro Rojas, Pablo, Rokita, Przemyslaw Stefan, Bazo Alba, Jose Luis, Ronchetti, Federico, Rosano, Antonina, Dominguez Rosas, Edgar, Roslon, Krystian, Rossi, Andrea, Rotondi, Alberto, Roy, Ankhi, Roy, Pradip Kumar, Vazquez Rueda, Omar, Rui, Rinaldo, Bearden, Ian Gardner, Rumyantsev, Boris, Rustamov, Anar, Ryabinkin, Evgeny, Ryabov, Yury, Rybicki, Andrzej, Rytkonen, Heidi Maria, Saarimaki, Oskari Antti Matti, Sadek, Rita, Sadhu, Samrangy, Sadovskiy, Sergey, Beattie, Caitlin, Safarik, Karel, Saha, Sumit Kumar, Sahoo, Baidyanath, Sahoo, Pragati, Sahoo, Raghunath, Sahoo, Sarita, Sahu, Pradip Kumar, Saini, Jogender, Sakai, Shingo, Sambyal, Sanjeev Singh, Ahammed, Zubayer, Bedda, Cristina, Samsonov, Vladimir, Sarkar, Debojit, Sarkar, Nachiketa, Sarma, Pranjal, Mantovani Sarti, Valentina, Sas, Mike Henry Petrus, Scapparone, Eugenio, Schambach, Johann Joachim, Scheid, Horst Sebastian, Schiaua, Claudiu Cornel, Behera, Nirbhay Kumar, Schicker, Rainer Martin, Schmah, Alexander, Schmidt, Christian Joachim, Schmidt, Hans Rudolf, Schmidt, Marten Ole, Schmidt, Martin, Schmidt, Nicolas, Schmier, Austin Robert, Schukraft, Jurgen, Schutz, Yves Roland, Belikov, Iouri, Schwarz, Kilian Eberhard, Schweda, Kai Oliver, Scioli, Gilda, Scomparin, Enrico, Seger, Janet Elizabeth, Sekiguchi, Yuko, Sekihata, Daiki, Selyuzhenkov, Ilya, Senyukov, Serhiy, Serebryakov, Dmitry, Bell Hechavarria, Ailec, Sevcenco, Adrian, Shabanov, Arseniy, Shabetai, Alexandre, Shahoyan, Ruben, Shaikh, Wadut, Shangaraev, Artem, Sharma, Anjali, Sharma, Ankita, Sharma, Himanshu, Sharma, Meenakshi, Bellini, Francesca, Sharma, Natasha, Sharma, Sheetal, Sheibani, Oveis, Shigaki, Kenta, Hachiya Shimomura, Maya, Shirinkin, Sergey, Shou, Qiye, Sibiryak, Yury, Siddhanta, Sabyasachi, Siemiarczuk, Teodor, Bellwied, Rene, Silvermyr, David Olle Rickard, Simatovic, Goran, Simonetti, Giuseppe, Singh, Bhawani, Singh, Ranbir, Singh, Randhir, Singh, Ravindra, Singh, Vivek, Singhal, Vikas, Sarkar - Sinha, Tinku, Belyaev, Vladimir, Sitar, Branislav, Sitta, Mario, Skaali, Bernhard, Slupecki, Maciej, Smirnov, Nikolai, Snellings, Raimond, Soncco Meza, Carlos, Song, Jihye, Songmoolnak, Arnon, Soramel, Francesca, Bencedi, Gyula, Sorensen, Soren Pontoppidan, Sputowska, Iwona Anna, Stachel, Johanna, Stan, Ionel, Steffanic, Patrick John, Stenlund, Evert Anders, Stiefelmaier, Stephan Friedrich, Stocco, Diego, Storetvedt, Maksim Melnik, Dello Stritto, Luigi, Beole, Stefania, Alarcon Do Passo Suaide, Alexandre, Sugitate, Toru, Suire, Christophe Pierre, Suleymanov, Mais Kazim Oglu, Suljic, Miljenko, Sultanov, Rishat, Sumbera, Michal, Sumberia, Vikash, Sumowidagdo, Suharyo, Swain, Sagarika, Bercuci, Alexandru, Szabo, Alexander, Szarka, Imrich, Tabassam, Uzma, Taghavi, Seyed Farid, Taillepied, Guillaume, Takahashi, Jun, Tambave, Ganesh Jagannath, Tang, Siyu, Tarhini, Mohamad, Tarzila, Madalina-gabriela, Ahmad, Shakeel, Berdnikov, Yaroslav, Tauro, Arturo, Tejeda Munoz, Guillermo, Telesca, Adriana, Terlizzi, Livia, Terrevoli, Cristina, Thakur, Dhananjaya, Thakur, Sanchari, Thomas, Deepa, Thoresen, Freja, Tieulent, Raphael Noel, Berenyi, Daniel, Tikhonov, Anatoly, Timmins, Anthony Robert, Toia, Alberica, Topilskaya, Nataliya, Toppi, Marco, Torales Acosta, Fernando, Rojas Torres, Solangel, Trifiro, Antonio, Tripathy, Sushanta, Tripathy, Tulika, Bertens, Redmer Alexander, Trogolo, Stefano, Trombetta, Giuseppe, Tropp, Lukas, Trubnikov, Victor, Trzaska, Wladyslaw Henryk, Trzcinski, Tomasz Piotr, Trzeciak, Barbara Antonina, Tumkin, Alexandr, Turrisi, Rosario, Tveter, Trine Spedstad, Berzano, Dario, Ullaland, Kjetil, Umaka, Ejiro Naomi, Uras, Antonio, Usai, Gianluca, Vala, Martin, Valle, Nicolo', Vallero, Sara, Van Der Kolk, Naomi, Van Doremalen, Lennart, Van Leeuwen, Marco, Besoiu, Mihaela Gabriela, Vande Vyvre, Pierre, Varga, Dezso, Varga, Zoltan, Varga-kofarago, Monika, Diozcora Vargas Trevino, Aurora, Vasileiou, Maria, Vasiliev, Andrey, Vazquez Doce, Oton, Vechernin, Vladimir, Vercellin, Ermanno, Betev, Latchezar, Vergara Limon, Sergio, Vermunt, Lucas Anne, Vernet, Renaud, Vertesi, Robert, Vickovic, Linda, Vilakazi, Zabulon, Villalobos Baillie, Orlando, Vino, Gioacchino, Vinogradov, Alexander, Virgili, Tiziano, Bhasin, Anju, Vislavicius, Vytautas, Vodopyanov, Alexander, Volkel, Benedikt, Volkl, Martin Andreas, Voloshin, Kirill, Voloshin, Sergey, Volpe, Giacomo, Von Haller, Barthelemy, Vorobyev, Ivan, Voscek, Dominik, Bhat, Inayat Rasool, Vrlakova, Janka, Wagner, Boris, Weber, Michael, Weber, Steffen Georg, Wegrzynek, Adam Tadeusz, Wenzel, Sandro Christian, Wessels, Johannes Peter, Wiechula, Jens, Wikne, Jon, Wilk, Grzegorz Andrzej, Bhat, Mohammad Asif, Wilkinson, Jeremy John, Willems, Guido Alexander, Willsher, Emily Jade, Windelband, Bernd Stefan, Winn, Michael Andreas, Witt, William Edward, Wright, Josephina Rae, Wu, Yitao, Xu, Ran, Yalcin Kuzu, Serpil, Bhatt, Himani, Yamaguchi, Yorito, Yamakawa, Kosei, Yang, Shiming, Yano, Satoshi, Yin, Zhongbao, Yokoyama, Hiroki, Yoo, In Kwon, Yoon, Jin Hee, Yuan, Shiming, Yuncu, Alperen, Acharya, S., Adamova, D., Adler, A., Adolfsson, J., Aggarwal, M. M., Rinella, G. A., Agnello, M., Agrawal, N., Ahammed, Z., Ahmad, S., Ahn, S. U., Akbar, Z., Akindinov, A., Al-Turany, M., Alam, S. N., Albuquerque, D. S. D., Aleksandrov, D., Alessandro, B., Alfanda, H. M., Molina, R. A., Ali, B., Ali, Y., Alici, A., Alizadehvandchali, N., Alkin, A., Alme, J., Alt, T., Altenkamper, L., Altsybeev, I., Anaam, M. N., Andrei, C., Andreou, D., Andronic, A., Angeletti, M., Anguelov, V., Anson, C., Anticic, T., Antinori, F., Antonioli, P., Apadula, N., Aphecetche, L., Appelshauser, H., Arcelli, S., Arnaldi, R., Arratia, M., Arsene, I. C., Arslandok, M., Augustinus, A., Averbeck, R., Aziz, S., Azmi, M. D., Badala, A., Baek, Y. W., Bagnasco, S., Bai, X., Bailhache, R., Bala, R., Balbino, A., Baldisseri, A., Ball, M., Balouza, S., Banerjee, D., Barbera, R., Barioglio, L., Barnafoldi, G. G., Barnby, L. S., Barret, V., Bartalini, P., Bartels, C., Barth, K., Bartsch, E., Baruffaldi, F., Bastid, N., Basu, S., Batigne, G., Batyunya, B., Bauri, D., Alba, J. L. B., Bearden, I. G., Beattie, C., Bedda, C., Behera, N. K., Belikov, I., Hechavarria, A. D. C. B., Bellini, F., Bellwied, R., Belyaev, V., Bencedi, G., Beole, S., Bercuci, A., Berdnikov, Y., Berenyi, D., Bertens, R. A., Berzano, D., Besoiu, M. G., Betev, L., Bhasin, A., Bhat, I. R., Bhat, M. A., Bhatt, H., Bhattacharjee, B., Bianchi, A., Bianchi, L., Bianchi, N., Bielcik, J., Bielcikova, J., Bilandzic, A., Biro, G., Biswas, R., Biswas, S., Blair, J. T., Blau, D., Blume, C., Boca, G., Bock, F., Bogdanov, A., Boi, S., Bok, J., Boldizsar, L., Bolozdynya, A., Bombara, M., Bonomi, G., Borel, H., Borissov, A., Bossi, H., Botta, E., Bratrud, L., Braun-Munzinger, P., Bregant, M., Broz, M., Bruna, E., Bruno, G. E., Buckland, M. D., Budnikov, D., Buesching, H., Bufalino, S., Bugnon, O., Buhler, P., Buncic, P., Buthelezi, Z., Butt, J. B., Bysiak, S. A., Caffarri, D., Caliva, A., Villar, E. C., Camacho, J. M. M., Camacho, R. S., Camerini, P., Canedo, F. D. M., Capon, A. A., Carnesecchi, F., Caron, R., Castellanos, J. C., Castro, A. J., Casula, E. A. R., Catalano, F., Sanchez, C. C., Chakraborty, P., Chandra, S., Chang, W., Chapeland, S., Chartier, M., Chattopadhyay, S., Chauvin, A., Cheshkov, C., Cheynis, B., Barroso, V. C., Chinellato, D. D., Cho, S., Chochula, P., Chowdhury, T., Christakoglou, P., Christensen, C. H., Christiansen, P., Chujo, T., Cicalo, C., Cifarelli, L., Cilladi, L. D., Cindolo, F., Ciupek, M. R., Clai, G., Cleymans, J., Colamaria, F., Colella, D., Collu, A., Colocci, M., Concas, M., Balbastre, G. C., del Valle, Z. C., Contin, G., Contreras, J. G., Cormier, T. M., Morales, Y. C., Cortese, P., Cosentino, M. R., Costa, F., Costanza, S., Crochet, P., Cuautle, E., Cui, P., Cunqueiro, L., Dabrowski, D., Dahms, T., Dainese, A., Damas, F. P. A., Danisch, M. 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N., Foertsch, S., Foka, P., Fokin, S., Fragiacomo, E., Frankenfeld, U., Fuchs, U., Furget, C., Furs, A., Girard, M. F., Gaardhoje, J. J., Gagliardi, M., Gago, A. M., Gal, A., Galvan, C. D., Ganoti, P., Garabatos, C., Garcia, J. R. A., Garcia-Solis, E., Garg, K., Gargiulo, C., Garibli, A., Garner, K., Gasik, P., Gauger, E. F., Ducati, M. B. G., Germain, M., Ghosh, J., Ghosh, P., Ghosh, S. K., Giacalone, M., Gianotti, P., Giubellino, P., Giubilato, P., Glaenzer, A. M. C., Glassel, P., Ramirez, A. G., Gonzalez, V., Gonzalez-Trueba, L. H., Gorbunov, S., Gorlich, L., Goswami, A., Gotovac, S., Grabski, V., Graczykowski, L. K., Graham, K. L., Greiner, L., Grelli, A., Grigoras, C., Grigoriev, V., Grigoryan, A., Grigoryan, S., Groettvik, O. S., Grosa, F., Grosse-Oetringhaus, J. F., Grosso, R., Guernane, R., Guittiere, M., Gulbrandsen, K., Gunji, T., Gupta, A., Gupta, R., Guzman, I. B., Haake, R., Habib, M. K., Hadjidakis, C., Hamagaki, H., Hamar, G., Hamid, M., Hannigan, R., Haque, M. R., Harlenderova, A., Harris, J. W., Harton, A., Hasenbichler, J. A., Hassan, H., Hassan, Q. U., Hatzifotiadou, D., Hauer, P., Havener, L. B., Hayashi, S., Heckel, S. T., Hellbar, E., Helstrup, H., Herghelegiu, A., Herman, T., Hernandez, E. G., Corral, G. H., Herrmann, F., Hetland, K. F., Hillemanns, H., Hills, C., Hippolyte, B., Hohlweger, B., Honermann, J., Horak, D., Hornung, A., Hornung, S., Hosokawa, R., Hristov, P., Huang, C., Hughes, C., Huhn, P., Humanic, T. J., Hushnud, H., Husova, L. A., Hussain, N., Hussain, S. A., Hutter, D., Iddon, J. P., Ilkaev, R., Ilyas, H., Inaba, M., Innocenti, G. M., Ippolitov, M., Isakov, A., Islam, M. S., Ivanov, M., Ivanov, V., Izucheev, V., Jacak, B., Jacazio, N., Jacobs, P. M., Jadlovska, S., Jadlovsky, J., Jaelani, S., Jahnke, C., Jakubowska, M. J., Janik, M. A., Janson, T., Jercic, M., Jevons, O., Jin, M., Jonas, F., Jones, P. G., Jung, J., Jung, M., Jusko, A., Kalinak, P., Kalweit, A., Kaplin, V., Kar, S., Uysal, A. K., Karatovic, D., Karavichev, O., Karavicheva, T., Karczmarczyk, P., Karpechev, E., Kazantsev, A., Kebschull, U., Keidel, R., Keil, M., Ketzer, B., Khabanova, Z., Khan, A. M., Khan, S., Khanzadeev, A., Kharlov, Y., Khatun, A., Khuntia, A., Kileng, B., Kim, B., Kim, D., Kim, D. J., Kim, E. J., Kim, H., Kim, J., Kim, J. S., Kim, M., Kim, S., Kim, T., Kirsch, S., Kisel, I., Kiselev, S., Kisiel, A., Klay, J. L., Klein, C., Klein, J., Klein, S., Klein-Bosing, C., Kleiner, M., Kluge, A., Knichel, M. L., Knospe, A. G., Kobdaj, C., Kohler, M. K., Kollegger, T., Kondratyev, A., Kondratyeva, N., Kondratyuk, E., Konig, J., Konigstorfer, S. A., Konopka, P. J., Kornakov, G., Koska, L., Kovalenko, O., Kovalenko, V., Kowalski, M., Kralik, I., Kravcakova, A., Kreis, L., Krivda, M., Krizek, F., Gajdosova, K. K., Kruger, M., Kryshen, E., Krzewicki, M., Kubera, A. M., Kucera, V., Kuhn, C., Kuijer, P. G., Kumar, L., Kundu, S., Kurashvili, P., Kurepin, A., Kurepin, A. 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C., Zardoshti, N., Zarochentsev, A., Zavada, P., Zaviyalov, N., Zbroszczyk, H., Zhalov, M., Zhang, S., Zhang, X., Zhang, Z., Zherebchevskii, V., Zhi, Y., Zhou, D., Zhou, Y., Zhou, Z., Zhu, J., Zhu, Y., Zichichi, A., Zinovjev, G., Zurlo, N., Laboratoire de physique subatomique et des technologies associées (SUBATECH), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Laboratoire de Physique des 2 Infinis Irène Joliot-Curie (IJCLab), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Département de Physique Nucléaire (ex SPhN) (DPHN), Institut de Recherches sur les lois Fondamentales de l'Univers (IRFU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Laboratoire de Physique de Clermont (LPC), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut de Physique Nucléaire de Lyon (IPNL), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), Laboratoire de Physique Subatomique et de Cosmologie (LPSC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Centre de Calcul de l'IN2P3 (CC-IN2P3), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), ALICE, Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), S. 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Ryabov, A. Rybicki, H. Rytkonen, O. A. M. Saarimaki, R. Sadek, S. Sadhu, S. Sadovsky, K. Šafařík, S. K. Saha, B. Sahoo, P. Sahoo, R. Sahoo, S. Sahoo, P. K. Sahu, J. Saini, S. Sakai, S. Sambyal, V. Samsonov, D. Sarkar, N. Sarkar, P. Sarma, V. M. Sarti, M. H. P. Sas, E. Scapparone, J. Schambach, H. S. Scheid, C. Schiaua, R. Schicker, A. Schmah, C. Schmidt, H. R. Schmidt, M. O. Schmidt, M. Schmidt, N. V. Schmidt, A. R. Schmier, J. Schukraft, Y. Schutz, K. Schwarz, K. Schweda, G. Scioli, E. Scomparin, J. E. Seger, Y. Sekiguchi, D. Sekihata, I. Selyuzhenkov, S. Senyukov, D. Serebryakov, A. Sevcenco, A. Shabanov, A. Shabetai, R. Shahoyan, W. Shaikh, A. Shangaraev, A. Sharma, A. Sharma, H. Sharma, M. Sharma, N. Sharma, S. Sharma, O. Sheibani, K. Shigaki, M. Shimomura, S. Shirinkin, Q. Shou, Y. Sibiriak, S. Siddhanta, T. Siemiarczuk, D. Silvermyr, G. Simatovic, G. Simonetti, B. Singh, R. Singh, R. Singh, R. Singh, V. K. Singh, V. Singhal, T. Sinha, B. Sitar, M. Sitta, T. B. Skaali, M. Slupecki, N. Smirnov, R. J. M. Snellings, C. Soncco, J. Song, A. Songmoolnak, F. Soramel, S. Sorensen, I. Sputowska, J. Stachel, I. Stan, P. J. Steffanic, E. Stenlund, S. F. Stiefelmaier, D. Stocco, M. M. Storetvedt, L. D. Stritto, A. A. P. Suaide, T. Sugitate, C. Suire, M. Suleymanov, M. Suljic, R. Sultanov, M. Šumbera, V. Sumberia, S. Sumowidagdo, S. Swain, A. Szabo, I. Szarka, U. Tabassam, S. F. Taghavi, G. Taillepied, J. Takahashi, G. J. Tambave, S. Tang, M. Tarhini, M. G. Tarzila, A. Tauro, G. Tejeda Muñoz, A. Telesca, L. Terlizzi, C. Terrevoli, D. Thakur, S. Thakur, D. Thomas, F. Thoresen, R. Tieulent, A. Tikhonov, A. R. Timmins, A. Toia, N. Topilskaya, M. Toppi, F. Torales-Acosta, S. R. Torres, A. Trifiró, S. Tripathy, T. Tripathy, S. Trogolo, G. Trombetta, L. Tropp, V. Trubnikov, W. H. Trzaska, T. P. Trzcinski, B. A. Trzeciak, A. Tumkin, R. Turrisi, T. S. Tveter, K. Ullaland, E. N. Umaka, A. Uras, G. L. Usai, M. Vala, N. Valle, S. Vallero, N. van der Kolk, L. V. R. van Doremalen, M. van Leeuwen, P. Vande Vyvre, D. Varga, Z. Varga, M. Varga-Kofarago, A. Vargas, M. Vasileiou, A. Vasiliev, O. Vázquez Doce, V. Vechernin, E. Vercellin, S. Vergara Limón, L. Vermunt, R. Vernet, R. Vértesi, L. Vickovic, Z. Vilakazi, O. Villalobos Baillie, G. Vino, A. Vinogradov, T. Virgili, V. Vislavicius, A. Vodopyanov, B. Volkel, M. A. Völkl, K. Voloshin, S. A. Voloshin, G. Volpe, B. von Haller, I. Vorobyev, D. Voscek, J. Vrláková, B. Wagner, M. Weber, S. G. Weber, A. Wegrzynek, S. C. Wenzel, J. P. Wessels, J. Wiechula, J. Wikne, G. Wilk, J. Wilkinson, G. A. Willems, E. Willsher, B. Windelband, M. Winn, W. E. Witt, J. R. Wright, Y. Wu, R. Xu, S. Yalcin, Y. Yamaguchi, K. Yamakawa, S. Yang, S. Yano, Z. Yin, H. Yokoyama, I.-K. Yoo, J. H. Yoon, S. Yuan, A. Yuncu, V. Yurchenko, V. Zaccolo, A. Zaman, C. Zampolli, H. J. C. Zanoli, N. Zardoshti, A. Zarochentsev, P. Závada, N. Zaviyalov, H. Zbroszczyk, M. Zhalov, S. Zhang, X. Zhang, Z. Zhang, V. Zherebchevskii, Y. Zhi, D. Zhou, Y. Zhou, Z. Zhou, J. Zhu, Y. Zhu, A. Zichichi, G. Zinovjev & N. Zurlo, Helsinki Institute of Physics, Sub Subatomic Physics (SAP), Afd Subatomic Physics (SAP), Sub Algemeen Physics Education, and Subatomic Physics

Subjects
EXCHANGE-POTENTIAL APPROACH, Strange quark, ALICE Collaboration, Hadron, Nuclear Theory, Strong interaction, hadron collisions, Position and momentum space, hiukkasfysiikka, nucl-ex, 7. Clean energy, 01 natural sciences, VDP::Fysikk: 430, High Energy Physics - Experiment, High Energy Physics - Experiment (hep-ex), Hadron-Hadron scattering (experiments), scattering [hadron], p p scattering, [PHYS.HEXP]Physics [physics]/High Energy Physics - Experiment [hep-ex], scattering [p p], Nuclear Experiment (nucl-ex), Experimental nuclear physics, NUCLEON, Nuclear Experiment, VDP::Physics: 430, Physics, Multidisciplinary, Large Hadron Collider, strong interaction, lattice [space-time], Publisher Correction, PRIRODNE ZNANOSTI. Fizika, BARYON-BARYON SCATTERING, CERN LHC Coll, LHC, ddc:500, Nucleon, Particle Physics - Experiment, discrete [space-time], Quark, Particle physics, CERN Lab, General Science & Technology, FOS: Physical sciences, short-range, Hadron, strong interaction, LHC, 114 Physical sciences, Fysikk: 430 [VDP], Article, hadron scattering, quark, ultrarelativistic proton–proton collisions, LHC, ALICE, 0103 physical sciences, Nuclear Physics - Experiment, General, 010306 general physics, Physics: 430 [VDP], interaction [hadron hadron], hep-ex, 010308 nuclear & particles physics, High Energy Physics::Phenomenology, effect [strong interaction], hadron-hadron interaction, strong interaction: effect, space-time: discrete, space-time: lattice, correlation, NATURAL SCIENCES. Physics, Baryon, Hypernuclei, Neutron Stars, Strangeness, Physics::Accelerator Physics, High Energy Physics::Experiment, hadron, Experimental particle physics
Abstract

One of the key challenges for nuclear physics today is to understand from first principles the effective interaction between hadrons with different quark content. First successes have been achieved using techniques that solve the dynamics of quarks and gluons on discrete space-time lattices1,2. Experimentally, the dynamics of the strong interaction have been studied by scattering hadrons off each other. Such scattering experiments are difficult or impossible for unstable hadrons3–6 and so high-quality measurements exist only for hadrons containing up and down quarks7. Here we demonstrate that measuring correlations in the momentum space between hadron pairs8–12 produced in ultrarelativistic proton–proton collisions at the CERN Large Hadron Collider (LHC) provides a precise method with which to obtain the missing information on the interaction dynamics between any pair of unstable hadrons. Specifically, we discuss the case of the interaction of baryons containing strange quarks (hyperons). We demonstrate how, using precision measurements of proton–omega baryon correlations, the effect of the strong interaction for this hadron–hadron pair can be studied with precision similar to, and compared with, predictions from lattice calculations13,14. The large number of hyperons identified in proton–proton collisions at the LHC, together with accurate modelling15 of the small (approximately one femtometre) inter-particle distance and exact predictions for the correlation functions, enables a detailed determination of the short-range part of the nucleon-hyperon interaction., Correlations in momentum space between hadrons created by ultrarelativistic proton–proton collisions at the CERN Large Hadron Collider provide insights into the strong interaction, particularly the short-range dynamics of hyperons—baryons that contain strange quarks.

Published
2020
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4. Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation

Author

Stafford, Che A., primary, Gassauer, Alicia-Marie, additional, de Oliveira Mann, Carina C., additional, Tanzer, Maria C., additional, Fessler, Evelyn, additional, Wefers, Benedikt, additional, Nagl, Dennis, additional, Kuut, Gunnar, additional, Sulek, Karolina, additional, Vasilopoulou, Catherine, additional, Schwojer, Sophia J., additional, Wiest, Andreas, additional, Pfautsch, Marie K., additional, Wurst, Wolfgang, additional, Yabal, Monica, additional, Fröhlich, Thomas, additional, Mann, Matthias, additional, Gisch, Nicolas, additional, Jae, Lucas T., additional, and Hornung, Veit, additional

Published
2022
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6. Structural basis for sequestration and autoinhibition of cGAS by chromatin

Author

Joseph Bartho, Che A. Stafford, Veit Hornung, Carina C. de Oliveira Mann, Karl-Peter Hopfner, Katja Lammens, Gregor Witte, and Sebastian Michalski

Subjects
Models, Molecular, Microbial DNA, THP-1 Cells, Autoantigens, Binding, Competitive, Histones, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Catalytic Domain, Animals, Humans, Nucleosome, Amino Acid Sequence, 030304 developmental biology, 0303 health sciences, Binding Sites, Multidisciplinary, Innate immune system, biology, ATP synthase, Cryoelectron Microscopy, DNA, Nucleotidyltransferases, Chromatin, Immunity, Innate, Nucleosomes, Cell biology, Nuclear DNA, Enzyme Activation, Histone, chemistry, biology.protein, Protein Multimerization, Hydrophobic and Hydrophilic Interactions, 030217 neurology & neurosurgery
Abstract

Cyclic GMP–AMP synthase (cGAS) is an innate immune sensor for cytosolic microbial DNA1. After binding DNA, cGAS synthesizes the messenger 2′3′-cyclic GMP–AMP (cGAMP)2–4, which triggers cell-autonomous defence and the production of type I interferons and pro-inflammatory cytokines via the activation of STING5. In addition to responding to cytosolic microbial DNA, cGAS also recognizes mislocalized cytosolic self-DNA and has been implicated in autoimmunity and sterile inflammation6,7. Specificity towards pathogen- or damage-associated DNA was thought to be caused by cytosolic confinement. However, recent findings place cGAS robustly in the nucleus8–10, where tight tethering of chromatin is important to prevent autoreactivity to self-DNA8. Here we show how cGAS is sequestered and inhibited by chromatin. We provide a cryo-electron microscopy structure of the cGAS catalytic domain bound to a nucleosome, which shows that cGAS does not interact with the nucleosomal DNA, but instead interacts with histone 2A–histone 2B, and is tightly anchored to the ‘acidic patch’. The interaction buries the cGAS DNA-binding site B, and blocks the formation of active cGAS dimers. The acidic patch robustly outcompetes agonistic DNA for binding to cGAS, which suggests that nucleosome sequestration can efficiently inhibit cGAS, even when accessible DNA is nearby, such as in actively transcribed genomic regions. Our results show how nuclear cGAS is sequestered by chromatin and provides a mechanism for preventing autoreactivity to nuclear self-DNA. Biochemical and structural analyses show how tethering of the nucleotidyltransferase cGAS to chromatin prevents autoimmune recognition of nuclear DNA.

Published
2020
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7. Fourth defence molecule completes antiviral line-up

Author

Schmacke, Niklas A. and Hornung, Veit

Subjects
Interferon -- Production processes, Immune response -- Analysis, Toll-like receptors -- Analysis, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Toll-like receptors can initiate an immune response when they detect signs of a viral or microbial threat. New insight into how such receptor activation drives defence programs should aid our efforts to understand autoimmune diseases. Key adaptor protein found in a pathway that drives interferon production., Author(s): Niklas A. Schmacke, Veit Hornung Author Affiliations: Fourth defence molecule completes antiviral line-up Cells of the innate branch of the immune system can detect infectious agents outside the cell [...]

Published
2020
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8. Comet 67P/Churyumov-Gerasimenko sheds dust coat accumulated over the past four years

Author

Schulz, Rita, Hilchenbach, Martin, Langevin, Yves, Kissel, Jochen, Silen, Johan, Briois, Christelle, Engrand, Cecile, Hornung, Klaus, Baklouti, Donia, Bardyn, Anaïs, Cottin, Hervé, Fischer, Henning, Fray, Nicolas, Godard, Marie, Lehto, Harry, Le Roy, Léna, Merouane, Sihane, Orthous-Daunay, François-Régis, Paquette, John, Rynö, Jouni, Siljeström, Sandra, Stenzel, Oliver, Thirkell, Laurent, Varmuza, Kurt, and Zaprudin, Boris

Published
2015
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9. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP

Author

Ablasser, Andrea, Schmid-Burgk, Jonathan L., Hemmerling, Inga, Horvath, Gabor L., Schmidt, Tobias, Latz, Eicke, and Hornung, Veit

Subjects
Cellular immunity -- Research, Cyclic adenylic acid -- Properties, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The innate immune defence of multicellular organisms against microbial pathogens requires cellular collaboration. Information exchange allowing immune cells to collaborate is generally attributed to soluble protein factors secreted by pathogen-sensing cells. Cytokines, such as type I interferons (IFNs), serve to alert non-infected cells to the possibility of pathogen challenge (1). Moreover, in conjunction with chemokines they can instruct specialized immune cells to contain and eradicate microbial infection. Several receptors and signalling pathways exist that couple pathogen sensing to the induction of cytokines, whereas cytosolic recognition of nucleic acids seems to be exquisitely important for the activation of type I IFNs, master regulators of antiviral immunity (2). Cytosolic DNA is sensed by the receptor cyclic GMP-AMP (cGAMP) synthase (cGAS), which catalyses the synthesis of the second messenger cGAMP(2'-5') (3-8). This molecule in turn activates the endoplasmic reticulum (ER)-resident receptor STING (9-11), thereby inducing an antiviral state and the secretion of type I IFNs. Here we find in murine and human cells that cGAS-synthesized cGAMP (2'-5') is transferred from producing cells to neighbouring cells through gap junctions, where it promotes STING activation and thus antiviral immunity independently of type I IFN signalling. In line with the limited cargo specificity of connexins, the proteins that assemble gap junction channels, most connexins tested were able to confer this bystander immunity, thus indicating a broad physiological relevance of this local immune collaboration. Collectively, these observations identify cGAS-triggered cGAMP(2'-5') transfer as a novel host strategy that serves to rapidly convey antiviral immunity in a transcription-independent, horizontal manner., On recognition of virus-derived nucleic acids, innate immune signalling initiates cell-autonomous antiviral effector mechanisms that aim to block viral propagation. Moreover, virus-infected cells alert non-infected neighbouring cells, a process largely [...]

Published
2013

10. cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that activates STING

Author

Ablasser, Andrea, Goldeck, Marion, Caviar, Taner, Deimling, Tobias, Witte, Gregor, Rohl, Ingo, Hopfner, Karl-Peter, Ludwig, Janos, and Hornung, Veit

Subjects
Immune response -- Genetic aspects, Nucleotides -- Properties, Cellular signal transduction -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Detection of cytoplasmic DNA represents one of the most fundamental mechanisms of the innate immune system to sense the presence of microbial pathogens (1). Moreover, erroneous detection of endogenous DNA by the same sensing mechanisms has an important pathophysiological role in certain sterile inflammatory conditions (2,3). The endoplasmic-reticulum-resident protein STING is critically required for the initiation of type I interferon signalling upon detection of cytosolic DNA of both exogenous and endogenous origin (4-8). Next to its pivotal role in DNA sensing, STING also serves as a direct receptor for the detection of cyclic dinucleotides, which function as second messenger molecules in bacteria (9-13). DNA recognition, however, is triggered in an indirect fashion that depends on a recently characterized cytoplasmic nucleotidyl transferase, termed cGAMP synthase (cGAS), which upon interaction with DNA synthesizes a dinucleotide molecule that in turn binds to and activates STING (14,15). We here show in vivo and in vitro that the cGAS-catalysed reaction product is distinct from previously characterized cyclic dinucleotides. Using a combinatorial approach based on mass spectrometry, enzymatic digestion, NMR analysis and chemical synthesis we demonstrate that cGAS produces a cyclic GMP-AMP dinucleotide, which comprises a 2'-5' and a 3'-5' phosphodiester linkage >Gp(2'-5')Ap(3'-5')>. We found that the presence of this 2'-5' linkage was required to exert potent activation of human STING. Moreover, we show that cGAS first catalyses the synthesis of a linear 2' -5'-linked dinucleotide, which is then subject to cGAS-dependent cyclization in a second step through a 3'-5' phosphodiester linkage. This 13-membered ring structure defines a novel class of second messenger molecules, extending the family of 2' -5'-linked antiviral biomolecules., Recently, it has been demonstrated that upon intracellular DNA delivery, a cytoplasmic enzyme dubbed cyclic GMP-AMP synthase (cGAS) produces a ribo-dinucleotide, which in turn binds to and activates STING (14,15). [...]

Published
2013
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11. Structural mechanism of cytosolic DNA sensing by cGAS

Author

Civril, Filiz, Deimling, Tobias, de Oliveira Mann, Carina C., Ablasser, Andrea, Moldt, Manuela, Witte, Gregor, Hornung, Veit, and Hopfner, Karl-Peter

Subjects
Cytosol -- Genetic aspects, Transferases -- Properties -- Testing, Immune response -- Observations, Nucleotides -- Properties, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Cytosolic DNA arising from intracellular bacterial or viral infections is a powerful pathogen-associated molecular pattern (PAMP) that leads to innate immune host defence by the production of type I interferon and inflammatory cytokines. Recognition of cytosolic DNA by the recently discovered cyclic-GMP-AMP (cGAMP) synthase (cGAS) induces the production of cGAMP to activate the stimulator of interferon genes (STING). Here we report the crystal structure of cGAS alone and in complex with DNA, ATP and GTP along with functional studies. Our results explain the broad DNA sensing specificity of cGAS, show how cGAS catalyses dinucleotide formation and indicate activation by a DNA-induced structural switch. cGAS possesses a remarkable structural similarity to the antiviral cytosolic double-stranded RNA sensor 2' -5'oligoadenylate synthase (OAS1), but contains a unique zinc thumb that recognizes B-form double-stranded DNA. Our results mechanistically unify dsRNA and dsDNA innate immune sensing by OAS1 and cGAS nucleotidyl transferases., Recognition of pathogen- or danger-associated molecular patterns (PAMPs or DAMPs) is crucial for host defence. Innate immunity ensures this recognition through germline-encoded pattern recognition receptors (PRRs) and triggers signalling cascades [...]

Published
2013
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12. Low-energy control of electrical turbulence in the heart

Author

Luther, Stefan, Fenton, Flavio H., Kornreich, Bruce G., Squires, Amgad, Bittihn, Philip, Hornung, Daniel, Zabel, Markus, Flanders, James, Gladuli, Andrea, Campoy, Luis, Cherry, Elizabeth M., Luther, Gisa, Hasenfuss, Gerd, Krinsky, Valentin I., Pumir, Alain, Gilmour, Jr., Robert F., and Bodenschatz, Eberhard

Subjects
Biological rhythms -- Physiological aspects -- Health aspects, Arrhythmia -- Physiological aspects -- Health aspects, Heart -- Physiological aspects -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Controlling the complex spatio-temporal dynamics underlying life-threatening cardiac arrhythmias such as fibrillation is extremely difficult, because of the nonlinear interaction of excitation waves in a heterogeneous anatomical substrate (1-4). In the absence of a better strategy, strong, globally resetting electrical shocks remain the only reliable treatment for cardiac fibrillation (5-7). Here we establish the relationship between the response of the tissue to an electric field and the spatial distribution of heterogeneities in the scale-free coronary vascular structure. We show that in response to a pulsed electric field, E, these heterogeneities serve as nucleation sites for the generation of intramural electrical waves with a source density ρ(E) and a characteristic time, τ, for tissue depolarization that obeys the power law τ [varies] [E.sup.α]. These intramural wave sources permit targeting of electrical turbulence near the cores of the vortices of electrical activity that drive complex fibrillatory dynamics. We show in vitro that simultaneous and direct access to multiple vortex cores results in rapid synchronization of cardiac tissue and therefore, efficient termination of fibrillation. Using this control strategy, we demonstrate low-energy termination of fibrillation in vivo. Our results give new insights into the mechanisms and dynamics underlying the control of spatio-temporal chaos in heterogeneous excitable media and provide new research perspectives towards alternative, life-saving low-energy defibrillation techniques., Spatially extended non-equilibrium systems display spatio-temporal dynamics that can range from ordered to turbulent. Controlling such systems is one of the central problems in nonlinear science and has far-reaching technological [...]

Published
2011
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13. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals

Author

Duewell, Peter, Kono, Hajime, Rayner, Katey J., Sirois, Cherilyn M., Vladimer, Gregory, Bauernfeind, Franz G., Abela, George S., Franchi, Luigi, Nunez, Gabriel, Schnurr, Max, Espevik, Terje, Lien, Egil, Fitzgerald, Katherine A., Rock, Kenneth L., Moore, Kathryn J., Wright, Samuel D., Hornung, Veit, and Latz, Eicke

Subjects
Cellular proteins -- Health aspects -- Research, Interleukins -- Health aspects -- Research, Hypercholesterolemia -- Complications and side effects -- Research, Atherosclerosis -- Risk factors -- Care and treatment -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The inflammatory nature of atherosclerosis is well established but the agent(s) that incite inflammation in the artery wall remain largely unknown. Germ-free animals are susceptible to atherosclerosis, suggesting that endogenous substances initiate the inflammation (1). Mature atherosclerotic lesions contain macroscopic deposits of cholesterol crystals in the necrotic core, but their appearance late in atherogenesis had been thought to disqualify them as primary inflammatory stimuli. However, using a new microscopic technique, we revealed that minute cholesterol crystals are present in early diet-induced atherosclerotic lesions and that their appearance in mice coincides with the first appearance of inflammatory cells. Other crystalline substances can induce inflammation by stimulating the caspase-1-activating NLRP3 (NALP3 or cryopyrin) inflarnmasome (2,3), which results in cleavage and secretion of interleukin (IL)-1 family cytokines. Here we show that cholesterol crystals activate the NLRP3 inflammasome in phagocytes in vitro in a process that involves phagolysosomal damage. Similarly, when injected intraperitoneally, cholesterol crystals induce acute inflammation, which is impaired in mice deficient in components of the NLRP3 inflammasome, cathepsin B, cathepsin L or IL-1 molecules. Moreover, when mice deficient in low-density lipoprotein receptor (LDLR) were bone-marrow transplanted with NLRP3-deficient, ASC (also known as PYCARD)-deficient or IL-1α/β-deficient bone marrow and fed on a high-cholesterol diet, they had markedly decreased early atherosclerosis and inflammasome-dependent IL-18 levels. Minimally modified LDL can lead to cholesterol crystallization concomitant with NLRP3 inflammasome priming and activation in macrophages. Although there is the possibility that oxidized LDL activates the NLRP3 inflammasome in vivo, our results demonstrate that crystalline cholesterol acts as an endogenous danger signal and its deposition in arteries or elsewhere is an early cause rather than a late consequence of inflammation. These findings provide new insights into the pathogenesis of atherosclerosis and indicate new potential molecular targets for the therapy of this disease., Cholesterol, an indispensable lipid in vertebrates^ is effectively insoluble in aqueous environments, and elaborate molecular mechanisms have evolved that regulate cholesterol synthesis and its transport in fluids (4). Cholesterol crystals [...]

Published
2010
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14. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC

Author

Hornung, Veit, Ablasser, Andrea, Charrel-Dennis, Marie, Bauernfeind, Franz, Horvath, Gabor, Caffrey, Daniel R., Latz, Eicke, and Fitzgerald, Katherine A.

Subjects
Gene expression -- Research, DNA -- Research, Macrophages -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation, Research
Abstract

The innate immune system senses nucleic acids by germline-encoded pattern recognition receptors. RNA is sensed by Toll-like receptor members TLR3, TLR7 and TLR8, or by the RNA helicases RIG-I (also known as DDX58) and MDA-5 (IFIHI) (1). Little is known about sensors for cytoplasmic DNA that trigger antiviral and/or inflammatory responses (2-6). The best characterized of these responses involves activation of the TANK-binding kinase (TBKI)-interferon regulatory factor 3 (IRF3) signalling axis to trigger transcriptional induction of type I interferon genes (2, 3). A second, less well-defined pathway leads to the activation of an 'inflammasome' that, via caspase-1, controls the catalytic cleavage of the pro-forms of the cytokines IL1β and IL18 (refs 6, 7). Using mouse and human cells, here we identify the PYHIN (pyrin and HIN domain-containing protein) (8) family member absent in melanoma 2 (AIM2) as a receptor for cytosolic DNA, which regulates caspase-1. The HIN200 domain of AIM2 binds to DNA, whereas the pyrin domain (but not that of the other PYHIN family members) associates with the adaptor molecule ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) to activate both NF-κB and caspase-1. Knockdown of Aim2 abrogates caspase-1 activation in response to cytoplasmic double-stranded DNA and the double-stranded DNA vaccinia virus. Collectively, these observations identify AIM2 as a new receptor for cytoplasmic DNA, which forms an inflammasome with the ligand and ASC to activate caspase-1., Our current understanding of the mechanisms sensing cytoplasmic DNA is limited (9). A candidate receptor called DAI (DNA-dependent activator of interferon (IFN) -regulatory factors) has been implicated in the DNA-induced [...]

Published
2009

15. cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming proteinDNA ladders

Author

Andreeva, Liudmila, Hiller, Bjrn, Kostrewa, Dirk, Lassig, Charlotte, de Oliveira Mann, Carina C., Drexler, David Jan, Maiser, Andreas, Gaidt, Moritz, Leonhardt, Heinrich, Hornung, Veit, and Hopfner, Karl-Peter

Subjects
Enzyme activation -- Research, Cytosol -- Physiological aspects -- Research, DNA binding -- Physiological aspects -- Research, Cellular immunity -- Physiological aspects -- Research, Second messengers (Cytochemistry) -- Physiological aspects -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Liudmila Andreeva [1, 2]; Bjrn Hiller [1, 2]; Dirk Kostrewa [1, 2]; Charlotte Lssig [1, 2]; Carina C. de Oliveira Mann [1, 2]; David Jan Drexler [1, 2]; Andreas [...]

Published
2017
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16. Fourth defence molecule completes antiviral line-up

Author

Veit Hornung and Niklas A. Schmacke

Subjects
0301 basic medicine, Multidisciplinary, Signal transducing adaptor protein, Biology, Cell biology, 03 medical and health sciences, Interferon production, 030104 developmental biology, 0302 clinical medicine, Immune system, Receptor, Receptor activation, 030217 neurology & neurosurgery, Interferon regulatory factors
Abstract

Toll-like receptors can initiate an immune response when they detect signs of a viral or microbial threat. New insight into how such receptor activation drives defence programs should aid our efforts to understand autoimmune diseases. Key adaptor protein found in a pathway that drives interferon production.

Published
2020
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17. High-molecular-weight organic matter in the particles of comet 67P/ChuryumovGerasimenko

Author

Fray, Nicolas, Bardyn, Anas, Cottin, Herv, Altwegg, Kathrin, Baklouti, Donia, Briois, Christelle, Colangeli, Luigi, Engrand, Ccile, Fischer, Henning, Glasmachers, Albrecht, Grn, Eberhard, Haerendel, Gerhard, Henkel, Hartmut, Hfner, Herwig, Hornung, Klaus, Jessberger, Elmar K., Koch, Andreas, Krger, Harald, Langevin, Yves, Lehto, Harry, Lehto, Kirsi, Le Roy, Lna, Merouane, Sihane, Modica, Paola, Orthous-Daunay, Franois-Rgis, Paquette, John, Raulin, Franois, Ryn, Jouni, Schulz, Rita, Siln, Johan, Siljestrm, Sandra, Steiger, Wolfgang, Stenzel, Oliver, Stephan, Thomas, Thirkell, Laurent, Thomas, Roger, Torkar, Klaus, Varmuza, Kurt, Wanczek, Karl-Peter, Zaprudin, Boris, Kissel, Jochen, and Hilchenbach, Martin

Subjects
Organic compounds -- Properties -- Natural history, Cosmochemistry -- Research, Chemical research, Molecular weights -- Research, Comets -- Properties -- Natural history, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Nicolas Fray (corresponding author) [1]; Anas Bardyn [1, 2]; Herv Cottin [1]; Kathrin Altwegg [3]; Donia Baklouti [4]; Christelle Briois [2]; Luigi Colangeli [5]; Ccile Engrand [6]; Henning Fischer [...]

Published
2016
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19. cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA ladders

Author

Karl-Peter Hopfner, Dirk Kostrewa, Björn Hiller, Veit Hornung, Moritz M. Gaidt, Andreas Maiser, Carina C. de Oliveira Mann, Liudmila Andreeva, Heinrich Leonhardt, Charlotte Lässig, and David Jan Drexler

Subjects
0301 basic medicine, Models, Molecular, Mitochondrial DNA, Base pair, Biology, DNA-binding protein, Cell Line, Mitochondrial Proteins, 03 medical and health sciences, chemistry.chemical_compound, Mice, HMGB Proteins, Animals, Humans, Nucleotide, Transcription factor, Mitochondrial nucleoid, chemistry.chemical_classification, Multidisciplinary, High Mobility Group Proteins, DNA, TFAM, Nucleotidyltransferases, Cell biology, DNA-Binding Proteins, 030104 developmental biology, chemistry, Biochemistry, Nucleic Acid Conformation, Female, Nucleotides, Cyclic, Protein Multimerization, Transcription Factors
Abstract

Cytosolic DNA arising from intracellular pathogens triggers a powerful innate immune response. It is sensed by cyclic GMP-AMP synthase (cGAS), which elicits the production of type I interferons by generating the second messenger 2'3'-cyclic-GMP-AMP (cGAMP). Endogenous nuclear or mitochondrial DNA can also be sensed by cGAS under certain conditions, resulting in sterile inflammation. The cGAS dimer binds two DNA ligands shorter than 20 base pairs side-by-side, but 20-base-pair DNA fails to activate cGAS in vivo and is a poor activator in vitro. Here we show that cGAS is activated in a strongly DNA length-dependent manner both in vitro and in human cells. We also show that cGAS dimers form ladder-like networks with DNA, leading to cooperative sensing of DNA length: assembly of the pioneering cGAS dimer between two DNA molecules is ineffective; but, once formed, it prearranges the flanking DNA to promote binding of subsequent cGAS dimers. Remarkably, bacterial and mitochondrial nucleoid proteins HU and mitochondrial transcription factor A (TFAM), as well as high-mobility group box 1 protein (HMGB1), can strongly stimulate long DNA sensing by cGAS. U-turns and bends in DNA induced by these proteins pre-structure DNA to nucleate cGAS dimers. Our results suggest a nucleation-cooperativity-based mechanism for sensitive detection of mitochondrial DNA and pathogen genomes, and identify HMGB/TFAM proteins as DNA-structuring host factors. They provide an explanation for the peculiar cGAS dimer structure and suggest that cGAS preferentially binds incomplete nucleoid-like structures or bent DNA.

Published
2017

20. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP

Author

Gabor Horvath, Veit Hornung, Andrea Ablasser, Inga Hemmerling, Eicke Latz, Jonathan L. Schmid-Burgk, and Tobias Schmidt

Subjects
Intrinsic immunity, Cell signaling, Vaccinia virus, Cell Communication, Biology, Second Messenger Systems, Article, Mice, 03 medical and health sciences, Cytosol, 0302 clinical medicine, Immune system, Interferon, medicine, Animals, Humans, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Cyclic GMP-AMP synthase, Innate immune system, Pattern recognition receptor, Gap Junctions, Membrane Proteins, Bystander Effect, DNA, Nucleotidyltransferases, Immunity, Innate, Cell biology, HEK293 Cells, 030220 oncology & carcinogenesis, Nucleotides, Cyclic, Signal transduction, medicine.drug
Abstract

The innate immune defence of multicellular organisms against microbial pathogens requires cellular collaboration. Information exchange allowing immune cells to collaborate is generally attributed to soluble protein factors secreted by pathogen-sensing cells. Cytokines, such as type I interferons (IFNs), serve to alert non-infected cells to the possibility of pathogen challenge1. Moreover, in conjunction with chemokines they can instruct specialized immune cells to contain and eradicate microbial infection. Several receptors and signalling pathways exist that couple pathogen sensing to the induction of cytokines, whereas cytosolic recognition of nucleic acids seems to be exquisitely important for the activation of type I IFNs, master regulators of antiviral immunity2. Cytosolic DNA is sensed by the receptor cyclic GMP-AMP (cGAMP) synthase (cGAS), which catalyses the synthesis of the second messenger cGAMP(2′-5′)3, 4, 5, 6, 7, 8. This molecule in turn activates the endoplasmic reticulum (ER)-resident receptor STING9, 10, 11, thereby inducing an antiviral state and the secretion of type I IFNs. Here we find in murine and human cells that cGAS-synthesized cGAMP(2′-5′) is transferred from producing cells to neighbouring cells through gap junctions, where it promotes STING activation and thus antiviral immunity independently of type I IFN signalling. In line with the limited cargo specificity of connexins, the proteins that assemble gap junction channels, most connexins tested were able to confer this bystander immunity, thus indicating a broad physiological relevance of this local immune collaboration. Collectively, these observations identify cGAS-triggered cGAMP(2′-5′) transfer as a novel host strategy that serves to rapidly convey antiviral immunity in a transcription-independent, horizontal manner.

Published
2013
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21. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING

Author

Taner Cavlar, Veit Hornung, Gregor Witte, Karl-Peter Hopfner, Ingo Röhl, Marion Goldeck, Tobias Deimling, Andrea Ablasser, and Janos Ludwig

Subjects
Models, Molecular, Magnetic Resonance Spectroscopy, Biology, Second Messenger Systems, Article, Cell Line, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Animals, Humans, Transferase, Cyclic GMP, 030304 developmental biology, 0303 health sciences, Oligoribonucleotides, Multidisciplinary, Cyclic GMP-AMP synthase, Molecular Structure, IFI16, HEK 293 cells, Membrane Proteins, Nucleotidyltransferases, Adenosine Monophosphate, HEK293 Cells, Biochemistry, chemistry, Cyclization, 030220 oncology & carcinogenesis, Stimulator of interferon genes, Phosphodiester bond, Second messenger system, Biocatalysis, DNA
Abstract

Detection of cytoplasmic DNA represents one of the most fundamental mechanisms of the innate immune system to sense the presence of microbial pathogens1. Moreover, erroneous detection of endogenous DNA by the same sensing mechanisms has an important pathophysiological role in certain sterile inflammatory conditions2, 3. The endoplasmic-reticulum-resident protein STING is critically required for the initiation of type I interferon signalling upon detection of cytosolic DNA of both exogenous and endogenous origin4, 5, 6, 7, 8. Next to its pivotal role in DNA sensing, STING also serves as a direct receptor for the detection of cyclic dinucleotides, which function as second messenger molecules in bacteria9, 10, 11, 12, 13. DNA recognition, however, is triggered in an indirect fashion that depends on a recently characterized cytoplasmic nucleotidyl transferase, termed cGAMP synthase (cGAS), which upon interaction with DNA synthesizes a dinucleotide molecule that in turn binds to and activates STING14, 15. We here show in vivo and in vitro that the cGAS-catalysed reaction product is distinct from previously characterized cyclic dinucleotides. Using a combinatorial approach based on mass spectrometry, enzymatic digestion, NMR analysis and chemical synthesis we demonstrate that cGAS produces a cyclic GMP-AMP dinucleotide, which comprises a 2′-5′ and a 3′-5′ phosphodiester linkage >Gp(2′-5′)Ap(3′-5′)>. We found that the presence of this 2′-5′ linkage was required to exert potent activation of human STING. Moreover, we show that cGAS first catalyses the synthesis of a linear 2′-5′-linked dinucleotide, which is then subject to cGAS-dependent cyclization in a second step through a 3′-5′ phosphodiester linkage. This 13-membered ring structure defines a novel class of second messenger molecules, extending the family of 2′-5′-linked antiviral biomolecules.

Published
2013
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22. Low-energy Control of Electrical Turbulence in the Heart

Author

James A. Flanders, Eberhard Bodenschatz, Stefan Luther, Amgad Squires, Flavio H. Fenton, Valentin Krinsky, Gerd Hasenfuss, Andrea Gladuli, Alain Pumir, Markus Zabel, Philip Bittihn, Bruce G. Kornreich, Robert F. Gilmour, Daniel Hornung, Elizabeth M. Cherry, Luis Campoy, and Gisa E. Luther

Subjects
Field (physics), Defibrillation, medicine.medical_treatment, Electric Countershock, Contrast Media, 01 natural sciences, Article, 010305 fluids & plasmas, Synchronization (alternating current), Electrocardiography, Dogs, Electric field, 0103 physical sciences, Atrial Fibrillation, medicine, Animals, Humans, 010306 general physics, Electrodes, Physics, Fibrillation, Multidisciplinary, Electric shock, Depolarization, Heart, Mechanics, X-Ray Microtomography, medicine.disease, Coronary Vessels, Ventricular Fibrillation, medicine.symptom, Excitation
Abstract

Cardiac defibrillation is usually achieved using a single high-energy electric shock of up to 4,000 volts, which can be damaging to the heart tissue. Eberhard Bodenschatz and colleagues show how the disordered electrical dynamics that underlie cardiac fibrillation can be controlled using low-energy electrical pulses. They show, in tests on dogs, that intrinsic homogeneities in the cardiac tissue (such as the vasculature) serve as nucleation sites for the generation of waves of electrical activity that can target the instabilities and bring the tissue dynamics back into synchrony. The new technique, called low-energy antifibrillation pacing or LEAP, delivers five sequential low-energy electrical field pulses to the fibrillating heart — an average energy reduction of 84% compared to standard defibrillation. Controlling the complex spatio-temporal dynamics underlying life-threatening cardiac arrhythmias such as fibrillation is extremely difficult, because of the nonlinear interaction of excitation waves in a heterogeneous anatomical substrate1,2,3,4. In the absence of a better strategy, strong, globally resetting electrical shocks remain the only reliable treatment for cardiac fibrillation5,6,7. Here we establish the relationship between the response of the tissue to an electric field and the spatial distribution of heterogeneities in the scale-free coronary vascular structure. We show that in response to a pulsed electric field, E, these heterogeneities serve as nucleation sites for the generation of intramural electrical waves with a source density ρ(E) and a characteristic time, τ, for tissue depolarization that obeys the power law τ ∝ Eα. These intramural wave sources permit targeting of electrical turbulence near the cores of the vortices of electrical activity that drive complex fibrillatory dynamics. We show in vitro that simultaneous and direct access to multiple vortex cores results in rapid synchronization of cardiac tissue and therefore, efficient termination of fibrillation. Using this control strategy, we demonstrate low-energy termination of fibrillation in vivo. Our results give new insights into the mechanisms and dynamics underlying the control of spatio-temporal chaos in heterogeneous excitable media and provide new research perspectives towards alternative, life-saving low-energy defibrillation techniques.

Published
2011

23. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals

Author

Katherine A. Fitzgerald, Katey J. Rayner, Franz Bauernfeind, Samuel D. Wright, Egil Lien, Cherilyn M. Sirois, Kenneth L. Rock, Max Schnurr, Gregory I. Vladimer, George S. Abela, Veit Hornung, Terje Espevik, Eicke Latz, Kathryn J. Moore, Hajime Kono, Luigi Franchi, Peter Duewell, and Guillermo Gabriel Nuñez

Subjects
medicine.medical_specialty, Multidisciplinary, biology, Cholesterol, NALP3, Inflammation, PYCARD, Inflammasome, Cathepsin B, AIM2, chemistry.chemical_compound, Endocrinology, chemistry, Internal medicine, LDL receptor, Immunology, medicine, biology.protein, medicine.symptom, medicine.drug
Abstract

The inflammatory nature of atherosclerosis is well established but the agent(s) that incite inflammation in the artery wall remain largely unknown. Germ-free animals are susceptible to atherosclerosis, suggesting that endogenous substances initiate the inflammation. Mature atherosclerotic lesions contain macroscopic deposits of cholesterol crystals in the necrotic core, but their appearance late in atherogenesis had been thought to disqualify them as primary inflammatory stimuli. However, using a new microscopic technique, we revealed that minute cholesterol crystals are present in early diet-induced atherosclerotic lesions and that their appearance in mice coincides with the first appearance of inflammatory cells. Other crystalline substances can induce inflammation by stimulating the caspase-1-activating NLRP3 (NALP3 or cryopyrin) inflammasome, which results in cleavage and secretion of interleukin (IL)-1 family cytokines. Here we show that cholesterol crystals activate the NLRP3 inflammasome in phagocytes in vitro in a process that involves phagolysosomal damage. Similarly, when injected intraperitoneally, cholesterol crystals induce acute inflammation, which is impaired in mice deficient in components of the NLRP3 inflammasome, cathepsin B, cathepsin L or IL-1 molecules. Moreover, when mice deficient in low-density lipoprotein receptor (LDLR) were bone-marrow transplanted with NLRP3-deficient, ASC (also known as PYCARD)-deficient or IL-1alpha/beta-deficient bone marrow and fed on a high-cholesterol diet, they had markedly decreased early atherosclerosis and inflammasome-dependent IL-18 levels. Minimally modified LDL can lead to cholesterol crystallization concomitant with NLRP3 inflammasome priming and activation in macrophages. Although there is the possibility that oxidized LDL activates the NLRP3 inflammasome in vivo, our results demonstrate that crystalline cholesterol acts as an endogenous danger signal and its deposition in arteries or elsewhere is an early cause rather than a late consequence of inflammation. These findings provide new insights into the pathogenesis of atherosclerosis and indicate new potential molecular targets for the therapy of this disease.

Published
2010
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24. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC

Author

Veit Hornung, Andrea Ablasser, Katherine A. Fitzgerald, Franz Bauernfeind, Marie Charrel-Dennis, Daniel R. Caffrey, Eicke Latz, and Gabor Horvath

Subjects
Caspase 1, Vaccinia virus, Biology, Pyrin domain, Article, Cell Line, 03 medical and health sciences, AIM2, Mice, 0302 clinical medicine, Cytosol, Poly dA-dT, NLRC4, medicine, Animals, Humans, 030304 developmental biology, Inflammation, 0303 health sciences, Multidisciplinary, Cell Death, Nuclear Proteins, Inflammasome, DNA, Molecular biology, 3. Good health, Cell biology, CARD Signaling Adaptor Proteins, DNA-Binding Proteins, Enzyme Activation, Cytoskeletal Proteins, TLR3, Apoptosis Regulatory Proteins, Inflammasome complex, NLRP3 inflammasome complex, 030215 immunology, medicine.drug, Protein Binding
Abstract

The innate immune system senses nucleic acids by germline-encoded pattern recognition receptors. RNA is sensed by Toll-like receptor members TLR3, TLR7 and TLR8, or by the RNA helicases RIG-I (also known as DDX58) and MDA-5 (IFIH1). Little is known about sensors for cytoplasmic DNA that trigger antiviral and/or inflammatory responses. The best characterized of these responses involves activation of the TANK-binding kinase (TBK1)-interferon regulatory factor 3 (IRF3) signalling axis to trigger transcriptional induction of type I interferon genes. A second, less well-defined pathway leads to the activation of an 'inflammasome' that, via caspase-1, controls the catalytic cleavage of the pro-forms of the cytokines IL1beta and IL18 (refs 6, 7). Using mouse and human cells, here we identify the PYHIN (pyrin and HIN domain-containing protein) family member absent in melanoma 2 (AIM2) as a receptor for cytosolic DNA, which regulates caspase-1. The HIN200 domain of AIM2 binds to DNA, whereas the pyrin domain (but not that of the other PYHIN family members) associates with the adaptor molecule ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) to activate both NF-kappaB and caspase-1. Knockdown of Aim2 abrogates caspase-1 activation in response to cytoplasmic double-stranded DNA and the double-stranded DNA vaccinia virus. Collectively, these observations identify AIM2 as a new receptor for cytoplasmic DNA, which forms an inflammasome with the ligand and ASC to activate caspase-1.

Published
2008

25. Genetics: relatedness among east African coelacanths

Author

Manfred, Schartl, Ute, Hornung, Karen, Hissmann, Jürgen, Schauer, and Hans, Fricke

Subjects
Haplotypes, Oceans and Seas, Fishes, Animals, Genetic Variation, Africa, Eastern, DNA, Mitochondrial, Phylogeny, Microsatellite Repeats
Abstract

Coelacanths were discovered in the Comoros archipelago to the northwest of Madagascar in 1952. Since then, these rare, ancient fish have been found to the south off Mozambique, Madagascar and South Africa, and to the north off Kenya and Tanzania -- but it was unclear whether these are separate populations or even subspecies. Here we show that the genetic variation between individuals from these different locations is unexpectedly low. Combined with earlier results from submersible and oceanographic observations, our findings indicate that a separate African metapopulation is unlikely to have existed and that locations distant from the Comoros were probably inhabited relatively recently by either dead-end drifters or founders that originated in the Comoros.

Published
2005

26. Erratum: NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals

Author

Duewell, Peter, primary, Kono, Hajime, additional, Rayner, Katey J., additional, Sirois, Cherilyn M., additional, Vladimer, Gregory, additional, Bauernfeind, Franz G., additional, Abela, George S., additional, Franchi, Luigi, additional, Nuñez, Gabriel, additional, Schnurr, Max, additional, Espevik, Terje, additional, Lien, Egil, additional, Fitzgerald, Katherine A., additional, Rock, Kenneth L., additional, Moore, Kathryn J., additional, Wright, Samuel D., additional, Hornung, Veit, additional, and Latz, Eicke, additional

Published
2010
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27. Erratum: NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals

Author

Terje Espevik, Gregory I. Vladimer, Hajime Kono, Egil Lien, Gabriel Núñez, Luigi Franchi, Franz Bauernfeind, Max Schnurr, Kenneth L. Rock, Katherine A. Fitzgerald, Samuel D. Wright, Cherilyn M. Sirois, George S. Abela, Kathryn J. Moore, Peter Duewell, Katey J. Rayner, Eicke Latz, and Veit Hornung

Subjects
Multidisciplinary, Biochemistry, Cholesterol crystals, Biology
Published
2010
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28. Composition of comet Halley dust particles from Giotto observations

Author

Kissel, J, Buechler, K, Fechtig, H, Gruen, E, Jessberger, E. K, Brownlee, D. E, Clark, B. C, Hornung, K, Igenbergs, E. B, and Sekanina, Z

Subjects
Astrophysics
Abstract

Mass spectra of cometary dust particles measured by the PIA dust particle analyzer aboard the Giotto spacecraft show some unexpected and striking features. First, small particles below 10 to the -14th g are much more abundant than anticipated by models. Second, most of the particles are rich in light elements such as H, C, N, and O, suggesting the validity of models that describe the cometary dust as including organic material. Third, the light elements specifically seem to have a low ratio of mass to volume. Three examples of original mass spectra showing typical compositions are given; these have been measured, and are compared with a computer-simulated mass spectrum.

Published
1986
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29. Genetics: Relatedness among east African coelacanths

Author

Schartl, Manfred, Hornung, Ute, Hissmann, Karen, Schauer, Jurgen, and Fricke, Hans

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Manfred Schartl [1]; Ute Hornung [1]; Karen Hissmann [2]; Jürgen Schauer [2]; Hans Fricke (corresponding author) [2] Coelacanths were discovered in the Comoros archipelago to the northwest of Madagascar [...]

Published
2005
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30. Relatedness among east African coelacanths

Author

Hans Fricke, Jürgen Schauer, Ute Hornung, Manfred Schartl, and Karen Hissmann

Subjects
education.field_of_study, Multidisciplinary, geography.geographical_feature_category, biology, Ecology, Population, Metapopulation, Subspecies, biology.organism_classification, Tanzania, Geography, parasitic diseases, Genetic variation, Archipelago, Genetic variability, education, Living fossil
Abstract

Scattered groups of these ancient fish may all stem from a single remote population. The presumed home of African coelacanths, the ‘living fossil’ fish, is in the Comoros archipelago off Madagascar. Occasional sightings thousands of miles away, off South Africa, Tanzania and Kenya, raised the possibility of separate populations, even subspecies. But now a genetic study suggests that these disparate populations are all related to the Comoros fish. Coelacanths were discovered in the Comoros archipelago to the northwest of Madagascar in 1952. Since then, these rare, ancient fish have been found to the south off Mozambique, Madagascar and South Africa, and to the north off Kenya and Tanzania — but it was unclear whether these are separate populations or even subspecies. Here we show that the genetic variation between individuals from these different locations is unexpectedly low. Combined with earlier results from submersible and oceanographic observations1,2, our findings indicate that a separate African metapopulation is unlikely to have existed and that locations distant from the Comoros were probably inhabited relatively recently by either dead-end drifters or founders that originated in the Comoros.

Published
2005
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31. Unique Bedrock and Soils associated with the Teesdale Flora

Author

G. A. L. Johnson, M. Hornung, and D. Robinson

Subjects
Flora, geography, Multidisciplinary, geography.geographical_feature_category, Bedrock geology, Bedrock, Soil water, Geochemistry, Soil science, Geology
Abstract

This article describes the geological factors which have contributed to the formation of the unique bedrock geology and soils of the metamorphosed limestones on Widdybank and Cronkley fells in Upper Teesdale. The survival of the relict arctic–alpine flora is probably directly related to the distinctive geology of the area.

Published
1971
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32. Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation

Author

Che A. Stafford, Alicia-Marie Gassauer, Carina C. de Oliveira Mann, Maria C. Tanzer, Evelyn Fessler, Benedikt Wefers, Dennis Nagl, Gunnar Kuut, Karolina Sulek, Catherine Vasilopoulou, Sophia J. Schwojer, Andreas Wiest, Marie K. Pfautsch, Wolfgang Wurst, Monica Yabal, Thomas Fröhlich, Matthias Mann, Nicolas Gisch, Lucas T. Jae, and Veit Hornung

Subjects
Nod2 Signaling Adaptor Protein, Peptidoglycan, enzymology [Macrophages], Mice, chemistry [Peptidoglycan], Cell Wall, chemistry [Bacteria], chemistry [Cell Wall], genetics [Phosphotransferases (Alcohol Group Acceptor)], Animals, deficiency [Phosphotransferases (Alcohol Group Acceptor)], metabolism [Acetylmuramyl-Alanyl-Isoglutamine], Phosphorylation, metabolism [Phosphotransferases (Alcohol Group Acceptor)], immunology [Peptidoglycan], Multidisciplinary, Bacteria, biosynthesis [Hexosamines], Macrophages, Hexosamines, metabolism [Nod2 Signaling Adaptor Protein], immunology [Macrophages], pharmacology [Acetylmuramyl-Alanyl-Isoglutamine], Immunity, Innate, agonists [Nod2 Signaling Adaptor Protein], Phosphotransferases (Alcohol Group Acceptor), immunology [Acetylmuramyl-Alanyl-Isoglutamine], immunology [Bacteria], ddc:500, chemistry [Acetylmuramyl-Alanyl-Isoglutamine], Acetylmuramyl-Alanyl-Isoglutamine
Abstract

Bacterial cell wall components provide various unique molecular structures that are detected by pattern recognition receptors (PRRs) of the innate immune system as non-self. Most bacterial species form a cell wall that consists of peptidoglycan (PGN), a polymeric structure comprising alternating amino sugars that form strands cross-linked by short peptides. Muramyl dipeptide (MDP) has been well documented as a minimal immunogenic component of peptidoglycan1–3. MDP is sensed by the cytosolic nucleotide-binding oligomerization domain-containing protein 24 (NOD2). Upon engagement, it triggers pro-inflammatory gene expression, and this functionality is of critical importance in maintaining a healthy intestinal barrier function5. Here, using a forward genetic screen to identify factors required for MDP detection, we identified N-acetylglucosamine kinase (NAGK) as being essential for the immunostimulatory activity of MDP. NAGK is broadly expressed in immune cells and has previously been described to contribute to the hexosamine biosynthetic salvage pathway6. Mechanistically, NAGK functions upstream of NOD2 by directly phosphorylating the N-acetylmuramic acid moiety of MDP at the hydroxyl group of its C6 position, yielding 6-O-phospho-MDP. NAGK-phosphorylated MDP—but not unmodified MDP—constitutes an agonist for NOD2. Macrophages from mice deficient in NAGK are completely deficient in MDP sensing. These results reveal a link between amino sugar metabolism and innate immunity to bacterial cell walls.

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33. Unique Bedrock and Soils associated with the Teesdale Flora

Author

JOHNSON, G. A. L., ROBINSON, D., and HORNUNG, M.

Abstract

This article describes the geological factors which have contributed to the formation of the unique bedrock geology and soils of the metamorphosed limestones on Widdybank and Cronkley fells in Upper Teesdale. The survival of the relict arctic–alpine flora is probably directly related to the distinctive geology of the area.

Published
1971
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34. Distribution of butanol molecules along bullfrog olfactory mucosa

Author

David E. Hornung, Robert D. Lansing, and Maxwell M. Mozell

Subjects
Multidisciplinary, Rana catesbeiana, Butanol, Butanols, Partial Pressure, Conclusive evidence, Anatomy, Tritium, Smell, chemistry.chemical_compound, Olfactory mucosa, medicine.anatomical_structure, chemistry, Olfactory Mucosa, Bullfrog, Odorants, medicine, Biophysics, Molecule, Animals, Concentration gradient
Abstract

ALTHOUGH electrophysiological1 and gas chromatographic2 studies have indicated that odorant molecules drawn into the intact frog olfactory sac establish a concentration gradient along the olfactory mucosa, conclusive evidence for such gradients requires a direct determination of how the molecules are actually distributed. This requirement is met here by labelling butanol molecules with tritium and directly mapping their sorption along the mucosa.

Published
1975

38. New Hydroxamic Acids as Antitubercular Agents

Author

Venulet J, Slopek S, Hornung S, and Urbanski T

Subjects
Anthelmintics, Multidisciplinary, business.industry, Antitubercular Agents, Pharmacology, Hydroxamic Acids, Hydroxylamines, Salicylates, Salicylhydroxamic acid, chemistry.chemical_compound, chemistry, Salicylic acid derivatives, Pulmonary tuberculosis, Tuberculosis, Medicine, business
Abstract

PREVIOUSLY, one of us suggested using salicylhydroxamic acid as an antitubercular agent1. The substance was subjected to clinical examination by another of us (S.H.) and showed promising results in fifteen cases of pulmonary tuberculosis. The substance was well tolerated by the patients, when large doses of 10–20 gm./day were administered.

Published
1952
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