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Winter, Hanna ; Winski, Greg ; Busch, Albert Franz Jakob ; Chernogubova, Ekaterina ; Fasolo, Francesca ; Wu, Zhiyuan ; Bäcklund, Alexandra ; Khomtchouk, Bohdan B. ; Van Booven, Derek J. ; Sachs, Nadja ; Eckstein, Hans-Henning ; Wittig, Ilka ; Boon, Reinier ; Jin, Hong ; Mägdefessel, Lars
Long non-coding RNAs (lncRNAs) orchestrate various biological processes and regulate the development of cardiovascular diseases. Their potential therapeutic benefit to tackle disease progression has recently been extensively explored. Our study investigates the role of lncRNA Nudix Hydrolase 6 (NUDT6) and its antisense target fibroblast growth factor 2 (FGF2) in two vascular pathologies: abdominal aortic aneurysms (AAA) and carotid artery disease. Using tissue samples from both diseases, we detected a substantial increase of NUDT6, whereas FGF2 was downregulated. Targeting Nudt6 in vivo with antisense oligonucleotides in three murine and one porcine animal model of carotid artery disease and AAA limited disease progression. Restoration of FGF2 upon Nudt6 knockdown improved vessel wall morphology and fibrous cap stability. Overexpression of NUDT6 in vitro impaired smooth muscle cell (SMC) migration, while limiting their proliferation and augmenting apoptosis. By employing RNA pulldown followed by mass spectrometry as well as RNA immunoprecipitation, we identified Cysteine and Glycine Rich Protein 1 (CSRP1) as another direct NUDT6 interaction partner, regulating cell motility and SMC differentiation. Overall, the present study identifies NUDT6 as a well-conserved antisense transcript of FGF2. NUDT6 silencing triggers SMC survival and migration and could serve as a novel RNA-based therapeutic strategy in vascular diseases.
Fasolo, Francesca ; Winski, Greg ; Li, Zhaolong ; Wu, Zhiyuan ; Winter, Hanna ; Ritzer, Julia ; Glukha, Nadiya ; Roy, Joy ; Hultgren, Rebecka ; Pauli, Jessica ; Busch, Albert Franz Jakob ; Sachs, Nadja ; Knappich, Christoph Magnus ; Eckstein, Hans-Henning ; Boon, Reinier ; Paloschi, Valentina ; Mägdefessel, Lars
An abdominal aortic aneurysm (AAA) is a pathological widening of the aortic wall characterized by loss of smooth muscle cells (SMCs), extracellular matrix degradation, and local inflammation. This condition is often asymptomatic until rupture occurs, leading to high morbidity and mortality rates. Diagnosis is mostly accidental and the only currently available treatment option remains surgical intervention. Circular RNAs (circRNAs) represent a novel class of regulatory non-coding RNAs that originate from backsplicing. Their highly stable loop structure, combined with a remarkable enrichment in body fluids, make circRNAs promising disease biomarkers. We investigated the contribution of circRNAs to AAA pathogenesis and their potential application to improve AAA diagnostics. Gene expression analysis revealed the presence of deregulated circular transcripts stemming from AAA-relevant gene loci. Among these, the circRNA to the Ataxia Telangiectasia Mutated gene (cATM) was upregulated in human AAA specimens, in AAA-derived SMCs, and serum samples collected from aneurysm patients. In primary aortic SMCs, cATM increased upon angiotensin II and doxorubicin stimulation, while its silencing triggered apoptosis. Higher cATM levels made AAA-derived SMCs less vulnerable to oxidative stress, compared with control SMCs. These data suggest that cATM contributes to elicit an adaptive oxidative-stress response in SMCs and provides a reliable AAA disease signature.
Abelev, Betty ; Adam, Jaroslav ; Adamová, Dagmar ; Adare, A. M. ; Aggarwal, Madan Mohan ; Aglieri Rinella, Gianluca ; Agnello, Michelangelo ; Agocs, A. G. ; Agostinelli, A. ; Ahammed, Zubayer ; Ahmad, Nazeer ; Ahmad Masoodi, A. ; Ahn, S. A. ; Ahn, Sang Un ; Aimo, Ilaria ; Ajaz, Muhammad ; Akindinov, Alexander ; Aleksandrov, Dmitry ; Alessandro, Bruno ; Alici, Andrea ; Alkin, Anton ; Almaráz Aviña, E. ; Alme, Johan ; Alt, Torsten ; Altini, V. ; Altinpinar, Sedat ; Altsybeev, Igor ; Andrei, Cristian ; Andronic, Anton ; Anguelov, Venelin ; Anielski, Jonas ; Anson, Christopher Daniel ; Antičić, Tome ; Antinori, Federico ; Antonioli, Pietro ; Aphecetche, Laurent Bernard ; Appelshäuser, Harald ; Arbor, N. ; Arcelli, Silvia ; Arend, A. ; Armesto, Néstor ; Arnaldi, Roberta ; Aronsson, Tomas Robert ; Arsene, Ionut Cristian ; Arslandok, Mesut ; Asryan, A. ; Augustinus, Andre ; Averbeck, Ralf Peter ; Awes, T. C. ; Äystö, J. ; Azmi, Mohd Danish ; Bach, Matthias ; Badalà, Angela ; Baek, Yong Wook ; Bailhache, Raphaëlle ; Bala, Renu ; Baldini Ferroli, Rinaldo ; Baldisseri, Alberto ; Baltasar Dos Santos Pedrosa, Fernando ; Bán, J. ; Baral, Rama Chandra ; Barbera, Roberto ; Barile, Francesco ; Barnaföldi, Gergely Gábor ; Barnby, Lee Stuart ; Barret, Valérie ; Bartke, Jerzy ; Basile, Maurizio ; Bastid, Nicole ; Basu, Sumit ; Bathen, Bastian ; Batigne, Guillaume ; Battistin, M. ; Batyunya, Boris ; Baudot, Jérome ; Baumann, C. ; Bavontaweepanya, R. ; Bearden, Ian Gardner ; Beck, Hans ; Behera, Nirbhay Kumar ; Belikov, Iouri ; Bellini, Francesca ; Bellwied, Rene ; Belmont-Moreno, Ernesto ; Bencédi, Gyula ; Beolè, Stefania ; Berceanu, Ionela ; Bercuci, Alexandru ; Berdnikov, Yaroslav ; Berényi, Dániel ; Berger, M. ; Bergognon, A. A.E. ; Berzano, Dario ; Betev, Latchezar ; Bhasin, Anju ; Bhati, Ashok Kumar ; Bhom, Jihyun ; Bianchi, Livio ; Bianchi, Nicola ; Bielčík, Jaroslav ; Bielčíková, Jana ; Bilandzic, Ante ; Bjelogrlic, Sandro ; Blanco, Fernando ; Blanco, Fernando ; Blau, Dmitry S. ; Blume, Christoph ; Boccioli, M. ; Böttger, Stefan ; Bogdanov, Alexey A. ; Bøggild, Hans ; Bogolyubsky, M. ; Boldizsár, László ; Bombara, Marek ; Book, Julian ; Borel, Hervé ; Borissov, Alexander ; Bossú, Francesco ; Bortolin, C. ; Botelho Direito, J. A. ; Botje, Michiel ; Botta, Elena ; Braidot, E. ; Braun-Munzinger, Peter ; Bregant, Marco ; Breitner, Timo ; Broker, Theo Alexander ; Browning, Tyler Allen ; Broz, M. ; Brun, René ; Bruna, Elena ; Bruno, Giuseppe Eugenio ; Budnikov, Dmitry ; Büsching, Henner ; Bufalino, Stefania ; Bunčić, Predrag ; Busch, Oliver ; Buthelezi, Edith Zinhle ; Caballero Orduna, D. ; Caffarri, Davide ; Cai, Xiao ; Caines, Helen Louise ; Calvo Villar, Ernesto ; Camerini, Paolo ; Canoa Roman, Veronica ; Cara Romeo, G. ; Carena, Wisla ; Carena, Francesco ; Carlin Filho, N. ; Carminati, F. ; Casanova Díaz, A. ; Castillo Castellanos, Javier Ernesto ; Castillo Hernandez, Juan Francisco ; Casula, E. A.R. ; Catanescu, V. ; Caudron, T. ; Cavicchioli, Costanza ; Ceballos Sanchez, Cesar ; Čepila, Jan ; Cerello, Piergiorgio ; Chang, B. ; Chankhunthot, N. ; Chapeland, Sylvain ; Charvet, Jean-Luc Fernand ; Chattopadhyay, S. ; Chattopadhyay, S. ; Chawla, I. ; Cherney, Michael Gerard ; Cheshkov, Cvetan Valeriev ; Cheynis, Brigitte ; Chibante Barroso, Vasco Miguel ; Chinellato, David Dobrigkeit ; Chochula, Peter ; Chojnacki, Marek ; Choudhury, Subikash ; Christakoglou, Panagiotis ; Christensen, Christian Holm ; Christiansen, Peter L. ; Chujo, Tatsuya ; Chung, Suh-Urk ; Cicalò, Corrado ; Cifarelli, Luisa ; Cindolo, Federico ; Cleymans, Jean Willy Andre ; Coccetti, F. ; Colamaria, Fabio Filippo ; Colella, Domenico ; Collu, Alberto ; Conesa Balbastre, Gustavo ; Conesa del Valle, Zaida ; Connors, Megan Elizabeth ; Contin, Giacomo ; Contreras Nuno, Jesus Guillermo ; Cormier, Thomas Michael ; Corrales Morales, Yasser ; Cortese, Pietro ; Cortés Maldonado, Ismael ; Cosentino, Mauro Rogerio ; Costa, Filippo ; Cotallo, M. E. ; Crescio, E. ; Crochet, Philippe ; Cruz Alaniz, E. ; Cruz Albino, Rigoberto ; Cuautle Flores, Eleazar ; Cunqueiro Mendez, Leticia ; Dainese, Andrea ; Dalsgaard, H. H. ; Danu, Andrea ; Da Riva, E. ; Das, Indranil ; Das, Debasish ; Das, Supriya ; Das, K. ; Dash, Ajay Kumar ; Dash, Sadhana ; De, Sudipan ; De Barros, G. O.V. ; De Caro, Annalisa ; De Cataldo, Giacinto ; Decosse, C. ; Cuveland, Jan de ; De Falco, Alessandro ; De Gruttola, Daniele ; Delagrange, H. ; Deloff, Andrzej ; De Marco, Nora ; Dénes, Ervin Sandor ; De Pasquale, Salvatore ; Deppman, A. ; D Erasmo, G. ; De Rooij, R. ; Diaz Corchero, Miguel Angel ; Di Bari, Domenico ; Dietel, Thomas ; Di Giglio, C. ; Di Liberto, S. ; Di Mauro, Antonio ; Di Nezza, Pasquale ; Divià, Roberto ; Djuvsland ; Dobrin, Alexandru Florin ; Dobrowolski, Tadeusz Antoni ; Dönigus, Benjamin ; Dordic, Olja ; Driga, O. ; Dubey, Anand Kumar ; Dubla, Andrea ; Ducroux, Laurent ; Dulinski, W. ; Dupieux, Pascal ; Dutta Majumdar, A. K. ; Elia, Domenico ; Emschermann, D. ; Engel, Heiko ; Erazmus, Barbara Ewa ; Erdal, H. A. ; Espagnon, Bruno ; Estienne, Magali Danielle ; Esumi, ShinIchi ; Evans, David ; Eyyubova, Gyulnara ; Fabbietti, Laura ; Fabris, Daniela ; Faivre, Julien ; Falchieri, D. ; Fantoni, Alessandra ; Fasel, Markus ; Fearick, R. ; Fehlker, D. ; Feldkamp, Linus ; Felea, Daniel ; Feliciello, Alessandro ; Fenton-Olsen, B. ; Feofilov, Grigori A. ; Ferencei, Jozef ; Fernández Téllez, Arturo ; Ferretti, Alessandro ; Festanti, Andrea ; Figiel, Jan ; Figueredo, M. A.S. ; Filchagin, Sergey ; Finogeev, Dmitry ; Fionda, Fiorella Maria Celeste ; Fiore, Enrichetta Maria ; Floratos, E. ; Floris, Michele ; Förtsch, Siegfried ; Foka, Panagiota ; Fokin, Sergey ; Fragiacomo, Enrico ; Francescon, Andrea ; Frankenfeld, Ulrich ; Fuchs, Ulrich ; Furget, Christophe ; Fusco Girard, Mario ; Gaardhøje, Jens Jørgen ; Gagliardi, Martino ; Gago Medina, Alberto Martín ; Gallio, Mauro ; Gangadharan, Dhevan Raja ; Ganoti, Paraskevi ; Garabatos, Chilo ; Garcia-Solis, Edmundo Javier ; Gargiulo, Corrado ; Garishvili, I. ; Gasik, Piotr ; Gerhard, J. ; Germain, Marie ; Geuna, C. ; Gheata, Mihaela ; Gheata, Andrei George ; Ghidini, B. ; Ghosh, Premomoy ; Gianotti, Paola ; Girard, M. 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H. ; Hanratty, Luke David ; Hansen, Alexander ; Harmanová-Tóthová, Z. ; Harris, John W. ; Hartig, M. ; Harton, Austin Vincent ; Hatzifotiadou, Despina ; Hayashi, Shinichi ; Hayrapetyan, A. ; Heckel, Stefan Thomas ; Heide, Markus ; Helstrup, Håvard ; Herghelegiu, Andrei Ionut ; Herrera Corral, Gerardo Antonio ; Herrmann, Norbert ; Hess, Benjamin Andreas ; Hetland, Kristin Fanebust ; Hicks, B. ; Hillemanns, Hartmut ; Hippolyte, Boris ; Hoenle, A. ; Hori, Y. ; Hristov, Peter ; Ȟrivnáčová, I. ; Hu, C. ; Huang, M. ; Humanic, Thomas J. ; Hwang, Dae Sung ; Ichou, R. ; Igolkin, S. ; Ijzermans, P. ; Ilkaev, Radiy ; Ilkiv, Iryna ; Inaba, Motoi ; Incani, E. ; Innocenti, P. G. ; Innocenti, G. M. ; Ippolitov, Mikhail ; Irfan, M. ; Ivan, C. ; Ivanov, V. ; Ivanov, A. ; Ivanov, Marian ; Ivanytskyi, O. ; Jacholkowski, Adam Wlodzimierz ; Jacobs, Peter Martin ; Jang, Haeng Jin ; Janik, Malgorzata Anna ; Janik, R. ; Yasassri Jayarathna, Pahula Hewage Sandun ; Jena, Satyajit ; Jha, D. M. ; Jiménez Bustamante, Raúl Tonatiuh ; Jones, Peter Graham ; Jung, H. ; Junique, Antoine Jean-Simon ; Jusko, Anton ; Kaidalov, A. B. ; Kalcher, S. ; Kaliňák, Peter ; Kalliokoski, T. ; Kalweit, Alexander Philipp ; Kang, Ju Hwan ; Kaplin, Vladimir ; Karasu Uysal, Ayben ; Karavichev, Oleg V. ; Karavicheva, Tatiana L. ; Karpechev, Evgeny ; Kazantsev, Andrey ; Kebschull, Udo ; Keidel, Ralf ; Ketzer, Bernhard ; Khan, P. ; Khan, Shuaib Ahmad ; Khan, M. M. ; Khan, K. H. ; Khanzadeev, Alexei ; Kharlov, Yury ; Kileng, Bjarte ; Kim, B. ; Kim, J. S. ; Kim, J. H. ; Kim, D. J. ; Kim, D. 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S. ; Nilsson, M. S. ; Noferini, Francesco ; Nomokonov, Petr V. ; Nooren, Gerardus ; Novitzky, Norbert ; Nyanin, Alexander ; Nyatha, A. ; Nygaard, C. ; Nystrand, Joakim Ingemar ; Ochirov, A. ; Oeschler, Helmut ; Oh, Saehanseul ; Oh, Sun Kun ; Oleniacz, Janusz ; Silva, Antonio Carlos Oliveira da ; Oppedisano, Chiara ; Ortiz Velasquez, Antonio ; Oskarsson, Anders Nils Erik ; Ostrowski, P. ; Otwinowski, Jacek Tomasz ; Oyama, Ken ; Ozawa, K. ; Pachmayer, Yvonne C. ; Pachr, Miloš ; Padilla, F. ; Pagano, Paola ; Paić, Guy ; Painke, F. ; Pajares Vales, Carlos ; Pal, Susanta Kumar ; Palaha, A. ; Palmeri, A. ; Papikyan, Vardanush ; Pappalardo, Giuseppe Salvatore ; Park, WooJin ; Passfeld, Annika ; Pastirčák, B. ; Pastore, C. ; Patalakha, D. 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B. ; Salgado, Carlos A. ; Salzwedel, Jai ; Sambyal, Sanjeev Singh ; Samsonov, Vladimir ; Sanchez Castro, Xitzel ; Šándor, Ladislav ; Sandoval, Andres ; Sano, Masato ; Santagati, Gianluca ; Santoro, R. ; Sarkamo, J. ; Scapparone, Eugenio ; Scarlassara, Fernando ; Scharenberg, Rolf Paul ; Schiaua, Claudiu Cornel ; Schicker, Rainer ; Schmidt, Christian Joachim ; Schmidt, Hans Rudolf ; Schuchmann, Simone ; Schukraft, Jürgen ; Schuster, Tim ; Schutz, Yves Roland ; Schwarz, Kilian ; Schweda, Kai ; Scioli, Gilda ; Scomparin, Enrico ; Scott, P. 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ALICE (A Large Ion Collider Experiment) is studying the physics of strongly interacting matter, and in particular the properties of the Quark–Gluon Plasma (QGP), using proton–proton, proton–nucleus and nucleus–nucleus collisions at the CERN LHC (Large Hadron Collider). The ALICE Collaboration is preparing a major upgrade of the experimental apparatus, planned for installation in the second long LHC shutdown in the years 2018–2019. These plans are presented in the ALICE Upgrade Letter of Intent, submitted to the LHCC (LHC experiments Committee) in September 2012. In order to fully exploit the physics reach of the LHC in this field, high-precision measurements of the heavy-flavour production, quarkonia, direct real and virtual photons, and jets are necessary. This will be achieved by an increase of the LHC Pb–Pb instant luminosity up to 6×1027 cm−2s−1 and running the ALICE detector with the continuous readout at the 50 kHz event rate. The physics performance accessible with the upgraded detector, together with the main detector modifications, are presented.
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